WO2024112764A1

WO2024112764A1 - Synthesis of pyrrolo[3,4-c]pyrroles

Info

Publication number: WO2024112764A1
Application number: PCT/US2023/080702
Authority: WO
Inventors: George P. Luke; Sonia Rodriguez; Stephane G. Ouellet; Gilles Gorins; Khalid DIKER; Aurélie BEAUDENON; Jonathan COUSIN
Original assignee: Novo Nordisk Health Care AG
Current assignee: Novo Nordisk Health Care AG
Priority date: 2022-11-21
Filing date: 2023-11-21
Publication date: 2024-05-30
Anticipated expiration: 2025-05-21
Also published as: EP4622958A1; JP2025536754A; CN120225503A

Abstract

Novel synthetic methods of making pyrrolo[3,4-c]pyrroles, derivatives thereof, and intermediates thereto are provided. Also provided are methods using pyrrolo[3,4-c]pyrroles in the processes for preparing bioactive compounds (e.g. PKR Activating Compounds).

Description

SYNTHESIS OF PYRROLO[3,4-C]PYRROLES TECHNICAL FIELD [0001] This disclosure relates to novel synthetic methods of making pyrrolo[3,4-c]pyrroles, derivatives thereof, and intermediates thereto. The disclosure further relates to synthetic processes for preparing bioactive compounds using pyrrolo[3,4-c]pyrroles, derivatives thereof, and intermediates thereto. BACKGROUND [0002] Pyrrolo[3,4-c]pyrroles are useful as bioactive compounds, e.g., as dual inhibitors of autotaxin and carbonic anhydrase (WO 2017/050791, WO 2017/050792), inhibitors of stearoyl- CoA desaturase (WO 2008/135141, WO 2010/028761), agonists of kappa opioid receptors (WO 2016/181408), inhibitors of dipeptidyl dipeptidase-IV (WO 2014/061031), and Pyruvate Kinase R activating compounds (WO 2018/175474). Current methods to synthesize pyrrole[3,4- c]pyrroles utilize mono- and/or bis-protected pyrrolo[3,4-c]pyrroles, such as N-Boc-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrole:

However, the synthesis of mono-protected pyrrole[3,4-c]pyrroles presents several challenges, including difficulty producing on large scale, poor atom economy, generation of large quantities of bromine and low yields (Heterocycles 1995, 41, 1291; WO 2016/046837). Therefore, there is a need for improved methods of synthesizing pyrrolo[3,4-c]pyrroles. SUMMARY [0003] In a first aspect, the present disclosure provides a novel process for preparing a compound according to formula (III-Y) which is useful as a key intermediate for synthesis of pyrrolo[3,4-c]pyrroles, and in particular, for making pyrrolo[3,4-c]pyrroles substituted with different groups on each nitrogen:

(III-Y) or a salt thereof, where: R12 is -CR2R3-(C6-C10 aryl), where the C6-C10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C₁-C₆ alkyl; and R4 is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or -OSO2R7, wherein each R7 is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or C6-C10 aryl, where C6-C10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. [0004] Intermediate compounds of formula (III-Y) can be used for preparing bioactive compounds, such as PKR Activating Compounds. Such PKR Activating Compounds can increase the activity of wild-type and mutant PKR enzymes. [0005] In some embodiments, the present disclosure relates to a process for preparing a compound of formula (III-Y). [0006] In some embodiments, the process includes a further step of transforming the compound of formula (III-Y) into a compound of formula (III-Z) by reacting with R1-Cl, wherein R1 is -C(O) C₁-C₆ alkoxy:

[0007] In some embodiments, the process further includes transforming the compound of formula (III-Z) into a compound of formula (V-Z) by reacting the compound of formula (III-Z) with a sulfonamide:

(V-Z) [0008] In a second aspect, the present disclosure relates to key intermediate in the synthesis of pyrrolo[3,4-c]pyrroles, wherein said intermediate is the compound of formula (III-Y) or a salt thereof. [0009] In a third aspect, the present disclosure relates to key intermediate in the synthesis of pyrrolo[3,4-c]pyrroles, wherein said intermediate is the compound of formula (III-Z) or a salt thereof. [0010] In a fourth aspect, the present disclosure relates to key intermediate in the synthesis of pyrrolo[3,4-c]pyrroles, wherein said intermediate is the compound of formula (V-Z) or a salt thereof. [0011] In a fifth aspect, the present disclosure relates to the use of intermediate compounds of formula (III-Y), (III-Z) or (V-Z) useful for the synthesis of a compound of formula (I), (S)-1- (5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one also known as etavopivat:

or for the synthesis of a compound of formula (II), (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-2- sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one: (II). DETAILED DESCRIPTION [0012] The term “C₁-C₆ alkyl” as used herein refers to a saturated, branched or straight chain hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of C₁-C₆ alkyl include but are not limited to methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, 2-pentyl, 3-pentyl, isoamyl, 2-methylbutyl, neopentyl, 3-methylbutyl, tert-amyl, 1- hexanol, 2-hexanol, 3-hexanol, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2- methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methyl-3-pentyl, 3-methyl-3-pentyl, 2,2-dimethyl-1-butanyl, 2,3-dimethyl-1-butyl, 3,3-dimethyl-1-butyl. [0013] The term “C₆-C₁₀ aryl” as used herein refers to a cyclic aromatic group comprising from 6-10 carbon atoms. Such aryl group may be substituted or unsubstituted. Examples of C₆- C10 aryl include but are not limited to phenyl, naphthyl and the like. [0014] The term “halo” as used herein refers to fluoro, chloro, bromo and iodo. [0015] The term “C₁-C₆ haloalkyl” as used herein refers to a C₁-C₆ alkyl group as defined herein comprising at least one halo group as defined herein. Specific examples of C₁-C₆ haloalkyl include but are not limited to trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl etc. [0016] The term “C₁-C₆ alkoxy” as used herein refers to the group -OC₁-C₆ alkyl. Examples of C₁-C₆ alkoxy include but are not limited to methoxy, ethoxy, 1-propoxy, iso-propoxy, n- butoxy, tert-butoxy etc. [0017] The term “C₁-C₆ haloalkoxy” as used herein refers to a C₁-C₆ alkoxy as defined herein comprising at least one halo group as defined herein. Specific examples of C₁-C₆ haloalkoxy include but are not limited to trifluoromethoxy, difluoromethoxy, pentafluoroethyl, trichloromethyl etc. [0018] The term “6-10 membered heteroaryl” as used herein refers to a 6-10 membered cyclic aromatic ring system having ring carbon atoms and 1-3 heteroatoms selected from the group consisting of O, N or S. Such 6-10 membered heteroaryl may be substituted or unsubstituted. Examples of 6-10 membered heteroaryl include but are not limited to 2-pyridyl, 3- pyridyl, 4-pyridyl, 5-benzofuranyl, 6-benzofuranyl, 6-benzooxazol, 6-benzothiazolyl. [0019] In one aspect, the present disclosure sets forth synthetic methods, intermediates, and reaction parameters for the efficient preparation of pyrrolo[3,4-c]pyrroles. The present disclosure also encompasses the recognition that intermediate compounds of formula (III-Y), (III-Z) and (III): (i) can be synthesized efficiently from commercially available starting materials; (ii) can be purified without chromatography; and (iii) can be used to synthesize pyrrolo[3,4-c]pyrroles with differentially substituted nitrogen atoms. [0020] Intermediate compounds of formula (III-Y), (III-Z) and (III) can be used for preparing bioactive compounds, such as PKR (Pyruvate Kinase R) Activating Compounds. Such PKR Activating Compounds can increase the activity of wild-type and mutant PKR enzymes. [0021] In some embodiments, the PKR Activating Compound prepared using an intermediate compound of formula (III-Y), (III-Z) or (III) is a compound of formula (I):

which can also be referred to as (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)- 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one or etavopivat. [0022] The compound of formula (I) is a selective, orally bioavailable PKR Activating Compound that decreases 2,3-DPG (diphosphoglyceric acid), increases ATP, and has anti- sickling effects on red blood cells (RBCs) in disease models with a wide therapeutic margin relative to preclinical toxicity. The compound of formula (I) is a potent activator of PKR and a multi-modal metabolic modulator of RBCs. Activation of PKR simultaneously reduces 2,3-DPG concentrations, which increases hemoglobin-oxygen affinity and decreases sickling, while also increasing intracellular ATP, which improves RBC health and reduces hemolysis, or RBC death. [0023] The compound of formula (I) is an allosteric activator of recombinant wild type (WT) PKR and a mutant enzyme, PKR R510Q which is one of the most prevalent PKR mutations in North America. PKR exists in both a dimeric and tetrameric state, but functions most efficiently as a tetramer. PKR is the isoform of pyruvate kinase expressed in RBCs, and is the rate limiting enzyme in the glycolytic pathway. The compound of formula (I) stabilizes the tetrameric form of PKR, thereby lowering the Michaelis-Menten constant (Km) for its substrate, phosphoenolpyruvate (P). [0024] In some embodiments, the PKR Activating Compound prepared using an intermediate compound of formula (III-Y), (III-Z) or (III) is a compound of formula (II):

which can also be referred to as (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-2-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one. Intermediate Compounds of the Disclosure and Methods for Preparing the Same [0025] In one aspect, the present disclosure relates to a process for preparing a compound of formula (III-Y) according to Scheme A1. The compound of formula (III-Y) may further be used for efficient synthesis of pyrrolo[3,4-c]pyrroles. The reaction according to Scheme A1 comprises reacting an azomethine precursor of formula (III-W) with an electron-poor alkyne of formula (III-X) in the presence of an acid: Scheme A1

where R12 is -CR2R3-(C6-C10 aryl), where the C6-C10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C₁-C₆ alkyl; and R4 is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or -OSO₂R7, wherein each R7 is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or C6-C10 aryl, where C6-C10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R9 is a suitable silyl protecting group selected from the group consisting of trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), or dimethylisopropylsilyl (DMIPS); and R10 is C₁-C₆ alkyl. [0026] In some embodiments, R12 of the azomethine precursor of formula (III-W) of is -CH₂-Ph (benzyl) or 4-methoxybenzyl. In one embodiment, R12 of formula (III-W) is benzyl. In some embodiments, the suitable silyl group R9 of (III-W) is selected from the group consisting of TMS, DMPS, TES, TBS or DMIPS. In one embodiment, the suitable silyl group R9 is TMS. In some embodiments, R10 of formula (III-W) is a C₁-C₆ alkyl or a straight chain C₁-C₆ alkyl. In one embodiments, R10 is selected from the group consisting of methyl, ethyl, 1- propyl, 1-butyl. In some embodiments, R10 is methyl. [0027] In some embodiments, R5 and R6 of the electron poor alkyne of formula (III-X) are each independently selected from chloro, bromo, iodo or -OSO₂R7. In one embodiment, R5 and R6 are each chloro. In one embodiment, R5 and R6 are each bromo. [0028] In some embodiments, the reaction according to Scheme A1 is performed in the presence of an acid. In some embodiments, the acid is selected from the group consisting of TFA, TMSOTf, TMSI, TMSOTf in combination with CsF, or TMSI in combination with any one of CsF, LiF, ZnCl2 or a combination thereof. In one embodiment, the acid is TFA. In some embodiments, the acid is present in a substoichiometric amount or catalytic amount of about 0.01-0.2, such as e.g.0.03-0.07 equivalents or about 0.05 equivalents. [0029] In some embodiments, the reaction of Scheme A1 is performed in a non-polar solvent, e.g. selected from the group consisting of toluene, DCM or a mixture thereof. In one embodiment, the solvent is toluene. In some embodiments, about 1 equivalent of the compound of formula (III-W) is reacted with about 1.1 to 3 equivalents of the compound of formula (III-X), such as 1.5-2 equivalents. [0030] In one embodiment, the reaction according to Scheme A1 is performed in a non-polar solvent selected from DCM, toluene or a mixture thereof using about 0.01-0.2 equivalents of an acid selected from the group consisting of TFA, TMSOTf, TMSI, TMSOTf in combination with CsF, or TMSI in combination with any one of CsF, LiF, ZnCl₂ or a combination thereof, about 1 equivalent of the compound of formula (III-W) and 1.1 to 3 equivalents of the compound of formula (III-X). [0031] In some embodiments, the reaction of Scheme A1 is performed using a compound of formula (III-W1) according to Scheme A1’ and results in preparation of a compound of formula (III-Y1), wherein R5, R6, R9, R10 are defined as above: Scheme A1’

(III-W1) (III-X) (III-Y1) [0032] In a specific embodiment, the process according to Scheme A1 is a process according to Scheme A wherein the compound of formula (III-Y) is a compound of formula (III-B) which can be prepared, for example, via the process depicted in Scheme A and described more fully in Examples 1 and 2. Scheme A

[0033] In some embodiments, Step 1^A uses an azomethine precursor (e.g., N- (methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-poor alkyne (e.g., dichlorobutyne, III-C) in the presence of a substoichiometric amount (e.g., 0.1 eq or 0.05 eq) of a suitable acid (e.g., trifluoroacetic acid (TFA)) in a suitable solvent (e.g., toluene or dichloromethane (DCM)). In some embodiments, Step 1^A uses an azomethine precursor (e.g., N- (methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-poor alkyne (e.g., dichlorobutyne, III-C) in the presence of a substoichiometric amount (e.g., 0.1 eq or 0.05 eq) of trimethylsilyl trifluoromethanesulfonate (i.e. Me₃SiOTf) in a suitable solvent (e.g., toluene or DCM). In some embodiments, Step 1^A uses an azomethine precursor (e.g., N-(methoxymethyl)- N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-poor alkyne (e.g., dichlorobutyne, III-C) in the presence of a substoichiometric amount (e.g., 0.1 eq or 0.05 eq) of trimethylsilyl trifluoromethanesulfonate (i.e. Me₃SiOTf) and CsF in a suitable solvent (e.g., toluene or DCM). In some embodiments, Step 1^A uses an azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-poor alkyne (e.g., dichlorobutyne, III-C) in the presence of a substoichiometric amount (e.g., 0.1 eq or 0.05 eq) of trimethylsilyl iodide (i.e. Me₃SiI) in a suitable solvent (e.g., toluene or DCM). In some embodiments, Step 1^A uses an azomethine precursor (e.g., N-(methoxymethyl)-N- (trimethylsilylmethyl)benzylamine, III-D) and an electron-poor alkyne (e.g., dichlorobutyne, III-C) in the presence of a substoichiometric amount (e.g., 0.1 eq or 0.05 eq) of trimethylsilyl iodide (i.e. Me3SiI) and an additive selected from CsF, LiF, ZnCl2, and combinations thereof, in a suitable solvent (e.g., toluene or DCM). One of ordinary skill in the art would be capable of identifying a suitable acid and suitable solvent without the burden of undue experimentation. [0034] While not wishing to be bound by any particular theory, it is believed that the choice of electron-poor alkyne is useful for avoiding side products and to reduce the number of steps in the process. In some aspects of the disclosure, the stoichiometric ratio between the azomethine precursor and the electron-poor alkyne is selected in order to avoid side products and to facilitate purification. In some embodiments, 1.0 eq of azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and 2.0 eq of electron- poor alkyne (e.g., dichlorobutyne, III-C) is used. In other embodiments, 1.0 eq of azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and 1.5 eq of electron-poor alkyne (e.g., dichlorobutyne, III-C) is used. [0035] In some embodiments, the process for making the compound of formula (III-Y), (III- Y1) or (III-B) may involve isolating the product as a salt. In some embodiments, the process for making the compound of formula (III-Y), (III-Y1) or (III-B) may involve carrying over the product to a further reaction step without prior purification. [0036] In some embodiments, the process further involves a step of transforming the compound of formula (III-Y) into a compound of formula (III-Z) e.g. by contacting a compound of formula (III-Y) with R1-Cl according to Scheme A2: Scheme A2 R12 N R1 R1-Cl N R5 Step 2 ^A2 R5 R6 R6 (III-Y) (III-Z) wherein R1 is selected from the group consisting of C₁-C₆ alkoxycarbonyl (e.g. tert- butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e. Cbz), C₆-C₁₀ aryloxy (e.g. phenoxycarbonyl), C₁-C₆ alkylcarbonyl (e.g. acetyl), haloalkylcarbonyl (e.g. trifluoroacetyl), and -SO2-(C6-C10 aryl) (e.g. tosyl). In one embodiment, R1 is -C(O)(C₁-C₆ alkoxy). In one embodiment, R1 is -C(O)(C₁-C₆ alkoxy) wherein C₁-C₆ alkoxy is straight chain C₁-C₆ alkoxy selected from the methoxy, ethoxy, 1-propoxy, 1-butoxy, 1-pentoxy or 1-hexoxy. In one embodiment, R1 is -C(O)OCH3. [0037] In some embodiment, the process including Scheme A1 and A2 together is represented by Scheme B1, wherein R9, R10, R12, R5, R6 and R1 are defined as above for Schemes A1 and A2: Scheme B1

[0038] In some embodiment, the process of Scheme A2 is according to Scheme A2’: Scheme A2’

or the process including Schemes A1’ and A2’ together is represented by Scheme B2 wherein R9, R10, R5, R6 and R1 are as defined above for Schemes A1’ and A2’: Scheme B2

[0039] In a specific embodiment, the process according to Scheme B1 or B2 is the process depicted in Scheme B wherein the compound of formula (III-A) can be prepared, for example as described more fully in Examples 1 and 2. Scheme B

