WO2024163640A2

WO2024163640A2 - Methods and intermediates for the preparation of bile acid derivatives

Info

Publication number: WO2024163640A2
Application number: PCT/US2024/013811
Authority: WO
Inventors: Gabriel Galvin; Antimo GIOIELLO
Original assignee: Intercept Pharmaceuticals Inc
Current assignee: Intercept Pharmaceuticals Inc
Priority date: 2023-02-01
Filing date: 2024-01-31
Publication date: 2024-08-08
Anticipated expiration: 2025-08-01
Also published as: WO2024163640A3

Abstract

The present disclosure relates to methods and novel intermediates useful in the preparation of a compound of formula (I), or pharmaceutically acceptable salt, solvate or amino acid, sulfate or glucuronide conjugate, or prodrug thereof.

Description

METHODS AND INTERMEDIATES FOR THE PREPARATION OF BILE ACID DERIVATIVES CROSS-REFERENCE TO RELATED APPLCIATIONS This application claims priority to, and the benefit of, U.S. Provisional Application No.63/442,534, filed February 1, 2023, the contents which are incorporated by reference in their entirety for all purposes. BACKGROUND Bile acids (BAs) and their derivatives have been shown to modulate farnesoid X receptor (FXR) and regulate FXR-mediated diseases and conditions (Gioiello, et al., Curr. Top. Med. Chem.14 (2014), 2159). Natural bile acids such as chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), and the taurine and glycine conjugates thereof are known FXR ligands. A semi-synthetic bile acid analogue, 3Į,7Į- dihydroxy-6Į-ethyl-5ȕ-cholan-24-oic acid (6-ethyl-chenodeoxycholic acid (6-ECDCA) or obeticholic acid (OCA)), disclosed in WO 2002/75298 is a highly potent FXR modulator, which is currently marketed as OCALIVA^® for the treatment of primary biliary cholangitis (PBC). Another semi-synthetic bile acid analog, 3Į,7Į,11ȕ-trihydroxy-6Į-ethyl-5ȕ-cholan- 24-oic acid (compound 100) while being a potent FXR agonist, also showed specificity against G protein-coupled receptor TGR5 (GP-BAR1, M-BAR, GPBAR, or GPR131).

100. Identification of potent and selective bile acid based FXR agonists is fundamental not only to further explore the physiological roles and pathological implications of bile acid signaling, but also to advance novel therapeutic opportunities associated with the selective modulation of the receptors by bile acid analogs. More efficacious and selective bile acid- based FXR agonists may demonstrate added therapeutic value by avoiding potential side effects associated with TGR5 activation (e.g., itching, gallbladder filling, and cholesterol gallstone formation) (Pellicciari et al., J. Med. Chem.59 (2016), 9201-9214). Methods of synthesizing compound 100 and its analogs have been described in WO 2014/184271 and more recently in WO 2017/062763. A reductive dehalogenation at position C-12 may be required in the preparation of compound 100 and its analogs. The use of nickel- based catalysts for reducing the C-12-iodine bond in steroid intermediates under a hydrogen atmosphere has been shown (see, e.g., US 3,277,121), but the combination of nickel and hydrogen may not be amenable to larger scale manufacturing due to safety hazards (e.g., spontaneous combustion). Thus, there remains a need for more efficient and safer methods of preparing selective FXR modulators, such as compound 100 and its analogs, including processes with a reduced number of steps, increased yields, and providing high purity of intermediates and final products. The present disclosure addresses this need. SUMMARY The present disclosure provides methods of preparing bile acid derivatives. In one aspect, the present disclosure relates to a method of preparing a compound of formula I

or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate or prodrug thereof, wherein R¹, R², R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, m, n, and p are as described herein. In another aspect, the present disclosure relates to a method of preparing a compound of formula II:

or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate or prodrug thereof, wherein R¹, R², R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, m, n, and p are as described herein. In another aspect, the present disclosure relates to a method of preparing a compound of formula III:

or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate or prodrug thereof, wherein R², R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, m, n, and p are as described herein. Compounds of formula I, formula II, and formula III may also be depicted as

respectively, wherein X is

. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although methods and materials similar to or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict, the present specification, including definitions, will control. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. Other features and advantages of the application will be apparent from the following detailed description. DETAILED DESCRIPTION Definitions Certain terms used in the specification and claims are collected here. As used herein, the phrase “a compound of the disclosure” refers to a compound of any one of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, C2, and compound 100 or any other compound explicitly disclosed herein. The term “C1-C6 alkyl” or “Alk” or “alkyl,” as used herein, refers to a straight-chain or branched hydrocarbon moiety having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of C1-C6 alkyl moieties include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, and n-hexyl. “C₁-C₄ alkyl” refers to a straight-chain or branched hydrocarbon moiety having 1, 2, 3, or 4 carbon atoms. The term “alkenyl” refers to a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon double bond. Both the trans and cis isomers of the carbon-carbon double bond are encompassed under the term “alkenyl.” Examples of alkenyl moieties include, but are not limited to, vinyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl, and 2- hexenyl. As used herein, “alkynyl” refers to a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon triple bond. Examples of alkynyl moieties include, but are not limited to, ethynyl, 2-propynyl, 5-but-1-en-3-ynyl, and 3-hexynyl. The term “alkoxy” refers to a straight-chain or branched saturated hydrocarbon covalently attached to an oxygen atom. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropyloxy, n-propoxy, n-butoxy, t-butoxy, and pentoxy. As used herein, the term “halogen” or “Hal” refers to fluorine, bromine, chlorine, and iodine. As used herein, the terms “carbocycle,” “carbocyclic,” or “carbocyclic ring” are intended to include any stable monocyclic or bicyclic ring having the specified number of carbons, any of which may be saturated, unsaturated, or aromatic. Carbocyclic ring includes cycloalkyl and aryl. For example, a C₃ -C₈ carbocyclic ring is intended to include a monocyclic or bicyclic ring having 3, 4, 5, 6, 7, or 8 carbon atoms. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, and phenyl. As used herein, the terms “heterocycle,” “heterocyclic,” or “heterocyclic group” include any ring structure (saturated, unsaturated, or aromatic) which contains at least one ring heteroatom (e.g., N, O or S). Heterocycle includes heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, oxetane, pyran, tetrahydropyran, azetidine, and tetrahydrofuran. Examples of heterocyclic groups include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, pyridinyl, pyridyl, and pyrimidinyl. As used herein, the term “cycloalkyl” refers to a saturated or unsaturated nonaromatic hydrocarbon mono- or multi-ring (e.g., fused, bridged, or spiro rings) system having 3 to 10 carbon atoms (e.g., C₃-C₆). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. As used herein, a straight and dashed bond (e.g., “ ”) represents a single or a double bond. As used herein, any recited moiety which includes, but is not limited to, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring, heterocyclic ring, cycloalkyl, etc. can be optionally substituted. The term "optionally substituted" refers to the indicated moiety which may or may not be substituted, and when substituted is mono-, di-, or tri-substituted, such as with 1, 2, or 3 substituents. In some instances, the substituent is halogen or OH. As used herein, the term “protecting group” refers to an appropriate moiety for masking, for example, a hydroxyl functionality, which is stable/non-reactive under the reaction condition (e.g., non-reactive with an agent used in the reaction). One skilled in the art will recognize the particular moieties employed for protecting certain functional groups, e.g., hydroxyl group, instead of another functionality, e.g., carboxylic acid. The protecting group reagents include, but are not limited to acylating agents (e.g., acetic anhydride, benzoyl chloride, pivaloyl chloride, etc.), silylating agents (e.g., TMS-Cl, TES-Cl, TBDMS-Cl, etc.), ether forming reagents (MOM-Cl, MEM-Cl, dihydropyran, ethyl vinyl ether, haloalkanes such as iodomethane, bromomethane, iodoethane, bromoethane, etc.), chloroformates (methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, benzyl chloroformate, etc.), in the presence of an appropriate base (e.g., carbonate salts, bicarbonate salts, pyridine, triethylamine, diisopropyl ethylamine, N-methylmorpholine, etc.). Alternatively, an ester- based solvent (e.g., methyl acetate, ethyl acetate, isopropyl acetate, ethyl formate, methyl trifluoroacetate, methyl propionate, etc.) can be used in conjunction with an acid (e.g., methanesulfonic acid, p-toluenesulfonic acid, conc. sulfuric acid, etc.) to selectively acylate the disclosed compounds, e.g., at the C-3 position. As used herein, an asterisk (“*”) is used to designate moieties that may be optionally protected by a suitable protecting group. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations, including the use of protective groups, can be obtained from the relevant scientific literature or from standard reference textbooks in the field. Although not limited to any one or several sources, recognized reference textbooks of organic synthesis include: Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5^th ed.; John Wiley & Sons: New York, 2001; and Wuts, P.G. M. Greene's Protective Groups in Organic Synthesis, 5^th ed.; John Wiley & Sons, 2014, the contents of which are herein incorporated by reference in their entireties for all purposes. In some embodiments, the suitable protecting group is R¹¹, wherein R¹¹ is selected from acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, and silyl protecting groups. In some embodiments, when a moiety comprises OH, the suitable protecting group for that moiety is R¹¹. In some embodiments, when a moiety comprises OH, one or more OH are replaced with OR¹¹. In some embodiments, R¹¹ is selected from C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzoyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, and silyl protecting groups. In some embodiments, -OR¹¹ is a silyl ether, wherein the silyl ether is selected from trimethylsilyl ether, triethylsilyl ether, triisopropylsilyl ether, tert-butyldimethylsilyl ether, and tert-butyldiphenylsilyl ether. In some embodiments, the R¹¹ protecting group is benzoyl or acetyl. In some embodiments, the R¹¹ protecting group is C(O)C₁-C₄ alkyl. In some embodiments, the R¹¹ protecting group is acetyl. In some embodiments R¹¹ is H. In some embodiments, R^1* is R¹ or R¹ protected by R¹¹ or by another suitable protecting group. In some embodiments, R^2* is R² or R² protected by R¹¹ or by another suitable protecting group. In some embodiments, R^3* is R³ or R³ protected by R¹¹ or by another suitable protecting group. In some embodiments, R^4* is R⁴ or R⁴ protected by R¹¹ or by another suitable protecting group. In some embodiments, R^5* is R⁵ or R⁵ protected by R¹¹ or by another suitable protecting group. In some embodiments, R^6* is R⁶ or R⁶ protected by R¹¹ or by another suitable protecting group. In some embodiments, R^7* is R⁷, CO2Me, or R⁷ protected by R¹¹ or by another suitable protecting group. In some embodiments, R^7* is R⁷ or R⁷ protected by R¹¹ or by another suitable protecting group. In some embodiments, R^8* is R⁸ or R⁸ protected by R¹¹ or by another suitable protecting group. In some embodiments, R^9* is R⁹ or R⁹ protected by R¹¹ or by another suitable protecting group. In some embodiments, R^10* is R¹⁰ or R¹⁰ protected by R¹¹ or by another suitable protecting group. In some embodiments, R^1* is R¹ or R¹ protected by R¹¹. In some embodiments, R^2* is R² or R² protected by R¹¹. In some embodiments, R^3* is R³ or R³ protected by R¹¹. In some embodiments, R^4* is R⁴ or R⁴ protected by R¹¹. In some embodiments, R^5* is R⁵ or R⁵ protected by R¹¹. In some embodiments, R^6* is R⁶ or R⁶ protected by R¹¹. In some embodiments, R^7* is R⁷, CO₂Me, or R⁷ protected by R¹¹. In some embodiments, R^7* is CO₂Me. In some embodiments, R^7* is R⁷ or R⁷ protected by R¹¹. In some embodiments, R^8* is R⁸ or R⁸ protected by R¹¹. In some embodiments, R^9* is R⁹ or R⁹ protected by R¹¹. In some embodiments, R^10* is R¹⁰ or R¹⁰ protected by R¹¹. In some embodiments, when R¹ is OH, R¹ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R² is OH, R² may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R² is OSO₃H, R² may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R² is OPO3H2, R² may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R² is alkyl optionally substituted with one or more OH, R² may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R³ is OH, R³ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R³ is OSO₃H, R³ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R³ is OPO3H2, R³ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R³ is alkyl optionally substituted with one or more OH, R³ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁴ is alkyl optionally substituted with one or more OH, R⁴ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁵ is OH, R⁵ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁵ is OSO3H, R⁵ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁵ is OPO₃H₂, R⁵ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁵ is alkyl optionally substituted with one or more OH, R⁵ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁶ is OH, R⁶ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁶ is OSO₃H, R⁶ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁶ is OPO₃H₂, R⁶ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁶ is alkyl optionally substituted with one or more OH, R⁶ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is OH, R⁷ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is OSO₃H, R⁷ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is SO3H, R⁷ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is OSO2NH2, R⁷ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is SO₂NH₂, R⁷ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is OPO3H2, R⁷ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is PO3H2, R⁷ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is CO2H, R⁷ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is CO₂H, R⁷ may be protected by a C₁-C₆ alkyl protecting group. In some embodiments, when R⁷ is CO₂H, R⁷ may be protected by a C₁-C₃ alkyl protecting group. In some embodiments, when R⁷ is CO₂H, R⁷ may be protected by a methyl protecting group (e.g., R^7* is methyl ester, i.e., CO2Me). In some embodiments, when R⁷ is C(O)NHOH, R⁷ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is NH(CH2)2SO3H, R⁷ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is NHCH₂CO₂H, R⁷ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is optionally substituted tetrazolyl, R⁷ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is optionally substituted oxadiazolyl, R⁷ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is optionally substituted thiadiazolyl, R⁷ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is optionally substituted 5-oxo-1,2,4-oxadiazolyl, R⁷ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is optionally substituted 5-oxo-1,2,4-thiadiazolyl, R⁷ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is optionally substituted oxazolidine-dionyl, R⁷ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is optionally substituted thiazolidine-dionyl, R⁷ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is optionally substituted 3-hydroxyisoxazolyl, R⁷ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is optionally substituted 3-hydroxyisothiazolyl, R⁷ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is optionally substituted pyrimidine, R⁷ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is optionally substituted 3,5-difluoro-4- hydroxyphenyl, R⁷ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁷ is optionally substituted 2,4-difluoro-3- hydroxyphenyl, R⁷ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁸ is OH, R⁸ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁸ is alkyl optionally substituted with one or more OH, R⁸ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁹ is OH, R⁹ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R⁹ is alkyl optionally substituted with one or more OH, R⁹ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R¹⁰ is OH, R¹⁰ may be protected by acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. In some embodiments, when R¹⁰ is alkyl optionally substituted with one or more OH, R¹⁰ may be protected by acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2- methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, or silyl protecting groups. As used herein, the term "leaving group" or “LG” refers to a labile functionality that has a propensity to dissociate from carbon (e.g., Cl, Br, I, sulfonated alcohols such as methane sulfonates, p-toluenesulfonates, trifluoromethane sulfonates, trifluoroacetates, sulforylated alcohols, phosphorylated alcohols, etc.). An “activating agent” may be employed to convert a functional group (e.g., an OH group) into a suitable leaving group. Examples of suitable activating agents are sulphonating agents (such as methanesulfonyl or toluenesulfonyl halides, for example methanesulfonyl chloride or toluenesulfonyl chloride, and methanesulfonic- or toluenesulfonic anhydrides, for example methanesulfonic anhydride or toluenesulfonic anhydride), and halogenating agents, such as thionyl halides (for example, thionyl chloride) or phosphorous halides (for example, phosphorous tribromide). The leaving groups can be either replaced with another functional group or eliminated, e.g., to produce an unsaturated compound, such as, for example, a compound of formula B. As used herein, the term “pharmaceutically acceptable salt” refers to base addition salts including, but are not limited to, alkali metal salts selected from sodium, lithium or potassium salt or alkaline earth metal salts selected from calcium or magnesium. Base addition salts further include inorganic and organic amine salts including, but are not limited to, ammonium, methylammonium, ethylammonium, diethylammonium, triethylammonium, lysine, arginine, N-methylglucamine, and choline. Conventional non-toxic salts also include, but are not limited to, those derived from inorganic and organic acids selected from 2- acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycolyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic. “Solvate,” as used herein, refers to a solvent addition form of a compound of the disclosure (e.g., a compound of any one of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, C2, and/or compound 100) that contains either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrates. The phrase “pharmaceutically acceptable carrier” is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition from one organ, or portion of the body, to another organ, or portion of the body. Each carrier is “acceptable” in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non- toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutical composition” is a formulation containing a compound of the disclosure (e.g., a compound of any one of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, C2, and/or compound 100) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The quantity of an active ingredient (e.g., a formulation of a compound of the disclosure or salts thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it may be necessary to make routine variations to the dosage depending, for example, on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, ocular, ophthalmic, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In another embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required. As used herein, the term “amino acid conjugates” refers to conjugates of a compound of the disclosure with any suitable amino acid. Taurine (-NH(CH₂)₂SO₃H), glycine (- NHCH₂CO₂H), and sarcosine (-N(CH₃)CH₂CO₂H) are examples of amino acid conjugates. Suitable amino acid conjugates of the compounds have the added advantage of enhanced integrity in bile or intestinal fluids. Suitable amino acids include, but are not limited to taurine, glycine, and sarcosine. The amino acid conjugates of the compounds of the disclosure can be prepared according to methods known in the art. For example, a free or protected bile acid or bile acid derivative can be coupled to an amino acid (protected or unprotected), e.g., glycine, sarcosine, or taurine amino acid, using standard peptide coupling conditions (e.g., in the presence of a base (e.g., triethylamine, diisopropyl ethylamine (DIPEA), etc.) and specific coupling reagents, for example, N-Ethoxycarbonyl-2-ethoxy-1,2- dihydroquinoline (EEDQ), 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), etc.). As defined herein, the term “metabolite” refers to glucuronidated and sulfated derivatives of the compounds described herein, wherein one or more glucuronic acid or sulfate moieties are linked to the compound of the disclosure. Glucuronic acid moieties may be linked to the compounds through glycosidic bonds with the hydroxyl groups of the compounds (e.g., 3-hydroxyl, 7-hydroxyl, 11-hydroxyl, and/or the hydroxyl of the R⁷ group). Sulfated derivatives of the compounds may be formed through sulfation of the hydroxyl groups (e.g., 3-hydroxyl, 7-hydroxyl, 11-hydroxyl, and/or the hydroxyl of the R⁷ group). Examples of metabolites include, but are not limited to, 3-O-glucuronide, 7-O-glucuronide, 11-O-glucuronide, 3-O-7-O-diglucuronide, 3-O-11-O-triglucuronide, 7-O-11-O- triglucuronide, and 3-O-7-O-11-O-triglucuronide, of the compounds described herein, and 3- sulfate, 7-sulfate, 11-sulfate, 3,7-bisulfate, 3,11-bisulfate, 7,11-bisulfate, and 3,7,11-trisulfate, of the compounds described herein. Many drug molecules have been conjugated to glucuronic acid in order to obtain the required derivatives as tools for improving insights on their absorption, metabolism and bioavailability. Isolation of the metabolites is often laborious and analytical standards are necessary as reference compounds for quantification of metabolite levels in clinical samples and for further pharmacological evaluation. The study of metabolites of drugs can contribute to the toxicity, research, and safety assessment of the drug molecules. Some glucuronides have similar or even greater biological activity compared to their corresponding parent drug molecules. For example, well-known active glucuronide is morphine 6-O-glucuronide, which has even more analgesic action than morphine (Ritter, Chem. Biol. Interact.129 (2000) 171-193). Methods of chemical and enzymatic synthesis of glucuronides are well-known in the art. The Koenigs-Knorr reaction is one of the most widely applied methods for the synthesis of alkyl and aryl O-glucuronide compounds. In this reaction, the aglycone (starting alcohol or phenol) is coupled with, for example, methyl acetobromo-Į-D-glucuronate in the presence of, for example, silver salts. If the substrate molecule (aglycone) has multiple glucuronidation sites, chemical synthesis can yield a mixture of mono- and polyglucuronides unless the unwanted glucuronidation sites are protected. The reaction gives glucuronides in variable yields depending on the catalyst, solvent, aglycone, and the ratio of the starting materials used. Other methods have been used for the synthesis of glucuronides including flow methods (Mostarda, et al. Org. Biomol. Chem.12 (2014) 9592-9600); the main differences between the reactions are in the glycosyl donor (Stachulski, et al., J. Med. Chem.49 (2006) 6931-6945; Kaspersen, et al., Xenobiotica 17 (1987) 1451-1471 (methods of chemical synthesis of sulfate and glucuronide conjugates.); Stachulski, et al., Nat. Prod. Rep.15 (1998) 173-186). The term “prodrug” as used herein, refers to a bile acid derivative or other compound that, after administration, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Inactive prodrugs are pharmacologically inactive medications that are metabolized into an active form within the body. Instead of administering a drug directly, a corresponding prodrug might be used instead to improve how a medicine is absorbed, distributed, metabolized, and excreted (ADME). Prodrugs are often designed to improve bioavailability when a drug itself is poorly absorbed from the gastrointestinal tract. A prodrug may be used to improve how selectively the drug interacts with cells or processes that are not its intended target. This can reduce adverse or unintended effects of a drug, especially important in treatments having severe unintended and undesirable side effects. The term “treating,” as used herein, refers to relieving, lessening, reducing, eliminating, modulating, or ameliorating, i.e., causing regression of the disease state or condition. The term “preventing,” as used herein, refers to completely or almost completely stopping a disease state or condition from occurring in a patient or subject, especially when the patient or subject is predisposed to such or at risk of contracting a disease state or condition. Preventing can also include inhibiting, i.e., arresting the development, of a disease state or condition, and relieving or ameliorating, i.e., causing regression of the disease state or condition, for example when the disease state or condition may already be present. The phrase “reducing the risk of,” as used herein, refers to lowering the likelihood or probability of a central nervous system disease, inflammatory disease and/or metabolic disease from occurring in a patient, especially when the subject is predisposed to such occurrence. An “effective amount” of a compound of the disclosure, or a combination of compounds is an amount (quantity or concentration) of compound or compounds. In some embodiments, when a therapeutically effective amount of a compound is administered to a subject in need of treatment symptoms arising from the disease are ameliorated immediately or after administration of the compound one or more times. The amount of the compound to be administered to a subject will depend on the particular disorder, the mode of administration, coadministered compounds, if any, and the characteristics of the subject, such as general health, other diseases, age, sex, genotype, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The term “prophylactically effective amount” means an amount (quantity or concentration) of a compound of the present disclosure, or a combination of compounds, that is administered to prevent or reduce the risk of a disease – in other words, an amount needed to provide a preventative or prophylactic effect. The amount of the present compound to be administered to a subject will depend on the particular disorder, the mode of administration, coadministered compounds, if any, and the characteristics of the subject, such as general health, other diseases, age, sex, genotype, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The term “temporal proximity” is used herein to describe events, actions, etc. that occur relatively close in time to each other. A “subject” includes mammals, e.g., humans, companion animals (e.g., dogs, cats, birds, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like), and laboratory animals (e.g., rats, mice, guinea pigs, and the like). Typically, the subject is human. The term “about” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, in some embodiments ±5%, in some embodiments ±1%, and in some embodiments ±0.1% from the specified value, as such variations are appropriate to practice the disclosed methods or to make and used the disclosed compounds and in the claimed methods. Methods of the Disclosure In one aspect, the present disclosure relates to a method of preparing a compound of formula I:

or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, wherein: R¹ is OH, alkoxy, or oxo; R² and R³ are each independently H, OH, OSO3H, OC(O)CH3, OPO3H2, halogen, or alkyl optionally substituted with one or more halogen or OH, or R² and R³ taken together with the carbon atom to which they are attached form a carbonyl; R⁴ is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl; R⁵ and R⁶ are each independently H, OH, OSO₃H, OC(O)(C₁-C₆ alkyl), OPO₃H₂, halogen, or alkyl optionally substituted with one or more halogen or OH, or R⁵ and R⁶ taken together with the carbon atom to which they are attached form a carbonyl; R⁷ is OH, OSO₃H, SO₃H, OSO₂NH₂, SO₂NH₂, OPO₃H₂, PO₃H₂, CO₂H, C(O)NHOH, NH(CH₂)₂SO₃H, NHCH₂CO₂H, or optionally substituted tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3- hydroxyisoxazolyl, 3-hydroxyisothiazolyl, pyrimidine, 3,5-difluoro-4-hydroxyphenyl or 2,4- difluoro-3-hydroxyphenyl; R⁹, and R¹⁰ are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R⁸ and R⁹ taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S, or R⁹ and R¹⁰ taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S; m is 0, 1, or 2; n is 0 or 1; and p is 0 or 1; the method comprising the Steps (A)1-(A)8 as shown in Scheme A. Scheme A:

are as described above; each R^2* is independently R² or R² protected by R¹¹ or by another suitable protecting group; each R^3* is independently R³ or R³ protected by R¹¹ or by another suitable protecting group; each R^4* is independently R⁴ or R⁴ protected by R¹¹ or by another suitable protecting group; each R^5* is independently R⁵ or R⁵ protected by R¹¹ or by another suitable protecting group; each R^6* is independently R⁶ or R⁶ protected by R¹¹ or by another suitable protecting group; each R^7* is independently R⁷, CO2Me, or R⁷ protected by R¹¹ or by another suitable protecting group; each R^8* is independently R⁸ or R⁸ protected by R¹¹ or by another suitable protecting group; each R^9* is independently R⁹ or R⁹ protected by R¹¹ or by another suitable protecting group; each R^10* is independently R¹⁰ or R¹⁰ protected by R¹¹ or by another suitable protecting group; In some embodiments, according to Scheme A, the process of preparing the compound of formula I comprises the steps of Step (A)1: optionally protecting a compound of formula I-1 to provide a compound of formula I-2 (as shown herein below); in some embodiments, the compound of formula I-2 is a compound of formula I-2-x (as shown herein below); Step (A)2: treating the compound of formula I-1 or I-2 with an appropriate activating agent to provide a compound of formula I-3, wherein LG is a leaving group; Step (A)3: treating the compound of formula I-3 with a base to prepare a compound of formula I-4; Step (A)4: reacting the compound of formula I-4 with a halogenating (e.g., brominating) reagent to provide a compound of formula I-5; Step (A)5: reacting the compound of formula I-5 with an oxidizing agent to prepare a compound of formula I-6; Step (A)6: reacting the compound of formula I-6 with a reducing agent to prepare a compound of formula I-7 (reductive dehalogenation or debromination); Step (A)7: optionally deprotecting the compound of formula I-7 to obtain a compound of formula I-8;

and Step (A)8: reacting the compound of formula I-7 or I-8 with a reducing agent to provide a compound of formula I or of formula I-9 (i.e., when R¹ is OH). Some embodiments of the present disclosure relate to a method of preparing a compound of formula I:

or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, m, n, and p are as described herein and R⁷ is OH, OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C(O)NHOH, NH(CH2)2SO3H, NHCH2CO2H or optionally substituted tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3-hydroxyisothiazolyl, pyrimidine, 3,5-difluoro-4- hydroxyphenyl or 2,4-difluoro-3-hydroxyphenyl; the method comprising the Steps (A-A)1- (A-A)8 as shown in Scheme A-A.

Scheme A-A: ,

p are as described above; each R^1* is independently R¹ or R¹ wherein one or more OH is replaced with OR¹¹; each R^2* is independently R² or R² wherein one or more OH is replaced with OR¹¹; e^{ach R3*} _{is independently R} ³ _{or R} ³ _{wherein one or more OH is replaced with OR} ¹¹ _; each R^4* is independently R⁴ or R⁴ wherein one or more OH is replaced with OR¹¹; each R^5* is independently R⁵ or R⁵ wherein one or more OH is replaced with OR¹¹; each R^6* is independently R⁶ or R⁶ wherein one or more OH is replaced with OR¹¹; each R^7* is independently R⁷, CO₂Me, or R⁷ wherein one or more OH is replaced with OR¹¹; each R^8* is independently R⁸ or R⁸ wherein one or more OH is replaced with OR¹¹; each R^9* is independently R⁹ or R⁹ wherein one or more OH is replaced with OR¹¹; each R^10* is independently R¹⁰ or R¹⁰ wherein one or more OH is replaced with OR¹¹; wherein R¹¹ is H or any suitable protecting group; Hal is halogen (e.g., Br, I, or as described herein) and LG is a suitable leaving group. In some embodiments, according to Scheme A-A, the process of preparing the compound of formula I comprises the steps of Step (A-A)1: optionally protecting a compound of formula I-1 to provide a compound of formula I-2; Step (A-A)2: treating the compound of formula I-1 or I-2 with an appropriate activating agent to provide a compound of formula I-3, wherein LG is a leaving group; Step (A-A)3: treating the compound of formula I-3 with a base to prepare a compound of formula I-4; Step (A-A)4: reacting the compound of formula I-4 with a halogenating (e.g., brominating or iodinating) reagent to provide a compound of formula I-5a; Step (A-A)5: reacting the compound of formula I-5a with an oxidizing agent to prepare a compound of formula I-6a; Step (A-A)6: reacting the compound of formula I-6a with a reducing agent to prepare a compound of formula I-7 (reductive dehalogenation, e.g., debromination or deiodination); Step (A-A)7: optionally deprotecting the compound of formula I-7 to obtain a compound of formula I-8; and Step (A-A)8: reacting the compound of formula I-7 or I-8 with a reducing agent to provide a compound of formula I or of formula I-9 (i.e., when R¹ is OH). In some embodiments X is

, wherein R⁸, R⁹, and R¹⁰ are as described herein. In some embodiments X* is , wherein R^8*, R^9*, and R^10* are as described herein. In certain embodiments, Hal is iodine. In some embodiments Hal is bromine. In some embodiments, compounds of the disclosure, or pharmaceutically acceptable salts, solvates, or amino acid conjugates thereof are isotopically labeled (or radiolabeled). Examples of isotopes that can be incorporated into compounds of the disclosure, or pharmaceutically acceptable salts, solvates, or amino acid conjugates thereof include isotopes of hydrogen, carbon, nitrogen, fluorine, such as ²H, ³H, ¹¹C, ¹³C ,¹⁴C, and ¹⁸F. In some embodiments, compounds of the disclosure are deuterated, i.e., incorporate ²H, tritiated, i.e., incorporate ³H, and radiolabeled with carbon-14, i.e., ¹⁴C. Isotopically labeled compounds of the disclosure, or pharmaceutically acceptable salts, solvates, or amino acid conjugates thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In certain embodiments, the present disclosure relates to a method of preparing a compound of formula I or of formula I-9 (i.e., when R¹ is OH), wherein R¹ is alpha-hydroxy, which is a compound of formula I-9a:

or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, wherein R²-R¹⁰, m, n, and p are as described herein. Compounds of formula I-9a can also be depicted as

wherein

In some embodiments, the compound of formula I or I-9 or I-9a, wherein R⁷ is OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C(O)NHOH, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine- dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3-hydroxyisothiazolyl, pyrimidine, 3,5- difluoro-4-hydroxyphenyl or 2,4-difluoro-3-hydroxyphenyl, all of which can be optionally further substituted, can be prepared using synthetic procedures described in WO 2017/062763, US20160130297, US20160145295, US20160145296, US20160185815, US20160229886, US20160289262, and WO 2018/081285 or using other procedure known in the art. The presently disclosed method provides an efficient synthesis of intermediates that can be further elaborated to various side chain analogs, including, but not limited to compounds with the following side chains:

wherein each Z is independently any appropriate substituent, Y is any heteroatom (e.g., O, N, or S), and HC is any appropriate heterocycle (e.g., aromatic or non-aromatic 4-6-membered ring), which, for example, can include, but is not limited to the following groups

. In some embodiments, in Scheme A-A, Step (A-A)1 is further described by Step (X- 1)1 of Scheme X-1: Scheme X-1

1-2-x (i.e., when R^5*=OR¹¹ wherein Step (X-1)1 is protecting a compound of formula I-1 to provide a compound of formula I-2; in some embodiments the compound of formula I-2 is a compound of formula I-2-x (i.e., when R^5* is OR¹¹), wherein R¹¹ is a protecting group); and Step (A-A)1 is further described by Step (X-1)2 is treating the compound of formula I-1 or I-2 (e.g., a compound of formula I-2-x) with an appropriate activating agent to provide a compound of formula I-3, wherein LG is a leaving group, which can be performed sequentially in one pot without isolation of intermediates via a telescopic process (two-step, one-pot procedure). In certain embodiments, the present disclosure relates to a method of preparing a compound of formula I:

or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, wherein R¹ is OH, alkoxy, or oxo; R² and R³ are each independently H, OH, OSO3H, OC(O)CH3, OPO3H2, halogen, or alkyl optionally substituted with one or more halogen or OH, or R² and R³ taken together with the carbon atom to which they are attached form a carbonyl; R⁴ is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl; R⁵ and R⁶ are each independently H, OH, OSO3H, OC(O)CH3, OPO3H2, halogen, or alkyl optionally substituted with one or more halogen or OH, or R⁵ and R⁶ taken together with the carbon atom to which they are attached form a carbonyl; R⁷ is OH, OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C(O)NHOH, NH(CH2)2SO3H, NHCH2CO2H or optionally substituted tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3- hydroxyisoxazolyl, 3-hydroxyisothiazolyl, pyrimidine, 3,5-difluoro-4-hydroxyphenyl or 2,4- difluoro-3-hydroxyphenyl; R⁸, R⁹, and R¹⁰ are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R⁸ and R⁹ taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S, or R⁹ and R¹⁰ taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S; m is 0, 1, or 2; n is 0 or 1; and p is 0 or 1; the method comprising the steps of Step (A-A)1: optionally protecting a compound of formula I-1 to provide a compound of formula I-2; Step (A-A)2: treating the compound of formula I-1 or I-2 with an appropriate activating agent to provide a compound of formula I-3, wherein LG is a leaving group; Step (A-A)3: treating the compound of formula I-3 with a base to prepare a compound of formula I-4; Step (A-A)4: reacting the compound of formula I-4 with a halogenating (e.g., brominating or iodinating) reagent to provide a compound of formula I-5a; Step (A-A)5: reacting the compound of formula I-5a with an oxidizing agent to prepare a compound of formula I-6a; Step (A-A)6: reacting the compound of formula I-6a with a reducing agent to prepare a compound of formula I-7 (reductive dehalogenation or debromination or deiodination); Step (A-A)7: optionally deprotecting the compound of formula I-7 to obtain a compound of formula I-8; and Step (A-A)8: reacting the compound of formula I-7 or I-8 with a reducing agent to provide a compound of formula I. In certain embodiments the compound of formula I is a compound of formula I-9

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, m, n, and p are as described above. In certain embodiments the compound of formula I is a compound of formula I-9-1, I- 9-2, or I-9-3,

I^-9-1 _I-9-2 I-9-3 wherein

n, and p are as described above. In some embodiments, the method of preparing a compound of formula I or formula I-9 comprises alternative steps starting from a compound of I-5b as shown in Scheme A-1. Scheme A-1:

According to Scheme A-1, the method of preparing a compound of I-9-1 starting from a compound of I-5b comprises the steps of: Step (A-1)5b: reacting a compound of formula I-5b with a reducing agent to prepare a compound of formula I-5c (reductive dehalogenation (e.g., debromination, deiodination, etc.); Step (A-1)6b: reacting the compound of formula I-5c with a reducing agent to provide a compound of formula I-5d (ketone reduction in the presence of protecting groups at position C-3); Step (A-1)7b: deprotecting the compound of formula I-5d to provide a compound of formula I-9-1. In some embodiments Step (A-1)6b or other reductions of a C-7 ketone are conducted in the presence of protecting groups at position C-3 via, for example borohydride reduction or catalytic hydrogenation. In some embodiments Step (A-1)7b deprotection of X (e.g., R⁷ is methyl ester) and removal of protecting group R¹¹ at position C-3 may be done selectively and occur in a stepwise fashion or may occur simultaneously. In some embodiments, a C-3 hydroxy can be protected as, for example, an alkyloxycarbonyl or a carbonate, then both the side chain X ^{protecting group (e.g., R7 is methyl ester) and a C-3 hydroxy protecting group can be} removed simultaneously under basic conditions. In other embodiments, a C-3 hydroxy can be protected as, for example, a pivolate, then the side chain X protecting group (e.g., R⁷ is methyl ester) can be removed first keeping the C-3 hydroxy protecting group intact. Stepwise deprotection allows for isolation of penultimate intermediates of compounds of formula I or formula I-9 (e.g., compound 100), thereby providing alternative opportunities for purification (e.g., crystallization) of intermediates (e.g., compounds of formula I-5d) and final products (e.g., compounds of formula I or I-9). In some embodiments the order of Step (A-1)6b and Step (A-1)7b may be reversed, such that the deprotection step as described above may occur prior to the ketone reduction step. Some embodiments of the present disclosure relate to a method of preparing a compound of formula I:

or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, m, n, and p are as described herein and R⁷ is OH, OSO₃H, SO₃H, OSO₂NH₂, SO₂NH₂, OPO₃H₂, PO₃H₂, CO₂H, C(O)NHOH, NH(CH₂)₂SO₃H, NHCH₂CO₂H or optionally substituted tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3-hydroxyisothiazolyl, pyrimidine, 3,5-difluoro-4- hydroxyphenyl or 2,4-difluoro-3-hydroxyphenyl; the method comprising the Steps (B-1)1- (B-1)8 as shown in Scheme B-1. Scheme B-1:

described above; each R^4* is independently R⁴ or R⁴ wherein one or more OH is replaced with OR¹¹; each R^5* is independently R⁵ or R⁵ wherein one or more OH is replaced with OR¹¹; each R^6* is independently R⁶ or R⁶ wherein one or more OH is replaced with OR¹¹; each R^7* is independently R⁷, CO₂Me, or R⁷ wherein one or more OH is replaced with OR¹¹; each R^8* is independently R⁸ or R⁸ wherein one or more OH is replaced with OR¹¹; each R^9* is independently R⁹ or R⁹ wherein one or more OH is replaced with OR¹¹; each R^10* is independently R¹⁰ or R¹⁰ wherein one or more OH is replaced with OR¹¹; wherein R¹¹ is selected from acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, and silyl protecting groups; and LG is a suitable leaving group. According to Scheme B-1, the process of preparing the compound of formula I comprises the steps of Step (B-1)1: optionally protecting a compound of formula I-1a to provide a compound of formula I-2a;

Step (B-1)2:treating the compound of formula I-1a or I-2 with an appropriate activating agent to provide a compound of formula I-3a, wherein LG is a leaving group; Step (B-1)3:treating the compound of formula I-3a with a base to prepare a compound of formula I-4a; Step (B-1)4:reacting the compound of formula I-4 with a halogenating (e.g., iodinating) reagent to provide a compound of formula I-5e; Step (B-1)5:reacting the compound of formula I-5e with one or more reducing agent to prepare a compound of formula I-7b (e.g., deiodination, ketone reduction); Step (B-1)6:optionally deprotecting the compound of formula I-7b to obtain a compound of formula I-9-2. Some embodiments of the present disclosure relate to a method of preparing a compound of formula I:

or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, m, n, and p are as described herein and R⁷ is OH, OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C(O)NHOH, NH(CH2)2SO3H, NHCH2CO2H or optionally substituted tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3-hydroxyisothiazolyl, pyrimidine, 3,5-difluoro-4- hydroxyphenyl or 2,4-difluoro-3-hydroxyphenyl; the method comprising the Steps (B-2)1- (B-2)8 as shown in Scheme B-2. Scheme B-2:

I-9-3 ,

are as described above; each R^4* is independently R⁴ or R⁴ wherein one or more OH is replaced with OR¹¹; each R^8* is independently R⁸ or R⁸ wherein one or more OH is replaced with OR¹¹; each R^9* is independently R⁹ or R⁹ wherein one or more OH is replaced with OR¹¹; each R^10* is independently R¹⁰ or R¹⁰ wherein one or more OH is replaced with OR¹¹; wherein R¹¹ selected from acetyl, benzoyl, C(O)C1-C4 alkyl, C1-C6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, and silyl protecting group; and LG is a suitable leaving group. According to Scheme B-2, the process of preparing the compound of formula I comprises the steps of Step (B-2)1: protecting a compound of formula I-1b to provide a compound of formula I-2b; Step (B-2)2: treating the compound of formula I-2b with an appropriate activating agent to provide a compound of formula I-3b, wherein LG is a leaving group; Step (B-2)3: treating the compound of formula I-3b with a base to prepare a compound of formula I-4a; Step (B-2)4: reacting the compound of formula I-4b with an iodinating reagent to provide a compound of formula I-5f; Step (B-2)5: reacting the compound of formula I-5f with one or more reducing agent to prepare a compound of formula I-7c (e.g., deiodination, ketone reduction); Step (B-2)6: deprotecting the compound of formula I-7c to obtain a compound of formula I-9-3. In some embodiments, the method of preparing a compound of formula I or I-9 comprises alternative steps starting from a compound of e.g., I-5b as shown in Scheme B-3. Scheme B-3:

. According to Scheme B-3, the method of preparing a compound of formula I or I-9 starting from a compound of e.g., I-5b comprises the steps of: Step (B-3)A: reacting a compound of formula I-5b with one or more reducing agents (using e.g., Ni/NaBH4 or LiBH4 with Rh(OAc)2) to prepare a compound of formula I-5d; and Step (B-3)B: deprotecting the compound of formula I-5d to provide the compound of formula I-9-1. In some embodiments, Step (B-3)A is performed with two reducing agents. In some embodiments, Step (B-3)A is performed with two reducing agents, wherein the two reducing agents are added in temporal proximity. In some embodiments, Step (B-3)A is performed with two reducing agents, wherein some two reducing agents is added after the other. In some embodiments, Step (B-3)A is performed with a Ni-based catalyst and a Na- based reducing agent. In some embodiments, Step (B-3)A is performed with a Ni(OAc)2 catalyst. In some embodiments, Step (B-3)A is performed with a Ni(OAc)2Â4H2O. In some embodiments, Step (B-3)A is performed with NaBH4. In some embodiments, Step (B-3)A is performed with LiBH4. In some embodiments, Step (B-3)A is performed with two reducing agents, wherein the two reducing agents are added simultaneously. In some embodiments, a second reducing agent is formed in situ. For example, a first reducing agent (e.g., NaBH4 or LiBH4) can react with Ni salt or other metal salt, e.g., Rh salt, forming a second reducing agent, e.g., Ni (or other metal) boride, which reduces a C-12 halogen while access of the first reducing agent (e.g., NaBH₄) reduces ketone at the C-3 position. Both reducing agents are present during the process. For example, Ni salt is added first before NaBH₄ is added. In some embodiments, Step (B-3)A is performed with NaBH₄ and Ni(OAc)₂Â4H₂O in a molar ratio of about 6,200:1. In some embodiments, Step (B-3)A is performed with NaBH₄ and Ni(OAc)₂Â4H₂O in a molar ratio of about 6,150:1. In some embodiments, Step (B-3)A is performed with NaBH₄ and Ni(OAc)₂Â4H₂O in a molar ratio of about 6,100:1. In some embodiments, Step (B-3)A is performed with NaBH4 and Ni(OAc)2Â4H2O in a molar ratio of about 6,050:1. In some embodiments, Step (B-3)A is performed with NaBH4 and Ni(OAc)2Â4H2O in a molar ratio of about 6,000:1. In some embodiments, Step (B-3)A is performed with NaBH4 and Ni(OAc)2Â4H2O in a molar ratio of about 5,950:1. In some embodiments, Step (B-3)A is performed with NaBH4 and Ni(OAc)2Â4H2O in a molar ratio of about 5,900:1. In some embodiments, Step (B-3)A is performed with NaBH4 and Ni(OAc)2Â4H2O in a molar ratio of about 5,850:1. In some embodiments, Step (B-3)A is performed with NaBH4 and Ni(OAc)2Â4H2O in a molar ratio of about 5,800:1. In some embodiments, Step (B-3)A is performed with NaBH4 and Ni(OAc)2Â4H2O in a molar ratio of about 5,974:1. In some embodiments, metal salts or metal reagents (e.g., metal reducing agents) that can be used with NaBH₄ or LiBH₄ (or other reducing agents) include but are not limited to Pd/C, Rh/C, Raney Ni, Ni(OAc)₂ (e.g., Ni(OAc)₂Â4H₂O), NiCl₂, Pd(OAc)₂, Pd(MeCN)₂Cl₂, Rh(OAc)₂, Cu(OAc)₂, or Cu(Acac)₂. In some embodiments, deprotection of X* (e.g., R^7* is methyl ester) and removal of protecting group R¹¹ at position C-3 may be done selectively and occur in a stepwise fashion or may occur simultaneously. In some embodiments, a C-3 hydroxy can be protected as, for example, an alkyloxycarbonyl or a carbonate, then both the side chain X protecting group (e.g., R⁷ is methyl ester) and a C-3 hydroxy protecting group can be removed simultaneously under basic conditions. In other embodiments, a C-3 hydroxy can be protected as, for example, a pivolate, then the side chain X protecting group (e.g., R⁷ is methyl ester) can be removed first keeping the C-3 hydroxy protecting group intact. Stepwise deprotection allows for isolation of penultimate intermediates of compound I or I-9 (e.g., penultimate intermediates of compound 100), thereby providing alternative opportunities for purification (e.g., crystallization) of intermediates (e.g., compounds of formula I-5d) and final products (e.g., compounds of formula I or I-9). In some embodiments, the compound of formula I-5d is compound 49b

. In some embodiments, the compound of formula I-7b or I-7c is compound 49b

. In some embodiments, a compound of formula I-9 is obtained by treating a compound of formula I-5d with a base. In some embodiments, the base is NaOH. In some embodiments, compound 49b is converted to compound 100 by treating compound 49b with NaOH.

. In some embodiments, a compound of formula I-7a can be prepared from compound I-4 (e.g., wherein R² and R³ form a carbonyl). In a certain embodiment, the compound of formula I-7a can be prepared from a compound of formula I-4 (e.g., a compound of formula I-4a) via a telescopic procedure. In some embodiments, the method of preparing the compound of formula I or I-9 comprises alternative steps from a compound from formula I-7 (e.g., I-7a) as shown in Scheme A-2. Scheme A-2:

I-7a I^-8a _I-9-1 According to Scheme A-2, an alternative process of preparing the compound of formula I or I-9 starting from a compound of formula I-7a comprises the steps of: Step (A-2)6c: reacting compound of formula I-7a with a reducing agent to provide compound of formula I-8a; Step (A-2)7c: deprotecting the compound of formula I-8a to obtain the compound of formula I-9-1. The synthetic processes of the present disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt, ester, prodrug, or amino acid, sulfate, or glucuronide conjugate thereof. In some embodiments, the compound of formula I-1 is a compound of formula A’

. In some embodiments, the compound of formula I-1 is a compound of formula A

In some embodiments, the compound of formula I-1 is a compound of formula A’’

In some embodiments, the compound of formula I-1 is a compound of formula A’’’

In some embodiments, the compound of formula I-1 is compound 1

. In some embodiments, the present disclosure relates to a process of making a compound of formula C2 as shown in Scheme 1. Scheme 1:

each R^7* is independently R⁷, CO₂Me, or R⁷ protected by R¹¹ or by another suitable protecting group; each R^8* is independently R⁸ or R⁸ protected by R¹¹ or by another suitable protecting group; each R^9* is independently R⁹ or R⁹ protected by R¹¹ or by another suitable protecting group; each R^10* is independently R¹⁰ or R¹⁰ protected by R¹¹ or by another suitable protecting group. In some embodiments, Step(1)1 comprises simultaneous protection of a C-3 hydroxy and R⁷ with suitable R¹¹ protecting groups to provide a compound of formula A1 (e.g., R⁷ can be protected as a terminal methyl ester and C-3 hydroxy protected as an acetoxy group). According to Scheme 1, the process of preparing the compound of formula C2 comprises the steps of Step(1)1: protecting a compound of formula A to provide a compound of formula A1; Step(1)2: treating the compound of formula A1 with an appropriate activating agent to provide a compound of formula A2, wherein LG is a leaving group; Step(1)3: treating the compound of formula A2 with a base to prepare a compound of formula B; Step(1)4: reacting the compound of formula B with a brominating reagent to provide a compound of formula B1; Step(1)5: reacting the compound of formula B1 with an oxidizing agent to prepare a compound of formula B2; Step(1)6: reacting the compound of formula B2 with a reducing agent to prepare a compound of formula C (reductive dehalogenation or debromination); Step(1)7: deprotecting the compound of formula C to obtain a compound of formula C1; and Step(1)8: reacting the compound of formula C1 with a reducing agent to provide a compound of formula C2. In some embodiments, the compound A is a compound of formula A’’’. In certain embodiments, the present disclosure relates to a process of making compound of formula C2 as shown in Scheme 1A. Scheme 1A:

wherein R¹¹ is a protecting group, X is

is

described herein; each R^7* is independently R⁷, CO2Me, or R⁷ protected by R¹¹ or by another suitable protecting group; each R^8* is independently R⁸ or R⁸ protected by R¹¹ or by another suitable protecting group; each R^9* is independently R⁹ or R⁹ protected by R¹¹ or by another suitable protecting group; each R^10* is independently R¹⁰ or R¹⁰ protected by R¹¹ or by another suitable protecting group; According to Scheme 1A, the process of preparing the compound of formula C2 comprises the steps of Step (1A)1: protecting a compound of formula A to provide a compound of formula A1; Step (1A)2: treating the compound of formula A1 with an appropriate activating agent to provide a compound of formula A2, wherein LG is a leaving group; Step (1A)3:treating the compound of formula A2 with a base to prepare a compound of formula B; Step (1A)4:reacting the compound of formula B with a halogenating (e.g., brominating or iodinating) reagent to provide a compound of formula B1a; Step (1A)5:reacting the compound of formula B1a with an oxidizing agent to prepare a compound of formula B2a; Step (1A)6:reacting the compound of formula B2a with a reducing agent to prepare a compound of formula C (reductive dehalogenation e.g., debromination or deiodination); Step (1A)7:deprotecting the compound of formula C to obtain a compound of formula C1; and Step (1A)8:reacting the compound of formula C1 with a reducing agent to provide a compound of formula C2. In some embodiments X is , and X* is ^(CHR8*)_m (CHR^{9*)n (CHR10*)p CO2Me} , wherein R⁸, R⁹, R¹⁰, R^8*, R^9*, R^10*, m, n, and p are as described herein. In certain embodiments, the compound of formula A is compound of formula A’’’. In some embodiments, the present disclosure relates to a process of making a compound of formula A2 as shown in Scheme 1A-1, comprising the following steps: Step (A1-1)1: protecting a compound of formula A to provide a compound of formula A1, and Step (A1-1)2: treating the compound of formula A1 with an appropriate activating agent to provide a compound of formula A2, wherein LG is a leaving group. These two steps can be executed sequentially without work-up or isolation of an intermediate compound of formula A1 (i.e., a telescopic, or two-step, one-pot procedure) thereby improving the overall efficiency of manufacturing operations. Scheme 1A-1:

are as described herein. In certain embodiments, the compound of formula A is a compound of formula A’’’. In some embodiments, the compound of formula I-9 or formula C2 is further transformed into a compound of formula I, wherein R⁷ is OSO₃H, SO₃H, OSO₂NH₂, SO2NH2, OPO3H2, PO3H2, C(O)NHOH, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4- oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3- hydroxyisoxazolyl, 3-hydroxyisothiazolyl, or 2,4-difluoro-3-hydroxyphenyl, and R¹ is alkoxy or oxo using known synthetic procedures. In some embodiments, the compound of formula I-9 or C2 is further transformed into a compound of formula I, wherein R⁷ is OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C(O)NHOH, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5- oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3- hydroxyisothiazolyl, pyrimidine, 3,5-difluoro-4-hydroxyphenyl or 2,4-difluoro-3- hydroxyphenyl, all of which can be optionally further substituted, and R¹ is alkoxy or oxo using synthetic procedures described in WO 2017/062763, US20160130297, US20160145295, US20160145296, US20160185815, US20160229886, US20160289262, and WO2018/081285 or using other procedure known in the art. For example, compounds wherein R⁷ is tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo- 1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3- hydroxyisoxa-zolyl, 3-hydroxyisothiazolyl, or 2,4-difluoro-3-hydroxyphenyl can be prepared from the corresponding carboxylic acid via a coupling with the required R⁷-containing boronic acids as shown in Scheme X-2:

. In some embodiments, the R¹¹ protecting group is selected from C(O)C₁-C₄ alkyl, C₁- C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzoyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, and silyl protecting groups. In some embodiments, -OR¹¹ is a silyl ether, wherein the silyl ether is selected from trimethylsilyl ether, triethylsilyl ether, triisopropylsilyl ether, tert- butyldimethylsilyl ether, and tert-butyldiphenylsilyl ether. In some embodiments, the R¹¹ protecting group is benzoyl or acetyl. In some embodiments, the R¹¹ protecting group is C(O)C1-C4 alkyl. In some embodiments, the R¹¹ protecting group is acetyl. In some embodiments R¹¹ is H. Compounds of formula I can be prepared in 6 to 9 steps with overall yield of about 40 to about 60%. In some embodiments, the overall yield of the compound of formula I, formula I-9 or formula C2 is about 50%. Various modifications to the process of Scheme A or Scheme A-A are disclosed in Schemes 1-13. In some of the aspects, the present disclosure relates to a method of preparing the compound of formula B from the compound of formula A1 in one step, the method comprising the steps shown in Scheme 2. Scheme 2:

, wherein R^4*, R^11* and X* are as described herein. In some embodiments, the step of Scheme 2 is performed on a C-7-protected compound, as, for example, shown in Scheme 2A. Scheme 2A:

In some embodiments, the compound of formula A1 is treated with a dehydrating reagent (e.g., phosphorus oxychloride (POCl3), PCl5, P2O5, Burgess reagent, dicyclohexylcarbodiimide (DCC), 2-chloro-1,3-dimethylimidazolinium chloride (DMC), H3PO4, etc.) in the presence of a base (e.g., pyridine, lutidine, triethylamine, diisopropylethyl amine, LiBr, Li2CO3, AcOK, trimethylpyridine, etc.) to provide the compound of formula B. In some embodiments, the reaction is carried out at about 40 °C, about 45 °C, about 50 °C, about 55 °C, or about 60 °C. In some embodiments, the compound of formula B prepared by the dehydration reaction is obtained in about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or more than 95% yield. The compound of formula B can be purified (e.g., by chromatography or crystallization) or used for the next step without purification. In some embodiments, the compound of formula B is crystallized and optionally recrystallized. In some embodiments, the compound of formula B is used without purification. In some embodiments, the compound of formula A1 is first converted into the compound of formula A2 as shown in Step (1)2 of Scheme 1. In some embodiments, a C-12- alcohol A1 is treated with an activating reagent (or an electrophile, e.g., mesyl (methanesulfonyl) chloride, tosyl (toluenesulfonyl) chloride, trifluoromethanesulfonic (triflic) anhydride, thionyl chloride, SO3-pyridine, phosphoryl chloride, phosphoryl bromide, nonafluorobutanesulfonyl chloride, or any other reagent providing a suitable leaving group at the C-12 position) in the presence of a base (e.g., pyridine, triethylamine, diisopropylethylamine (DIPEA), imidazole, etc.) at about 20 °C, about 25 °C, about 30 °C, about 35 °C, about 40 °C, about 45 °C, about 50 °C, about 55 °C, about 60 °C, about 65 °C or up to the reflux temperature of an appropriate reaction solvent (e.g., pyridine, methylene chloride (DCM), etc.). In some embodiments, an additional base can be used as a nucleophilic catalyst (e.g., 4-dimethylaminopyridine (DMAP)). In some embodiments, about 2 equivalents, about 3 equivalents, about 4 equivalents, about 5 equivalents, about 6 equivalents, about 7 equivalents, about 8 equivalents, about 9 equivalents, or about 10 equivalents of the base are used (molar equivalents, based on the molar amount of the compound of formula A1). In some embodiments, about 2 equivalents, about 2.5 equivalents, about 3 equivalents, about 3.5 equivalents, about 4 equivalents, about 4.5 equivalents, about 5 equivalents, about 5.5 equivalents, or about 6 equivalents of the activating reagent (electrophile) are used (molar equivalents, based on the molar amount of the compound of formula A1). In some embodiments, the compound of formula A2 is prepared in about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, about 95% or more than 95% yield. In some embodiments, the compound of formula A2 can be prepared in quantitative yield, e.g., about 100%. In some embodiments, the compound of formula A2 is used without purification. In some embodiments, the compound of formula A2 is treated with a suitable base to provide the compound of formula B. In some embodiments, suitable bases include, but are not limited to, metal alkoxides (e.g., potassium tert-butoxide (t-BuOK), sodium amylate, etc.), acetate salts (e.g., potassium acetate (KOAc), lithium acetate (LiOAc), sodium acetate (NaOAc), or cesium acetate (CsOAc)), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, pyridine, etc. In some embodiments, elimination reaction of Step (1)3 of Scheme 1, is carried out in a suitable solvent, such as a high-boiling solvent (e.g., hexamethylphosphoramide (HMPA), 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), etc.) or a low boiling solvent (e.g., DCM, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), etc.) at elevated temperatures, for example, at about 80 °C, about 90 °C, about 100 °C, about 110 °C, about 120 °C or at reflux temperature of the reaction solvent. In some embodiments, the compound of formula B is prepared in about 60%, about 70%, about 80%, about 85%, about 90%, about 95% or more than 95% yield. In some embodiments, the compound of formula B can be prepared in quantitative yield, e.g., about 100%. In some embodiments, the compound of formula B is used without purification. In some of the embodiments, the compound of formula B is purified by chromatography or crystallization. In some embodiments, the compound of formula B is crystallized from a suitable organic solvent (e.g., heptanes, n-heptane, hexanes, ethyl acetate, methanol, water). In some embodiments, the purity of the isolated compound of formula B is about 80%, about 85%, about 90%, about 95% or more than 95% (by weight). In some embodiments, purity of the compound of formula B is about 97%. In some embodiments, the purity of the compound of formula B is more than about 97%. Some embodiments of the present disclosure relate to methods of converting the compound of formula B into the compound of formula C. In certain embodiments, the compound of formula B is treated with an oxidizing agent to provide the compound of formula C in a single step as shown in Scheme X-3(Step (X-3)4a): Scheme X-3