[0040] In some embodiments, Step 1^B is substantially the same as described above with respect to Step 1^A. [0041] In some embodiments, Step 2^B is completed by contacting a compound of formula (III-B) with methyl chloroformate in the presence of a suitable solvent (e.g. toluene or DCM). Without wishing to be bound by any particular theory, it is believed that the choice of methyl carbamate (e.g., instead of benzyl or phenyl carbamate) as a protecting group facilitates purification, increases stability of intermediate compound (III-A), and simplifies the deprotection of the later intermediate (V-A) (e.g. removal of the methyl carbamate to afford the free secondary amine). [0042] In some embodiments, Steps 1^B and 2^B are performed in the same reaction vessel. In some embodiments, Steps 1^B and 2^B are performed without any intervening isolation or purification steps. In other embodiments, Steps 1^B and 2^B are performed sequentially in distinct vessels. In other embodiments, Steps 1^B and 2^B are performed sequentially in distinct vessels without any intervening isolation or purification steps. In other embodiments, Steps 1^B and 2^B are performed sequentially in distinct vessels, where the Step 1^B is performed in a first vessel and the product of Step 1^B is transferred to a second vessel containing a C₁-C₆ alkyl chloroformate to complete Step 2^B. [0043] Specific examples and more detailed experimental conditions for the preparation of compounds of formula (III-A) and (III-B) are presented in Examples 1 and 2, below. [0044] In another aspect, the present disclosure relates to a process for preparing a compound of formula (III-Z), wherein R1 is –C(O)(C₁-C₆ alkoxy), as depicted below in Scheme C. Scheme C

where: R₅ and R₆ are each, independently, halo or –OSO₂R₇; each R₇ is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or C6-C10 aryl, where the C6-C10 aryl is optionally substituted with 1 to 3 R8; and each R₈ is independently halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. [0045] In some embodiments, R5 and R6 are each halo. In some embodiments, R5 and R6 are each chloro. In some embodiments, R5 and R6 are each bromo. In some embodiments, R5 and R6 are each iodo. In some embodiments, R₅ and R₆ are each –OSO₂R₇. In some embodiments, R₇ is C₁-C₆ alkyl. In some embodiments, R7 is methyl. In some embodiments, R7 is C6-C10 aryl substituted with one R8. In some embodiments, R8 is C₁-C₆ alkyl. In some embodiments, R8 is methyl. In some embodiments, R₇ is phenyl substituted with one methyl. In some embodiments, the compound of formula (III-X) is 1,4-dichloro-2-butyne. In some embodiments, the compound of formula (III-X) is 1,4-dibromo-2-butyne. In some embodiments, the compound of formula (III-X) is 1,4-diiodo-2-butyne. In some embodiments, the compound of formula (III-X) is but-2-yne-1,4-diyl bis(methanesulfonate). In some embodiments, the compound of formula (III- X) is but-2-yne-1,4-diyl bis(4-methylbenzenesulfonate). [0046] In some embodiments, Step 1^C is completed substantially as described above with respect to Step 1^A. [0047] In some embodiments, Step 2^C is completed by contacting a compound of formula (III-Y1) with ClC(O)(C₁-C₆ alkoxy) (i.e. a C₁-C₆ alkyl chloroformate) in the presence of a suitable solvent (e.g. toluene or DCM). [0048] In some embodiments, a process for preparing a compound of formula (III-Z), wherein R₁ is –C(O)(C₁-C₆ alkoxy), includes a step of transforming 1-benzyl-3,4- bis(substituted)-2,5-dihydro-1H-pyrrole (III-Y1) (e.g.1-benzyl-3,4-bis(chloromethyl-2,5- dihydro-1H-pyrrole (III-B)) to the compound of formula (III-Z) (i.e. Step 2^C) (e.g. compound (III)). In some embodiments, the step of transforming the compound of formula (III-Y1) to the compound of formula (III-Z) includes contacting the compound of formula (III-Y1) with ClC(O)(C₁-C₆ alkoxy) (i.e. a C₁-C₆ alkyl chloroformate). In some embodiments, R1 is – C(O)OCH3. In some embodiments, the compound of formula (III-Z) is methyl 3,4- bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (i.e. compound III-A, R1 is methoxycarbonyl and R5, R6 are each chloro). In some embodiments, for example, wherein R1 is –C(O)OCH3 and/or the compound of formula (III-Z) is compound (III-A), the step of transforming the compound of formula (III-Y1) to the compound of formula (III-Z) includes contacting the compound of formula (III-Y1) with methyl chloroformate. [0049] In some embodiments, a process for preparing a compound of formula (III-Z), wherein R₁ is –C(O)(C₁-C₆ alkoxy), includes a step of contacting dichlorobutyne (III-C, (III-X) where each R5, R6 are chloro) with N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (III-D) to afford the compound of formula (III-Y1) wherein R5, R6 are each chloro (i.e. (III-B)) (i.e. Step 1^C). In some embodiments, contacting a compound of formula (III-C) with a compound of formula (III-D) is performed in the presence of an acid. In some embodiments, the acid is TFA. In some embodiments, contacting a compound of formula (III-C) with a compound of formula (III-D) is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is toluene. [0050] In some embodiments, Steps 1^C and 2^C are performed in the same vessel. In some embodiments, Steps 1^C and 2^C are performed without any intervening isolation or purification steps. In other embodiments, Steps 1^C and 2^C are performed sequentially in distinct vessels. In other embodiments, Steps 1^C and 2^C are performed sequentially in distinct vessels without any intervening isolation or purification steps. In other embodiments, Steps 1^C and 2^C are performed sequentially in distinct vessels, where the Step 1^C is performed in a first vessel and the product of Step 1^C is transferred to a second vessel containing a C₁-C₆ alkyl chloroformate to complete Step 2^C. [0051] In some embodiments, the process further involves a step of transforming the compound of formula (III-Z) into a compound of formula (V-Z) by reacting the compound of formula (III-Z) with a compound of formula (IV-Y) in the presence of a base according to Scheme A3: Scheme A3 , wherein R11 is C6-C10 aryl or 6-10 membered heteroaryl comprising 1-3 O, N, S, wherein C6-C10 aryl and 6-10 membered heteroaryl are each optionally substituted with one or more substituents selected from R13 and -OR13; each R13 is independently -H, -C₁-C₆ alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, -F, -Cl, -Br, -I, -CN, - NO₂; or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring; wherein R1 is selected from the group consisting of C₁-C₆ alkoxycarbonyl (e.g. tert- butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e. Cbz), C6-C10 aryloxy (e.g. phenoxycarbonyl), C₁-C₆ alkylcarbonyl (e.g. acetyl), haloalkylcarbonyl (e.g. trifluoroacetyl), and -SO2-(C6-C10 aryl) (e.g. tosyl), and R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or -OSO2R7, wherein each R7 is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or C6-C10 aryl, where C6-C10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. [0052] In some embodiments, R11 is a 6-10 membered heteroaryl as defined above such as e.g.2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-ylm, R1 is C₁-C₆ alkoxycarbonyl, and R5, R6 are each halo. In one embodiment, R11 is a 6-10 membered heteroaryl as defined above such as e.g.2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-7-yl; R1 is C₁-C₆ alkoxycarbonyl, and R5, R6 are each chloro. [0053] In some embodiment, the reaction according to Step 1^A3 is performed in the presence on a base such as K₂CO₃ or Cs₂CO₃. In one embodiment, the base is K₂CO₃. In some embodiment, the reaction according to Scheme A3 is performed in a suitable solvent selected from the group consisting of DMSO, toluene or a mixture thereof. [0054] In some embodiments, the process according to scheme A3 relates to a process for preparing a compound of formula (V) according to scheme A3’: Scheme A3’

that includes the step of: contacting a compound of formula (III-Z) e.g. (III):

with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV):

to afford the compound of formula (V), wherein R₁ is a protecting group. In some embodiments, R1 is a protecting group, wherein the protecting group is –C(O)(C₁-C₆ alkyl), –C(O)(C₁-C₆ haloalkyl), –C(O)(C₁-C₆ alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)2(tolyl). In some embodiments, R₁ is –C(O)(C₁-C₆ alkoxy). In some embodiments, R₁ is –C(O)OCH₃. [0055] In some embodiments, the step of contacting a compound of formula (III) with a compound of formula (IV) is performed in the presence of a base. In some embodiments, the base is Cs2CO3 or K2CO3. In some embodiments, the base is Cs2CO3. In some embodiments, the base is K₂CO₃. In some embodiments, the compound of formula (V) is formed in the presence of a suitable solvent. In some embodiments, the suitable solvent is DMSO, toluene, or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is a combination of DMSO and toluene. [0056] In some embodiments, the compound of formula (III) is a compound of formula (III-A):

which can also be referred to as methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1- carboxylate. [0057] In some embodiments, the compound of formula (V) is a compound of formula (V-A):

which can also be referred to as methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7- yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. [0058] In some embodiments, the present disclosure relates to an intermediate compound of formula (III):

where: R1 is H, –CR2R3-(C6-C10 aryl), or a protecting group, where the C6-C10 aryl is optionally substituted with 1 to 3 R4; R₂ and R₃ are each independently H or C₁-C₆ alkyl; and R₄ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. Compounds of formula (III) are useful for preparing bioactive compounds, for example, PKR Activating Compounds. In some embodiments, a compound of formula (III) is used in a process for preparing a compound of formula (I). In other embodiments, a compound of formula (III) is used in a process for preparing a compound of formula (II). [0059] In some embodiments, R1 is H. In some embodiments, R1 is a protecting group. In some embodiments, R₁ is –CR₂R₃-(C₆-C₁₀ aryl). In some embodiments where R₁ is –CR2R3-(C6-C10 aryl), R2 and R3 are each H. In some embodiments where R1 is –CR2R3-(C6-C10 aryl), R2 is C₁-C₆ alkyl and R3 is H. In some embodiments where R1 is –CR₂R₃-(C₆-C₁₀ aryl), R₂ is methyl and R₃ is H. In some embodiments where R₁ is –CR₂R₃-(C₆-C₁₀ aryl), the C₆-C₁₀ aryl is unsubstituted. In some embodiments where R₁ is –CR2R3-(C6-C10 aryl), the C6-C10 alkyl is substituted with one C₁-C₆ alkoxy. In some embodiments where R₁ is –CR₂R₃-(C₆-C₁₀ aryl), the C₆-C₁₀ aryl is substituted with one methoxy. In some embodiments where R₁ is –CR₂R₃-(C₆-C₁₀ aryl), the C₆-C₁₀ aryl is phenyl. In some embodiments where R1 is –CR2R3-(C6-C10 aryl), the C6-C10 aryl is 4-methoxyphenyl. In some embodiments, R1 is benzyl (i.e. –Bn, which may also be shown as –CH2-Ph). In some embodiments, R₁ is 4-methoxybenzyl. [0060] The term “protecting group”, as used with respect to R1, refers to any group capable of preventing the amine group of the compound of formula (III) from participating in or affecting reactions on other parts of the molecule (e.g. reactions with either or both of the chloromethyl groups of the compound), while being removable under conditions that do not adversely affect the rest of the molecule. Examples of amine protecting groups that may be suitable for the disclosed process include alkoxycarbonyl (such as tert-butoxycarbonyl, or BOC, and methoxycarbonyl), benzyloxycarbonyl (i.e. Cbz), C₆-C₁₀ aryloxycarbonyl (e.g. phenoxycarbonyl), C₁-C₆ alkylcarbonyl (e.g. acetyl), haloalkylcarbonyl (e.g. trifluoroacetyl), and tosyl. The skilled artisan would understand that other compounds of formula (III), in which other amine protecting groups are used, are considered within the scope of the compound of formula (III). [0061] In some embodiments, R1 is a protecting group, wherein the protecting group is –C(O)(C₁-C₆ alkyl), –C(O)(C₁-C₆ haloalkyl), –C(O)(C₁-C₆ alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)₂(tolyl). In some embodiments, R₁ is a protecting group, wherein the protecting group is –C(O)(C₁-C₆ alkoxy). In some embodiments, R₁ is a protecting group, wherein the protecting group is –C(O)OCH3. [0062] In some embodiments, the present disclosure relates to a compound of formula (III), wherein the compound is: (i) methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate; or (ii) 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole. [0063] In some embodiments, the compound of formula (III) is a compound of formula (III-A):

which may also be referred to as methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1- carboxylate. [0064] In some embodiments, the compound of formula (III) is a compound of formula (III-B):

which may also be referred to as 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole. [0065] In some embodiments, the present disclosure relates to an intermediate compound of formula (V):

wherein R₁ is a protecting group. [0066] In some embodiments, R1 is –C(O)(C₁-C₆ alkyl), –C(O)(C₁-C₆ haloalkyl), –C(O)(C₁-C₆ alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)2(tolyl). In some embodiments, R₁ is –C(O)OCH₃. [0067] In some embodiments, the compound of formula (V) is a compound of formula (V-A):

which may also be referred to as methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7- yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. [0068] In some embodiments, the present disclosure relates to a compound of formula (V- A):

wherein the compound is prepared by a process that includes the step of: contacting methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A) with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV) in the presence of a base. In some embodiments, the base is Cs2CO3 or K2CO3. In some embodiments, the base is Cs2CO3. In some embodiments, the base is K2CO3. In some embodiments, the compound of formula (V- A) is formed in the presence of a suitable solvent. In some embodiments, the suitable solvent is dimethyl sulfoxide (DMSO), toluene, or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is a combination of DMSO and toluene. [0069] In another aspect, the present disclosure relates to an intermediate compound of formula (IV):

which may also be referred to as 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide. [0070] In another aspect, the present disclosure relates to a process for preparing a compound of formula (IV), as depicted in Scheme D and described more fully in Example 3. In some embodiments, a compound of formula (IV) is obtained via the process depicted in Scheme D and described more fully in Example 3. Scheme D

[0071] In some embodiments, the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-D) to a compound of formula (IV-C) (i.e. Step 1^D). In some embodiments, Step 1^D includes contacting a compound of formula (IV-D) with 1,2-dibromoethane to afford the compound of formula (IV-C). In some embodiments, Step 1^D is performed in the presence of a base. One of ordinary skill in the art will appreciate that there are many bases that would be compatible with the process of Step 1^D. For example, in some embodiments, the base is potassium carbonate. In some embodiments, Step 1^D is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is water, ethanol (EtOH), or a combination thereof. In some embodiments, the suitable solvent is a mixture of EtOH and water. In some embodiments, the suitable solvent is a mixture of EtOH and water in a ratio of about 80:20 to 98:2, such as about 85:15 or about 95:5. [0072] In some embodiments, the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-C) to the compound of formula (IV-B) (i.e. Step 2^D). In some embodiments, Step 2^D includes contacting the compound of formula (IV-C) with a brominating reagent. One of ordinary skill in the art will appreciate that there are many brominating reagents that would be compatible with the process of Step 2^D. For example, in some embodiments, the brominating reagent is N-bromosuccinimide (NBS). In some embodiments, Step 2^D is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is ethyl acetate (EtOAc), N,N-dimethylformamide (DMF), or a combination thereof. [0073] In some embodiments, the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-B) to the compound of formula (IV-A) (i.e. Step 3^D). In some embodiments, Step 3^D includes contacting the compound of formula (IV-B) with a Grignard reagent, a C_1-C₆ alkyl lithium, and sulfuryl chloride. In some embodiments, Step 3^D includes contacting the compound of formula (IV-B) with isopropyl magnesium chloride, butyl lithium, and sulfuryl chloride. In some embodiments, Step 3^D includes first contacting the compound of formula (IV-B) with a Grignard reagent to afford a first metalated intermediate compound, contacting the first metalated intermediate compound with C₁-C₆ alkyl lithium (e.g. butyl lithium, n-butyl lithium or hexyl lithium) to afford a second metalated intermediate compound, and subsequently contacting the second metalated intermediate compound with sulfuryl chloride to afford the compound of formula (IV-A). In some embodiments, Step 3^D includes first contacting the compound of formula (IV-B) with isopropyl magnesium chloride to afford a first metalated intermediate compound, subsequently contacting the first metalated intermediate compound with butyl lithium to afford a second metalated intermediate compound, and then subsequently contacting the second metalated intermediate compound with sulfuryl chloride to afford the compound of formula (IV-A). In some embodiments, the butyl lithium is selected from n-butyl lithium, sec-butyl lithium, and tert- butyl lithium. In some embodiments, the butyl lithium is n-butyl lithium. In some embodiments, the butyl lithium is sec-butyl lithium. In some embodiments, the butyl lithium is tert-butyl lithium. In some embodiments, Step 3^D is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is tetrahydrofuran (THF). [0074] In some embodiments, the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-A) to the compound of formula (IV) (i.e. Step 4^D). In some embodiments, Step 4^D includes contacting a compound of formula (IV-A) with ammonia to obtain the compound of formula (IV). In some embodiments, Step 4^D is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is methanol (MeOH). [0075] In another aspect, the present disclosure relates to a process for preparing a compound of formula (IV), as depicted in Scheme E and described more fully in Example 4. In some embodiments, a compound of formula (IV) is obtained via the process depicted in Scheme E and described more fully in Example 4. Scheme E

[0076] In some embodiments, the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-F) to the compound of formula (IV-E) (i.e. Step 1^E). In some embodiments, Step 1^E includes contacting the compound of formula (IV-F) with bromine, hydrohalic acid (e.g. hydrochloric acid or hydrobromic acid), and sulfamic acid. In some embodiments, Step 1^E includes first contacting the compound of formula (IV-F) with a first portion of bromine, subsequently contacting the compound of formula (IV-F) with hydrochloric acid, subsequently contacting the compound of formula (IV-F) with a second portion of bromine, and finally contacting the compound of formula (IV-F) with sulfamic acid. In some embodiments, Step 1^E includes first contacting the compound of formula (IV-F) with a first portion of bromine, subsequently contacting the compound of formula (IV-F) with hydrobromic acid, subsequently contacting the compound of formula (IV-F) with a second portion of bromine, and finally contacting the compound of formula (IV-F) with sulfamic acid. In some embodiments, Step 1^E includes first contacting the compound of formula (IV-F) with a first portion of bromine to afford a first intermediate compound, subsequently contacting the first intermediate compound with hydrochloric acid to afford a second intermediate compound, subsequently contacting the second intermediate compound with a second portion of bromine to afford a third intermediate compound, and finally contacting the third intermediate compound with sulfamic acid to afford the compound of formula (IV-E). In some embodiments, Step 1^E includes first contacting the compound of formula (IV-F) with a first portion of bromine to afford a first intermediate compound, subsequently contacting the first intermediate compound with hydrobromic acid to afford a second intermediate compound, subsequently contacting the second intermediate compound with a second portion of bromine to afford a third intermediate compound, and finally contacting the third intermediate compound with sulfamic acid to afford the compound of formula (IV-E). In some embodiments, Step 1^E is performed in a suitable solvent. In some embodiments, the suitable solvent is water. [0077] In some embodiments, the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-E) to the compound of formula (IV-B) (i.e. Step 2^E). In some embodiments, Step 2^E includes contacting a compound of formula (IV-E) with 1,2-dibromoethane to afford the compound of formula (IV-B). In some embodiments, Step 2^E is performed in the presence of a base. One of ordinary skill in the art will appreciate that there are many bases that would be compatible with the process of Step 2^E. For example, in some embodiments, the base is potassium carbonate. In some embodiments, Step 2^E is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is water, EtOH, or a combination thereof. In some embodiments, the suitable solvent is a combination of water and EtOH. In some embodiments, the suitable solvent is a combination of water and EtOH in a ratio of about 1 to about 1. [0078] In some embodiments, the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-B) to the compound of formula (IV-A) (i.e. Step 3^E). In some embodiments, Step 3^E includes contacting the compound of formula (IV-B) with a Grignard reagent, a C_1-C₆ alkyl lithium, and sulfuryl chloride. In some embodiments, Step 3^E includes contacting the compound of formula (IV-B) with isopropyl magnesium chloride, butyl lithium, and sulfuryl chloride. In some embodiments, Step 3^E includes first contacting the compound of formula (IV-B) with a Grignard reagent (e.g. isopropyl magnesium chloride) to afford a first metalated intermediate compound, contacting the first metalated intermediate compound with C₁-C₆ alkyl lithium (e.g. butyl lithium, n-butyl lithium or hexyl lithium) to afford a second metalated intermediate compound, and then subsequently contacting the second metalated intermediate compound with sulfuryl chloride to afford the compound of formula (IV-A). In some embodiments, Step 3^E includes first contacting the compound of formula (IV-B) with isopropyl magnesium chloride to afford a first metalated intermediate compound, subsequently contacting the first metalated intermediate compound with butyl lithium to afford a second metalated intermediate compound, and then subsequently contacting the second metalated intermediate compound with sulfuryl chloride to afford the compound of formula (IV-A). In some embodiments, the butyl lithium is selected from n-butyl lithium, sec-butyl lithium, and tert-butyl lithium. In some embodiments, the butyl lithium is n- butyl lithium. In some embodiments, the butyl lithium is sec-butyl lithium. In some embodiments, the butyl lithium is tert-butyl lithium. In some embodiments, Step 3^E is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is THF. [0079] In some embodiments, the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-A) to the compound of formula (IV) (i.e. Step 4^E). In some embodiments, Step 4^E includes contacting a compound of formula (IV-A) with ammonia to obtain the compound of formula (IV). In some embodiments, Step 4^E is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is MeOH. [0080] In another aspect, the present disclosure relates to an intermediate compound of formula (VII):

which may also be referred to as (S)-tropic acid. (S)-Tropic acid may be prepared as described below or alternatively from racemic tropic acid by optical resolution via diastereomeric salt formation with e.g. (1R,2S)-2-amino-1,2-diphenylethanol ((1R,2S)-ADPE) using e.g. EtOH, isopropanol (IPA) or a mixture of EtOH/water or IPA/water such as described in Tetrahedron 70 (2014) 7923-7928. [0081] In another aspect, the present disclosure relates to a process for preparing an intermediate compound of formula (VII), as depicted in Scheme F and described more fully in Example 5. In some embodiments, a compound of formula (VII) is obtained via the process depicted in Scheme F and described more fully in Example 5. Scheme F

[0082] In some embodiments, the process for preparing a compound of formula (VII) includes the step of transforming a compound of formula (VII-C) to a compound of formula (VII-B) (i.e. Step 1^F). In some embodiments, Step 1^F includes contacting the compound of formula (VII-C) with methyl formate to afford the compound of formula (VII-B). In some embodiments, Step 1^F is performed in the presence of a base. One of ordinary skill in the art will appreciate that there are many bases that would be compatible with the process of Step 1^F. In some embodiments, the base is sodium tert-butoxide or sodium methoxide. In some embodiments, the base is sodium tert-butoxide. In some embodiments, the base is sodium methoxide. In some embodiments, Step 1^F is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is toluene, THF, or methyl tert-butyl ether (MTBE). In some embodiments, the suitable solvent is toluene. In some embodiments, the suitable solvent is THF. In some embodiments, the suitable solvent is MTBE. [0083] In some embodiments, the process for preparing a compound of formula (VII) includes the step of transforming a compound of formula (VII-B) to a compound of formula (VII-A) (i.e. Step 2^F). In some embodiments, Step 2^F includes contacting the compound of formula (VII-B) with a reducing agent. Step 2^F includes contacting the compound of formula (VII-B) with a reducing agent in the presence of an enzyme. In some embodiments, the reducing agent is an enzyme. In some embodiments, the reducing agent is NADPH. In some embodiments, the enzyme is carbonyl reductase (CRED). In some embodiments, the enzyme is an engineered form of CRED. In some embodiments, Step 2^F is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is phosphate buffer, toluene, MTBE or a combination thereof. In some embodiments, the suitable solvent is phosphate buffer. In some embodiments, the suitable solvent is a combination of phosphate buffer and toluene. In some embodiments, the suitable solvent is a combination of phosphate buffer and MTBE. In some embodiments, the phosphate buffer has a pH of about 6.5-7. In some embodiments, the phosphate buffer includes one or more additional reagents and enzyme cofactors. In some embodiments, the one or more additional reagents and enzyme cofactors include thiamine•HCl, L-lysine, GDP, NADP, or a combination thereof. In some embodiments, the one or more additional reagents and enzyme cofactors include each of thiamine•HCl, L-lysine, GDP, and NADP. In some embodiments, Step 2^F includes the step of isolating or purifying (S)-methyl tropate. In some embodiments, Step 2^F includes the step of isolating or purifying (S)-methyl tropate from a mixture of (R)-methyl tropate and (S)-methyl tropate. The isolation or purification step can be performed via any methods commonly known to those of ordinary skill in the art. For example, in some embodiments, the isolation or purification step includes a chromatography step (e.g. chiral resolution via HPLC, UPLC, or SFC). In other embodiments, the isolation or purification step includes a recrystallization step. In some embodiments, the isolation or purification step can include derivatizing the mixture of (R)- tropic acid and (S)- tropic acid to form a mixture of diastereomers, and then isolating the derivatized diastereomers via any method commonly known to those of ordinary skill in the art. [0084] In some embodiments, the process for preparing a compound of formula (VII) includes the step of transforming a compound of formula (VII-A) to the compound of formula (VII) (i.e. Step 3^F). In some embodiments, Step 3^F includes contacting the compound of formula (VII-A) with a base or an enzyme. In some embodiments, Step 3^F includes contacting the compound of formula (VII-A) with a base. One of ordinary skill in the art will appreciate that many bases would be compatible the process of Step 3^F. In some embodiments, the base is sodium hydroxide (i.e. NaOH). In some embodiments, Step 3^F is performed in the presence of an enzyme. In some embodiments, Step 3^F is performed in the presence of a lipase. In some embodiments, Step 3^F is performed in the presence of Candida antarctica lipase B (CALB). In some embodiments, Step 3^F is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is toluene or MTBE. In some embodiments, the suitable solvent is toluene. In some embodiments, the suitable solvent is MTBE. [0085] In yet another aspect, the present disclosure relates to a composition including a compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein R1 is a protecting group. [0086] In some embodiments, the composition including a compound of formula (III) further includes a compound of formula (IV):

or a pharmaceutically acceptable salt thereof. [0087] In some embodiments, the composition including a compound of formula (III) further includes a base. In some embodiments, the base is Cs₂CO₃ or K₂CO₃. In some embodiments, the base is Cs2CO3. In some embodiments, the base is K2CO3. [0088] In some embodiments, the composition including a compound of formula (III) further includes a compound of formula (V):

or a pharmaceutically acceptable salt thereof, wherein R₁ is a protecting group. [0089] In some embodiments of the composition including a compound of formula (III), the R1 group present on the compound of formula (III) and/or the compound of formula (V) is –C(O)(C₁-C₆ alkyl), –C(O)(C₁-C₆ haloalkyl), –C(O)(C₁-C₆ alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)₂(tolyl). In some embodiments, R₁ is –C(O)(C₁-C₆ alkoxy). In some embodiments, R1 is –C(O)OCH3. [0090] In some embodiments of the composition including a compound of formula (III), the compound of formula (III) is a compound of formula (III-A):

which can also be referred to as methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1- carboxylate. [0091] In some embodiments of the composition including a compound of formula (III), the compound of formula (V) is a compound of formula (V-A):

which can also be referred to as methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7- yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. Methods of Preparing PKR Activating Compounds [0092] In another aspect, the present disclosure relates to a process for preparing a compound of formula (I), (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one also known as etavopivat:

as depicted in Scheme G and described more fully in Examples 6 to 12. Scheme G

[0093] In some embodiments, the process for preparing a compound of formula (I) includes the step of contacting a compound of formula (III) with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine- 7-sulfonamide (IV) to afford a compound of formula (V); and transforming the compound of formula (V) to the compound of formula (I), wherein R1 is a protecting group (i.e. Step 1^G, followed by Steps 2^G and 3^G). In some embodiments, Step 1^G is performed in the presence of a base. In some embodiments, the base is Cs₂CO₃ or K₂CO₃. In some embodiments, the base is Cs2CO3. In some embodiments, the base is K2CO3. In some embodiments, Step 1^G is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is DMSO, toluene, or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is a mixture of DMSO and toluene. [0094] In some embodiments, R1 is –C(O)(C₁-C₆ alkyl), –C(O)(C₁-C₆ haloalkyl), –C(O)(C₁-C₆ alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)₂(tolyl). In some embodiments, R₁ is –C(O)(C₁-C₆ alkoxy). In some embodiments, R₁ is –C(O)OCH₃. [0095] In some embodiments, the compound of formula (III) is obtained by the process depicted in Scheme C. In some embodiments, the compound of formula (III) is a compound of formula (III-A). In some embodiments, the compound of formula (III) is a compound of formula (III-A), wherein the compound of formula (III-A) is obtained by the process depicted in Scheme B and described more fully in Examples 1 and 2. [0096] In some embodiments, the compound of formula (IV) is obtained by the process depicted in one of Schemes D or E and described more fully in Examples 3 and 4, respectively. [0097] In some embodiments, the compound of formula (V) is obtained by the process described above for preparing a compound of formula (V). In some embodiments, the compound of formula (V) is a compound of formula (V-A). [0098] In some embodiments, the process for preparing a compound of formula (I) includes the step of transforming the compound of formula (V) to a compound of formula (VI) (i.e. Step 2^G). In some embodiments, Step 2^G includes deprotecting the compound of formula (V) to afford a compound of formula (VI). In some embodiments, deprotecting the compound of formula (V) to afford the compound of formula (VI) comprises contacting the compound of formula (V) with an acid. One of ordinary skill in the art will appreciate that there are many acids that would be compatible with the process of Step 2^G. In some embodiments, the acid includes HBr and acetic acid. In other embodiments, the acid includes dibutylsulfane and methanesulfonic acid (MSA). In other embodiments, the acid includes dibutylsulfane, TFA and MSA. In some embodiments, Step 2^G further includes the step of neutralizing the acid with a suitable base. In some embodiments, the suitable base is ammonium hydroxide. In some embodiments, Step 2^G further includes contacting the compound of formula (VI) with (S)-tropic acid (VII) to form a complex of compounds (VI) and (VII). In some embodiments, Step 2^G is performed neat, without the presence of an additional solvent (e.g. the dibutylsulfane and MSA are present in sufficient quantities to solubilize the compound of formula (VI)). It will be appreciated that Step 2^G could be run in the presence of a suitable solvent or co-solvent. [0099] In some embodiments, the process for preparing a compound of formula (I) includes the step of contacting (VI) with (S)-tropic acid (VII) to afford the compound of formula (I) (i.e. Step 3^G). In some embodiments, Step 3^G includes coupling the compound of formula (VI) with (S)-tropic acid (VII) to afford the compound of formula (I). In some embodiments, Step 3^G is performed in the presence of a coupling reagent. In some embodiments, the coupling reagent is a carbodiimide coupling reagent. In some embodiments, Step 3^G is performed in the presence of a coupling reagent and an additive. Step 3^G is performed in the presence of a carbodiimide coupling reagent and an additive. One of ordinary skill in the art will appreciate that there are many coupling reagents (e.g. carbodiimide coupling reagents, such as EDC (N-(3- dimethylaminopropyl)-N’-etylcarbodiimide), or HATU (hexafluorophosphate azabenzotriazole tetramethyl uronium), etc.) and additives (e.g. ethyl (hydroxyamino)cyanoacetate (OxymaPure^®), 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), or 2-hydroxypyridine N-oxide (HOPO), etc.) that would be compatible with the process of Step 3^G. In some embodiments, for example, the coupling reagent includes EDC. In some embodiments, the coupling reagent includes propylphosphonic anhydride (T3P^®). In some embodiments, the coupling reagent includes T3P^® and EDC. In some embodiments, Step 3^G is performed in the presence of EDC and an additive, where the additive is OxymaPure^®. In some embodiments, Step 3^G is performed in the presence of EDC and an additive, where the additive is HOPO. In some embodiments, Step 3^G is performed in the presence of T3P^® and EDC and an additive, where the additive is OxymaPure^®. In some embodiments, Step 3^G is performed in the presence of T3P^® and EDC and an additive, where the additive is HOPO. In some embodiments, Step 3^G is performed in the presence of T3P^® and an additive, where the additive is OxymaPure^®. In some embodiments, Step 3^G is performed in the presence of T3P^® and an additive, where the additive is HOPO. In some embodiments, Step 3^G is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is DMSO, N,N-dimethylacetamide (DMAc), EtOH, DCM, 2- methyl tetrahydrofuran (2-MeTHF) or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is DMAc. In some embodiments, the suitable solvent is EtOH. In some embodiments, the suitable solvent is DCM. In some embodiments, the suitable solvent is a combination of DMAc and EtOH. In some embodiments, the suitable solvent is 2-MeTHF. In some embodiments, the suitable solvent is a combination of 2-MeTHF and DMAc. In some embodiments, the suitable solvent is a combination of 2-MeTHF and EtOH. In some embodiments, the suitable solvent is a combination of EtOH, DMAc and 2- MeTHF. [0100] In yet another aspect, the present disclosure relates to a process for preparing a compound of formula (II), (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-2-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one:

as depicted in Scheme H and described more fully in Example 13. Scheme H

[0101] In some embodiments, the process for preparing a compound of formula (II) includes the step of contacting a compound of formula (III) with pyridine-2-sulfonamide (VIII-A) to afford a compound of formula (VIII); and transforming the compound of formula (VIII) to the compound of formula (II), wherein R1 is a protecting group (i.e. Step 1^H, followed by Steps 2^H and 3^H). In some embodiments, Step 1^H is performed in the presence of a base. In some embodiments, the base is Cs₂CO₃ or K₂CO₃. In some embodiments, the base is Cs₂CO₃. In some embodiments, the base is K2CO3. In some embodiments, Step 1^H is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is DMSO, toluene, or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is a mixture of DMSO and toluene. [0102] In some embodiments, R1 is –C(O)(C₁-C₆ alkyl), –C(O)(C₁-C₆ haloalkyl), –C(O)(C₁-C₆ alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)₂(tolyl). In some embodiments, R₁ is –C(O)(C₁-C₆ alkoxy). In some embodiments, R₁ is –C(O)OCH₃. [0103] In some embodiments, the compound of formula (III) is obtained by the process depicted in Scheme C. In some embodiments, the compound of formula (III) is a compound of formula (III-A). In some embodiments, the compound of formula (III) is a compound of formula (III-A), wherein the compound of formula (III-A) is obtained by the process depicted in Scheme B and described more fully in Examples 1 and 2. [0104] In some embodiments, the process for preparing a compound of formula (II) includes the step of transforming the compound of formula (VIII) to a compound of formula (IX) (i.e. Step 2^H). In some embodiments, Step 2^H includes deprotecting the compound of formula (VIII) to afford a compound of formula (IX). In some embodiments, deprotecting the compound of formula (VIII) to afford the compound of formula (IX) comprises contacting the compound of formula (VIII) with an acid. One of ordinary skill in the art will appreciate that there are many acids that would be compatible with the process of Step 2^H. In some embodiments, the acid includes HBr and acetic acid. In other embodiments, the acid includes dibutylsulfane, TFA and MSA. In other embodiments, the acid includes dibutylsulfane and MSA. In some embodiments, Step 2^H further includes the step of neutralizing the acid with a suitable base. In some embodiments, the suitable base is ammonium hydroxide. In some embodiments, deprotecting the compound of formula (VIII) to afford the compound of formula (IX) includes contacting the compound of formula (VIII) with a strong base. In some embodiments, the strong base is potassium hydroxide. In some embodiments, Step 2^H further includes contacting the compound of formula (IX) with (R)-2-hydroxy-2-phenylacetic acid (XI) to form a complex of compounds (IX) and (XI). In some embodiments, Step 2^H is performed neat, without the presence of an additional solvent (e.g. the dibutylsulfane and MSA are present in sufficient quantities to solubilize the compound of formula (VI)). It will be appreciated that Step 2^H could be run in the presence of a suitable solvent or co-solvent. For example, in some embodiments, Step 2^H is performed in the presence of water. [0105] In some embodiments, the process for preparing a compound of formula (II) includes the step of contacting (IX) with (R)-2-hydroxy-2-phenylacetic acid (XI) to afford the compound of formula (II) (i.e. Step 3^H). In some embodiments, Step 3^H includes coupling the compound of formula (IX) with (R)-2-hydroxy-2-phenylacetic acid (XI) to afford the compound of formula (II). In some embodiments, Step 3^H is performed in the presence of a coupling reagent. In some embodiments, the coupling reagent is a carbodiimide coupling reagent. In some embodiments, Step 3^H is performed in the presence of a coupling reagent and an additive. Step 3^H is performed in the presence of a carbodiimide coupling reagent and an additive. One of ordinary skill in the art will appreciate that there are many coupling reagents (e.g. carbodiimide coupling reagents, such as EDC, or HATU, or T3P^® etc.) and additives (e.g. OxymaPure^® (ethyl (hydroxyamino)cyanoacetate), HOBt, HOSu, or HOPO, etc.) that would be compatible with the process of Step 3^H. In some embodiments, for example, the coupling reagent includes EDC. In some embodiments, the coupling reagent includes T3P^®. In some embodiments, the coupling reagent includes T3P^® and EDC. In some embodiments, Step 3^G is performed in the presence of EDC and an additive, where the additive is OxymaPure^®. In some embodiments, Step 3^G is performed in the presence of EDC and an additive, where the additive is HOPO. In some embodiments, Step 3^G is performed in the presence of T3P^® and an additive, where the additive is OxymaPure^®. In some embodiments, Step 3^G is performed in the presence of T3P^® and EDC and an additive, where the additive is OxymaPure^®. In some embodiments, the coupling reagent includes OxymaPure^® and EDC•HCl. In some embodiments, the coupling reagent includes HOBt and EDC. In some embodiments, the coupling reagent includes HOPO and EDC. In some embodiments, Step 3^H is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is DMSO, DMAc, EtOH, DCM, 2-MeTHF or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is DMAc. In some embodiments, the suitable solvent is EtOH. In some embodiments, the suitable solvent is DCM. In some embodiments, the suitable solvent is 2-MeTHF. In some embodiments, the suitable solvent is a combination of DMAc and EtOH. In some embodiments, the suitable solvent is a combination of 2-MeTHF and DMAc. In some embodiments, the suitable solvent is a combination of 2-MeTHF and EtOH. In some embodiments, the suitable solvent is a combination of EtOH, DMAc and 2-MeTHF. In some embodiments, the suitable solvent is DMSO. List of embodiments [0106] The invention is further described by the following non-limiting embodiments: 1. A compound of formula (III):

or a salt thereof, wherein: R1 is H, –CR2R3-(C6-C10 aryl), or a protecting group, where the C6-C10 aryl is optionally substituted with 1 to 3 R₄; R2 and R3 are each independently H or C₁-C₆ alkyl; and R4 is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. 2. The compound of embodiment 1, wherein R₁ is –CR₂R₃-(C₆-C₁₀ aryl). 3. The compound of embodiment 1 or 2, wherein R₂ and R₃ are each H. 4. The compound of embodiment 1, wherein R1 is a protecting group. 5. The compound of embodiment 1 or 4, wherein R₁ is –C(O)(C₁-C₆ alkyl), –C(O)(C₁-C₆ haloalkyl), –C(O)(C₁-C₆ alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)2(tolyl). 6. The compound of any one of embodiments 1, 4, or 5 wherein R1 is –C(O)(C₁-C₆ alkoxy). 7. The compound of any one of embodiments 1 or 4 to 6, wherein the compound is: methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate, or a salt thereof. 8. The compound of any one of embodiments 1 to 3, wherein the compound is:

1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole, or a salt thereof. 9. A process for preparing a compound of formula (III):

wherein R₁ is –C(O)(C₁-C₆ alkoxy), comprising a step (i): (i) transforming a compound of formula (III-B):

to the compound of formula (III). 10. The process of embodiment 9, wherein transforming the compound of formula (III-B) to the compound of formula (III) comprises contacting the compound of formula (III-B) with ClC(O)(C₁-C₆ alkoxy). 11. The process of embodiment 9, wherein R₁ is –C(O)OCH₃. 12. The process of embodiment 11, wherein transforming the compound of formula (III-B) to the compound of formula (I) comprises contacting the compound of formula (III-B) with methyl chloroformate. 13. The process of any one of embodiments 9 to 12, wherein the compound of formula (III- B) is obtained by a step (ii) comprising: (ii) contacting a compound of formula (III-X) with a compound of formula (III-D):

to afford the compound of formula (III-B), wherein: R5 and R6 are each, independently, halo or –OSO2R7 each R₇ is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or C6-C10 aryl, where the C6-C10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. 14. The process of embodiment 13, wherein R₅ and R₆ are each halo. 15. The process of embodiment 14, wherein R5 and R6 are each chloro, i.e. the compound of formula (III-C). 16. The process of any one of embodiments 13 to 15, wherein contacting a compound of formula (III-C) or (III-X) with a compound of formula (III-D) is performed in the presence of an acid. 17. The process of embodiment 16, wherein the acid is trifluoroacetic acid. 18. The process of any one of embodiments 13 to 15, wherein contacting a compound of formula (III-C) or (III-X) with a compound of formula (III-D) is performed in the presence of trimethylsilyl trifluoromethanesulfonate. 19. The process of any one of embodiments 13 to 15, wherein contacting a compound of formula (III-C) or (III-X) with a compound of formula (III-D) is performed in the presence of trimethylsilyl trifluoromethanesulfonate and CsF. 20. The process of any one of embodiments 13 to 15, wherein contacting a compound of formula (III-C) or (III-X) with a compound of formula (III-D) is performed in the presence of trimethylsilyl iodide. 21. The process of any one of embodiments 13 to 15, wherein contacting a compound of formula (III-C) or (III-X) with a compound of formula (III-D) is performed in the presence of trimethylsilyl iodide and an additive selected from CsF, LiF, ZnCl₂, and combinations thereof. 22. A compound of formula (III-A):

prepared by a process consisting essentially of the steps of: (i) contacting a compound of formula (III-C):

with a compound of formula (III-D):

in the presence of an acid to afford a compound of formula (III-B):

(ii) contacting the compound of formula (III-B) with methyl chloroformate to afford the compound of formula (III-A). 23. The compound of embodiment 22, wherein the acid is trifluoroacetic acid. 24. A compound of formula (IV):

or a salt thereof. 25. A process for preparing a compound of formula (IV):

comprising contacting a compound of formula (IV-A):

with ammonia to obtain the compound of formula (IV). 26. The process of embodiment 25, wherein the compound of formula (IV-A) is obtained by: transforming a compound of formula (IV-B):

to the compound of formula (IV-A). 27. The process of embodiment 26, wherein transforming the compound of formula (IV-B) to the compound of formula (IV-A) comprises contacting the compound of formula (IV-B) with a Grignard reagent, C₁-C₆ alkyl lithium, and sulfuryl chloride. 28. The process of embodiment 26 or 27, wherein transforming the compound of formula (IV-B) to the compound of formula (IV-A) comprises the steps of: contacting the compound of formula (IV-B) with a Grignard reagent to afford a first metalated intermediate compound (IV-B1); contacting the first metalated intermediate (IV-B1) compound with C₁-C₆ alkyl lithium (e.g. butyl lithium, n-butyl lithium or hexyl lithium) to afford a second metalated intermediate compound (IV-B2); and contacting the second metalated intermediate compound (IV-B₂) with sulfuryl chloride to afford the compound of formula (IV-A). 29. The process of embodiment 27 or 28, wherein the Grignard reagent is isopropyl magnesium chloride. 30. The process of any one of embodiments 27 to 29, wherein the C₁-C₆ alkyl lithium is butyl lithium, e.g. n-butyl lithium. 31. The process of any one of embodiments 26 to 30, wherein the compound of formula (IV- B) is obtained by transforming a compound of formula (IV-C):

to the compound of formula (IV-B). 32. The process of embodiment 31, wherein transforming the compound of formula (IV-C) to the compound of formula (IV-B) comprises contacting the compound of formula (IV-C) with a brominating reagent. 33. The process of embodiment 32, wherein the brominating reagent is N-bromosuccinimide. 34. The process of any one of embodiments 31 to 33, wherein the compound of formula (IV- C) is obtained by contacting a compound of formula (IV-D): (IV-D) with 1,2-dibromoethane to afford the compound of formula (IV-C). 35. The process of embodiment 34, wherein contacting the compound of formula (IV-D) with 1,2-dibromoethane is performed in the presence of a first base. 36. The process of embodiment 35, wherein the first base is K2CO3. 37. The process of any one of embodiments 26 to 30, wherein the compound of formula (IV- B) is obtained by contacting a compound of formula (IV-E):

with 1,2-dibromoethane to afford the compound of formula (IV-B). 38. The process of embodiment 37, wherein contacting a compound of formula (IV-E) with 1,2-dibromoethane is performed in the presence of a first base. 39. The process of embodiment 38, wherein the first base is K2CO3. 40. The process of any one of embodiments 37 to 39, wherein the compound of formula (IV- E) is obtained by transforming a compound of formula (IV-F):

to the compound of formula (IV-E). 41. The process of embodiment 40, wherein transforming a compound of formula (IV-F) to the compound of formula (IV-E) comprises contacting the compound of formula (IV-F) with bromine, a hydrohalic acid, and sulfamic acid. 42. The process of embodiment 40 or 41, wherein transforming a compound of formula (IV- F) to the compound of formula (IV-E) comprises the steps of: contacting the compound of formula (IV-F) with a first portion of bromine to afford a first intermediate compound (IV-F₁); contacting the first intermediate compound (IV-F1) with a hydrohalic acid to afford a second intermediate compound (IV-F₂); contacting the second intermediate compound (IV-F₂) with a second portion of bromine to afford a third intermediate compound (IV-F3); and contacting the third intermediate compound (IV-F3) with sulfamic acid to afford the compound of formula (IV-E). 43. The process of embodiment 41 or 42, wherein the hydrohalic acid is hydrochloric acid. 44. The process of embodiment 41 or 42, wherein the hydrohalic acid is hydrobromic acid. 45. A compound of formula (IV):

prepared by a process consisting essentially of the steps of: (i) contacting a compound of formula (IV-D):

with 1,2-dibromoethane in the presence of a base to afford a compound of formula (IV-C):

(ii) contacting the compound of formula (IV-C) with a brominating reagent to afford a compound of formula (IV-B):

(iii) contacting the compound of formula (IV-B) with a Grignard reagent, C₁-C₆ alkyl lithium, and sulfuryl chloride to afford a compound of formula (IV-A):

(iv) contacting the compound of formula (IV-A) with ammonia to obtain the compound of formula (IV). 46. The compound of embodiment 45, wherein step (iii) further comprises the steps of: contacting the compound of formula (IV-B) with a Grignard reagent to afford a first metalated intermediate compound (IV-B1); contacting the first metalated intermediate (IV-B₁) compound with C₁-C₆ alkyl lithium (e.g. butyl lithium, n-butyl lithium or hexyl lithium) to afford a second metalated intermediate compound (IV-B₂); and contacting the second metalated intermediate compound (IV-B2) with sulfuryl chloride to afford the compound of formula (IV-A). 47. The compound of embodiment 45 or 46, wherein the base is K₂CO₃. 48. The compound of any one of embodiments 45 to 47, wherein the brominating reagent is N-bromosuccinimide. 49. The compound of any one of embodiments 45 to 48, wherein the Grignard reagent is isopropyl magnesium chloride. 50. The compound of any one of embodiments 45 to 49, wherein the C₁-C₆ alkyl lithium is butyl lithium, e.g. n-butyl lithium. 51. A compound of formula (IV):

prepared by a process consisting essentially of the steps of: (i) contacting a compound of formula (IV-F):

with bromine, a hydrohalic acid, and sulfamic acid to afford a compound of formula (IV-E):

(ii) contacting the compound of formula (IV-E) with 1,2-dibromoethane in the presence of a base to afford a compound of formula (IV-B):

(iv) contacting the compound of formula (IV-A) with ammonia to obtain the compound of formula (IV). 52. The compound of embodiment 51, wherein step (i) further comprises the steps of: contacting the compound of formula (IV-F) with a first portion of bromine to afford a first intermediate compound (IV-F₁); contacting the first intermediate compound (IV-F₁) with a hydrohalic acid to afford a second intermediate compound (IV-F2); contacting the second intermediate compound (IV-F₂) with a second portion of bromine to afford a third intermediate compound (IV-F₃); and contacting the third intermediate compound (IV-F3) with sulfamic acid to afford the compound of formula (IV-E). 53. The compound of embodiment 51 or 52, wherein step (iii) further comprises the steps of: contacting the compound of formula (IV-B) with a Grignard reagent to afford a first metalated intermediate compound (IV-B₁); contacting the first metalated intermediate (IV-B₁) compound with C₁-C₆ alkyl lithium (e.g. butyl lithium, n-butyl lithium or hexyl lithium) to afford a second metalated intermediate compound (IV-B₂); and contacting the second metalated intermediate compound (IV-B2) with sulfuryl chloride to afford the compound of formula (IV-A). 54. The compound of any one of embodiments 51 to 53, wherein the hydrohalic acid is hydrochloric acid. 55. The compound of any one of embodiments 51 or 53, wherein the hydrohalic acid is hydrobromic acid. 56. The compound of any one of embodiments 51 to 55, wherein the base is K₂CO₃. 57. The compound of any one of embodiments 51 to 56, wherein the Grignard reagent is isopropyl magnesium chloride. 58. The compound of any one of embodiments 51 to 57, wherein the C₁-C₆ alkyl lithium is butyl lithium, e.g. n-butyl lithium. 59. A process for preparing a compound of formula (V):

Comprising contacting a compound of formula (III):

with a compound of formula (IV):

to afford the compound of formula (V), wherein R₁ is a protecting group. 60. The process of embodiment 59, wherein contacting a compound of formula (III) with a compound of formula (IV) is performed in the presence of a base. 61. The process of embodiment 60, wherein the base is Cs₂CO₃ or K₂CO₃. 62. The process of any one of embodiments 59 to 61, wherein R1 is –C(O)(C₁-C₆ alkyl), –C(O)(C₁-C₆ haloalkyl), –C(O)(C₁-C₆ alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)₂(tolyl). 63. The process of any one of embodiments 59 to 62, wherein R1 is –C(O)(C₁-C₆ alkoxy). 64. The process of any one of embodiments 59 to 63, wherein R1 is –C(O)OCH3. 65. A compound of formula (V-A):

or a salt thereof. 66. A compound of formula (V-A): (V-A), or a salt thereof, prepared by a process consisting essentially of contacting methyl 3,4- bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate:

(III-A) with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide:

in the presence of a base. 67. The compound of embodiment 66, wherein the base is Cs₂CO₃ or K₂CO₃. 68. A process for preparing a compound of formula (I):

Comprising contacting a compound of formula (III): with a compound of formula (IV):

to afford a compound of formula (V):

transforming the compound of formula (V) to the compound of formula (I), wherein R₁ is a protecting group. 69. The process of embodiment 68, wherein contacting a compound of formula (III) with a compound of formula (IV) is performed in the presence of a first base. 70. The process of embodiment 69, wherein the first base is Cs₂CO₃ or K₂CO₃. 71. The process of any one of embodiments 68 to 70, wherein transforming the compound of formula (V) to the compound of formula (I) comprises: deprotecting the compound of formula (V) to afford a compound of formula (VI):

or a salt thereof. 72. The process of embodiment 71, wherein deprotecting the compound of formula (V) to afford the compound of formula (VI) comprises contacting the compound of formula (V) with a first acid. 73. The process of embodiment 72, wherein: the first acid comprises HBr and acetic acid; or the first acid comprises dibutylsulfane, trifluoroacetic acid and methanesulfonic acid; or the first acid comprises dibutylsulfane and methanesulfonic acid. 74. The process of any one of embodiments 68 to 73, wherein transforming the compound of formula (V) to the compound of formula (I) further comprises: coupling the compound of formula (VI) with a compound of formula (VII):

to afford the compound of formula (I). 75. The process of embodiment 74, wherein coupling the compound of formula (VI) with a compound of formula (VII) is performed in the presence of a coupling reagent. 76. The process of embodiment 74 or 75, wherein the coupling reagent comprises EDC. 77. The process of embodiment 75 or 76, wherein coupling the compound of formula (VI) with a compound of formula (VII) is further performed in the presence of an additive. 78. The process of embodiment 77, wherein the additive is ethyl (hydroxyimino)cyanoacetate or 2-hydroxypyridine-N-oxide. 79. The process of any one of embodiments 68 to 78, wherein R1 is –C(O)(C₁-C₆ alkyl), –C(O)(C₁-C₆ haloalkyl), –C(O)(C₁-C₆ alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)₂(tolyl). 80. The process of any one of embodiments 68 to 79, wherein R₁ is –C(O)(C₁-C₆ alkoxy). 81. The process of any one of embodiments 68 to 80, wherein R1 is –C(O)OCH3. 82. The process of any one of embodiments 68 to 79, wherein R₁ is –C(O)(C₁-C₆ alkoxy) and the compound of formula (III) is obtained by a step (i): (i) transforming a compound of formula (III-B): (III-B) to the compound of formula (III). 83. The process of embodiment 82, wherein transforming the compound of formula (III-B) to the compound of formula (III) comprises contacting the compound of formula (III-B) with ClC(O)(C₁-C₆ alkoxy). 84. The process of embodiment 82, wherein R1 is –C(O)OCH3. 85. The process of embodiment 84, wherein transforming the compound of formula (III-B) to the compound of formula (I) comprises contacting the compound of formula (III-B) with methyl chloroformate. 86. The process of any one of embodiments 82 to 85, wherein the compound of formula (III- B) is obtained by a step (ii): (ii) contacting a compound of formula (III-C) with a compound of formula (III-D):

to afford the compound of formula (III-B), wherein: R₅ and R₆ are each, independently, halo or –OSO₂R₇; each R7 is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or C6-C10 aryl, where the C6-C10 aryl is optionally substituted with 1 to 3 R8; and each R₈ is independently halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. 87. The process of embodiment 86, wherein R5 and R6 are each halo. 88. The process of embodiment 87, wherein R₅ and R₆ are each chloro. 89. The process of any one of embodiments 86 to 88, wherein contacting a compound of formula (III-C) with a compound of formula (III-D) is performed in the presence of a second acid. 90. The process of embodiment 89, wherein the second acid is trifluoroacetic acid. 91. The process of any one of embodiments 86 to 88, wherein contacting a compound of formula (III-C) with a compound of formula (III-D) is performed in the presence of trimethylsilyl trifluoromethanesulfonate. 92. The process of any one of embodiments 86 to 88, wherein contacting a compound of formula (III-C) with a compound of formula (III-D) is performed in the presence of trimethylsilyl trifluoromethanesulfonate and CsF. 93. The process of any one of embodiments 86 to 88, wherein contacting a compound of formula (III-C) with a compound of formula (III-D) is performed in the presence of trimethylsilyl iodide. 94. The process of any one of embodiments 86 to 88, wherein contacting a compound of formula (III-C) with a compound of formula (III-D) is performed in the presence of trimethylsilyl iodide and an additive selected from CsF, LiF, ZnCl₂, and combinations thereof. 95. The process of any one of embodiments 68 to 94, wherein the compound of formula (IV) is obtained by contacting a compound of formula (IV-A):

with ammonia to obtain the compound of formula (IV). 96. The process of embodiment 95, wherein the compound of formula (IV-A) is obtained by: transforming a compound of formula (IV-B):

to the compound of formula (IV-A). 97. The process of embodiment 96, wherein transforming the compound of formula (IV-B) to the compound of formula (IV-A) comprises contacting the compound of formula (IV-B) with a Grignard reagent, C₁-C₆ alkyl lithium, and sulfuryl chloride. 98. The process of embodiment 96 or 97, wherein transforming the compound of formula (IV-B) to the compound of formula (IV-A) comprises the steps of: contacting the compound of formula (IV-B) with a Grignard reagent to afford a first metalated intermediate compound (IV-B1); contacting the first metalated intermediate (IV-B1) compound with C₁-C₆ alkyl lithium (e.g. butyl lithium, n-butyl lithium or hexyl lithium) to afford a second metalated intermediate compound (IV-B2); and contacting the second metalated intermediate compound (IV-B₂) with sulfuryl chloride to afford the compound of formula (IV-A). 99. The process of embodiment 97 or 98, wherein the Grignard reagent is isopropyl magnesium chloride. 100. The process of any one of embodiments 97 to 99, wherein the C₁-C₆ alkyl lithium is butyl lithium, e.g. n-butyl lithium. 101. The process of any one of embodiments 96 to 100, wherein the compound of formula (IV-B) is obtained by transforming a compound of formula (IV-C):

to the compound of formula (IV-B). 102. The process of embodiment 101, wherein transforming the compound of formula (IV-C) to the compound of formula (IV-C) comprises contacting the compound of formula (IV-C) with a brominating reagent. 103. The process of embodiment 102, wherein the brominating reagent is N- bromosuccinimide. 104. The process of any one of embodiments 101 to 103, wherein the compound of formula (IV-C) is obtained by contacting a compound of formula (IV-D):

with 1,2-dibromoethane to afford the compound of formula (IV-C). 105. The process of embodiment 104, wherein contacting the compound of formula (IV-D) with 1,2-dibromoethane is performed in the presence of a second base. 106. The process of embodiment 105, wherein the second base is K₂CO₃. 107. The process of any one of embodiments 96 to 100, wherein the compound of formula (IV-B) is obtained by contacting a compound of formula (IV-E):

with 1,2-dibromoethane to afford the compound of formula (IV-B). 108. The process of embodiment 107, wherein contacting a compound of formula (IV-E) with 1,2-dibromoethane is performed in the presence of a second base. 109. The process of embodiment 108, wherein the second base is K₂CO₃. 110. The process of any one of embodiments 107 to 109, wherein the compound of formula (IV-E) is obtained by transforming a compound of formula (IV-F):

to the compound of formula (IV-E). 111. The process of embodiment 110, wherein transforming a compound of formula (IV-F) to the compound of formula (IV-E) comprises contacting the compound of formula (IV-F) with bromine, a hydrohalic acid, and sulfamic acid. 112. The process of embodiment 110 or 111, wherein transforming a compound of formula (IV-F) to the compound of formula (IV-E) comprises the steps of: contacting the compound of formula (IV-F) with a first portion of bromine to afford a first intermediate compound (IV-F1); contacting the first intermediate compound (IV-F1) with a hydrohalic acid to afford a second intermediate compound (IV-F₂); contacting the second intermediate compound (IV-F2) with a second portion of bromine to afford a third intermediate compound (IV-F3); and contacting the third intermediate compound (IV-F₃) with sulfamic acid to afford the compound of formula (IV-E). 113. The process of embodiment 111 or 112, wherein the hydrohalic acid is hydrochloric acid. 114. The process of embodiment 111 or 112, wherein the hydrohalic acid is hydrobromic acid. 115. The process of any one of embodiments 74 to 114, wherein the compound of formula (VII) is obtained by transforming a compound of formula (VII-A):