, wherein R^4*, R¹¹ and X* are as described herein. In some embodiments, the oxidation step can be performed on C-7 protected compounds, wherein a substituent at position C-7 is OR¹¹. In certain embodiments, the compound of formula B is contacted with a metal salt or metal complex (e.g., salts or complexes of ruthenium, rhodium, vanadium, molybdenum, platinum, iron, iridium, etc.), in the presence of an oxidant (e.g., molecular oxygen, hydrogen peroxide, tert-butyl hydroperoxide, etc.) to generate the compound of formula C. In some embodiments, the compound of formula C can be prepared via Wacker-type oxidation. The compound of formula B in a suitable organic solvent (e.g., dimethylformamide, dimethylacetamide, 1,2-diethoxyethane, etc.), optionally containing water, is treated with a catalytic amount of a palladium salt (e.g., PdCl2, Pd(Quinox)Cl2, etc.), optionally in the presence of a copper salt (e.g., CuCl, CuCl2, Cu(OAc)2, etc.) or a silver salt (e.g., AgOAc, AgSbF₆, etc.), and an oxidant (e.g., molecular oxygen, tert-butyl hydrogen peroxide, etc.) to provide the compound of formula C. In some embodiments, the compound of formula B is contacted with a metal salt or metal complex (e.g., salts or complexes of ruthenium, rhodium, vanadium, molybdenum, platinum, iron, iridium, etc.) in the presence of an oxidant (e.g., molecular oxygen, hydrogen peroxide, tert-butyl hydroperoxide, etc.) to provide the compound of formula C. In some embodiments, the compound of formula B is contacted with a bromide containing salt (e.g., LiBr, NaBr, KBr, CsBr, tetraalkylammonium bromide, etc.) and an oxidant (e.g., H2O2, Oxone or other salts of peroxysulfate, mCPBA, peracetic acid, sodium periodate, periodic acid, etc.) to provide the compound of formula C. Suitable solvents include, but are not limited to acetone, acetic acid, and mixture thereof. Optionally, solvents used for bromination may contain water. In some embodiments, the compound of formula B is contacted with a hypobromite salt (e.g., LiOBr, NaOBr, KOBr, tetraalkylammonium hypobromite, Ca(OBr)2, etc.), or bromite salt (e.g., LiO2Br, NaO2Br, KO2Br, tetraalkylammonium hypobromite, Ca(BrO2)2, etc.) in a suitable organic solvent (e.g., acetone, acetic acid, etc.), optionally in the presence of water, to generate the compound of formula C. In some of the embodiments, the present disclosure relates to a method of preparing the compound of formula C as shown in Scheme 1 and Scheme 3. Scheme 3:

, wherein R^4*, R¹¹ and X* are as described herein. According to Scheme 3, the process of preparing the compound of formula C comprises the steps of Step (3)4: reacting the compound of formula B with a brominating reagent to provide the compounds of formula B1; Step (3)5:reacting the compound of formula B1 with an oxidizing agent to prepare the compound of formula B2; and Step (3)6:reacting the compound of formula B2 with a reducing agent to prepare the compound of formula C (reductive debromination). In certain embodiments, the disclosure relates to a method of making the compound C according to Scheme 3A comprising the following steps: Step (3A)4b: contacting the compound of formula B with a halogenation reagent (e.g., N-bromosuccinimide, N-iodosuccinimide, etc.) in the presence of an alcohol (e.g., methanol, ethanol, isopropanol, etc.) to form an intermediate a vicinal halo (e.g., bromo or iodo) ether of formula B’; Step (3A)5b: treating of the vicinal halo (e.g., bromo or iodo) ether B’ with a suitable base (e.g., DBU, triethyl amine, metal alkoxide bases, etc.) to generate an alkoxy enol ether B’’ via elimination of the halogen; and Step (3A)6b: treating of the alkoxy enol ether with an acid in the presence of water, the compound of formula C is generated by hydrolyzing the alkoxy enol ether B’’. Scheme 3A.

. wherein and X*, R^4* and R¹¹ are as described herein and R¹² is alkyl. In some embodiments, the present disclosure relates to a method of preparing the compound of formula C as shown in Scheme 3B. Scheme 3B:

wherein R^4*, R¹¹ and X* are as described herein. According to Scheme 3B, the process of preparing the compound of formula C comprises the steps of Step (3B)4c: reacting the compound of formula B with a halogenating (e.g., brominating or iodinating) reagent to provide the compounds of formula B1a; Step (3B)5c: reacting the compound of formula B1a with an oxidizing agent to prepare the compound of formula B2a; and Step (3B)6c:reacting the compound of formula B2a with a reducing agent to prepare the compound of formula C (reductive halogenation, e.g., debromination or deiodination). The present disclosure also relates to the methods described herein which alternatively apply to C-7 protected compounds, i.e., position C-7 is substituted with OR¹¹ instead of oxo group. Some embodiments of the present disclosure relate to the manipulation of protection and/or deprotection steps for the ease of purification (e.g., by crystallization) of intermediates. In some embodiments, the presence of R⁷ as methyl ester protected COOH facilitates purification of intermediates including the penultimate intermediate. In some embodiments, retention of the protecting group at position C-3 facilitates the purification of intermediates including the penultimate compounds. In certain embodiments, the compound of formula B in a suitable organic solvent (e.g., THF, acetonitrile (ACN), methyl acetate (AcOMe), dichloromethane (DCM), acetone, etc. or mixtures thereof) optionally containing water and/or optionally containing a buffer salt (e.g., potassium phosphate, sodium acetate, sodium bicarbonate, etc.) is treated with a halogenating reagent (halogen donor reagent) to generate the compound of formula B1, B’ or B1a. In some embodiments, the halogenating reagent is a brominating reagent (bromine donor reagent). In some embodiments, the halogenating reagent is an iodinating reagent (iodine donor reagent). In certain embodiments, the compound of formula B in a suitable organic solvent (e.g., THF, acetonitrile (ACN), methyl acetate (AcOMe), dichloromethane (DCM), acetone, etc. or mixtures thereof) optionally containing water and/or optionally containing a buffer salt (e.g., potassium phosphate, sodium acetate, sodium bicarbonate, etc.) is treated with a brominating agent (bromine donor reagent) to generate the compound of formula B1. In certain embodiments, the solvent is a mixed solvent system. In some of the embodiments, the solvent is a THF/water, AcOMe/water, or ACN/water system. In some embodiments, the solvent is an acetonitrile-water system. In some embodiments, the solvent is a THF-water system. In some embodiments, the solvent is a methyl acetate-water system. In certain embodiments, the solvents in a mixed solvent system are mixed in a fixed ratio, including, but not limited to e.g., 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1,1.5:1, or 1:1 (organic solvent:water). In a further embodiment, the solvent is a three-solvent system. In some embodiments, the solvent system is acetone-THF-water. In certain embodiments, the solvents in a mixed three-solvent system are mixed in a fixed ratio, including but not limited to e.g. 1.5:3:1, 1:3:1.5, or 1:3:1, 1.5:4:1, 1:4:1.5, 1:4:1, 1.5:5:1, 1:5:1.5, 1:5:1 (organic solvent 1:organic solvent 2:water). In some embodiments, the brominating reagent is an electrophilic brominating reagent. In some embodiments the brominating reagent is bromine. The brominating reagents or bromine donor reagents are commercially available or can be easily synthesized by a skilled artisan. The electrophilic brominating reagents include, but are not limited to, phenylselenium bromide, phenylselenium tribromide, pyridinium tribromide, N- bromophthalimide, N-bromosaccharine, acetylhypobromite, N-bromacetamide, tetramethylammonium tribromide, dibromohydantoin (DDH, 1,3-dibromo-5,5- dimethylhydantoin (DBDMH)), tribromoisocyanuric acid, dibromoisocyanuric acid, dibromamine-T (N,N-dibromo-p-toluenesulfonamide), dibromamine-B, N-bromosuccinimide (NBS), dimethylaminopyridine bromide, and bromodichloroisocyanuric acid (BDCCA):

. In certain embodiments, the brominating agent (reagent or donor) is dibromohydantoin (1,3-dibromo-5,5-dimethylhydantoin (DBDMH)), N-bromosuccinimide (NBS), N-bromosaccharine, dibromamine-T or bromodichloroisocyanuric acid (BDCCA). In some embodiments, the brominating reagent is dibromamine-T. In another embodiment, the brominating reagent is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). In another embodiment, the brominating reagent is NBS. In some embodiments NBS is used in combination with NH4OAc (e.g., catalytic, about 0.1 to about 0.2 equivalents (eq.), including about 0.11, about 0.12, about 0.13, about 0.14, about 0.15, about 0.16, about 0.17, about 0.18, about 0.19, or about 0.2 eq.). In some embodiments, the stoichiometry of the brominating reagent is from about 1.0 to about 2.5 eq., including about 1.05, about 1.1, about 1.15, about 1.2, about 1.25, about 1.3, about 1.35, about 1.4, about 1.45, about 1.5, about 1.55, about 1.6, about 1.65, about 1.7, about 1.75, about 1.8, about 1.85, about 1.9, about 2.0, about 2.05, about 2.1, about 2.15, about 2.2, about 2.25, about 2.3, about 2.35, about 2.4, about 2.45, or about 2.5 eq. In one aspect, the brominating reagent is optionally used in the presence of a nucleophilic organocatalyst. The nucleophilic organocatalysts include, but not limited to, dimethylformamide, dimethylacetamide, tetramethylguanidine, dimethylaminopyridine, and N-bromoamidine (e.g., ±-iso-amarine). In some embodiments, the bromohydration (hydroxy-bromination) reaction of Step (3B)4c is carried out at about -50 °C, about -40 °C, at about -30 °C, at about -20 °C, at about -10 °C, at about -5 °C, at about 0 °C, at about 5 °C, at about 10 °C, at about 15 °C, or at about 20 °C. In certain embodiments, the bromohydration reaction of Step (3B)4c is carried out at about 5 °C to about 10 °C. In some embodiments, the compound of formula B1, bromohydrin, is obtained in about 50%, in about 55%, about 60%, in about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or more than 95% yield. In some embodiments, the compound of formula B1 can be purified or used without purification. In some embodiments, compound B1 is obtained in about 63% yield using methyl acetate-water solvent system. In some embodiments, the compound of formula B1 is treated with a reducing agent (e.g., sodium bisulfite, sodium thiosulfate, trimethylphosphite, etc.) to stabilize the compound of formula B1 during work-up and isolation. In certain embodiments, the reducing agent is a mild reducing agent. In some embodiments, the reducing agent can be substituted with additional oxidant (e.g., NaOCl, tert-butyl hydroperoxide, hydrogen peroxide, peracetic acid, sodium periodate, etc.), and optionally in the presence of an oxidation catalyst (e.g., chromium salts, TEMPO, etc.), to generate the compound of formula B2, without isolation of the compound of formula B1. The product can be extracted into a suitable organic solvent (e.g., ethyl acetate, meth tert-butyl ether, dichloromethane, etc.) and concentrated as needed for the next reaction steps. In some embodiments, the halogenating reagent is an electrophilic halogenating reagent. In some embodiments, the iodinating reagent is an electrophilic iodinating reagent. In some embodiments the iodinating reagent is iodine. In another embodiment, the iodinating reagent is N-iodosuccinimide (NIS). The halogenating reagents (e.g., brominating or iodinating reagents) are commercially available or can be easily synthesized by a skilled artisan. The iodinating reagents or iodine donor reagents are commercially available or can be easily synthesized by a skilled artisan. The electrophilic iodinating reagents include, but are not limited to, HOI generated in situ from iodine in the presence of water, iodine in the presence of aqueous cerium sulfate, NaIO₄ with sodium bisulfite, N-iodosuccinimide, I-Cl, I- F, etc., with or without an oxidizing agent (e.g., HIO₃, HIO₄, H₅IO₆, HClO₄, HNO₃, H₂SO₄, trifluoroacetic acid, trichloroacetic acid, etc.). In certain embodiments, the iodinating agent (reagent or donor) is N-iodosuccinimide (NIS). In some embodiments NIS is used in combination with catalytic or non-catalytic H5IO6, HClO4, or H2SO4 (e.g., catalytic, about 0.1 to about 0.3 equivalents (eq.), including about 0.11, about 0.12, about 0.13, about 0.14, about 0.15, about 0.16, about 0.17, about 0.18, about 0.19, about 0.2 eq, about 0.21 eq, about 0.22 eq, about 0.23 eq, about 0.24 eq, about 0.25 eq, about 0.26 eq, about 0.27 eq, about 0.28 eq, about 0.29 eq, about 0.3 eq, or non- catalytic, at or above 1.0 eq). In some embodiments, the stoichiometry of the iodinating reagent is from about 1.0 to about 2.5 eq., including about 1.05, about 1.1, about 1.15, about 1.2, about 1.25, about 1.3, about 1.35, about 1.4, about 1.45, about 1.5, about 1.55, about 1.6, about 1.65, about 1.7, about 1.75, about 1.8, about 1.85, about 1.9, about 2.0, about 2.05, about 2.1, about 2.15, about 2.2, about 2.25, about 2.3, about 2.35, about 2.4, about 2.45, or about 2.5 eq. In certain embodiments, the compound of formula B in a suitable organic solvent (e.g., THF, acetonitrile (ACN), methyl acetate (AcOMe), dichloromethane (DCM), acetone, methyl tert-butyl ether (MTBE), dioxane etc. or mixtures thereof) optionally containing water and/or optionally containing a buffer salt (e.g., potassium phosphate, sodium acetate, sodium bicarbonate, etc.) is treated with an iodination agent (iodine donor reagent) to generate the compound of formula B1a. In certain embodiments, the solvent is a mixed solvent system. In some of the embodiments, the solvent is a dioxane/water, MTBE/water, or ACN/water system. In some embodiments, the solvent is a dioxane-water system. In some embodiments, the solvent is a MTBE-water system containing trifluoroacetic acid. In some embodiments, the solvent is a MTBE-water system. In certain embodiments, the solvents in a MTBE-water system are mixed in a fixed ratio, including, but not limited to e.g., 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1,1.5:1, or 1:1 (organic solvent:water). In certain embodiments, the solvents in a dioxane-water system are mixed in a fixed ratio, including, but not limited to e.g., 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1,1.5:1, or 1:1 (organic solvent:water). In some embodiments, the iodohydration (hydroxy-iodination) reaction of Step (3B)4c is carried out at about -10 °C, about -5 °C, at about 0 °C, at about 5 °C, at about 10 °C, at about 15 °C, at about 20 °C, at about 25 °C, at about 30 °C, at about 35 °C, at about 40 °C, at about 45 °C, or 50 °C. In certain embodiments, the iodohydration reaction of Step (3B)4c is carried out at about 0 °C to about 5 °C. In some embodiments, the compound of formula B1a, (e.g., iodohydrin when Hal is iodo), is obtained in about 50%, in about 55%, about 60%, in about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or more than 95% yield. In some embodiments, the compound of formula B1a can be purified or used without purification. In some embodiments, compound B1a is obtained in about 90% yield using dioxane-water solvent system. In some embodiments, the compound of formula B1a is treated with a reducing agent (e.g., sodium bisulfite, sodium thiosulfate, trimethylphosphite, etc.) to stabilize the compound of formula B1a during work-up and isolation. In certain embodiments, the reducing agent is a mild reducing agent. In some embodiments, the reducing agent can be substituted with additional oxidant (e.g., NaOCl, tert-butyl hydroperoxide, hydrogen peroxide, peracetic acid, sodium periodate, etc.), and optionally in the presence of an oxidation catalyst (e.g., ruthenium salts, chromium salts, TEMPO, etc.), to generate the compound of formula B2a, without isolation of the compound of formula B1a. The product can be extracted into a suitable organic solvent (e.g., ethyl acetate, meth tert-butyl ether, dichloromethane, etc.) and concentrated as needed for the next reaction steps. In certain embodiments, a compound of formula B1 in a suitable organic solvent (e.g., methyl tert-butyl ether, THF, dichloromethane, ethyl acetate, acetonitrile, etc.; or a mixture thereof), optionally containing water, is contacted with an oxidant to generate the compound of formula B2. The product can be extracted into a suitable organic solvent (e.g., ethyl acetate, meth tert-butyl ether, dichloromethane, etc.) and concentrated as needed for the next reaction steps. In certain embodiments, a compound of formula B1a (e.g., iodohydrin when Hal is iodo) in a suitable organic solvent (e.g., methyl tert-butyl ether, THF, dichloromethane, ethyl acetate, acetonitrile, etc.; or a mixture thereof), optionally containing water, is contacted with an oxidant to generate the compound of formula B2a. The product can be extracted into a suitable organic solvent (e.g., ethyl acetate, meth tert-butyl ether, dichloromethane, etc.) and concentrated as needed for the next reaction steps. In some embodiments, the oxidizing agents include, but are not limited to, chromic acid or chromium salts (e.g., Na₂Cr₂O₇), manganese salts (e.g., KMnO₄), silver salts (e.g., Ag₂CO₃), iron salts (e.g., K₂FeO₄), cerium salts (e.g., Ce(SO₄)₂), ruthenium salts (e.g., Na₂RuO₄), and N-bromo derivatives (e.g., N-bromosuccinimide, dimethyl dibromohydantoin, N-bromoacetamide, etc.) in stoichiometric excess, or in catalytic amounts in combination with a co-oxidant (e.g., ammonium nitrate, hydrogen peroxide, tert-butyl hydroperoxide, peracetic acid, NaOCl, Ca(OCl)2, etc.). In some embodiments, the oxidizing agent can be employed in the absence of metal salts. In certain embodiments, the oxidant can be employed during the bromination step to directly convert the intermediate compound of formula B1 to a compound of formula B2. In some embodiments, the oxidizing agents include, but are not limited to, chromic acid or chromium salts (e.g., Na2Cr2O7), manganese salts (e.g., KMnO4), silver salts (e.g., Ag₂CO₃), iron salts (e.g., K₂FeO₄), cerium salts (e.g., Ce(SO₄)₂), ruthenium salts (e.g., Na₂RuO₄), and N-halo derivatives (e.g., N-iodosuccinimide N-bromosuccinimide, dimethyl dibromohydantoin, N-bromoacetamide, etc.) in stoichiometric excess, or in catalytic amounts in combination with a co-oxidant (e.g., ammonium nitrate, hydrogen peroxide, tert-butyl hydroperoxide, peracetic acid, NaOCl, Ca(OCl)₂, etc.). In some embodiments, the oxidizing agent can be employed in the absence of metal salts. In certain embodiments, the oxidant can be employed during the halogenation, e.g., iodination step to directly convert the intermediate compound of formula B1a to a compound of formula B2a. The compound of formula B2, bromoketone, is obtained in about 80%, in about 85%, about 90%, in about 95%, or more than 95% yield. In some embodiments, the compound of formula B2 is prepared in quantitative yield, e.g., about 100%. In some embodiments, the compound of formula B2 can be purified or used without purification. In some embodiments, the compound of formula B2 in a suitable organic solvent (i.e., acetic acid, methanol, THF, etc.), optionally containing water, is contacted with a reducing agent to generate compound of formula C. In some embodiments, the compound of formula B2a, haloketone (e.g., bromoketone or iodoketone), is obtained in about 80%, in about 85%, about 90%, in about 95%, or more than 95% yield. In some embodiments, the compound of formula B2a is prepared in quantitative yield, e.g., about 100%. In some embodiments, the compound of formula B2a can be purified or used without purification. In some embodiments, the compound of formula B2a in a suitable organic solvent (i.e., acetic acid, methanol, THF, etc.), optionally containing water, is contacted with a reducing agent to generate a compound of formula C. The suitable reducing agents include, but are not limited to organosilanes (e.g., triethylsilane, hexamethyldisilane, etc.), trialkyl phosphines (e.g., triethyl phosphine, tributyl phosphine, etc.), triphenyl phosphine, 1,3-dialkyl-2-phenylbenzimidazolines (e.g., 1,3- dimethyl-2-phenylbenzimidazoline), iodide salts (e.g., LiI, NaI, KI, CsI, etc.) in the presence of a Lewis acid (e.g., BF3), hydroiodic acid, zinc-copper couple, zero valent metals (e.g., Li⁰, Na⁰, K⁰, Ca⁰, Al⁰, Fe⁰, Zn⁰, etc.) and their corresponding lower-valency metal salts (e.g., low valent salts of chromium, tin, samarium, manganese, titanium such as CrCl2, SnCl2, SmI2, Mn(OAc)3, TiCl3, respectively), aniline or substituted anilines (e.g., PhNH2, PhNHMe, etc.), and hydrogen in the presence of a catalyst (e.g., palladium, platinum, ruthenium, iron, nickel, etc.). In some embodiments, debromination is performed using Zn (dust) in the presence of acetate salt (e.g., AcONa) in a suitable solvent (e.g., AcOH) and elevated temperature (e.g., reflux). The diketone compound of formula C is obtained in about 70%, in about 75%, in about 80%, in about 85%, about 90%, in about 95%, or more than 95% yield. In some embodiments, the compound of formula C is prepared in quantitative yield, e.g., about 100%. In some embodiments, the compound of formula C can be purified or used without purification. Some embodiments of the present disclosure relate to a method of making compound of formula B2’ comprising the steps shown in Scheme 4. Scheme 4:

, wherein R^4*, R¹¹, and X* are as described herein. In some embodiments, the present disclosure relates to a method of making compound of formula B2’ comprising the steps shown in Scheme 4A. Scheme 4A:

, wherein R^4*, R¹¹, and X* are as described herein. A halogenated (e.g., brominated or iodinated) compound of formula B1a (halohydrin, e.g., bromohydrin or iodohydrin) in a suitable organic solvent (e.g., ethanol, acetic acid, etc. or mixture thereof) can be treated with a catalyst or metal reagent (e.g., Raney^®-Nickel (Raney Ni or Ra-Ni) or zero valent zinc or magnesium), or optionally in the presence of hydrogen and a catalyst (e.g., Pd, Pt, Rh, Ni, and salts thereof, etc.), to generate a compound of formula B2’. A halogenated compound of formula B1 or B1a (halohydrin or iodohydrin or bromohydrin) in a suitable organic solvent (e.g., ethanol, acetic acid, etc. or mixture thereof) can be treated with a catalyst or metal reagent (e.g., Raney^®-Nickel, Raney Ni, Ra-Ni), or optionally in the presence of hydrogen and a catalyst (e.g., Pd, Pt, Rh, Ni, and salts thereof, etc.), to generate a compound of formula B2 or B2a. A brominated compound of formula B1 (bromohydrin) in a suitable organic solvent (e.g., ethanol, acetic acid, etc. or mixture thereof) can be treated with a catalyst or metal reagent (e.g., Raney^®-Nickel, Raney Ni, Ra-Ni), or optionally in the presence of hydrogen and a catalyst (e.g., Pd, Pt, Rh, Ni, and salts thereof, etc.), to generate a compound of formula B2. In certain embodiments, reductive dehalogenation can be performed under neutral, basic or acidic conditions. In certain embodiments, the metal reagent can be used alone in stoichiometric amounts, or in catalytic amounts in the presence of hydrogen. In other embodiments, the reaction can be conducted under catalytic transfer hydrogenation using hydrogen donors (1,3-cyclohexadiene, 1,7- octadiene, cyclohexene, ammonium formate, potassium formate, formic acid, ethanol, i- propanol, etc.). In some embodiments, hydrogenation and catalytic transfer hydrogenation is performed under continuous flow conditions. The compound of formula B2’ is obtained in about 70%, in about 75%, in about 80%, in about 85%, about 90%, in about 95%, or more than 95% yield. In some embodiments, the compound of formula B2’ is prepared in quantitative yield, e.g., about 100%. In some embodiments, the compound of formula B2’ can be purified or used without purification. In some embodiments, the present disclosure relates to a method of making a compound of formula C comprising the steps shown in Scheme 5. Scheme 5:

, wherein R^4*, R¹¹, and X* are as described herein and BY2 – is a boron moiety, wherein Y can be, for example, an alkyl group, halogen, hydrogen, amine, or alcohol. The method of making of compound of formula C in Scheme 5 comprises the steps of: Step (5)4a: reacting a compound of formula B with a borane reagent to prepare a compound of formula B1’; Step (5)5a: reacting the compound of formula B1’ with an oxidizing reagent to provide a compound of formula B2’; and Step (5)6a: reacting the compound of formula B2’ with oxidizing reagent to prepare a compound of formula C. In certain embodiments of the present disclosure, the compound of formula B in an aprotic organic solvent (e.g., THF, dichloromethane, 1,2-diethoxyethane, heptane, etc.) is contacted with a borane reagent to form a compound of formula B1’. Upon completion of the reaction, the mixture is contacted with an oxidant to form a compound of formula B2’ bearing an alcohol at position C-11. The mixture can undergo work up via solvent extraction into a suitable organic solvent (e.g., ethyl acetate, dichloromethane, methyl tert-butyl ether, etc.), and the resulting solution is concentrated as needed, or solvent exchanged to a more appropriate solvent. A solution of the compound of formula B2’ is then contacted with an oxidant to generate a compound of formula C. The borane reagents (“B”) include, but are not limited to BH₃ and complexes there of (e.g., BH₃-THF, BH₃-DMS, BH₃-NH₃, etc.), monoalkylboranes of structure alkylBH₂ (e.g., mono-thexyl borane, mono-isopinocampheyl borane, etc.), dialkylboranes of structure dialkylBH (e.g., disiamylborane, dithexylborane, dicyclopentylborane, 9-BBN, etc.), mono- chloroborane and complexes thereof (e.g., ClBH₂-THF, ClBH₂-DMS, etc.), dichloroborane and complexes thereof (e.g., Cl₂BH-THF, Cl₂BH-DMS, etc.), and catecholborane. The oxidizing agents, for oxidizing the compound of formula B1’, include, but are not limited to, hydrogen peroxide, tert-butyl hydroperoxide, Oxone, and molecular oxygen. The oxidizing agents, for oxidizing the compound of formula B2’ include, but are not limited to, chromic acid or chromium salts (e.g., Na2Cr2O7), manganese salts (e.g., KMnO4), silver salts (e.g., Ag2CO3), iron salts (e.g., K2FeO4), cerium salts (e.g., Ce(SO4)2), ruthenium salts (e.g., Na2RuO4), etc. in stoichiometric excess, or in catalytic amounts in combination with a co-oxidant (e.g., ammonium nitrate, hydrogen peroxide, tert-butyl hydroperoxide, peracetic acid, NaOCl, Ca(OCl)2, NaIO4, H5IO6, etc.). In some embodiments, the oxidizing agent can be employed in the absence of metal salts. In some embodiments, an oxidation catalyst, for example TEMPO, may be employed. In some embodiments, the present disclosure relates to a method of preparing the compound of formula C2 according to the process of Scheme 5, wherein R⁴, R¹¹, X, R^4*, and X* are as described herein. Scheme 6:

. According to Scheme 6, the process of preparing the compound of formula C2 comprises the step of: Step (6)7: deprotecting the compound of formula C to provide the compound of formula C1 or a pharmaceutically acceptable salt thereof; and Step (6)8: reacting the compound of formula C1 with a reducing reagent to prepare a compound of formula C2. In some embodiments, the reducing reagents in step 8 include but are not limited to NaBH₄, NaCNBH₃, LiBH₄, (i-Bu₂AlH)₂, L-selectride, K-selectride. In some embodiments, the reducing reagent is NaBH₄ or LiBH₄. Reducing agents can be used in combination with added reagents such as, but not limited to CeCl₃, CoCl₂, and other Lewis acids, which can be used to enhance a ketone reduction, including, but are not limited to zinc(II), calcium(II), magnesium(II), aluminum(III) salts. In some embodiments, at least 2 molar equivalents of the reducing agent are used. In some embodiments, from about 2 equivalents to about 3 equivalents of the reducing agent are used. In another embodiment, the molar ratio (or molar equivalent) is about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0 equivalents. The reduction is performed in a suitable solvent. In some embodiments, the reduction is performed in water. In some embodiments, the reduction is performed in an alcoholic solvent. In some embodiments, the alcoholic solvent is methanol. In some embodiments, the alcoholic solvent is isopropanol. In some embodiments, the alcoholic solvent is ethanol. In some embodiments, reduction is performed in the presence of a base. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is sodium hydroxide and the solvent is water. In some embodiments, the reduction in Step (6)8 is conducted in a time period between about 2 hours and about 50 hours, e.g., about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 25 hours, about 30 hours, about 35 hours, about 40 hours, about 45 hours, or about 50 hours. In some embodiments, the reduction in Step (6)8 is performed at a temperature from between about 15 °C and about 100 °C, as well as any temperature increment in between, e.g., at about 20 °C, at about 25 °C, at about 30 °C, at about 40 °C, at about 50 °C, at about 60 °C, at about 70 °C, at about 80 °C, at about 90 °C, or at about 100 °C. In some embodiments, the reduction is performed at a temperature from between about -10 ºC and about 15 ºC, e.g., about - 10 ºC, about -5 ºC, about 0 ºC, about 3 ºC, about 5 ºC, about 7 ºC, about 10 ºC or about 15 ºC, as well as any temperature increment in between. In some embodiments, the reduction is performed at about 5 ºC. Deprotection reagents for Step (6)7depend on the chosen protecting groups and can be selected from standard reagents known by those skilled in the art (including the reagents discussed herein). In certain embodiments, a process described herein, e.g., the process of Scheme 1, provides a compound of formula II:

or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate or prodrug thereof. In certain embodiments, a process described herein, e.g., the process of Scheme 1, provides a compound of formula III:

or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate or prodrug thereof. In some embodiments, the present disclosure relates to a method of making a compound of formula IIIa:

or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof. In some embodiments, the present disclosure relates to a method of making a compound of formula IIIb:

or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof. In certain embodiments, the process of Scheme 1 provides compound 100:

or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁴ is in the Į-position. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9- 2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁴ is C1-C4 alkyl. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁴ is methyl, ethyl, or propyl. In some embodiments, R⁴ is ethyl. In another embodiment, R⁴ is alpha-ethyl. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁴ is H or halogen. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁴ is C₁-C₆ alkyl optionally substituted with one or more halogen or OH. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁴ is C₂-C₆ alkenyl or C₂-C₆ alkynyl. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁷ is OH, OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, or C(O)NHOH. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁷ is OH, OSO3H, OSO2NH2, OPO3H2, or CO2H. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁷ is OH. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁷ is CO₂H. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁷ is OSO₃H. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁷ is SO3H. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁷ is OSO2NH2 or SO2NH2. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁷ is OPO3H2, PO3H2, or C(O)NHOH. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁷ is tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3-hydroxyisothiazolyl, or 2,4-difluoro-3- hydroxyphenyl. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, IIIa, IIIb, or C2, wherein R⁷ is OH, OSO₃H, OSO₂NH₂, OPO₃H₂, CO₂H, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4- thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3- hydroxyisothiazolyl, or 2,4-difluoro-3-hydroxyphenyl. In some embodiments, the present disclosure provides compounds of formula I, wherein R⁵ is OSO3H, OC(O)CH3, or OPO3H2. In some embodiments, the present disclosure provides compounds of formula I, wherein R⁵ and R⁶ taken together with the carbon atom to which they are attached form a carbonyl. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, or C2, wherein m is 0. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, or C2, wherein m is 1. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, or C2, wherein m is 2. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, I-9-1, I-9-2, I-9-3, II, III, or C2, wherein n is 1. In some embodiments, the present disclosure provides compounds of I, Ia, Ib, I-9, II, III, or C2, wherein p is 0. In some embodiments, the present disclosure provides compounds of formula I, Ia, Ib, I-9, II, or C2, wherein R¹ is in the ȕ-position (beta-position). In some embodiments, the compound prepared by the methods of the present disclosure is compound 100:

In one aspect, the method of the present disclosure produces a substantially pure compound of formula I, or a pharmaceutically acceptable salt thereof. The term “purity” as used herein refers to the amount of the compound of formula I based on analytic methods commonly used in the art (e.g., HPLC). In some embodiments, the compound of formula I has a purity of greater than about 90%. In some embodiments, the compound of formula I has a purity of greater than about 95%. In some embodiments, the compound of formula I has a purity of greater than about 98%. For example, the purity of the synthesized compound of Formula I is about 96.0%, about 97.0%, about 98.0%, about 99.0%, or about 100%. For example, the purity of the synthesized compound of formula I is 98.5%, 99.0%, or 99.5%. In some embodiments, the purity is determined by HPLC. The present disclosure provides methods for the synthesis of highly pure compounds of formula I which are safe and which can produce compounds of formula I on a large scale. In some embodiments, the method of the present disclosure produces compounds of formula I in high yield (>98%) and with limited number of impurities. The compounds of the disclosure have asymmetric centers and can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the disclosure and can be isolated as a mixture of isomers or as separate isomeric forms. All chiral, diastereomeric, racemic, and geometric isomeric forms of a structure are intended, unless specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present disclosure and intermediates made therein are considered to be part of the present disclosure. All tautomers of shown or described compounds are also considered to be part of the present disclosure. Furthermore, the disclosure also includes metabolites of the compounds described herein. The disclosure also comprehends isotopically-labeled compounds of the disclosure, or pharmaceutically acceptable salts, solvates, or amino acid conjugates thereof, which are identical to those recited in formulae of the application and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure, or pharmaceutically acceptable salts, solvates, or amino acid conjugates thereof include isotopes of hydrogen, carbon, nitrogen, fluorine, such as ²H, ³H, ¹¹C, ¹³C ,¹⁴C, and ¹⁸F. Deuterated, i.e., ²H, tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes may be used for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be used in some circumstances. Isotopically labeled compounds of the disclosure, or pharmaceutically acceptable salts, solvates, or amino acid conjugates thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. However, one skilled in the art will recognize that not all isotopes can be included by substitution of the non-isotopically labeled reagent. In some embodiments, compounds of the disclosure, or pharmaceutically acceptable salts, solvates, or amino acid conjugates thereof are not isotopically labeled. In some embodiments, deuterated compounds of the disclosure are useful for bioanalytical assays. In another embodiment, compounds of the disclosure, or pharmaceutically acceptable salts, solvates, or amino acid conjugates thereof are radiolabeled. Methods of Treatment The compounds of the disclosure (e.g., compounds of formula I, Ia, Ib, I-9, I-9-1, I-9- 2, I-9-3, II, III, IIIa, IIIb, C2, and compound 100) are useful for therapy in subjects such as mammals, including humans. In particular, the compounds of the disclosure are useful in a method of treating or preventing a disease or condition in a subject comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disease or condition is FXR-mediated (e.g., FXR plays a role in the initiation or progress of the disease or condition). In some embodiments, the disease or condition is mediated by decreased FXR activity. In some embodiments, the disease or condition is selected from cardiovascular disease, chronic liver disease, lipid disorder, gastrointestinal disease, renal disease, metabolic disease, cancer, and neurological disease. In some embodiments, the disclosure relates to a method of treating or preventing cardiovascular disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of treating cardiovascular disease. In some embodiments, cardiovascular disease selected from atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesteremia, hyperlipidemia, hyperlipoproteinemia, and hypertriglyceridemia. The term "hyperlipidemia" refers to the presence of an abnormally elevated level of lipids in the blood. Hyperlipidemia can appear in at least three forms: (1) hypercholesterolemia, i.e., an elevated cholesterol level; (2) hypertriglyceridemia, i.e., an elevated triglyceride level; and (3) combined hyperlipidemia, i.e., a combination of hypercholesterolemia and hypertriglyceridemia. The term "dyslipidemia" refers to abnormal levels of lipoproteins in blood plasma including both depressed and/or elevated levels of lipoproteins (e.g., elevated levels of LDL, VLDL and depressed levels of HDL). In some embodiments, the disclosure relates to a method selected from reducing cholesterol levels or modulating cholesterol metabolism, catabolism, absorption of dietary cholesterol, and reverse cholesterol transport in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate or prodrug thereof. In another embodiment, the disclosure relates to a method of treating or preventing a disease affecting cholesterol, triglyceride, or bile acid levels in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of lowering triglycerides in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of treating or preventing a disease state associated with an elevated cholesterol level in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of treating a disease state associated with an elevated cholesterol level in a subject. In some embodiments, the disclosure relates to a method of preventing a disease state associated with an elevated cholesterol level in a subject. In some embodiments, the disease state is selected from coronary artery disease, angina pectoris, carotid artery disease, strokes, cerebral arteriosclerosis, and xanthoma. In some embodiments, the disclosure relates to a method of treating or preventing a lipid disorder in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of treating a lipid disorder. In some embodiments, the disclosure relates to a method of preventing a lipid disorder. Lipid disorders are the term for abnormalities of cholesterol and triglycerides. Lipid abnormalities are associated with an increased risk for vascular disease, and especially heart attacks and strokes. Abnormalities in lipid disorders are a combination of genetic predisposition as well as the nature of dietary intake. Many lipid disorders are associated with being overweight. Lipid disorders may also be associated with other diseases including diabetes, the metabolic syndrome (sometimes called the insulin resistance syndrome), underactive thyroid or the result of certain medications (such as those used for anti-rejection regimens in people who have had transplants). In some embodiments, the disclosure relates to a method of treating or preventing one or more symptoms of disease affecting lipid metabolism (i.e., lipodystrophy) in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of treating one or more symptoms of a disease affecting lipid metabolism. In some embodiments, the disclosure relates to a method of preventing one or more symptoms of a disease affecting lipid metabolism. In some embodiments, the disclosure relates to a method of decreasing lipid accumulation in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of treating or preventing liver disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of treating chronic liver disease. In some embodiments, the disclosure relates to a method of preventing chronic liver disease. In some embodiments, the FXR mediated liver disease is selected from a cholestatic liver disease such as primary biliary cirrhosis (PBC) also known as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis, and liver fibrosis. Other examples of FXR mediated diseases also include portal hypertension, bile acid diarrhea, hyperlipidemia, high LDL-cholesterol, high HDL cholesterol, high triglycerides, and cardiovascular disease. Other liver diseases include cerebrotendinous xanthomatosis (CTX), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, Sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha 1- antitrypsin deficiency. In some embodiments, the disclosure relates to a method of treating or preventing one or more symptoms of cholestasis, including complications of cholestasis in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate or prodrug thereof. In some embodiments, the disclosure relates to a method of treating one or more symptoms of cholestasis. In some embodiments, the disclosure relates to preventing one or more symptoms of cholestasis. Cholestasis is typically caused by factors within the liver (intrahepatic) or outside the liver (extrahepatic) and leads to the accumulation of bile salts, bile pigment bilirubin, and lipids in the blood stream instead of being eliminated normally. Intrahepatic cholestasis is characterized by widespread blockage of small ducts or by disorders, such as hepatitis, that impair the body's ability to eliminate bile. Intrahepatic cholestasis may also be caused by alcoholic liver disease, primary biliary cirrhosis, cancer that has spread (metastasized) from another part of the body, primary sclerosing cholangitis, gallstones, biliary colic, and acute cholecystitis. It can also occur as a complication of surgery, serious injury, cystic fibrosis, infection, or intravenous feeding or be drug induced. Cholestasis may also occur as a complication of pregnancy and often develops during the second and third trimesters. Extrahepatic cholestasis is most often caused by choledocholithiasis (Bile Duct Stones), benign biliary strictures (non-cancerous narrowing of the common duct), cholangiocarcinoma (ductal carcinoma), and pancreatic carcinoma. Extrahepatic cholestasis can occur as a side effect of many medications. A compound of the disclosure may be used for treating or preventing one or more symptoms of intrahepatic or extrahepatic cholestasis, including without limitation, biliary atresia, obstetric cholestasis, neonatal cholestasis, drug induced cholestasis, cholestasis arising from Hepatitis C infection, chronic cholestatic liver disease such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). In some embodiments, the disclosure relates to a method of enhancing liver regeneration in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate or prodrug thereof. In some embodiments, the method is enhancing liver regeneration for liver transplantation. In some embodiments, the disclosure relates to a method of treating or preventing fibrosis in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate or prodrug thereof. In some embodiments, the disclosure relates to a method of treating fibrosis. In some embodiments, the disclosure relates to a method of preventing fibrosis. Accordingly, as used herein, the term fibrosis refers to all recognized fibrotic disorders, including fibrosis due to pathological conditions or diseases, fibrosis due to physical trauma ("traumatic fibrosis"), fibrosis due to radiation damage, and fibrosis due to exposure to chemotherapeutics. As used herein, the term "organ fibrosis" includes but is not limited to liver fibrosis, fibrosis of the kidneys, fibrosis of lung, and fibrosis of the intestine. "Traumatic fibrosis" includes but is not limited to fibrosis secondary to surgery (surgical scarring), accidental physical trauma, burns, and hypertrophic scarring. As used herein, "liver fibrosis" includes liver fibrosis due to any cause, including but not limited to virally-induced liver fibrosis such as that due to hepatitis B or C virus; exposure to alcohol (alcoholic liver disease), certain pharmaceutical compounds including but not limited to methotrexate, some chemotherapeutic agents, and chronic ingestion of arsenicals or vitamin A in megadoses, oxidative stress, cancer radiation therapy or certain industrial chemicals including but not limited to carbon tetrachloride and dimethylnitrosamine; and diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, fatty liver, obesity, non-alcoholic steatohepatitis, cystic fibrosis, hemochromatosis, auto-immune hepatitis, and steatohepatitis. Current therapy in liver fibrosis is primarily directed at removing the causal agent, e.g., removing excess iron (e.g., in the case of hemochromatosis), decreasing viral load (e.g., in the case of chronic viral hepatitis), or eliminating or decreasing exposure to toxins (e.g., in the case of alcoholic liver disease). Anti-inflammatory drugs such as corticosteroids and colchicine are also known for use in treating inflammation that can lead to liver fibrosis. As is known in the art, liver fibrosis may be clinically classified into five stages of severity (S0, S1, S2, S3, and S4), usually based on histological examination of a biopsy specimen. S0 indicates no fibrosis, whereas S4 indicates cirrhosis. While various criteria for staging the severity of liver fibrosis exist, in general early stages of fibrosis are identified by discrete, localized areas of scarring in one portal (zone) of the liver, whereas later stages of fibrosis are identified by bridging fibrosis (scarring that crosses zones of the liver). In some embodiments, the disclosure relates to a method of treating or preventing organ fibrosis in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the fibrosis is liver fibrosis. In some embodiments, the disclosure relates to a method of treating or preventing gastrointestinal disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate or prodrug thereof. In some embodiments, the disclosure relates to a method of treating gastrointestinal disease. In some embodiments, the disclosure relates to a method of preventing gastrointestinal disease. In some embodiments, the gastrointestinal disease is selected from inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), bacterial overgrowth, malabsorption, post-radiation colitis, and microscopic colitis. In some embodiments, the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis. In some embodiments, the disclosure relates to a method of treating or preventing renal disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of treating renal disease. In some embodiments, the disclosure relates to a method of preventing renal disease. In some embodiments, the renal disease is selected from diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, and polycystic kidney disease. In some embodiments, the disclosure relates to a method of treating or preventing metabolic disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of treating renal disease. In some embodiments, the disclosure relates to a method of preventing renal disease. In some embodiments, the metabolic disease is selected from insulin resistance, hyperglycemia, diabetes mellitus, diabesity, and obesity. In some embodiments, the diabetes mellitus is type I diabetes. In some embodiments, the diabetes mellitus is type II diabetes. Diabetes mellitus, commonly called diabetes, refers to a disease or condition that is generally characterized by metabolic defects in production and utilization of glucose which result in the failure to maintain appropriate blood sugar levels in the body. In the case of type II diabetes, the disease is characterized by insulin resistance, in which insulin loses its ability to exert its biological effects across a broad range of concentrations. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver. The resulting condition is elevated blood glucose, which is called “hyperglycemia.” Uncontrolled hyperglycemia is associated with increased and premature mortality due to an increased risk for microvascular and macrovascular diseases, including retinopathy (the impairment or loss of vision due to blood vessel damage in the eyes); neuropathy (nerve damage and foot problems due to blood vessel damage to the nervous system); and nephropathy (kidney disease due to blood vessel damage in the kidneys), hypertension, cerebrovascular disease, and coronary heart disease. Therefore, control of glucose homeostasis is a critically important approach for the treatment of diabetes. Insulin resistance has been hypothesized to unify the clustering of hypertension, glucose intolerance, hyperinsulinemia, increased levels of triglyceride and decreased HDL cholesterol, and central and overall obesity. The association of insulin resistance with glucose intolerance, an increase in plasma triglyceride and a decrease in high-density lipoprotein cholesterol concentrations, hypertension, hyperuricemia, smaller denser low- density lipoprotein particles, and higher circulating levels of plasminogen activator inhibitor-1, has been referred to as “Syndrome X.” Accordingly, methods of treating or preventing any disorders related to insulin resistance including the cluster of disease states, conditions or disorders that make up "Syndrome X" are provided. In some embodiments, the disclosure relates to a method of treating or preventing metabolic syndrome in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of treating metabolic syndrome. In another embodiment, the disclosure relates to a method of preventing metabolic syndrome. In some embodiments, the disclosure relates to a method of treating or preventing cancer in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of treating cancer. In some embodiments, the disclosure relates to a method of preventing cancer. In some embodiments, the cancer is selected from hepatocellular carcinoma, colorectal cancer, gastric cancer, renal cancer, prostate cancer, adrenal cancer, pancreatic cancer, breast cancer, bladder cancer, salivary gland cancer, ovarian cancer, uterine body cancer, and lung cancer. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is renal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is adrenal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is salivary gland cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is uterine body cancer. In some embodiments, the cancer is lung cancer. In another embodiment, at least one of an agent selected from Sorafenib, Sunitinib, Erlotinib, or Imatinib is co-administered with the compound of the disclosure to treat cancer. In some embodiments, at least one of an agent selected from Abarelix, Aldeleukin, Allopurinol, Altretamine, Amifostine, Anastozole, Bevacizumab, Capecitabine, Carboplatin, Cisplatin, Docetaxel, Doxorubicin, Erlotinib, Exemestane, 5-Fluorouracil, Fulvestrant, Gemcitabine, Goserelin Acetate, Irinotecan, Lapatinib Ditosylate, Letozole, Leucovorin, Levamisole, Oxaliplatin, Paclitaxel, Panitumumab, Pemetrexed Disodium, Profimer Sodium, Tamoxifen, Topotecan, and Trastuzumab is co-administered with the compound of the disclosure to treat cancer. Appropriate treatment for cancers depends on the type of cell from which the tumor derived, the stage and severity of the malignancy, and the genetic abnormality that contributes to the tumor. Cancer staging systems describe the extent of cancer progression. In general, the staging systems describe how far the tumor has spread and puts patients with similar prognosis and treatment in the same staging group. In general, there are poorer prognoses for tumors that have become invasive or metastasized. In one type of staging system, cases are grouped into four stages, denoted by Roman numerals I to IV. In stage I, cancers are often localized and are usually curable. Stage II and IIIA cancers are usually more advanced and may have invaded the surrounding tissues and spread to lymph nodes. Stage IV cancers include metastatic cancers that have spread to sites outside of lymph nodes. Another staging system is TNM staging which stands for the categories: Tumor, Nodes, and Metastases. In this system, malignancies are described according to the severity of the individual categories. For example, T classifies the extent of a primary tumor from 0 to 4 with 0 representing a malignancy that does not have invasive activity and 4 representing a malignancy that has invaded other organs by extension from the original site. N classifies the extent of lymph node involvement with 0 representing a malignancy with no lymph node involvement and 4 representing a malignancy with extensive lymph node involvement. M classifies the extent of metastasis from 0 to 1 with 0 representing a malignancy with no metastases and 1 representing a malignancy with metastases. These staging systems or variations of these staging systems or other suitable staging systems may be used to describe a tumor such as hepatocellular carcinoma. Few options only are available for the treatment of hepatocellular cancer depending on the stage and features of the cancer. Treatments include surgery, treatment with Sorafenib, and targeted therapies. In general, surgery is the first line of treatment for early stage localized hepatocellular cancer. Additional systemic treatments may be used to treat invasive and metastatic tumors. In some embodiments, the disclosure relates to a method of treating or preventing gallstones in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of treating gallstones. In some embodiments, the disclosure relates to a method of preventing gallstones. A gallstone is a crystalline concretion formed within the gallbladder by accretion of bile components. These calculi are formed in the gallbladder but may distally pass into other parts of the biliary tract such as the cystic duct, common bile duct, pancreatic duct, or the ampulla of Vater. Rarely, in cases of severe inflammation, gallstones may erode through the gallbladder into adherent bowel potentially causing an obstruction termed gallstone ileus. Presence of gallstones in the gallbladder may lead to acute cholecystitis, an inflammatory condition characterized by retention of bile in the gallbladder and often secondary infection by intestinal microorganisms, predominantly Escherichia coli, and Bacteroides species. The presence of gallstones in other parts of the biliary tract can cause obstruction of the bile ducts, which can lead to serious conditions such as ascending cholangitis or pancreatitis. In some embodiments, the disclosure relates to a method of treating or preventing cholesterol gallstone disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of treating cholesterol gallstone disease. In some embodiments, the disclosure relates to a method of preventing cholesterol gallstone disease. In some embodiments, the disclosure relates to a method of treating or preventing neurological disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a method of treating neurological disease. In some embodiments, the disclosure relates to a method of preventing neurological disease. In some embodiments, the neurological disease is stroke. In some embodiments, the disclosure relates to a method as described herein and further wherein, the compound is administered by a route selected from oral, parenteral, intramuscular, intranasal, sublingual, intratracheal, inhalation, ocular, vaginal, rectal, and intracerebroventricular. In some embodiments, the route is oral. In some embodiments, the compound utilized in one or more of the methods described herein is an FXR agonist. In some embodiments, the compound is a selective FXR agonist. In another embodiment, the compound does not activate TGR5. In some embodiments, the compound does not activate other nuclear receptors involved in metabolic pathways (e.g., as measured by an AlphaScreen assay). In some embodiments, such other nuclear receptors involved in metabolic pathways are selected from LXRȕ, PXR, CAR, PPARĮ, PPARį, PPARJ^^RAR, RARĮ, VDR, TR, PR, RXR, GR, and ER. In some embodiments, the compound induces apoptosis. In some embodiments, the disclosure relates to a method of regulating the expression level of one or more genes involved in bile acid homeostasis. In some embodiments, the disclosure relates to a method of down regulating the expression level of one or more genes selected from CYP7Įl and SREBP-IC in a cell by administering to the cell a compound of the disclosure. In some embodiments, the disclosure relates to a method of up regulating the expression level of one or more genes selected from OSTĮ, OSTȕ, BSEP, SHP, UGT2B4, MRP2, FGF-19, PPARȖ, PLTP, APOCII, and PEPCK in a cell by administering to the cell a compound of the disclosure. The disclosure also relates to the manufacture of a medicament for treating or preventing a disease or condition (e.g., a disease or condition mediated by FXR), wherein the medicament comprises a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to the manufacture of a medicament for treating or preventing one or more of the diseases or conditions described herein above, wherein the medicament comprises a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. The disclosure also relates to a composition for use in a method for treating or preventing a disease or condition (e.g., a disease or condition mediated by FXR), wherein the composition comprises a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. In some embodiments, the disclosure relates to a composition for use in a method for treating or preventing any one of the diseases or conditions described herein above, wherein the composition comprises a compound of the disclosure or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. The methods of the disclosure comprise the step of administering an effective amount of a compound of the disclosure. As used herein, the term an "effective amount" refers to an amount of a compound of the disclosure which is sufficient to achieve the stated effect. Accordingly, an effective amount of a compound of the disclosure used in a method for the prevention or treatment of FXR mediated diseases or conditions will be an amount sufficient to prevent or treat the FXR mediated disease or condition. Similarly, an effective amount of a compound of the disclosure for use in a method for the prevention or treatment of a cholestatic liver disease or increasing bile flow will be an amount sufficient to increase bile flow to the intestine. The amount of the compound of the disclosure which is required to achieve the desired biological effect will depend on a number of factors such as the use for which it is intended, the means of administration, and the recipient, and will be ultimately at the discretion of the attendant physician or veterinarian. In general, a typical daily dose for the treatment of a FXR mediated disease and condition, for instance, may be expected to lie in the range of from about 0.01 mg/kg to about 100 mg/kg. This dose may be administered as a single unit dose or as several separate unit doses or as a continuous infusion. Similar dosages would be applicable for the treatment of other diseases, conditions and therapies including the prevention and treatment of cholestatic liver diseases. In some embodiments, the present disclosure proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, and wherein the disease or condition is mediated by FXR. In some embodiments, the present disclosure proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I, wherein the disease is selected from cardiovascular disease, chronic liver disease, lipid disorder, gastrointestinal disease, renal disease, metabolic disease, cancer, and neurological disease. In some embodiments, the present disclosure proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I, wherein the disease is cardiovascular disease selected from atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesteremia, hyperlipidemia, hyperlipoproteinemia, and hypertriglyceridemia. In some embodiments, the present disclosure proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I, wherein the disease is liver disease selected from a cholestatic liver disease such as primary biliary cirrhosis (PBC) also known as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis, and liver fibrosis. Other examples of FXR mediated diseases also include portal hypertension, bile acid diarrhea, hyperlipidemia, high LDL-cholesterol, high HDL cholesterol, high triglycerides, and cardiovascular disease. Other liver diseases include cerebrotendinous xanthomatosis (CTX), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, Sarcoidosis, Wilson's disease, Gaucher' s disease, hemochromatosis, and alpha 1- antitrypsin deficiency. In some embodiments, the present disclosure proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I, wherein the disease is gastrointestinal disease selected from inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), bacterial overgrowth, malabsorption, post-radiation colitis, and microscopic colitis. In some embodiments, the present disclosure proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. In some embodiments, the present disclosure proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I, wherein the disease is renal disease selected from diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, and polycystic kidney disease. In some embodiments, the present disclosure proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I, wherein the disease is metabolic disease selected from insulin resistance, hyperglycemia, diabetes mellitus, diabesity, and obesity. In some embodiments, the present disclosure proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I, wherein the disease is cancer selected from hepatocellular carcinoma, colorectal cancer, gastric cancer, renal cancer, prostate cancer, adrenal cancer, pancreatic cancer, breast cancer, bladder cancer, salivary gland cancer, ovarian cancer, uterine body cancer, and lung cancer. EXAMPLES The following examples are intended to illustrate certain embodiments of the present disclosure, but do not exemplify the full scope of the application. Example 1. Synthesis of compound 100:

Exemplary Route 2:

Routes 1-3 can be also carried out with other protecting groups at C-3 hydroxy. Exemplary Route 4: Route 4 can be also carried out with other protecting groups at C-3 hydroxy (e.g., OAc). Example 1-1: Methyl 3Į,12Į-dihydroxy-6Į-ethyl-7-oxo-5ȕ-cholan-24-oate (2)

To a stirring solution of 6-ethyl-7-ketocholic acid (1, 25 g, 57.52 mmol) in CH2Cl2 (340 mL) was added MeOH (23 mL) followed by pTSAāH2O (1.1 g, 5.75 mmol). The resulting solution was heated at 40 °C for 20 h. The reaction mixture was poured into a mixture of brine (500 mL) and NaHCO3 (1.5 g). CH2Cl2 (500 mL) and brine (200 mL) were added, the layers were separated, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 24.91 g (97%) as an off-white solid (compound 2). ES-API Pos: 466.2 [M+H₂O].¹H-NMR (300 MHz, CDCl₃): į 0.68 (s, 3H, 18-CH₃), 0.80 (t, 3H, 26-CH₃), 0.96 (d, 3H, 21-CH₃), 1.20 (s, 3H, 19-CH₃), 3.43-3.59 (3, 1H, 3-CH), 3.66 (s, 3H, CO₂CH₃), 3.99 (br. s, 1H, 12-CH). Alternate Procedure of making compound 2: To a suspension of 6-ethyl-7-ketocholic acid (1, 2.5 kg, 5.75 mol) in MeOH (12 L) was added conc. H₂SO₄ (16.1 mL; 0.29 mol) and the mixture was heated to 65 °C for 3 h. The mixture was cooled, the pH was adjusted with 1N NaOH (aq) to ca. pH 9, and water (12.5 L) was added to precipitate product. The solids were filtered, washed with 1:1 MeOH- water and dried under vacuum. Compound 2 (2.37 kg) was produced in 91.8% yield. (e.g., Route 4). Example 1-2: Methyl 3Į-acetoxy-12Į-hydroxy-6Į-ethyl-7-oxo-5ȕ-cholan-24-oate (18)

To a stirring suspension of compound 2 (24.9 g, 55.5 mmol) in MeOAc (660 mL) was added pTsOHāH2O (1.01 g, 5.33 mmol). The resulting solution was heated at 75 °C for 4 days. EtOAc (950 mL) was added. The mixture was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure to afford 27.2 g (quantitative yield) of compound 18 as a white foam. This material was used without purification for the next reaction step. ES-API Pos: 508.8 [M+H₂O].¹H-NMR (400 MHz, CDCl₃): į 0.67 (s, 3H, 18-CH₃), 0.78 (t, J = 7.3 Hz, 3H, 26-CH₃), 0.96 (d, J = 6.1 Hz, 3H, 21-CH₃), 1.20 (s, 3H, 19- CH₃), 1.98 (s, 3H, OCOCH₃), 3.65 (s, 3H, CO₂CH₃), 3.98 (s, 1H, 12-CH), 4.59-4.63 (m, 1H, 3-CH). Alternate Procedure: A solution of compound 2 (2.36 kg, 5.26 mol) in MeOAc (20 L) was added pTsOHāH₂O (100 g, 0.526 mol). The mixture was heated to reflux for 13-65 h, then solvents were distilled and fresh MeOAc was added, and reflux continued. This was repeated three times until the reaction was complete. The mixture was concentrated and DCM (23.6L) was added. The organic layer was washed with water (23.6 L), 8% NaHCO3 (aq) (23.6 L) followed by saturated aqueous NaCl (11.8 l). The organic layer was separated and dried over Na2SO4, then filtered and concentrated to a final volume of 11.7 L. The DCM solution of compound 18 was used directly in the next step. Example 1-3: Methyl 3Į-Acetoxy-6Į-ethyl-7-keto-12D-((methylsulfonyl)oxy)-5ȕ-cholan- 24-oate (32)

To a solution of compound 18 (27.2 g, 55.43 mmol) in pyridine (270 mL) at room temperature was added MsCl (8.58 mL, 110.87 mmol). The reaction was stirred at 20-30 °C overnight. The reaction mixture was poured into ice water and EtOAc (1 L) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (3×150 mL). The combined organic phases were washed with 2M aq. HCl (3×150 mL). The combined organic phases were washed with sat. NaHCO3 (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. More EtOAc was added to remove the pyridine and the crude was dried under reduced pressure for three hours providing 31.13 g (99%) of product 32 as an off-white solid.¹H-NMR (400 MHz, CDCl3): į 0.75-0.81 (m, 6H, 18-CH3, 26-CH3), 0.96 (d, J = 6.4 Hz, 3H, 21-CH3), 1.21 (s, 3H, 19-CH3), 2.01 (s, 3H, OCOCH3), 3.04 (s, 3H, OSO2CH3), 3.67 (s, 3H, CO2CH3), 4.59-4.62 (m, 1H, 3-CH), 5.10 (s, 1H, 12-CH). Alternative Procedure: To a DCM solution of compound 18 (11.7 L, ca.5.26 mol) was added pyridine (2.13 L, 26.3 mol) and MsCl (0.814 L, 10.52 mol) at 15-25 °C. The mixture was stirred for 96 h, then diluted with DCM (12 L) and water (12 L). The organic layer was washed twice with 2N aq. HCl (12 L), 8% NaHCO₃ (aq) (12 L) then dried over Na₂SO₄, then concentrated to a final volume of 7.1 L. MTBE (24 L) was added in portions and concentrated to a final volume of 8 L. The resulting suspension was cooled and vacuum filtered. The solids were washed with 1:1 MTBE-heptane, then dried under vacuum to give compound 32 (2.576 kg) in 86.1% yield. Alternatively, mesylate 32b can be prepared via a telescoped process, a one-pot procedure using ethyl chloroformate as a protecting group for C-3-OH as shown in Example 1-3b. Ethyl carbonate protecting group which can be installed with high selectivity provides more crystalline solid and overcomes possible issues with completion of the reaction on larger scale. (Route 4) Example 1-3a: Methyl 3Į-(ethoxycarbonyl)oxy-12Į-(methansulfonyl)oxy-6Į-ethyl-7- oxo-5ȕ-cholan-24-oate (32b)