to the compound of formula (VII). 116. The process of embodiment 115, wherein transforming the compound of formula (VII-A) to the compound of formula (VII) comprises contacting the compound of formula (VII-A) with a third base. 117. The process of embodiment 116, wherein the third base is NaOH. 118. The process of embodiment 115, wherein transforming the compound of formula (VII-A) to the compound of formula (VII) comprises contacting the compound of formula (VII-A) with an enzyme. 119. The process of embodiment 118, wherein the enzyme is a lipase. 120. The process of embodiment 119, wherein the lipase is CALB. 121. The process of any one of embodiments 115 to 120, wherein the compound of formula (VII-A) is obtained by transforming a compound of formula (VII-B):

to the compound of formula (VII-A). 122. The process of embodiment 121, wherein transforming the compound of formula (VII-B) to the compound of formula (VII-A) comprises contacting the compound of formula (VII-B) with a reducing agent. 123. The process of embodiment 122, wherein the compound of formula (VII-B) is contacted with a reducing agent in the presence of an enzyme. 124. The process of embodiment 123, wherein the enzyme is carbonyl reductase (CRED). 125. The process of any one of embodiments 121 to 124, wherein the compound of formula (VII-B) is obtained by contacting a compound of formula (VII-C):

with methyl formate to afford the compound of formula (VII-B). 126. The process of embodiment 125, wherein contacting a compound of formula (VII-C) with methyl formate is performed in the presence of a fourth base. 127. The process of embodiment 126, wherein the fourth base is sodium tert-butoxide or sodium methoxide. 128. A composition comprising a compound of formula (III):

or a salt thereof, wherein R1 is a protecting group. 129. The composition of embodiment 128, further comprising a compound of formula (IV):

or a salt thereof. 130. The composition of embodiments 128 or 129, further comprising a base. 131. The composition of embodiment 130, wherein the base is Cs₂CO₃ or K₂CO₃. 132. The composition of any one of embodiments 128 to 131, further comprising a compound of formula (V):

or a salt thereof. 133. The composition of any one of embodiments 128 to 132, wherein R₁ is –C(O)(C₁-C₆ alkyl), –C(O)(C₁-C₆ haloalkyl), –C(O)(C₁-C₆ alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)₂(tolyl). 134. The composition of any one of embodiments 128 to 133, wherein R₁ is –C(O)(C₁-C₆ alkoxy). 135. The composition of any one of embodiments 128 to 134, wherein the compound of formula (III) is:

methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate. 136. The composition of any one of embodiments 132 to 135, wherein the compound of formula (V) is:

methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate. List of additional particular embodiments: [0107] The following are alternative non-limiting embodiments of the invention: 1. A process for preparing a compound according to formula (III-Y):

(III-Y) comprising reacting an azomethine precursor according to formula (III-W) with an electron-poor alkyne according to formula (III-X) according to Step 1^A1 Scheme A1, wherein Step 1^A1 is performed in the presence of an acid:

Scheme A1 wherein R12 is -CR2R3-(C6-C10 aryl), where the C6-C10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C₁-C₆ alkyl; and R4 is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or -OSO2R7, wherein each R7 is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or C₆-C₁₀ aryl, where C₆-C₁₀ aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R9 is a suitable silyl protecting group selected from the group consisting of trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), or dimethylisopropylsilyl (DMIPS); and R10 is C₁-C₆ alkyl. 2. The process according to embodiment 1, wherein R12 is -CH2Ph (benzyl) or 4- methoxybenzyl. 3. The process according to any of the preceding embodiments, wherein R12 is benzyl. 4. The process according to any of the preceding embodiments comprising reacting an azomethine precursor according to formula (III-W1) with an electron-poor alkyne according to formula (III-X) according to Step 1^A1’ Scheme A1’, wherein Step 1^A1’ is performed in the presence of an acid: Scheme A1’

wherein R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or -OSO₂R7, wherein each R7 is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁- C6 haloalkoxy, or C6-C10 aryl, where C6-C10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R9 is a suitable silyl protecting group selected from the group consisting of trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), or dimethylisopropylsilyl (DMIPS); and R10 is C₁-C₆ alkyl. 5. The process according to any of the preceding embodiments, wherein R9 is trimethylsilyl (TMS). 6. The process according to any of the preceding embodiments, wherein R10 is straight chain C₁-C₆ alkyl selected from the group consisting of methyl, ethyl, 1-propyl, 1-butyl, 1-pentyl or 1-hexyl. 7. The process according to any of the preceding embodiments, wherein R10 is C₁-C₄ alkyl selected from the group consisting of methyl, ethyl, 1-propyl or 1-butyl. 8. The process according to any of the preceding embodiments, wherein R10 is methyl. 9. The process according to any of the preceding embodiments, wherein R5 and R6 are each halo. 10. The process according to any of the preceding embodiments, wherein R5 and R6 are each selected from chloro, bromo, or iodo. 11. The process according to any of the preceding embodiments wherein R5 and R6 are each chloro. 12. The process according to any of the preceding embodiment, wherein the compound of formula (III-Y) or (III-Y1) is carried over to a further reaction step without prior purification. 13. The process according to any one of embodiments 1-11 wherein the compound of formula (III-Y) or (III-Y1) is isolated as a salt. 14. The process according to any one of the preceding embodiments, wherein about 1 equivalent of the compound of formula (III-W) or (III-W1) is reacted with about 1.1-3 equivalents of the compound of formula (III-X). 15. The process according to embodiment 14, wherein about 1 equivalent of the compound of formula (III-W) or (III-W1) is reacted with about 1.5-2 equivalents of the compound of formula (III-X). 16. The process according to embodiment 14-15, wherein about 1 equivalent of the compound of formula (III-W) or (III-W1) is reacted with about 1.5 or about 2 equivalents of the compound of formula (III-X). 17. The process according to any of the preceding embodiments, wherein the acid is present in a substoichiometric amount of about 0.01-0.2 equivalents. 18. The process according to any of the preceding embodiments, wherein the acid is present in a substoichiometric amount of about 0.03-0.07 equivalents, e.g. about 0.05 equivalents. 19. The process according to any of the preceding embodiments, wherein the acid is selected from the group consisting of TFA, TMSOTf, TMSI, TMSOTf in combination with CsF, or TMSI in combination with any one of CsF, LiF, ZnCl2 or a combination thereof. 20. The process according to any one of the preceding embodiments, wherein the acid is TFA. 21. The process according to any one of the preceding embodiments, wherein the reaction of the compound of formula (III-W) or (III-W1) and the compound of formula (III-X) is performed in a nonpolar solvent, e.g. selected from the group consisting of toluene, DCM or a mixture thereof. 22. The process according to embodiment 21, wherein the nonpolar solvent is toluene. 23. The process according to any one of embodiments 21-22, wherein the compound of formula (III-X) is dissolved in the nonpolar solvent, e.g. toluene and the mixture cooled to a temperature of about -10^oC to 10^oC followed by addition of the acid, e.g. TFA. 24. The process according to any one of embodiments 21-23, wherein the compound of formula (III-X) is dissolved in the nonpolar solvent, e.g. toluene and the mixture cooled to a temperature of about -5^oC to 5^oC followed by addition of TFA. 25. The process according to any one of embodiments 23-24, wherein the compound of formula (III-W) or (III-W1) is subsequently added. 26. The process according to any one of embodiments 23-25, wherein the compound of formula (III-W) or (III-W1) is subsequently added maintaining a temperature of about -10^oC to 20^oC during the addition. 27. The process according to any of the preceding embodiments further comprising a Step 2^A2 transforming the compound of formula (III-Y) or (III-Y1) into a compound of formula (III- Z) according to Scheme A2: Scheme A2 R12 N R1 Step 2 ^A2 N R5 R5 R6 R6 (III-Y) (III-Z) wherein R1 is selected from the group consisting of C₁-C₆ alkoxycarbonyl (e.g. tert- butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e. Cbz), C₆-C₁₀ aryloxy (e.g. phenoxycarbonyl), C₁-C₆ alkylcarbonyl (e.g. acetyl), haloalkylcarbonyl (e.g. trifluoroacetyl), and -SO2-(C6-C10 aryl) (e.g. tosyl). 28. The process according to embodiment 27, wherein the compound of formula (III-Y) is the compound of formula (III-Y1). 29. The process according to any one of embodiments 27-28, wherein R1 is –C(O)(C₁-C₆ alkoxy). 30. The process according to any one of embodiments 27-29, wherein R1 is -C(O)OCH₃. 31. The process according to any one of embodiments 27-30, wherein Step2^A2 is performed by contacting a compound according to formula (III-Y) or (III-Y1) with R1-Cl. 32. The process according to any one of embodiments 27-31, wherein Step 2^A2 is performed by contacting the compound of formula (III-Y) or (III-Y1) with ClC(O)(C₁-C₆ alkoxy). 33. The process according to any one of embodiments 27-32, wherein Step 2^A2 is performed by contacting the compound of formula (III-Y) or (III-Y1) with methyl chloroformate. 34. The process according to any one of embodiments 27-33, wherein Step 2^A2 is performed in a second nonpolar solvent. 35. The process according to embodiment 34, wherein the second nonpolar solvent is selected from the group consisting of toluene, DCM, n-heptane or combination thereof. 36. The process according to any one of embodiments 34-35, wherein the second nonpolar solvent is toluene, n-heptane or a combination of toluene and n-heptane. 37. The process according to any one of embodiments 27-36, wherein step 2^A2 is performed by adding the reaction mixture from step 1^A1 or step 1^A1’ comprising the compound of formula (III-Y) or (III-Y1) to a mixture of R1-Cl in n-heptane at a temperature of -20^oC to -5^oC while maintaining the temperature during the addition. 38. The process according to embodiment 37, wherein R1-Cl is ClC(O)(C₁-C₆ alkoxy), e.g. methyl chloroformate. 39. The process according to any one of embodiments 27-38, wherein step 2^A2 is performed by adding R1-Cl to the reaction mixture from step 1^A1 or step 1^A1’ comprising the compound of formula (III-Y) or (III-Y1) at a temperature of -10^oC to 0^oC while maintaining the temperature during the addition. 40. The process according to any one of embodiments 37-39, wherein R1-Cl is ClC(O)(C₁-C₆ alkoxy), e.g. methyl chloroformate. 41. The process according to any of the preceding embodiments, wherein the compound of formula (III-W) is a compound of formula (III-D):

(III-D) 42. The process according to any of the preceding embodiments, wherein the compound of formula (III-X) is a compound of formula (III-C):

(III-C) 43. The process according to any of the preceding embodiments, wherein the compound of formula (III-Y) or (III-Y1) is a compound of formula (III-B): (III-B) 44. The process according to any of the preceding embodiments, wherein the compound of formula (III-Z) is a compound of formula (III-A):

45. The process according to any one of embodiments 27-44 further comprising a Step 3^A3 reacting the compound of formula (III-Z) with a compound of formula (IV-Y) into a compound of formula (V-Z) according to Scheme A3: Scheme A3

(IV-Y) (III-Z) (V-Z) wherein R11 is C₆-C₁₀ aryl, 6-10 membered heteroaryl comprising 1-3 O, N, S, wherein aryl and heteroaryl are each optionally substituted with one or more substituents selected from -R13 and - OR13; each R13 is independently -H, -C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, -F, -Cl, -Br, -I, -CN, -NO2; or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring; wherein the reaction is performed in the presence of a base. 46. The process according to embodiment 45, wherein R11 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl. 47. The process according to any one of embodiment 45-46, wherein R11 is 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-7-yl. 48. The process according to any one of embodiments 45-47, wherein the base is selected from the group selected from the group consisting of Cs₂CO₃ and K₂CO₃. 49. The process according to any one of embodiments 45-48, wherein the base is K₂CO₃. 50. The process according to any one of embodiments 45-49, wherein the reaction according to scheme A3 is performed in a suitable solvent selected from the group consisting of DMSO, toluene or a mixture thereof. 51. The process according to any one of embodiments 45-50, wherein about 1 equivalent of the compound to formula (IV-Y) and about 1-2 equivalents of the base is mixed in DMSO and heated to a temperature about 75-110^oC followed by addition of about 1 equivalent the compound according to formula (III-Z) in toluene, DMSO or a mixture thereof. 52. The process according to embodiment 51, wherein the mixture of the compound of formula (IV-Y) and the base in DMSO is heated to a temperature of about 85-100^oC. 53. The process according to any one of embodiments 51-52, wherein the mixture of the compound of formula (IV-Y) and base in DMSO is heated to a temperature of about 100^oC. 54. The process according to any one of embodiments 45-53, wherein the compound of formula (III-Z) is in toluene. 55. The process according to any one of embodiments 45-53, wherein the compound of formula (III-Z) is in DMSO. 56. The process according to any one of embodiments 45-55, wherein the compound of formula (IV-Y) is a compound according to Formula (IV) or a compound of formula (VIII-A): (IV) (VIII-A) 57. A process for preparing a compound of formula (V-Z) comprising the steps of: a. reacting an azomethine precursor of formula (III-W) with an electron-poor alkyne of formula (III-X) according to Scheme A1, wherein the reaction is performed in the presence of an acid and in a first non-polar solvent: Scheme A1

, wherein R12 is -CR2R3-(C₆-C₁₀ aryl), where the C₆-C₁₀ aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C₁-C₆ alkyl; and R4 is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or -OSO2R7, wherein each R7 is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or C₆-C₁₀ aryl, where C₆-C₁₀ aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R9 is a suitable silyl protecting group selected from the group consisting of trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), or dimethylisopropylsilyl (DMIPS); and R10 is C₁-C₆ alkyl; b. transforming the compound of formula (III-Y) into a compound of formula (III-Z) according to Scheme A2 by reacting with R1-Cl in a second non-polar solvent: Scheme A2

(^{III-Y) (III-Z)} , wherein R1 is selected from the group consisting of C₁-C₆ alkoxycarbonyl (e.g. tert-butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e. Cbz), C6-C10 aryloxy (e.g. phenoxycarbonyl), C₁-C₆ alkylcarbonyl (e.g. acetyl), haloalkylcarbonyl (e.g. trifluoroacetyl), and -SO₂-(C₆-C₁₀ aryl) (e.g. tosyl); c. reacting the compound of formula (III-Z) with a compound of formula (IV-Y) according to Scheme A3 in the presence of a base in a suitable solvent into form compound (V-Z): Scheme A3

, wherein R11 is C6-C10 aryl, 6-10 membered heteroaryl comprising 1-3 O, N, S, wherein aryl and heteroaryl are each optionally substituted with one or more substituents selected from -R13 and - OR13; each R13 is independently -H, -C₁-C₆ alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, -F, -Cl, -Br, -I, -CN, -NO2; or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring. 58. The process according to embodiment 57, wherein R12 is benzyl. 59. The process according to any of embodiments 57-58, wherein R10 is methyl. 60. The process according to any of embodiments 57-59, wherein R9 is trimethylsilyl. 61. The process according to any of embodiments 57-60, wherein R5 and R6 are each chloro. 62. The process according to any of embodiments 57-61, wherein the first polar solvent is selected from DCM, toluene, or a mixture thereof. 63. The process according to any of embodiments 57-62, wherein the acid is TFA. 64. The process according to any of embodiments 57-63, wherein R1-Cl is ClC(O)(C₁-C₆ alkoxy). 65. The process according to any of embodiments 57-64, wherein R1-Cl is methyl chloroformate. 66. The process according to any of embodiments 57-65, wherein the second non-polar solvent is n-heptane, DCM, toluene, or a mixture thereof. 67. The process according to any of embodiments 57-66, wherein the compound of formula (IV-Y) is a compound of formula (IV) or (VIII-A):

(IV) (VIII-A) 68. The process according to any of embodiments 57-67, wherein the suitable solvent is selected from the group consisting of DMSO, toluene or a mixture thereof. 69. The process according to any of embodiments 57-68, wherein the base is K2CO3. 70. A compound of formula (III-Y) or a salt thereof:

(III-Y) wherein R12 is -CR2R3-(C₆-C₁₀ aryl), where the C₆-C₁₀ aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C₁-C₆ alkyl; and R4 is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or -OSO2R7, wherein each R7 is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or C₆-C₁₀ aryl, where C₆-C₁₀ aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. 71. The compound according to embodiment 70, wherein the compound is of formula (III- Y2) or a salt thereof:

, (III-Y2) wherein R12 is -CR2R3-(C6-C10 aryl), where the C6-C10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C₁-C₆ alkyl; and R4 is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. 72. The compound according to any one of embodiments 70-71, wherein R12 is benzyl, i.e. a compound of formula (III-B): (III-B) (1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate). 73. A compound of formula (III) or a salt thereof:

wherein R1 is -C(O)(C₁-C₆ alkyl), -C(O)(C₁-C₆ haloalkyl), -C(O)(C₁-C₆alkoxy), -C(O)(benzyloxy), -C(O)(ph enoxy), or –S(O)2(tolyl). 74. The compound according to embodiment 73, wherein R1 is –C(O)(C₁-C₆ alkoxy). 75. The compound according to any of embodiments 73-74, wherein the compound is of formula (III-A):

(III-A) (methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate), or a salt thereof. 76. A compound of formula (V-Z):

(V-Z) wherein R1 is –C(O)(C₁-C₆ alkyl), –C(O)(C₁-C₆ haloalkyl), –C(O)(C₁- C₆alkoxy), -C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)₂(tolyl); and R11 is R11 is C6-C10 aryl, 6-10 membered heteroaryl comprising 1-3 O, N, S, wherein aryl and heteroaryl are each optionally substituted with one or more substituents selected from -R13 and - OR13; each R13 is independently -H, -C₁-C₆ alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, -F, -Cl, -Br, -I, -CN, -NO2; or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring. 77. The compound according to embodiment 076, wherein the compound is of formula (V):

wherein R1 is –C(O)(C₁-C₆ alkyl). 78. The compound according to any one of embodiments 76-77, wherein the compound is of formula (V-A):

79. The compound according to embodiment 076, wherein the compound is formula (VIII):

wherein R1 is –C(O)(C₁-C₆ alkyl). 80. The compound according to any one of embodiments 76 or 790, wherein the compound is of formula (VIII-B):

(VIII-B) 81. Use of a compound according to any one of embodiments 70-80 for preparing a compound according to formula (I) or (II). 82. A process for preparing a compound according to formula (I):

comprising the steps of: a. reacting a compound of formula (III-D) with a compound of formula (III-C) according to Scheme B1’ Step 1^B1’ in the presence of a first acid and in a first non-polar solvent to afford the compound of formula (III-B): Scheme B1’

b. transforming the compound of formula (III-B) into a compound of formula (III) according to Scheme B1’ Step 2^B1’ by reacting with R1-Cl in a second non-polar solvent wherein R1 is -C(O)C₁-C₆ alkoxy (e.g. methoxycarbonyl); c. reacting the compound of formula (III), wherein R1 is C₁-C₆ alkoxycarbonyl (e.g. methoxycarbonyl) with a compound of formula (IV) according to Scheme G1 in the presence of a first base and in a suitable solvent to form compound (V): Scheme G1

; d. deprotecting the compound of formula (V) wherein R1 is C₁-C₆ alkoxycarbonyl (e.g. methoxycarbonyl) with a second acid followed by neutralization with a second base to afford the compound of formula (VI) or forming a salt of the compound of formula (VI) and (VII) by addition of compound (VII):

Scheme G2

; e. performing a coupling reaction of the compound of formula (VI) and a compound of formula (VII) according to Scheme G3 or performing a coupling reaction from the salt of formula (VI) ^(VII) according to Scheme G3’ using a coupling reagent and an additive in a second suitable solvent to afford the compound of formula (I): Scheme G3

Scheme G3’

83. The process according to embodiment 82, wherein the compound of formula (III-D) in step a. is the rate limiting reagent. 84. The process according to any one of embodiments 82-83, wherein about 1.5-2.0 equivalents of the compound of formula (III-C) is reacted with about 1 equivalent of the compound of formula (III-D) in step a. 85. The process according to any one of embodiments 82-84, wherein in step a. the compound of formula (III-C) is mixed with the first non-polar solvent and cooled to about -5 to 5^oC and the first acid added followed by addition of the compound of formula (III-D) in the first non-polar solvent while maintaining the temperature. 86. The process according to any one of embodiments 82-85, wherein the first acid is TFA. 87. The process according to any one of embodiments 82-86, wherein the first acid is TFA and about 0.05 equivalents are used. 88. The process according to any one of embodiments 82-87, wherein the first non-polar solvent is toluene. 89. The process according to any one of embodiments 82-88, wherein the reaction mixture from step a. is used without further purification in the next step b. 90. The process according to any one of embodiments 82-89, wherein the second non-polar solvent is toluene or a mixture of toluene and n-heptane. 91. The process according to any one of embodiments 82-90, wherein R1-Cl is mixed with n--heptane prior to addition of the reaction mixture from step a comprising the compound of formula (III-B). 92. The process according to any one of embodiments 82-91, wherein step b. is performed at a temperature of about -15^oC to about -5^oC. 93. The process according to any one of embodiments 82-92, wherein R1-Cl added to the reaction mixture from step a. at a temperature of about -15^oC to about -5^oC. 94. The process according to any one of embodiments 82-93, wherein R1-Cl is methyl chloroformate. 95. The process according to any one of embodiments 82-94, wherein in step c. the first base is K2CO3. 96. The process according to any one of embodiments 82-95, wherein in step c. about 1.1 equivalents of the first base is used. 97. The process according to any one of embodiments 82-96, wherein the suitable solvent in step c. is DMSO, toluene or a mixture thereof. 98. The process according to any one of embodiments 82-97, wherein the suitable solvent in step c. is a mixture of DMSO and toluene. 99. The process according to any one of embodiments 82-98, wherein in step c. the compound of formula (IV), the first base and the suitable solvent are mixed and heated to about 100^oC prior to addition of the compound of formula (III) in the suitable solvent. 100. The process according to any one of embodiments 82-99, wherein in step c. the compound of formula (IV), K₂CO₃ and DMSO are mixed and heated to about 100^oC prior to addition of the compound of formula (III) in toluene. 101. The process according to any one of embodiments 82-100, wherein in step c. the compound of formula (III) is the compound of formula (III-A). 102. The process according to any one of embodiments 82-101, wherein the suitable solvent in step c. is DMSO, toluene or a mixture thereof. 103. The process according to any one of embodiments 82-102, wherein in step d. the compound of formula V is a compound of formula (V-A). 104. The process according to any one of embodiments 82-103, wherein in step d. the second acid is a mixture of Bu₂S and MSA. 105. The process according to any one of embodiments 82-104, wherein in step d. the mixture of the compound of formula (V) and the second acid is heated to about 70^oC. 106. The process according to any one of embodiments 82-105, wherein in step d. the second base is aqueous NH₄OH. 107. The process according to any one of embodiments 82-106, wherein in step d. when a salt of the compound for formula (VI) and (VII) is formed about 1 equivalent of (VI) and about 1 equivalent of (VII) is mixed in DCM or MeCN. 108. The process according to any one of embodiments 82-107, wherein in step e. the reaction is performed using the salt of (VI) ^(VII) according to Scheme G3’. 109. The process according to any one of embodiments 82-108, wherein in step e. the coupling reagent selected from the group consisting of EDC, DCC, propylphosphonic anhydride (T3P^®), and HATU. 110. The process according to any one of embodiments 82-109, wherein in step e. the coupling reagent is EDC ^HCl. 111. The process according to any one of embodiments 82-110, wherein in step e. the additive is selected from the group consisting of ethyl (hydroxyamino)cyanoacetate (OxymaPure^®), HOBt, HOSu, HOPO. 112. The process according to any one of embodiments 82-111, wherein in step e. the additive is ethyl (hydroxyamino)cyanoacetate (OxymaPure^®) or HOPO. 113. The process according to any one of embodiments 82-112, wherein in step e. the coupling reagent is EDC ^HCl and the additive is ethyl (hydroxyamino)cyanoacetate (OxymaPure^®). 114. The process according to any one of embodiments 82-112, wherein in step e. the coupling reagent is EDC ^HCl and the additive is HOPO. 115. The process according to any one of embodiments 82-114, wherein in step e. the second suitable solvent is selected from the group of DMAc, 2-MeTHF, EtOH or a combination thereof. 116. The process according to any one of embodiments 82-115, wherein in step e. the second suitable solvent is a combination of DMAc and EtOH. 117. The process according to any one of embodiments 82-116, wherein in step e. the second suitable solvent is a combination of DMAc, EtOH and 2-MeTHF. 118. A compound of formula (VI) ^(VII):

. 119. Use of the compound according to embodiment 118 for preparing Etavopivat (I). 120. A process for preparing a compound according to formula (II):

comprising the steps of: a. reacting a compound of formula (III-D) with a compound of formula (III-C) according to Scheme B1’ Step 1^B1’ in the presence of a first acid in a first non-polar solvent: Scheme B1’

; b. transforming the compound of formula (III-B) into a compound of formula (III) according to Scheme B1’ Step 2^B1’ by reacting with R1-Cl in a second non-polar solvent wherein R1 is -C(O)C₁-C₆ alkoxy (e.g. methoxycarbonyl); c. reacting the compound of formula (III), wherein R1 is C₁-C₆ alkoxycarbonyl (e.g. methoxycarbonyl) with a compound of formula (VIII-A) according to Scheme H1 in the presence of a first base in a suitable solvent to form the compound of formula (VIII): Scheme H1

; d. Deprotecting the compound of formula (VIII) wherein R1 is C₁-C₆ alkoxycarbonyl (e.g. methoxycarbonyl) with a fourth base or a third acid to afford the compound of formula (IX) or a salt thereof:

; e. performing a coupling reaction of the compound of formula (IX) or a salt thereof with a compound of formula (XI) according to Scheme G4 using a coupling reagent and an additive in a third suitable solvent to afford the compound of formula (II): Scheme G4

. 121. The process according to embodiment 120, wherein the compound of formula (III-D) in step a. is the rate limiting reagent. 122. The process according to any one of embodiments 120-121, wherein about 1.5-2.0 equivalents of the compound of formula (III-C) is reacted with about 1 equivalent of the compound of formula (III-D) in step a. 123. The process according to any one of embodiments 120-122, wherein in step a. the compound of formula (III-C) is mixed with the first non-polar solvent and cooled to about -5 to 5^oC and the first acid added followed by addition of the compound of formula (III-D) in the first non-polar solvent while maintaining the temperature. 124. The process according to any one of embodiments 120-123, wherein the first acid is TFA. 125. The process according to any one of embodiments 120-124, wherein the first acid is TFA and about 0.05 equivalents are used. 126. The process according to any one of embodiments 120-125, wherein the first non-polar solvent is toluene. 127. The process according to any one of embodiments 120-126, wherein the reaction mixture from step a. is used without further purification in the next step b. 128. The process according to any one of embodiments 120-127, wherein the second non- polar solvent is toluene or a mixture of toluene and n-heptane. 129. The process according to any one of embodiments 120-128, wherein R1-Cl is mixed with n-heptane prior to addition of the reaction mixture from step a comprising the compound of formula (III-B). 130. The process according to any one of embodiments 120-129, wherein step b. is performed at a temperature of about -15^oC to about -5^oC. 131. The process according to any one of embodiments 120-130, wherein R1-Cl added to the reaction mixture from step a. at a temperature of about -15^oC to about -5^oC. 132. The process according to any one of embodiments 120-131, wherein R1-Cl is methyl chloroformate. 133. The process according to any one of embodiments 120-132, wherein in step c. the first base is K2CO3. 134. The process according to any one of embodiments 120-133, wherein in step c. about 1.1 equivalents of the first base is used. 135. The process according to any one of embodiments 120-134, wherein the suitable solvent in step c. is DMSO, toluene or a mixture thereof. 136. The process according to any one of embodiments 120-135, wherein the suitable solvent in step c. is DMSO. 137. The process according to any one of embodiments 120-136, wherein in step c. the compound of formula (VIII-A), the first base and the suitable solvent are mixed and heated to about 80-100^oC prior to addition of the compound of formula (III) in the suitable solvent. 138. The process according to any one of embodiments 120-137, wherein in step c. the compound of formula (VIII-A), K2CO3 and DMSO are mixed and heated to about 80-100^oC prior to addition of the compound of formula (III) in DMSO. 139. The process according to any one of embodiments 120-138, wherein in step c. the compound of formula (III) is the compound of formula (III-A). 140. The process according to any one of embodiments 120-139, wherein the suitable solvent in step c. is DMSO. 141. The process according to any one of embodiments 120-140, wherein in step d. the compound of formula (VIII) is a compound of formula (VIII-B):

. 142. The process according to any one of embodiments 120-141, wherein in step d. the fourth base is KOH. 143. The process according to embodiment 142, wherein the fourth base is KOH and the reaction is performed in MeOH. 144. The process according to any one of embodiments 142-143, wherein about 3M KOH in MeOH is used. 145. The process according to any one of embodiments 142-144, wherein step d. is performed by heating e.g. by heating to reflux. 146. The process according to any one of embodiments 120-141, wherein in step d. the third acid is selected from the group consisting of a mixture of HBr/AcOH, a mixture of Bu2S/MSA and a mixture of Bu2S, TFA and MSA. 147. The process according to embodiment 146, wherein the third acid is a mixture of HBr and AcOH. 148. The process according to embodiment 147, wherein the dihydrobromide salt of compound (IX) is formed. 149. The process according to embodiment 148, wherein the dihydrobromide (X) is neutralized with base, such as NH4OH or NaOH to form the compound of formula (IX). 150. The process according to any one of embodiments 120-149, wherein in step e. the coupling reagent selected from the group consisting of EDC, DCC, propylphosphonic anhydride (T3P^®), and HATU. 151. The process according to any one of embodiments 120-150, wherein in step e. the coupling reagent is EDC or EDC ^HCl. 152. The process according to any one of embodiments 120-151, wherein in step e. the additive is selected from the group consisting of ethyl (hydroxyamino)cyanoacetate (OxymaPure^®), HOBt, HOSu, HOPO. 153. The process according to any one of embodiments 120-152, wherein in step e. the additive is HOBt. 154. The process according to any one of embodiments 120-153, wherein in step e. the coupling reagent is EDC and the additive is HOBt. 155. The process according to any one of embodiments 120-154, wherein in step e. the third suitable solvent DMSO. Examples [0108] The compounds described in the present application are prepared using the inventive methods described below in detail. Exemplified below are embodiments of the claimed process. The skilled artisan would appreciate other embodiments that fall within the claimed process may be practiced using the examples below with some modifications that are within the skills of the artisan. The intermediate compounds and any final product were analyzed using conventional analytical techniques. List of abbreviations: ¹H NMR proton nuclear magnetic resonance 2,3-DPG 2,3-diphosphoglyceric acid 2-MeTHF 2-methyltetrahydrofuran Bn Benzyl CALB/Cal B Candida Antarctica Lipase B CDCl3 Deuterated chloroform CRED Carbonyl reductase d chemical shift DCC Dicyclohexylcarbodiimide DCM Dichloromethane DMAc N,N-dimethylacetamide DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide DMSO-d6 Deuterated dimethyl sulfoxide EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Eq Equivalent(s) EtOAc Ethyl acetate EtOH Ethanol GC Gas chromatography GDH Glucose dehydrogenase h hour(s) HATU hexafluorophosphate azabenzotriazole tetramethyl uronium HOBt hydroxybenzotriazole HOPO 2-hydroxypyridine N-oxide HOSu N-hydroxysuccinimide HPLC High Performance Liquid Chromatography HCl Hydrochloric acid IPA Isopropyl alcohol iPr Isopropyl iPrAc Isopropyl acetate KF Karl Fischer LCMS Liquid chromatography/mass spectrometry LOD Loss on drying Me Methyl MeCN Acetonitrile MeOH Methanol MHz Megahertz Min minute(s) MSA Methanesulfonic acid MTBE Methyl tert-butyl ether NADP Nicotinamide Adenine Dinucleotide phosphate NBS N-bromosuccinimide n-BuLi n-Butyl Lithium NLT No less than NMH No more than NMMNTB N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine PKR Pyruvate Kinase R ppm parts per million QNMR Quantitative NMR RBC Red blood cell rt room temperature SFC supercritical fluid chromatography T3P® propylphosphonic anhydride TfO Triflate, trifluoromethanesulfonate TFA Trifluoroacetic acid THF Tetrahydrofuran TMS Trimethylsilyl UPLC ultra-performance liquid chromatography UPLCMS ultra-performance liquid chromatography/mass spectrometry vol volumes Example 1 Synthesis of methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A) and 1- benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole (III-B)

[0109] Step 1: 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole (III-B) [0110] A first reactor was charged with 1,4-dichloro-2-butyne (1.163 kg, 1.5 eq) and toluene (2.84 L, 1.9 vol) under a nitrogen atmosphere and the mixture was cooled to a temperature of - 5°C to 5°C. TFA (0.036 kg, 0.05 eq) was added to the reactor while maintaining a temperature of -5°C to 5°C. The loading line was rinsed with toluene (0.075 L, 0.05 vol) and the wash was added to the reactor. N-(methoxymethyl)-N-(trimethyl-silylmethyl) benzylamine (NMMNTB) (1.496 kg, 1.0 eq, 1.0 vol; limiting reagent) was added to the reactor in portions over 1-2 h while maintain a temperature of at -5°C to 10°C. The loading line was rinsed with toluene (0.075 L, 0.05 vol) and the wash was added to the reactor. The reaction mixture was then stirred at -7°C to 10°C for approximately 1 h. A 2 mL aliquot of the reaction mixture was removed and quenched with 4 mL of saturated ice-cold aqueous sodium bicarbonate and assessed by ¹H NMR to confirm the completion of Step 1 and the formation of 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H- pyrrole, i.e. intermediate compound (III-B). [0111] ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.34-7.14 (m, 5H), 4.27 (s, 4H), 3.80 (s, 2H), 3.59 (s, 4H) ppm. [0112] Step 2: methyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A) [0113] A second reactor was charged with n-heptane (1.35 L, 0.9 vol) followed by methyl chloroformate (0.834 kg, 1.4 eq). The loading line was rinsed with n-heptane (0.15 L, 0.1 vol) and the wash was added to the second reactor. The second reactor was then cooled to a temperature of -15°C to -10°C and the contents of the first reactor were charged into the second reactor over a period of 1-2 h, while maintaining a temperature of -15°C to -10°C. The loading line was rinsed with n-heptane (0.15 L, 0.1 vol) and the wash was added to the second reactor. The reaction mixture was stirred for approximately 40 min at a temperature of -15°C to -5°C. Reaction progress was monitored by HPLC analysis and stirring was continued until reaction completion. [0114] The second reactor was then charged with deionized water (3.0 L, 2 vol) while maintaining a reaction mixture temperature of <20°C during the addition. The reaction mixture was stirred at 10°C overnight. The second reactor was then charged with n-heptane (13.5 L, 9.0 vol) over a period of at least 1 h, leading to precipitation of the product. The reaction mixture was cooled to -5°C to 2°C over a period of at least 1 h and then stirred for at least 1 h while maintaining a temperature of -5°C to 2°C. The reaction mixture was then filtered to obtain the solid product, which was then rinse-washed with deionized water (6×3.9 L; 6×2.6 vol), with stirring for at least 15 min during each wash. The filter-cake was then rinse-washed with n- heptane (2×3.9 L; 2×2.6 vol), with stirring for at least 15 min during each wash. The filter-cake was then dried under vacuum at 40°C to afford methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H- pyrrole-1-carboxylate (III-A, 1.3 kg, 70% yield) as a white to pale pink/beige solid in >95% purity, as assessed by HPLC. [0115] ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 4.38 (m, 2H), 4.35 (m, 2H), 4.19 (s, 4H), 3.75 (s, 3H) ppm.