Methyl 3Į,12Į-dihydroxy-6Į-ethyl-7-oxo-5ȕ-cholan-24-oate (2) (14.0 g, 31.2 mmol) was dissolved in pyridine (150 mL) and cooled to 0-5 °C. Ethyl chloroformate, ClCO₂Et, (4.0 g, 37.4 mmol) was added and the mixture was stirred for 2 hours allowing to reach room temperature. Additional ClCO₂Et (1.5 g, 13.5 mmol) was added and stirring continued until the reaction was complete (within 16 hours). The mixture was cooled to 0-5 °C and MsCl (7.1 g, 62.4 mmol) was added, and the mixture was allowed to reach ambient temperature. Additional MsCl (3.5 g, 31.2 mmol) was added over 2 hours and stirring continued until reaction was complete (within 16 h). Heptanes (200 mL) were added followed by water (500 mL). The resulting suspension was stirred for 1 hour then vacuum filtered. The solids were triturated in heptanes/EtOAc (100 mL; 4:1) for 1 hour, filtered and washed with 25 mL of heptanes/EtOAc (4:1), then dried under vacuum. Compound 32b (14.7g) was isolated as white solid in 83% yield.¹H-NMR (300 MHz, CDCl3): į 0.76 (s, 3H, 18-CH3), 0.81 (t, 3H, 26-CH3), 0.96 (d, 3H, 21-CH3), 1.22 (s, 3H, 19-CH3), 1.28 (t, J = 7.3 Hz, 3H, OC(O)OCH2CH3), 3.04 (s, 3H, OSO2CH3), 3.66 (s, 3H, CO2CH3), 4.15 (q, 2H, OC(O)OCH₂CH₃), 4.39-4.56 (m, 1H, 3-CH), 5.10 (br. s, 1H, 12-CH). (e.g., Route 4). Example 1-4: Methyl '^11,12-3Į-Acetoxy-6Į-ethyl-5ȕ-cholan-24-oate (19)

To a solution of 3-acetate 32 (45 g, 78.8 mmol) in HMPA (HMPT or DMPU) (500 mL) was added KOAc (64 g, 652 mmol). After stirring with overhead stirrer for 15 h at 98 °C ¹HNMR showed approximately 70% conversion. The heating was continued for an additional 24 h and the mixture was cooled to room temperature. Water (2 L) and heptanes (600 mL) were added. The organic layer was separated and the aqueous layer was extracted with heptanes (200 mL). The combined organic layers were washed with sat. aq. NaHCO₃ (300 mL) and brine (200 mL). The organic layer was dried over Na₂SO₄ treated with active carbon (3 g) and concentrated to provide 40 g (with some residual heptanes; about 98% yield) of crude compound 19. Material was of acceptable purity based on ¹H-NMR. Material was analyzed by ¹H-NMR and LCMS. ES-API Pos: 490.8 [M+H₂O].¹H-NMR (400 MHz, CDCl3): į 0.74 (s, 3H, 18-CH3), 0.82 (t, J = 7.3 Hz, 3H, 26-CH3), 1.00 (d, J = 6.3 Hz, 3H, 21- CH3), 1.16 (s, 3H, 19-CH3), 2.02 (s, 3H, OCOCH3), 3.66 (s, 3H, CO2CH3), 4.63-4.68 (m, 1H, 3-CH), 5.32 (d, J = 10.3 Hz, 1H, 12-CH), 6.18 (dd, J1 = 2.4 Hz, J2 = 10.3 Hz, 1H, 11-CH). Alternatively, compound 19 can be prepared according to the following procedure:

To a solution of 3-acetate 18 (0.5 g, 1.02 mmol) in pyridine (5 mL) was added POCl3 (1.5 mL, 2.25 g, 16 mmol). After stirring overnight at 50 °C the mixture was cooled to room temperature. The mixture was poured in a mixture of ice (20 mL) and ethyl acetate (30 mL). To the mixture was added brine (10 mL). The organic layer was separated and washed with (HCl 4 N), sat. NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated providing 480 mg of compound 19 (approximately 80% yield by NMR and HPLC/ELSD). The product can be used for the next step without purification. The product was analyzed by ¹H-NMR and LCMS. ES-API Pos: 490.8 [M+H₂O].¹H-NMR (400 MHz, CDCl₃): į 0.74 (s, 3H, 18-CH₃), 0.82 (t, J = 7.3 Hz, 3H, 26-CH₃), 1.00 (d, J = 6.3 Hz, 3H, 21- CH₃), 1.16 (s, 3H, 19-CH₃), 2.02 (s, 3H, OCOCH₃), 3.66 (s, 3H, CO₂CH₃), 4.63-4.68 (m, 1H, 3-CH), 5.32 (d, J = 10.3 Hz, 1H, 12-CH), 6.18 (dd, J₁ = 2.4 Hz, J₂ = 10.3 Hz, 1H, 11-CH). Alternatively, compound 19 can be prepared according to the following procedure:

To a solution of compound 32 (2.59 kg, 4.55 mol) in DMSO (20.2 L) was added CsOAc (3.93 kg, 20.5 mol) and the mixture was heated to 90-100 °C for 16-20 h. The mixture was cooled to ambient temperature and added to cold water (62.1 L) over 0.5-1 h. The resulting suspension was filtered, washed with water (3 x 20 L), then dried under vacuum. The solids were taken up in EtOAc and chromatographed on silica gel (10% EtOAc- Heptane). The product-rich fractions were pooled and concentrated to give compound 19 (1.69 kg) as a solid in 79% yield. (Route 3) Alternatively, Compound 19b can be prepared according to Example 1-4a. Example 1-4a: Methyl '^11,12-3Į-(ethoxycarbonyl)oxy-6Į-ethyl-5ȕ-cholan-24-oate (19b)

To a solution of methyl 3Į-(ethoxycarbonyl)oxy-12Į-(methansulfonyl)oxy-6Į-ethyl- 7-oxo-5ȕ-cholan-24-oate (32b) (14.4 g, 25.3 mmol) in DMSO (150 mL) was added CsOAc (19.6 g, 102 mmol). The mixture was stirred at 90-100 °C for 18 hours before it was cooled to room temperature. The mixture was added to water (500 mL) and the resulting precipitate was filtered, washed with water and dried on the funnel. A 5.9 g portion of crude compound 19b was dissolved in MeOH (5.9 mL) at reflux. Water (3 mL) was added, and the mixture was cooled to 25-35 °C, and product precipitated. Additional water (56 mL) was added at 20- 25 °C, the suspension was stirred for 1.5h then vacuum filtered and washed with water and dried under vacuum. Compound 19b (5.64 g) was isolated in 88.7% yield (from compound 32b). ¹H-NMR (300 MHz, CDCl3): į 0.75 (s, 3H, 18-CH3), 0.82 (t, J = 7.3 Hz, 3H, 26-CH3), 1.00 (d, J = 6.3 Hz, 3H, 21-CH₃), 1.17 (s, 3H, 19-CH₃), 1.29 (t, J = 7.3 Hz, 3H OC(O)OCH₂CH₃), 3.66 (s, 3H, CO₂CH₃), 4.15 (q, 2H, OC(O)OCH₂CH₃), 4.38-4.64 (m, 1H, 3-CH), 5.33 (d, J = 10.3 Hz, 1H, 12-CH), 6.18 (dd, J₁ = 2.3 Hz, J₂ = 10.3 Hz, 1H, 11- CH).(Route 4) Example 1-4b: Methyl ǻ^11,12-3Į-(ethoxycarbonyl)oxy-6Į-ethyl-5ȕ-cholan-24-oate (19b)

Cs₂CO₃ (278.6 g, 855.1 mmol) and AcOH (41.08 g, 39.1 mL, 684.0 mmol) were mixed in DMSO (1 L) and stirred for 30 min at 50-70 °C. Methyl 3Į-(ethoxycarbonyl)oxy-12Į- (methansulfonyl)oxy-6Į-ethyl-7-oxo-5ȕ-cholan-24-oate (32b) (102.4 g, 171.0 mmol) was added and the mixture was stirred at 90 °C for 18 hours. The mixture was cooled to ambient temperature and then was added slowly to 4 L of pre-cooled water (0-5 °C) containing 200 mL of concentrated HCl. The off-white precipitate was filtered, washed with water (3 × 1 L) and dried on a vacuum filter. The solids were taken up in heptanes (2 L) and heated. The remaining water was removed and the solution containing insoluble brown tar was filtered over a layer of Celite. The resulting filtrate was concentrated affording compound 19b (84.9 g, 98.8%) as light-brown solid. Example 1-5: Methyl 3Į-Acetoxy-12-bromo-6Į-ethyl-7-keto-11-hydroxy-5ȕ-cholan-24-oate (21)

To a solution of compound 19 (53.5 g, 113 mmol) in MeCN (455 mL) and H2O (116 mL) was added NBS (24.13 g, 135 mmol) at about -5 °C to about 5 °C in portions over 25 min. After complete addition, the mixture was stirred at room temperature. After 1.5 h the mixture was poured in 2.5% aq. NaHSO3 (1.5 L) and stirred at room temperature. The mixture was extracted with EtOAc:heptanes 10:1 (500 mL and 200 mL). The combined organic layer was washed with 5% aq. NaHSO3 (200 mL), 10% aq. NaHCO3 (400 mL), brine (200 mL), dried over Na₂SO₄, filtered and concentrated to give compound 21 (62 g) as a yellowish foam. This material was used without purification in the next reaction step. ES-API Pos: 586.6 [M+H₂O].¹H-NMR (400 MHz, CDCl₃): į 0.82 (s, 3H, 26-CH₃), 1.03-1.07 (m, 6H, 18-CH₃, 21-CH₃), 1.44 (s, 3H, 19-CH₃), 2.01 (s, 3H, OCOCH₃), 3.68 (s, 3H, CO₂CH₃), 4.37 (s, 1H, CH-11), 4.44 (s, 1H, CH-12), 4.63-4.69 (m, 1H, CH-3). Alternatively, to a water bath cooled solution of compound 19 (1.5 g, 3.17 mmol) in THF (11 mL) and H₂O (4 mL) was added NBS (677 mg, 3.8 mmol) in portions over 5 min. at 20 °C. At the end of the addition the color remained slightly orange. After complete addition, the mixture was stirred at room temperature. After 18 h the mixture was poured in 2.5% aq. NaHSO3 (20 mL) and stirred at room temperature. To the mixture brine (10 mL) was added and the mixture was extracted with EtOAc:heptanes 10:1 (40 mL and 20 mL). The combined organic layer was washed with 10% aq. NaHCO3 (15 mL), brine (20 mL) dried over Na2SO4, filtered and concentrated to give compound 21 (1.86 g) as a yellowish foam containing some EtOAc. This material was used without purification in the next reaction step. Alternatively, compound 21 can be prepared according to the following procedure: Dibromamine-T (TsNBr₂): To a solution of Chloramine-T (10 g, 40.7 mmol) in water 200 mL was added bromine (2 mL, 6.24 g, 78 mmol) in a dropwise fashion. After addition was completed, the mixture was stirred for 2 h. The mixture was filtered, and the filtrate was washed with water (2 × 20 mL) and dried under vacuum to provide 12 g (90% yield) of dibromamine-T. To a solution of compound 19 (416 mg, 1 mmol) in MeCN (4 mL) and H₂O (1 mL) was added dibromamine-T (329 mg, 1 mmol) in portions. After the addition was completed, the mixture was stirred at room temperature for about 5 to about 30 min. The mixture was quenched with sodium thiosulfate (284 mg, 1.8 mmol), diluted with water (20 mL) and extracted with EtOAc. The organic layer was washed with 10% NaHCO3, dried over Na2SO4 filtered and concentrated to produce crude compound 21. Alternatively, iodination of compound 19 using an iodination agent such as N- iodosuccinimide in the presence of TFA, followed by selective de-trifluoroacetylation of intermediate 21c can generate the halohydrin (iodohydrin) 21a. The procedure is shown in Example 1-5a. Example 1-5a: Methyl 3Į-Acetoxy-6Į-ethyl-12-iodo-7-keto-11E-trifluoroacetoxy-5ȕ- cholan-24-oate (21a)

To a mixture of compound 19 (10.0 g, 21.16 mmol), N-iodosuccinimide (6.66 g, 29.62 mmol), MTBE (100 mL) and water (6.47 mL) at 5-15 °C was charged trifluoroacetic acid (8.1 mL, 105.8 mmol). The mixture was warmed to 20-25 °C and stirred until reaction completion (within 7 h). A solution of 0.5M sodium bisulfite (50 mL) was added and the organic layer was separated and washed with saturated aqueous NaHCO3. To the MTBE solution containing compound 21c was added water (1 mL) and triethylamine (4.42 mL, 31.74 mmol) and stirred at 20-25 °C until reaction completion (within 74 h). The pH was adjusted with acetic acid as needed until pH 5-7 was reached. The organic layer was washed with water (2 x 30.0 mL) then concentrated under vacuum to generate iodohydrin 21a (12.7 g, 20.60 mmol) as an off-white solid in 97.3% yield. Alternatively, iodination of compound 19b using an iodination agent such as NIS in the presence of H₅IO₆ can generate the halohydrin 21b in a single step. The procedure is shown in Example 1-5b. Example 1-5b: Methyl 3Į-(ethoxycarbonyl)oxy-6Į-ethyl-11E-hydroxy-12-iodo-7-keto -5ȕ-

To a stirred mixture of compound 19b (4.1 g, 8.16 mmol), H5IO6 (0.45 g, 1.63 mmol), dioxane (41 mL), and water (10.3 mL) at 0-5 °C was added N-iodosuccinimide (2.75 g, 12.24 mmol). The mixture was stirred at 0-5 °C until reaction completion (within 3 h), then treated with 10wt% aqueous sodium bisulfite (20.5 mL), diluted with methanol (41 mL), then added to cold water (0-5 °C). The resulting precipitate was filtered and dried under vacuum to give 5.4 g of wet compound 21b which was used directly in the next step (reductive dehalogenation step).¹H-NMR (300 MHz, CDCl₃): į 0.82 (t, J = 7.3 Hz, 3H, 26-CH₃), 1.05 (d, 3H, 21-CH₃), 1.10 (s, 3H, 18-CH₃), 1.29 (t, J = 7.3 Hz, 3H OC(O)OCH₂CH₃), 1.41 (s, 3H, 19-CH3), 2.01 (s, 3H, OCOCH3), 3.66 (s, 3H, CO2CH3), 4.16 (q, 2H, OC(O)OCH2CH3), 4.39-4.59 (m, 2H, 3-CH, 11-CH), 4.64 (d, J = 7.3 Hz, 1H, 12-CH). Example 1-6: Methyl 3Į-Acetoxy-12-bromo-6Į-ethyl-7,11-diketo-5ȕ-cholan-24-oate (22).

To an ice bath cooled stirred solution of bromohydrin 21 (crude, about 113 mmol) at 6 °C in acetone (1 L) was added dropwise Jones reagent (32 mL) over approximately 15 min. The reaction mixture was stirred for 30 min at 6 °C. Isopropanol (45 mL) was added dropwise. After addition the reaction was stirred for 30 min. and filtered through Celite^®. The filtrate was concentrated under reduced pressure, taken up in CH2Cl2 (700 mL), washed with water (400 mL), 10% aq. NaHCO3 (100 mL) and dried over Na2SO4 and concentrated under reduced pressure to afford compound 22 (55 g). ES-API Pos: 584.2 [M+H2O].¹H-NMR (200 MHz, CDCl3): į 0.77-0.85 (m, 6H, 18-CH3, 26-CH3), 0.96 (d, J = 6.1 Hz, 3H, 21-CH3), 1.45 (s, 3H, 19-CH3), 2.02 (s, 3H, OCOCH3), 3.68 (s, 3H, CO2CH3), 4.28 (s, 1H, 12-CH), 4.59- 4.70 (m, 1H, 3-CH). Example 1-7: Methyl 3Į-Acetoxy-6Į-ethyl-7,11-diketo-5ȕ-cholan-24-oate (23a)

To a stirring solution of compound 22 (crude, about 113 mmol) in AcOH (1.2 L) was added NaOAc (64.5 g, 786 mmol) and Zn (56 g, 850 mmol). The resulting suspension was heated slowly to 78 °C. After 5 h a ¹H-NMR sample revealed full consumption of compound 22. The reaction mixture was allowed cool to room temperature and EtOAc (2.5 L) was added to the reaction mixture and the resulting suspension was filtered. The filtrate was washed with brine (2×500 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford a crude compound 23a. This crude material was suspended in CH2Cl2 (250 mL), purified by column chromatography (SiO2, 2.5 kg, EtOAc:heptanes 1:4), and analyzed by ¹H-NMR and LCMS. ES-API Pos: 506.8 [M+H2O].¹H-NMR (400 MHz, CDCl₃): į 0.60 (s, 3H, 18-CH₃), 0.77 (t, J = 7.3 Hz, 3H, 26-CH₃), 0.86 (d, J = 5.2 Hz, 3H, 21-CH3), 1.41 (s, 3H, 19-CH3), 1.96 (s, 3H, OCOCH3), 3.64 (s, 3H, CO2CH3), 4.58-4.63 (m, 1H, 3-CH). Alternatively, compound 23a can be prepared via a telescoped process, where compound 22 is prepared without isolation of intermediate 21 and compound 23a is prepared without isolation of compound 22. The telescoped procedure is shown below. Telescopic Procedure: Methyl 3Į-Acetoxy-6Į-ethyl-7,11-diketo-5ȕ-cholan-24-oate (23a)

A solution of compound 19 (1.67 kg, 3.53 mol) in acetone (3.3 L), THF (10 L) and water (3.3 L) was sparged with nitrogen and cooled to 0-5 °C. Dibromodimethyl hydantoin (DBH) (1.11 kg, 3.88 mol) was added in portions over 0.5 h. The mixture was stirred in the absence of light at 5-15 °C until the reaction was complete (within 12 h). The initial reaction mixture containing compound 21 was added to a stirred, pre-cooled (0-5 °C) mixture of DBH (1.01 kg, 3.53 mol), NaOAc (0.58 kg, 7.06 mol), and RuCl₃ (22 g, 0.106 mol) in acetonitrile (4.2 L) and water (4.2 L) over 0.5 h. The mixture was stirred at 4-10 °C until reaction completion (within 4 h). The reaction was quenched with 2.5 wt% NaHSO₃ (18 L) and partitioned with EtOAc (18 L). The aqueous layer was back washed with EtOAc and the combined organic layers were washed with 10 wt% Na2SO4 (aq) (2 x 10 L). The EtOAc solution of compound 22 was concentrated to a final volume of 8.4 L. To a vessel containing NaOAc (1.16 kg, 14.12 mol) and zinc dust (1.15 kg, 17.65 mol) was added a solution of compound 22 in EtOAc (8.4 L) followed by glacial AcOH (8 L). The mixture was heated to 70-80 °C and agitated until reaction completion (within 4 h). The mixture was cooled to ambient temperature and filtered through Celite^®, and the Celite^® was washed with EtOAc (3 x 4 L). The filtrate was washed sequentially with water (10 L), 8% NaHCO₃ (aq) (2 x 10 L) and water (10 L). The organic layer was dried over Na₂SO₄, concentrated to a residue (1.74 kg) and chromatographed on silica gel (5-10% EtOAc- Heptane). The product-rich fractions were pooled and concentrated to give compound 23a (0.882 kg) in 51.1% yield (from compound 19). Fractions containing compound 19 (a reaction byproduct) were pooled and concentrated to give 0.266 kg of recovered compound 19. Example 1-8: 3Į-hydroxy-7,11-diketo-6Į-ethyl-5ȕ-cholan-24-oic acid (40)