Example 2 Alternative Synthesis of methyl 3, 4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A) and 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole (III-B) Step 1: 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole (III-B)

[0116] 1,4-dichlorobut-2-yne (556 mL, 2.0 eq) and toluene (1.35 L, 2 vol) were charged into a 4 L reactor under nitrogen flow, and the solution was cooled to 0°C. TFA (10.9mL, 0.05 eq) was added at -2°C, and the mixture was stirred for 18 min. NMMNTB (750.0 g, 675.0 g pure, 1.0 eq) was then charged into the reactor at -3°C over 2 h and 39 min. An exothermic response was observed up to a maximum temperature of 14°C at the end of the addition. The mixture was stirred with cooling at -5-0°C. Conversion monitoring by

NMR after 1 h and 20 min showed 91.3% conversion to 1-benzyl-3,4-bis(chloromethyl)-2,5- dihydro-1H-pyrrole (III-B). The product was carried onto the next step without further purification. [0117] ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.34-7.14 (m, 5H), 4.27 (s, 4H), 3.80 (s, 2H), 3.59 (s, 4H) ppm. Step 2: methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A)

[0118] The product mixture from the first step was cooled to -8°C, and methyl chloroformate (208 mL, 1.4 eq) was added over 36 min. The reactor reached a maximum temperature of -3°C during the addition. The contact was continued at a temperature of -5°C. Product conversion monitoring by HPLC and ¹H NMR after 40 min showed 100% conversion to afford methyl 3,4- bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A). [0119] The reaction mixture was transferred into a 15 L reactor (cooled to a temperature of - 5°C) for the work-up. n-Heptane (675 mL, 1 vol) was added, followed by deionized water (1.35 L, 2 vol). An exothermic response up to a temperature of 10°C was observed and the mixture was warmed to a temperature of 15-20°C to facilitate phase separation. After decantation, three layers were observed: an upper organic layer (cloudy, yellowish), a middle aqueous layer (cloudy, white) and a bottom organic layer (dense, oily, orange). The bottom & middle layers were discarded, and the upper layer was washed first with deionized water (675 mL, 1 vol), then with saturated aqueous sodium bicarbonate (675 mL, 1 vol), and finally with brine (675 mL, 1 vol). After successively discarding the aqueous layers, the organic layer was cooled to 5°C and stored in the reactor overnight without stirring. No change of aspect was observed. [0120] The contents of the reactor were drained into a clean drum (Note: treatment of the solution with anhydrous sodium sulfate can be included at this stage to ensure no carry-over of aqueous layer in the isolation step) and the reactor was washed with deionized water (2 L) then with acetone (l L), and dried under vacuum. [0121] The resulting solution was filtered through fiberglass before being charged into the clean 15 L reactor. n-Heptane (6.1 L, 9 vol) was added at 18-20°C over 8 min, after which the mixture was cooled to -20°C over 1 h and 45 min. After stirring at -20°C for 1 h and 50 min, the resulting white suspension was filtered, washed with ice-cold n-heptane (2x1 L, 2x1.5 vol) and dried at 40°C under vacuum overnight to afford 361.8 g of product (57% yield, QNMR = 103%). [0122] Crude solid product (50.l g) and toluene (l00 mL, 2 vol) were charged into a 1 L reactor flushed with nitrogen, and the mixture was warmed to 25-30°C to obtain a brown solution. n-Heptane (50 mL, 1 vol) and deionized water (l00 mL, 2 vol) were then added, and the mixture was stirred at around 25°C for 9 min. [0123] The aqueous layer (pH = 2-3) was decanted and discarded. The organic layer was washed with saturated aqueous sodium bicarbonate (50 mL, 1 vol) and brine (50 mL, 1 vol). The 1 L reactor was cleaned with water and acetone, and dried. The organic layer was then filtered on fiberglass and transferred into the clean 1 L reactor under nitrogen. n-Heptane (450 mL, 9 vol) was added at 23°C over 2 min. Crystallization occurred at around half-addition, with the suspension becoming thick initially, then more fluid towards the end of the addition. [0124] The suspension was cooled to around -l5°C and stirred at this temperature for 17 min. The solid was filtered, washed with cold n-heptane (2x50 mL, 2xl vol) and dried at 40°C under vacuum. The product was obtained as a fine white solid (III-A ,23.2 g) with an HPLC purity of 99.5%. [0125] ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 4.38 (m, 2H), 4.35 (m, 2H), 4.19 (s, 4H), 3.75 (s, 3H) ppm. Example 3 Synthesis of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV) [0126] Step 1: 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-C)

[0127] A reactor was charged with EtOH (9.87 L, 8.5 vol) followed by 2,3- dihydroxypyridine (1.16 kg, 10.45 mol, 1 eq) and then deionized water (1.74 L, 1.5 vol). K₂CO₃ (3.61 kg, 2.5 eq) was then added to the reactor via manway. 1,2-dibromoethane (3.93 kg, 2.0 eq) was then slowly charged into the reactor. The loading line was rinsed with EtOH (approximately 1 L) and the wash was added to the reactor. The resulting suspension was heated to 75-85 ^C (reflux) and agitated at this temperature for 12 h. An aliquot of the reaction mixture was removed and analyzed by HPLC to confirm complete formation of the desired product. [0128] The EtOH in the reaction mixture was azeotropically distilled off (approximately 7 vol) at temperature 80-90°C until 3-4 vol of residual volume. Deionized water (5.81 L, 5 vol) was charged in to the reactor and distillation was resumed until mass temperature reached 99-100 ^C. Additional deionized water (2.31 L, 2 vol) was charged in to the reactor and distillation was resumed until mass temperature reached 99-100 ^C. The mixture was then cooled to < 30°C. EtOAc (5.81 L, 5 vol) was charged in to the reactor and the mixture agitated for 30 min at a temperature of <30°C. Agitation was ceased, the layers were allowed to separate for 30 min, and the bottom aqueous layer was discharged into a clean container. The first organic top layer was discharged into a separate clean container. [0129] The aqueous layer was charged back in to the reactor, which was then charged with EtOAc (5.81 L, 5 vol) and the resulting mixture agitated for 30 min at a temperature of <30°C. Agitation was ceased, the layers were allowed to separate for 30 min, and the bottom aqueous layer was discharged into a clean container. The first organic top layer was then charged into the reactor followed by brine (~5 vol, 4.35 L of water, and 1.45 kg of sodium chloride, ~ 25 wt% brine solution). The mixture was then agitated for 30 min, at which point agitation was ceased, the layers were allowed to separate for 30 min, and the bottom aqueous layer was discharged into a clean container. [0130] The combined organic extracts remaining in the reactor were then concentrated by distillation to approximately 2 volumes. The mixture was then cooled to 25°C and drained into a clean container. The reactor was rinsed with additional EtOAc and combined with the concentrated organic extracts. The resulting 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-C) was stored as a concentrated solution in EtOAc and carried on to the next step. [0131] ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 7.73 (dd, J = 4.8, 1.5 Hz, 1H), 7.28 (dd, J = ddd, 7.8, 1.5, 0.6 Hz, 1H), 6.95 (ddd, J = 7.8, 4.8, 0.3 Hz, 1H), 4.40-4.38 (m, 2H), 4.26-4.24 (m, 2H) ppm. [0132] Step 2: 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B)

[0133] The concentrated solution of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-C) (919.1 g pure, 1.0 eq) prepared in the first step was charged into a reaction vessel, along with DMF (4.5955 L, 5.0 vol). N-Bromosuccinimide (NBS) (1.5506 kg, 1.3 eq) was then charged in to the reactor via the hopper at 20-30 ^C. The resulting mixture was heated to 55-60 ^C and agitated at this temperature for 8 h. The mixture was cooled to 25°C and assessed by HPLC to confirm complete conversion to the desired product. The mixture was then further cooled to a temperature < 5°C and a solution of sodium metabisulfite (1.274 kg, 1.0 eq) in deionized water (9.191 L, 10 vol) was charged in to the reactor while maintaining the temperature at <15 ^C. The resulting mixture was further cooled to a temperature of 0-5°C and agitated for at least 2 h. The product precipitated from solution and was isolated by filtration. The filter cake was washed with deionized water (5x4.5955 L, 5x5 vol) and then dried under vacuum at 55°C for 16 h to afford 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B, 1.8900 kg, 62% yield) as an off- white to pale yellow powder. [0134] ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 7.85 (d, J = 2.1Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 4.44-4.41 (m, 2H), 4.29-4.27 (m, 2H) ppm. [0135] Step 3: 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV)

[0136] THF (14.051 L, 9 vol) was charged into a first reactor and the 7-bromo-2,3-dihydro- [1,4]dioxino[2,3-b]pyridine (IV-B, 1.8900 kg, 1.5612 kg pure) produced in step 2 was added to the reactor via manhole. The mixture was agitated for 15 min at 25°C. The mixture was assessed for water content and proceeded to the next step upon determination that the water content was <0.1% v/v. [0137] The reaction mixture was then cooled to -25°C to -18°C and the reactor charged with isopropyl magnesium chloride in THF (0.8696 kg, 1.17 eq) while maintaining a temperature between -25°C and -5 ^C. The charge lines were rinsed with THF (1.5612 L, 1 vol) and the wash was charged to reactor. n-Butyl lithium in hexanes (0.7268 kg, 1.57 eq) was then charged to the reactor while maintaining a temperature between -25°C and -5 ^C. The charge lines were rinsed with THF (1.5612 L, 1 vol) and the wash was charged to reactor. The mixture was agitated for 15-25 min at a temperature between -25°C and -5 ^C. [0138] Toluene (4.6836 L, 3 vol) was charged to a second reactor, followed by sulfuryl chloride (2.9262 kg, 3 eq) while maintaining a temperature <25°C. The charge lines were rinsed with toluene (1.5612 L, 1 vol) and the wash was charged to the second reactor. The reaction mixture from the first reactor was slowly added to the second reactor while maintaining a temperature between -25°C and -5 ^C. The first reactor was rinsed with THF and the wash was added to the second reactor. The resulting reaction mixture in the second reactor was agitated for at least 30 min while maintaining a temperature between -25°C and 0°C. After 30 min, an aliquot of the reaction mixture was removed, quenched with ice water, and analyzed via HPLC to confirm complete conversion to the desired product, intermediate compound 2,3-dihydro- [1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride (IV-A). [0139] The second reactor was charged with deionized water (6.2448 L, 4 vol) while maintaining a temperature <0 ^C. The mixture was agitated for 20 min at a temperature between -10°C and 0°C. After agitating, the layers were allowed to separate for at least 15 min and the bottom aqueous layer was transferred back to the first reactor while maintain a temperature <0 °C. A 20% w/w solution of sodium chloride (1.5612 kg) in deionized water (brine, 6.2448 L, 4 vol) was prepared in a separate container, half of which (ca.2 vol) was charged to the second reactor while maintaining a temperature <0°C. The mixture was then agitated for 20 min at a temperature <0°C. After agitating, the layers were allowed to separate for at least 15 min and the bottom aqueous layer was transferred back to the first reactor while maintain a temperature <0°C. The second half of the brine solution (ca.2 vol) was charged to the second reactor while maintaining a temperature <0°C. The mixture was then agitated for 15 min at a temperature <0°C. After agitating, the layers were allowed to separate for at least 15 min and the bottom aqueous layer was transferred back to the first reactor while maintain a temperature <0°C. [0140] The reactor, holding the aqueous washes, was charged with DCM (7.0860 L, 5 vol) and agitated for 15 min, while maintaining a temperature <5 ^C. After agitation, the layers were allowed to separate for approximately 60 min. The remaining organic layer in the second reactor was cooled to -15°C and the bottom organic layer from the first reactor was added to the second reactor. The combined organic extracts in the second reactor was cooled to -20°C. [0141] An ammonium solution in MeOH (0.9846 kg, 8.0 eq) was charged to the second reactor over 1 h while maintaining a temperature <5 ^C. The charge lines were rinsed with MeOH and the wash was charged to the second reactor. The reaction mixture was then agitated for 1-3 h while maintaining a temperature <0°C. An aliquot of the reaction mixture was removed and assessed via HPLC to confirm complete conversion to the desired product 2,3- dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV). [0142] The reaction mixture was cooled to -10°C and the reactor was charged with deionized water (7.806 L, 5 vol) while maintaining a temperature between -10°C and 0 ^C. The solid product was collected by filtration under vacuum. DCM (7.0860 L, 5 vol) was charged to the reactor and the collected solids were washed by allowing the washings from the reactor to penetrate the filter for 15 min, agitating the solids, and then filtering again under vacuum. Deionized water (3.122 L, 2 vol) was charged to the reactor and the collected solids were washed by allowing the washings from the reactor to penetrate the filter for 15 min, agitating the solids, and then filtering again under vacuum. [0143] The wet filter cake was transferred to a clean third reactor, which was then charged with deionized water (15.6 L, 10 vol). The resulting mixture was agitated for 1-2 h at reflux. After agitation, the slurry was cooled to 15-25°C and stirred for an additional 30 min. The solid product was collected by filtration under vacuum and the reactor was charged with deionized water (3.1 L, 2 vol). The collected solids were washed by allowing the washings from the reactor to penetrate the filter for 15 min, agitating the solids, and then filtering again under vacuum. An aliquot of the solid product was removed and assessed by HPLC to confirm product purity. [0144] DCM (3.750 L, 2.4 vol) was charged to the reactor, along with the wet cake collected via filtration in the preceding step. MeOH (1.250 L, 0.8 vol) was charged to the reactor and the mixture was agitated for at least 30 min at a temperature between 15-20°C. The solid product was isolated by filtration under vacuum and the reactor was charged with DCM (2.000 L, 1.3 vol). The collected solids were washed by allowing the washings from the reactor to penetrate the filter for 15 min, agitating the solids, and then filtering again under vacuum. An aliquot of the solid product was removed and assessed by HPLC to confirm product purity. The solids were dried under vacuum at 50°C for 16 h to yield 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7- sulfonamide (IV, 0.94 kg, 60% yield, 99.4% purity by HPLC) as a white to gray/beige powder. [0145] ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.15 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.47 (br s, 2H), 4.52-4.50 (m, 2H), 4.35-4.32 (m, 2H) ppm. Example 4 Alternative Synthesis of 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B) [0146] Step 1: 5-bromopyridine-2,3-diol (IV-E)

[0147] Furfural (IV-F, 5.8 g, 0.06 mol) in 70 g water was cooled to 0°C, and bromine (9.7 g, 0.06 mol) was added dropwise while maintaining temperature between 0-5°C. After 30 min of stirring, HBr (conc., 3 mL) was added in one portion and stirred for an additional 30 min at a temperature between 0-5°C. The resulting solution was then cooled to -10°C. To the reaction solution was added bromine (9.7 g, 0.06 mol) dropwise while maintaining temperature below 0°C. The reaction solution was stirred at -5°C for 1 h, which was subsequently added to a solution of sulfamic acid (6 g, 0.062 mol) in water (23 g) while maintaining a temperature between 45-55°C. The reaction was stirred at 50- 55°C for 30 min. The reaction mixture was then cooled to 0-10°C and stirred for an additional 1 h, and then ultimately filtered to collect the desired product as a precipitate. The precipitated product was then dried for 18 h at 50°C to collect the crude product, 5-bromopyridine-2,3-diol (IV-E), as a grey solid (65% yield). [0148] ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 11.84 (brs, 1H), 9.55 (br s, 1H), 7.06 (d, J = 2.4Hz, 1H), 6.78 (d, J = 2.4Hz, 1H). [0149] Step 2: 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B)

[0150] To a solution of 5-bromopyridine-2,3-diol (IV-E, 1.0 eq) in EtOH/H2O (10 vol/10 vol) was added K2CO3 (1.41 eq) and BrCH2CH2Br (1.76 eq). The mixture was heated to a temperature of 70-75°C for 44 h. Additional K₂CO₃ (0.35 eq) and BrCH₂CH₂Br (0.35 eq) was added and the heating was continued for 10 additional h. Reaction progress was monitored via HPLC to confirm complete consumption of the starting material. The reaction solution was subsequently concentrated to remove EtOH. EtOAc (20 vol) was added and the desired product extracted. The product solution in EtOAc was concentrated. DMF (1.5 vol) was added, followed by addition of H2O (7.5 vol). The precipitant was filtered and dried to give the desired product, 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B) (45% yield). ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 7.85 (d, J = 2.1Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 4.44-4.41 (m, 2H), 4.29-4.27 (m, 2H) ppm. Example 5 Synthesis of (S)-tropic acid (VII) [0151] Step 1: Methyl 2-formyl-phenylacetate (VII-B)

[0152] Sodium methoxide (1.3 eq) was charged to a clean, dry reactor under nitrogen, followed by MTBE (6 vol). The reactor contents were then heated to a temperature of 15-25°C and methyl phenylacetate (3.0 kg, 1 eq) was charged over at least 20 min while maintaining a temperature between 15-20°C. Additional MTBE (0.5 vol.) was used to rinse the charge lines and the wash was added to the reactor. The reactor contents were held and agitated for 30-60 min at a temperature between 15-25°C. Methyl formate (1.80 kg, 1.5 eq) was then charged to the reactor over at least 1 h while maintaining a temperature between 15-25°C. Additional MTBE (0.5 vol.) was used to rinse the charge lines and the wash was added to the reactor. The reactor contents were then heated to a temperature between 15-25°C and agitated for at least 5 h while maintaining the aforementioned temperature. Reaction progress was monitored by removing an aliquot of the reaction mixture and assessing the methyl phenylacetate content by ¹H NMR. [0153] The reaction mixture was subsequently cooled to -10°C to 5°C and water (4 vol.) was charged to the reactor while maintaining reactor temperature between -10°C and 5°C. The reactor contents were then agitated for at least 15 min while maintaining a temperature between -10°C and 5°C. The pH of the aqueous layer was determined and adjusted with either sodium hydroxide or citric acid until the pH was within the range of 11.5 to 12.5. [0154] The reactor contents were allowed to settle for at least 15 min and the bottom aqueous layer, containing the desired product, was discharged into a suitable container at stored at a temperature between -10°C and 5°C. The upper organic layer was subsequently drained from the reactor. The aqueous layer was charged back into the reactor and maintained at a temperature between -10°C and 5°C. MTBE (4 vol.) was charged into the reactor and the mixture agitated while maintaining a temperature between -10°C and 5°C. A 25% w/w aqueous solution of citric acid (3 vol.) was charged to the reactor while maintaining a temperature between -10°C and 5°C and the resulting mixture was agitated for at least 15 min. [0155] The reaction mixture was allowed to settle for at least 40 min and the layers separated. The top organic layer, containing the desired product, was set aside and the bottom aqueous layer was charged back into the reactor. The pH of the aqueous layer was monitored and adjusted until within a range between 4-5. MTBE (1.5 vol.) was charged into the reactor containing the aqueous layer and agitated for at least 10 min while maintaining a temperature between 5-20°C. The reactor contents were allowed to settle for at least 15 min and the bottom aqueous layer was removed. [0156] The combined organic layers were charged into the reactor, followed by a 20% w/w solution of sodium chloride (1.5 vol). The mixture was then agitated for at least 10 min while maintaining a temperature between 5-20°C. The reactor contents were allowed to settle for at least 15 min and the bottom aqueous layer was then removed. The reactor contents were then heated to a temperature between 28-35°C under reduced pressure until the combined organic layers were concentrated to approximately 4.5 vol. [0157] The reactor contents were cooled and the final product solution discharged into a clean container and stored at -20°C to yield methyl 2-formyl-phenylacetate (VII-B; 3.31 kg active, 93% yield). The final product solution was assayed by ¹H NMR to confirm product identity and purity. [0158] ¹H NMR, Enol Form (500 MHz, CDCl₃) δ (ppm): 12.0 (br s, 1 H), 7.20-7.40 (m, 5H), 3.78 (s, 3H). [0159] ¹H NMR, Aldehyde Hydrate Form (500 MHz, CDCl₃) δ (ppm): 7.90 (s, 1H), 7.20-7.40 (m, 5H), 3.70 (s, 3H). [0160] ¹H NMR, Aldehyde Form (500 MHz, CDCl₃) δ (ppm): 9.83 (s, 1H), 7.20-7.40 (m, 5H), 3.60 (s, 3H). [0161] Alternative Step 1: Methyl 2-formyl-phenylacetate (VII-B)