To a stirring solution of compound 23a (9.7 g, 19.8 mmol) in MeOH (170 mL) was added NaOH (9 g, 225 mmol). The resulting solution was heated at 45 °C for 18 h.¹H-NMR showed full conversion. The mixture was concentrated to approximately 30 mL. Water (150 mL) was added. The mixture was cooled in an ice bath and 3N aq. HCl was added dropwise to pH <2. The resulting suspension was stirred for an additional 0.5 h. The product was filtered off, washed with water (20 mL) and dried in vacuo to give 9.45 g of compound 40 as beige solid (about 100% yield), which was used without purification in the next reaction step. ES-API Pos: 450.6 [M+H

.¹H-NMR (400 MHz, CDCl₃): į 0.63 (s, 3H, 18- CH₃), 0.81 (t, J = 7.2 Hz, 3H, 26-CH₃), 0.91 (d, J = 5.2 Hz, 3H, 21-CH₃), 1.44 (s, 3H, 19- CH₃), 3.55-3.59 (m, 1H, 3-CH). Example 1-9: 3Į,7Į,11ȕ-Trihydroxy-6Į-ethyl-5ȕ-cholan-24-oic acid (100)

To a stirred ice-bath cooled solution of diketone 40 (about 6.7 g, 15.5 mmol) in a mixture of THF (160 mL) and water (30 mL), NaBH₄ (3.48 g, 91 mmol) was added in small portions. The resulting solution was stirred for 18 h at room temperature.¹H-NMR revealed full conversion. Brine (40 mL), EtOAc (100 mL) and 2N aq. HCl (to pH <2) were added, the layers were separated. The aqueous layer was extracted again with EtOAc (100 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4 and concentrated under reduced pressure to afford 6.2 g of compound 100. The final product was purified by column chromatography. ES-API Neg: 435.5 [M-H].¹H-NMR (400 MHz, CD3OD): į 0.89-0.92 (s, 6H, 18-CH3, 26-CH3), 1.00 (d, J = 6.35 Hz, 3H, 21-CH3), 1.18 (s, 3H, 19-CH3), 3.31-3.34 (m, 1H, 3-CH), 3.73 (s, 1H, 7-CH), 4.20 (s, 1H, 11-CH).¹³C-NMR (100.6 MHz, CD3OD): į 10.1, 12.7, 16.8, 21.6, 22.7, 25.7, 27.0, 30.0 (x 2), 30.3, 32.8, 34.4, 34.9 (x 2), 36.3 (x 2), 40.6, 40.8, 46.4, 48.1, 50.2, 55.8, 67.1, 69.4, 71.4, 177.4. Example 1-10: 3Į,7Į,11ȕ-Trihydroxy-6Į-ethyl-5ȕ-cholan-24-oic acid (100)

To a solution of compound 23a (442 mg, 0.91 mmol) in THF/MeOH (9 mL, 1:1), CeCl3^.7H2O (674 mg, 1.81 mmol) and LiBH4 (69 mg, 3.62 mmol) were sequentially added in one portion at 0 °C. The resulting mixture was stirred at 0 °C for 4 h. The mixture was diluted with CH2Cl2 (15 mL) and quenched at 0 °C by adding H2O (15 mL) and 3 N HCl (15 mL). The phases were separated, and the aqueous phase was extracted with CH2Cl2 (2 x 15 mL). The combined organic extracts were washed with H2O (20 mL), brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude (444 mg) was dissolved in MeOH/H₂O (4.5 mL, 9:1) and stirred overnight at room temperature in presence of NaOH (360 mg, 9.01 mmol). The mixture was concentrated under reduced pressure and the residue was dissolved in CH₂Cl₂ (20 mL) and acidified with 3 N HCl. The phases were separated and the aqueous phase was extracted with CH₂Cl₂ (3 x 20 mL). The combined organic extracts were washed with H₂O (30 mL), brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel affording 272 mg of pure compound 100 (0.62 mmol). ES-API Neg: 435.5 [M-H].¹H-NMR (400 MHz, CD3OD): į 0.89-0.92 (s, 6H, 18-CH3, 26-CH3), 1.00 (d, J = 6.35 Hz, 3H, 21-CH3), 1.18 (s, 3H, 19-CH3), 3.31-3.34 (m, 1H, 3-CH), 3.73 (s, 1H, 7- CH), 4.20 (s, 1H, 11-CH).¹³C-NMR (100.6 MHz, CD3OD): į 10.1, 12.7, 16.8, 21.6, 22.7, 25.7, 27.0, 30.0 (x 2), 30.3, 32.8, 34.4, 34.9 (x 2), 36.3 (x 2), 40.6, 40.8, 46.4, 48.1, 50.2, 55.8, 67.1, 69.4, 71.4, 177.4. Telescopic Procedure: 3Į,7Į,11ȕ-Trihydroxy-6Į-ethyl-5ȕ-cholan-24-oic acid (100) To a solution of methyl 3D-acetoxy-7-keto-'^11,12-6D-ethyl-5E-cholan-24-oate (19) (1.1 g, 2.4 mmol) in THF/H2O (24 mL, 4:1), freshly crystallized N-iodosuccinimide (807 mg, 3.59 mmol) and Jones reagent (2.4 mL) were sequentially added at room temperature and the resulting mixture was refluxed for 1 h. The mixture was allowed to cool to room temperature and then quenched by adding MeOH (25 mL) and 5% w/v aqueous solution of Na₂S₂O₃ (25 mL). The mixture was diluted with EtOAc and filtered on a pad of Celite. The organic phase was washed with aqueous saturated solution of NaHCO3, H2O, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude (1.39 g, 95% recovery) was dissolved in AcOH (24 mL) and refluxed for 1.5 h in presence of NaOAc (1.18 g, 14.3 mmol) and Zn dust (1.17 g, 17.9 mmol). The suspension was allowed to cool to room temperature and filtered on a short pad of Celite. The mixture was diluted with EtOAc and washed with H₂O, aqueous saturated solution of NaHCO₃, H₂O, brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure affording the crude diketo intermediate 23a (1.07 g, 92% recovery) as pale yellow solid. To a solution of methyl 3D-acetoxy-7,11-diketo-6D- ethyl-5E-cholan-24-oate (23a) (442 mg, 0.91 mmol) in anhydrous THF/MeOH (9 mL, 1:1), CeCl3^.7H2O (674 mg, 1.81 mmol) and LiBH4 (69 mg, 3.62 mmol) were sequentially added in one portion at 0 °C and the resulting mixture was stirred at 0 °C for 4 h. The mixture was diluted with CH₂Cl₂ and quenched at 0 °C by adding H₂O and 3 N HCl. The phases were separated and the aqueous phase was extracted with CH₂Cl₂. The combined organic extracts were washed with H₂O, brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude (444 mg) was dissolved in MeOH/H₂O (4.5 mL, 9:1) and stirred overnight at room temperature in presence of NaOH (360 mg). The mixture was concentrated under reduced pressure and the residue was dissolved in CH₂Cl₂ and acidified with 3 N HCl (pH= 2). The phases were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were washed with H2O, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, affording 280 mg of compound 100. Alternate Procedure: A solution of compound 40 (0.736 kg, 1.70 mol) in water (6.94 L) containing 50 wt% NaOH (0.734 kg, 9.18 mol) was heated to 74-80 °C. A solution of NaBH4 (0.135 kg, 3.57 mol) in water (0.37 L) containing 50 wt% NaOH (68 g, 0.85 mol) was added, and the mixture was stirred until reaction completion (within 21 h). The mixture was cooled, and MTBE (7.3 L) was charged, followed by addition of 3N HCl (aq) (ca.4.4 L) until pH 2 was reached. The aqueous layer was discarded, and the organic layer was washed with water (5.4 L), then dried over Na₂SO₄ and concentrated to 1.2 L. The product solution was diluted with heptane (0.25 L) and chromatographed on silica gel (75-80% MTBE-Heptane). The product-rich fractions were concentrated to a solid and dissolved in water (5 L) containing 50 wt% NaOH (0.242 kg). The solution was concentrated under vacuum to remove ca.2.2 L of distillates. The mixture was acidified to pH 2 with 2N HCl (1.55 L) and the suspension was further diluted with water (3 L). The suspension was heated to 40 °C for 1 h, cooled to 20-25 °C and vacuum filtered, washed with water (4 x 2 L) then dried under vacuum. Compound 100 (0.652 kg) was obtained in 88% yield. A synthesis analogous to one shown in Exemplary Route 4 can proceed through intermediate 47a, which can be prepared by reductive dehalogenation of the compound of formula 21a under mild hydrogenation conditions in the presence of catalytic palladium and a base as shown in Examples 1-10a and 1-10b. Example 1-10a: Methyl 3Į-Acetoxy-6Į-ethyl-11E-hydroxy-7-keto -5ȕ-cholan-24-oate (47a)

A mixture of compound 21a (100 mg, 0.16 mmol), Pd/C (12 mg), imidazole (54.5 mg, 0.80 mmol), MTBE (1.5 mL) and water (1 mL) was stirred under hydrogen atmosphere (1 atm) at 20-25 ^C. The mixture was stirred at 20-25 ^C until reaction completion. The mixture was filtered through Celite^® and Celite^® was washed with MTBE (2 mL). The organic layer was separated and washed with water (2 x 1 mL), then concentrated to generate compound 47a (67 mg) in 78.5% yield. Alternatively, as shown in Route 4, reductive dehalogenation of a compound of formula 21b under mild hydrogenation conditions in the presence of catalytic palladium and a base can produce compound 47b as shown in Example 1-10b. Example 1-10b: Methyl 3Į-(ethoxycarbonyl)oxy-6Į-ethyl-11E-hydroxy-7-keto-5ȕ-cholan- 24-oat

A mixture of compound 21b (5.4 g, wet weight), NaOAc (3.35 g, 40.8 mmol), Pd/C (0.41 g) in MeOH (82 mL) was stirred under a hydrogen atmosphere (0.5 to 2 bar) at 20-25 ^C until reaction completion (within 18 h). The mixture was filtered over Celite^® and the filtrate was added to a cold solution (0-5 ^C) of 0.2 wt% sodium bisulfite (aq). The resulting solids were filtered, washed with water and dried under vacuum to give compound 47b (3.6 g) as a solid in 84.8% yield (2-step yield from compound 19b).¹H-NMR (300 MHz, CDCl3): į 0.81 (t, J = 7.3 Hz, 3H, 26-CH3), 0.88 (s, 3H, 18-CH3), 0.91 (d, 3H, 21-CH3), 1.28 (t, J = 7.3 Hz, 3H OC(O)OCH₂CH₃), 1.46 (s, 3H, 19-CH₃), 3.66 (s, 3H, CO₂CH₃), 4.00-4.24 (m, 3H, OC(O)OCH₂CH₃, 11-CH), 4.39-4.69 (m, 1H, 3-CH). Example 1-11: Methyl 3Į-(ethoxycarbonyl)oxy-6Į-ethyl- oate

A solution of compound 47b (3.6 g, 6.91 mmol) in methanol (72 mL) was cooled to 0-5 ^C with stirring. To the cold solution was added NaBH4 (0.522 g, 13.82 mmol) in portions and continued to stir at 0-5 ^C until reaction completion (within 1.5 h). The reaction was quenched with 1N HCl and the resulting precipitate was filtered, washed with water, and dried under vacuum to generate compound 49b (3.26 g) as a solid in 90% yield.¹H-NMR (300 MHz, CDCl₃): į 0.80-1.00 (m, 6H, 26-CH₃, 21-CH₃), 0.91 (d, 3H, 21-CH₃), 1.15 (s, 3H, 18-CH₃), 1.29 (t, J = 7.3 Hz, 3H OC(O)OCH₂CH₃), 1.54 (s, 3H, 19-CH₃), 3.66 (s, 3H, CO₂CH₃), 4.18 (q, 3H, OC(O)OCH₂CH₃), 4.23(br. s, 1H, 11-CH) 4.30-4.55 (m, 1H, 3-CH). Example 1-12: 3Į,7Į,11ȕ-Trihydroxy-6Į-ethyl-5ȕ-cholan-24-oic acid (100)

To a solution of compound 49b (1.5 g, 2.8 mmol) in methanol (15 mL) at ambient temperature with stirring was added LiOH (0.20 g, 8.4 mmol). The mixture was warmed to 30-35 ^C and was stirred until reaction completion (within 36 h). Water (20 mL) was added and the mixture was concentrated under vacuum. The residue was diluted with water (20 mL) and MTBE (40 mL), then acidified with 1N HCl (aq) to pH 1-2. The solids were vacuum filtered and washed with water, then dried under vacuum to generate compound 100 (1.1 g, 2.5 mmol) in 91% yield. Example 2. Shortened Synthesis of compound 100 Exemplary Route 5:

Route 5 can be also carried out with other protecting groups at C-3 hydroxy (e.g., OAc). Example 2-1: Synthesis of Methyl ^Į-(ethoxycarbonyl)oxy-^Į-ethyl-^D,11E-dihydroxy-^ȕ- cholan-24-oate (49b) via LiBH₄/Rh(OAc)₂ reduction

To a solution of 21b ^^^^PJ^^^^^^^PPRO^^LQ^0H2+^7+)^^^^P/^^Y^Y^^^5K^OAc)₂ and LiBH₄ were sequentially added at 0 °C. The resulting mixture was stirred at 0 °C for 1 h and reacted for 6 h at 25 °C. The crude was filtered on celite, dried under reduced pressure and purified by silica gel flash chromatography to obtain 49b in 88% yield. Example 2-2: Synthesis of 0HWK\O^^Į-(ethoxycarbonyl)oxy-^Į-ethyl-^D,11E-dihydroxy-^ȕ- cholan-24-oate (49b) via NaBH₄/Ni(OAc)₂ reduction

NaBH4 (1.8 g, 6.0 Eq, 46 mmol) was dissolved in H2O (10 mL) and allowed to stand for 3 min. Compound 21b (5.0 g, 7.7 mmol) was dissolved in MeOH (100 mL). Ni(OAc)2ā4H2O(1.9 mg, 0.0010 eq, 7.7 μmol) was added. The mixture was cooled to 0 °C and the NaBH4 solution was added over 10 min while keeping the temperature between 5 and 10 °C. The mixture was stirred for another 50 min, upon which TLC showed full conversion of the 7-keto moiety (de-iodination cannot been seen on TLC). The mixture was poured into 1M aq. HCl (50 mL) which contained Na₂S₂O₅ (5 g) and stirred for 15 min. The product was extracted with MTBE (2×). The organic layers were washed with brine and dried over Na₂SO₄ and concentrated affording methyl (4R)-4-((3R,5S,6R,7R,10S,11S,13R,17R)-3- ((ethoxycarbonyl)oxy)-6-ethyl-7,11-dihydroxy-10,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)pentanoate (4.0 g, 99%) (49b) as a white foam.

Claims

CLAIMS 1. A method of preparing a compound of formula I:

or pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, wherein: R¹ is OH, alkoxy, or oxo; R² and R³ are each independently H, OH, OSO₃H, OC(O)CH₃, OPO₃H₂, halogen, or alkyl optionally substituted with one or more halogen or OH, or R² and R³ taken together with the carbon atom to which they are attached form a carbonyl; R⁴ is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl; R⁵ and R⁶ are each independently H, OH, OSO₃H, OC(O)CH₃, OPO₃H₂, halogen, or alkyl optionally substituted with one or more halogen or OH, or R⁵ and R⁶ taken together with the carbon atom to which they are attached form a carbonyl; R⁷ is OH, OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C(O)NHOH, NH(CH2)2SO3H, NHCH2CO2H or optionally substituted tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3- hydroxyisoxazolyl, 3-hydroxyisothiazolyl, pyrimidine, 3,5-difluoro-4-hydroxyphenyl or 2,4- difluoro-3-hydroxyphenyl; R⁸, R⁹, and R¹⁰ are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R⁸ and R⁹ taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S, or R⁹ and R¹⁰ taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S; m is 0, 1, or 2; n is 0 or 1; and p is 0 or 1; the method comprising Step (B-3)A: reducing a compound of formula I-5b with one or more reducing reagents to provide a compound of formula I-5d, and Step (B-3)B: deprotecting the compound of I-5d to provide a compound of formula I- 9-1

each R^4* is R⁴; each R^7* is independently R⁷, CO₂Me, or R⁷ protected by R¹¹; each R^8* is independently R⁸ or R⁸ protected by R¹¹; each R^9* is independently R⁹ or R⁹ protected by R¹¹; each R^10* is independently R¹⁰ or R¹⁰ protected by R¹¹; wherein R¹¹ is selected from acetyl, benzoyl, C(O)C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, 2-methoxyethoxymethyl, methoxymethyl, ethoxyethyl, p-methoxybenzyl, methylthiomethyl, triphenylmethyl, dimethoxytrityl, methoxytrityl, and silyl protecting groups. 2. The method of claim 1, wherein the compound of formula I is a compound of formula I-9-1

I^-9-1 or pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof. 3. The method of claim 1, wherein the compound of formula I is compound 100

100 or pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof. 4. The method of claim 1, wherein Step (B-3)A is performed with one or two reducing agents. 5. The method of claim 1, wherein Step (B-3)A is performed with two reducing agents. 6. The method of claim 1, wherein Step (B-3)A is performed with two reducing agents, wherein the two reducing reagents are added in temporal proximity. 7. The method of claim 1, wherein Step (B-3)A is performed with two reducing agents, wherein one of the two reducing reagents is added after the other. 8. The method of claim 5, wherein the two reducing reagents are added simultaneously. 9. The method of claim 5, wherein one of the two reducing agents is LiBH4 or NaBH4. 10. The method of claim 5, wherein one of the two reducing agents is Pd/C, Rh/C, Raney Ni, Ni(OAc)2 (e.g., Ni(OAc)2Â4H2O), NiCl2, Pd(OAc)2, Pd(MeCN)2Cl2, Rh(OAc)2, Cu(OAc)2, or Cu(Acac)2. 11. The method of claim 9, wherein one of the two reducing agents is LiBH₄. 12. The method of claim 9, wherein one of the two reducing agents is NaBH₄. 13. The method of claim 10, wherein one of the two reducing agents is Ni(OAc)₂ (Ni(OAc)₂Â4H₂O). 14. The method of claim 1, wherein the two reducing agents are NaBH4 and Ni(OAc)2Â4H2O. 15. The method of claim 14, wherein NaBH4 and Ni(OAc)2Â4H2O are present in a ratio of about 5,974:1. 16. The method of claim 1, wherein the compound of formula I-5d is compound 49b

or pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof. 17. The method of claim 16, further comprising converting compound 49b to compound 100 by treating compound 49b with NaOH

. 18. The method of claim 1, wherein R¹¹ is C(O)C₁-C₄ alkyl. 19. The method of claim 1, wherein R¹¹ is C(O)CH₂CH₃.