[0162] Sodium methoxide (30 g, 0.56mol) was added to a 1 L flask equipped with overhead stirring, followed by toluene (415 ml). Methyl phenylacetate (VII-C, 79 ml, 0.56 mol) was added dropwise over 30 min, and the mixture was stirred for an additional 10 min at rt. Methyl formate was added dropwise and the speed of addition was adjusted to maintain reaction temperature below 31°C. After all methyl formate was added, the reaction mixture was stirred at rt for 3.5 h and cooled down to 5°C.0.4M solution of citric acid (540 ml, 0.22 mol) was added dropwise with stirring. The layers were separated, and the aqueous layer extracted with toluene (415 ml). Combined toluene extracts were washed with brine and concentrated in vacuo to give 105.5 g of a colourless liquid which partially solidified on standing. The crude product contained 77% of methyl 2-formyl-2-phenylacetate (VII-B, 81.2 g; yield 82%), and 14% methyl phenylacetate. [0163] ¹H NMR, Enol Form (500 MHz, CDCl₃) δ (ppm): 12.0 (br s, 1 H), 7.20-7.40 (m, 5H), 3.78 (s, 3H). [0164] ¹H NMR, Aldehyde Hydrate Form (500 MHz, CDCl₃) δ (ppm): 7.90 (s, 1H), 7.20-7.40 (m, 5H), 3.70 (s, 3H). [0165] ¹H NMR, Aldehyde Form (500 MHz, CDCl₃) δ (ppm): 9.83 (s, 1H), 7.20-7.40 (m, 5H), 3.60 (s, 3H). [0166] Step 2: Crude (S)-tropic acid (VII)

[0167] Water (8.75 vol), KH2PO4 (0.178 eq), and glucose monohydrate (2.5 eq) were charged to a reactor and agitated at a temperature between 20-28°C for at least 5 min. The pH of the solution was adjusted to a value of 6.75±0.25 using 3M NaOH and the temperature of the solution was adjusted to be between 25-28°C. CRED-A231M165-GDH-102 lyophilized cell free extract (0.138 wt%) was charged to the reactor and the solution was agitated for at least 15 min at a temperature between 25-28°C. 2.2-2.6 wt% of the enzyme-glucose solution was removed and stored under ambient conditions for later charge. [0168] NADP disodium salt (0.002265 eq) and MTBE (7.25 vol) were then charged to the reactor and the solution was agitated while maintaining a temperature between 25-28°C. The product solution containing methyl 2-formyl-2-phenylacetate (VII-B) produced in Step 1, above, was then charged to the reactor at a constant rate over 4.5-5.5 h while maintaining a pH range of 6.75±0.25 using 3M NaOH and a reaction temperature of between 25-28°C. Following complete addition of methyl 2-formyl-2-phenylacetate (VII-B), the enzyme-glucose solution removed previously was added to the reactor in one portion. The remaining methyl 2-formyl-2- phenylacetate (VII-B) solution (1.51-1.81 vol) was then charged to the reactor at a constant rate over 5.5-6.5 h while maintaining a pH range of 6.75±0.25 using 3M NaOH and a reaction temperature of between 25-28°C. Agitate the reactor contents at a temperature between 25-28°C and pH 6.75±0.25 for a further 4 h. Reaction completion was assessed by NMR to confirm conversion to the desired product, (S)-methyl tropate (VII-A). [0169] ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.36-7.26 (m, 5H), 4.08-4.18 (m, 1H), 3.87- 3.80 (m, 2H), 3.71 (s, 3H), 2.35 (br s, 1H). [0170] The reactor contents were concentrated to a total of 10 vol. to 11.25 vol. under reduced pressure while maintaining a temperature below 40°C. After concentration, the reactor contents were heated to a temperature between 40-50°C and agitated for 5-15 min. Liquid CALB (0.5 wt%) was charged to the reactor in one portion and the resulting solution was agitated for 24 h while maintaining a temperature between 40-50°C, and a pH of 7.25±0.25. The pH of the reaction mixture was adjusted as needed using an aqueous solution of 3M NaOH. Reaction process was assessed by HPLC, and after determining the reaction was complete, the reactor contents were cooled to a temperature between 10-15°C and agitated for 5-15 min. [0171] The pH of the reactor contents was adjusted to a value between 1.0-1.5 using 25% hydrochloric acid (approx.1.4 vol) while maintaining a temperature between 10-15°C. Following pH adjustment, the reactor contents were agitated for at least 4 h, while maintaining a temperature between 10-15°C. The reactor contents were filtered to collect the solid product as a filter cake. Water (1.0 vol.) was charged to the reactor and cooled to a temperature between 10- 15°C, and subsequently used to wash the wet filter cake. The wet filter cake afforded crude (S)- tropic acid (VII, 1.51 kg active, 81% yield), which was assessed for purity (99.32%) and enantiopurity (99.3%) by HPLC. [0172] ¹H NMR (500 MHz, MeOD) δ (ppm): 7.25-7.35 (m, 5H), 4.90 (br s, 1H), 4.05- 4.15 (m, 1H), 3.69-3.77 (m, 2H). [0173] ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.17-7.27 (m, 5H), 6.90 (br s, 2H), 3.82- 3.77 (m, J = 1H), 3.42-3.56 (m, 2H). [0174] Alternative Step 2a: (S)-Methyl tropate (VII-A)

[0175] In a 1 L flask equipped with overhead stirring, glucose monohydrate (57.8 g, 1.3 eq.), L-Lysine hydrochloride (8.2 g, 0.2 eq.) and thiamine hydrochloride (7.6 g, 0.1 eq.) were dissolved in 0.1M potassium phosphate buffer (430 ml). The resulting solution was warmed to 30°C, and pH was adjusted to 6.5 using an aqueous solution of K₂CO₃ (20% w/w). NADP (0.6 g), GDH-102 (0.8 g, 2 wt%) and CRED-41 (4 g, 10 wt%) were added to the reaction mixture, followed by toluene (40 ml). A solution of methyl 2-formyl-2-phenylacetate (40 g, 1 eq.) in 40 ml of toluene was added over 10 h via syringe pump while maintaining the reaction temperature at 30°C and pH at 6.5. 5 h after start of the addition, more GDH-102 (0.8 g, 2 wt%) and CRED-41 (4 g, 10 wt%) were added. [0176] After stirring for 16 h, 100 ml of toluene were added and the reaction mixture was filtered through a layer of Celite. The layers were separated, and the aqueous phase was extracted with toluene (2x75 ml). Organic layers were combined and washed with brine (1x100 ml). Concentration under reduced pressure afforded 45.2 g of crude reaction mixture containing 57% (S)-methyl tropate (VII-A, ee 87% (S), yield 64%). [0177] ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.36-7.26 (m, 5H), 4.08-4.18 (m, 1H), 3.87- 3.80 (m, 2H), 3.71 (s, 3H), 2.35 (br s, 1H). [0178] Alternative Step 2b: Crude (S)-tropic acid (VII)

[0179] In a 1 L flask equipped with overhead stirring, a 1M NaOH solution in 15% aqueous NaCl was prepared (NaOH: 15 g (2 eq.); NaCl: 58 g; H2O: 393 ml). This solution was cooled to -10°C. A solution of crude (S)-methyl tropate (VII-A, 33 g, 1 eq.) in toluene (200 ml) was added dropwise over 2 h with vigorous stirring while maintaining the reaction temperature at - 10°C. After all the toluene solution was added, the stirring was continued for 1 additional hour. [0180] Aqueous hydrochloric acid (28%) was added to adjust the pH of the reaction mixture to 8, while maintaining the temperature below 0°C. MTBE (100 ml) was added with stirring, the phases were separated, and the organic layer was discarded. The aqueous phase was washed once more with 100 ml MTBE (organic layer discarded). [0181] Aqueous sulfuric acid (50%) was added to adjust pH to 2 followed by extraction with 2-MeTHF (3x100 ml). Combined organic layers were concentrated under reduced pressure to obtain crude (S)-tropic acid (VII, ee 86% (S), 27 g). [0182] ¹H NMR (500 MHz, MeOD) δ (ppm): 7.25-7.35 (m, 5H), 4.90 (br s, 1H), 4.05- 4.15 (m, 1H), 3.69-3.77 (m, 2H). [0183] ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.17-7.27 (m, 5H), 6.90 (br s, 2H), 3.82- 3.77 (m, J = 1H), 3.42-3.56 (m, 2H). [0184] Step 3: Recrystalization of (S)-tropic acid (VII) [0185] The crude (S)-tropic acid (VII, 1 eq.) prepared in the previous step was charged to a clean reactor. THF (6 vol., based on the Step 2 input) was charged into the reactor. The reactor contents were heated to a temperature between 35-45°C and held for a minimum of at least 1 h. [0186] The reactor contents were then filtered and the filter cake was washed twice with THF (3 vol.). The undissolved material remaining on the filter was discarded. The filtrate and THF washings were assayed by ¹H NMR to assess the (S)-tropic acid content in each solution. [0187] The reactor was conditioned by rinsing with THF. Then the THF filtrate and washings prepared during the initial filtration step were charged back in to the reactor and the mixture was concentrated to approximately 2 volumes via distillation under reduced pressure at a temperature between 35-45°C. [0188] Following concentration, the reactor contents were heated to a temperature between 35-45°C and water (4 vol.) was charged to the reactor. The contents of the reactor were then concentrated to approximately 4 volumes via distillation under reduced pressure at a temperature between 35-45°C. The THF content of the reaction mixture was assessed by ¹H NMR and confirmed to be between 3-10%. [0189] The reactor contents were then heated to a temperature between 35-45°C and toluene (2 vol.) was added while maintaining a temperature between 35-45°C. The reactor contents were then cooled to a temperature between 0-10°C over a period of at least 5 h and held at this temperature for at least 15 h. The reactor contents were then filtered, while maintaining a temperature between 0-10°C. The reactor was visually inspected for any residual solid and the mother liquor was used to rinse the reactor and collect any residual solid materials. [0190] The filter cake was subsequently washed with toluene (2 vol.) while maintaining a temperature of between 0-10°C. After washing, the filter cake was pull-dried under vacuum for at least 2 h. The resulting semi-dry filter cake was then assessed for purity, enantiopurity, and protein content by HPLC. After HPLC analysis, the filter cake was further dried by heating to a temperature of 35-45°C under reduced pressure for at least 24 h. The dried filter cake was assessed for water and solvent content by KF and GC, respectively. The dry product material was collected to afford (S)-tropic acid (VII, 92% yield) with 99.8% purity and 99.7% enantiopurity. [0191] ¹H NMR (500 MHz, MeOD) δ (ppm): 7.25-7.35 (m, 5H), 4.90 (br s, 1H), 4.05- 4.15 (m, 1H), 3.69-3.77 (m, 2H). [0192] ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.17-7.27 (m, 5H), 6.90 (br s, 2H), 3.82- 3.77 (m, J = 1H), 3.42-3.56 (m, 2H). [0193] Alternative Step 3: Recrystalization of (S)-tropic acid (VII) [0194] Crude (S)-tropic acid (10 g, ee 86% (S)) was suspended in 50 ml of 1:4 mixture of n- heptane:iPrAc, and the suspension heated to 60°C. After stirring at this temperature for 1 h, the mixture was left to cool to rt and equilibrate with stirring (approximately 20 h). Filtering and washing with 10 ml of cold n-heptane:iPrAc mixture (1:4) afforded (S)-tropic acid (ee 98.3 %, 7 g after drying at reduced pressure). [0195] ¹H NMR (500 MHz, MeOD) δ (ppm): 7.25-7.35 (m, 5H), 4.90 (br s, 1H), 4.05- 4.15 (m, 1H), 3.69-3.77 (m, 2H). [0196] ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.17-7.27 (m, 5H), 6.90 (br s, 2H), 3.82- 3.77 (m, J = 1H), 3.42-3.56 (m, 2H). Example 6 Synthesis of (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I)

[0197] Step 1: methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (V-A) [0198] To a 1 L jacketed reactor was added 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7- sulfonamide (IV, 31.00 g), K₂CO₃ (21.15 g, 1.1 eq), and DMSO (300 mL, 10 vol). The contents were heated to 100°C. A solution of methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1- carboxylate (III-A, 31.91 g, 1.0 eq) in toluene (270 mL, 9 vol) was slowly added over 2.5 h through an inline filter. Its container was rinsed with toluene (30 mL, 1 vol), and the rinse was added to the reaction vessel over 10 min. The contents of the reactor were stirred at 100°C for 1 h. A sample of the reaction mixture was taken and monitored by HPLC, which showed 0.1% remaining III-A. [0199] The reaction mixture was then cooled to rt over 6 h. The toluene was removed by distillation with a jacket temperature of 60°C. The contents of the reactor were cooled to rt. To the resulting thick mixture was added water (300 mL, 10 vol), over the course of 1 h while maintaining the temperature below 30°C. The mixture was allowed to age for 30 min. [0200] The solids were filtered and washed with water (2×300 mL, 10 vol) and MeCN (4×150 mL, 5 vol). The solids were then dried on the filter for 16 h, yielding white solids (42.219 g, 82.8%), with an HPLC purity of 97.8%. [0201] The solids (42 g) were added to a 1 L jacketed reactor with MeCN (420 mL, 10 vol). The mixture was heated to 80°C, where it stirred for 1 h. The slurry was cooled to rt over 4 h, where it was then stirred overnight. The solids were collected by filtration and washed with MeCN (210 mL, 5 vol). The solids were dried on the filter for 2 h, yielding white solids (40.21 g, 95.7% recovery, 78.9% overall), with an HPLC purity of 99.4%. [0202] ¹H NMR (300 MHz, CDCl3) δ (ppm): 8.30 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 4.54-4.51 (m, 2H), 4.34-4.32 (m, 2H), 4.13-4.07 (m, 8H), 3.72 (s, 3H) ppm. [0203] Step 2: 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro- [1,4]dioxino[2,3-b]pyridine (VI) [0204] A mixture of methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)- 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (V-A, 29.4 g, 80 mmol), Bu₂S (88.2 mL, 3 vol) and MSA (58.8 mL, 2 vol) was heated at 70ºC for 19 h. LCMS indicated the completion of the reaction. The mixture was cooled to 10ºC, diluted with water (240 mL) at ≤ 25ºC and extracted with n-heptane (3×120 mL). The aqueous solution was equally split into two portions. [0205] Portion 1 was cooled to 10ºC and neutralized with 28-30% NH4OH (120 mL) at ≤25ºC. The mixture stirred at rt for 1 hand extracted with DCM (3x: 120 mL, 60 mL and 60 mL). The combined DCM extracts were washed with 1N NaOH (120 mL), water (120 mL) and added to another flask charged with (S)-tropic acid (VII, 6.65 g, 40 mmol, 1.0 eq) and DCM (80 mL). The mixture was stirred at rt over the weekend. Solids were filtered, washed with DCM (30 mL) and dried in vacuum oven a 40ºC for 6 h.17.3 g (yield, 91.0%) of VIˑVII was obtained. [0206] Portion 2 was cooled to 10ºC and neutralized with 28-30% NH4OH (120 mL) at ≤25ºC. The mixture stirred at rt for 20 min, heated to 70ºC, and stirred for 1 h. The mixture was cooled to 15ºC, stirred for 0.5 h. The solids were collected by filtration and washed with water (30 mL). The free amine was reslurried in water (120 mL) at 70ºC for 20 h then cooled to 15ºC and stirred for 0.5 h. The solids were collected by filtration, washed with water (60 mL) and dried in a vacuum oven at 45ºC for 6 h. 10.1 g (yield, 81.6%) of 7-((3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI) was obtained. [0207] The 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro- [1,4]dioxino[2,3-b]pyridine and (S)-tropic acid (VII, 5.7 g, 34.3 mmol, 1.05 eq) in MeCN (202 mL)/water (2.0 mL) was stirred at rt for 18h. The solids were collected by filtration, washed with MeCN (60 mL) and dried in vacuum oven a 40ºC overnight. The process afforded 14.5 g (yield, 93.5%; overall yield, 76.2%) of VIˑVII. [0208] ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 8.18 (d, J = 3 Hz, 1H), 7.65 (d, J = 3 Hz, 1H), 7.27-7.18 (m, 5H), 7.0-6.2 (br, 3H) 4.53-4.50 (m, 2H), 4.35-4.32 (m, 2H), 4.03 (br s, 4H), 3.90-3.92 (m, 1H), 3.60-3.50 (m, 6H). [0209] Step 3: (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I) [0210] To a 10 dram scintillation vial was added VIˑVII (2.500 g), EDC•HCl (1.058 g, 0.525 eq), OxymaPure^® (0.300 g, 0.2 eq), and DMAc (10 mL, 2 vol). The contents of the vial were stirred at 20 ± 5°C for 1 h. The remainder of the VIˑVII (2.500 g) and EDC•HCl (1.058 g) was added, and the reaction mixture was allowed to stir for 3 h. An aliquot was sampled and analyzed by LCMS, which indicated 0% remaining 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI). To the reactor was charged 2-MeTHF (15 mL, 3 vol), and the contents of the vial were passed through a 0.45 µm inline filter. The vial was rinsed with DMAc (1 mL, 0.2 vol), and this solution was passed through the inline filter. To the vial was added EtOH (2.5 mL, 0.5 vol) and 2-MeTHF (10 mL, 2 vol), and the mixture stirred at rt overnight. [0211] To the reaction mixture was added water (60 mL, 12 vol). The slurry was aged at rt for 30 min prior to collection of the solids by filtration. The solids were washed with water (3×20 mL, 4 vol) and EtOH (1×20 mL, 4 vol). The solids were dried on the filter for 2 h, yielding (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I) as a white solid (4.29 g, 89.2% yield) with an HPLC purity of 98.6%. [0212] ¹H NMR (400 MHz, CDCl3) δ (ppm): 8.24 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.35-7.23 (m, 5H), 4.51-4.50 (m, 2H), 4.32-4.30 (m, 2H), 4.28-3.93 (m, 8H), 3.78-3.67 (m, 3H), 3.15-3.13 (m, 1H) ppm. Example 7 Reslurry of (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I) [0213] Crude (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I, 13.7 g) was suspended in EtOH (205.5 mL, 15 vol) and water (13.7 mL, 3 vol). The mixture was heated to reflux for 30 min before cooling to 70°C, where it aged for 3 h. The slurry was then cooled to 50°C over 4 h, where it stirred for 14 h. The slurry was then cooled to 20°C over 1 h, where it stirred for 1 h. The solids were collected by filtration, and washed with EtOH (41.1 mL, 3 vol). The solids were dried on the filter for 2 h before drying under full vacuum with a nitrogen bleed for 20 h. The isolated white solids were 12.561 g (91.7% recovery, 81.6% overall yield) with an HPLC purity of 99.6%. [0214] ¹H NMR (400 MHz, CDCl3) δ (ppm): 8.24 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.35-7.23 (m, 5H), 4.51-4.50 (m, 2H), 4.32-4.30 (m, 2H), 4.28-3.93 (m, 8H), 3.78-3.67 (m, 3H), 3.15-3.13 (m, 1H) ppm. Example 8 Large Scale Synthesis of methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)- 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (V-A)

[0215] To a 10 L jacketed reactor was added 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7- sulfonamide (IV, 516.5 g) and K₂CO₃ (352 g, 1.1 eq) and DMSO (5 L, 10 vol). The contents were heated to 100°C. A solution of methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1- carboxylate (III-A, 531.3 g, 1.0 eq) in toluene (3 L, 6 vol) was slowly added over 2.5 h through an inline filter. Its container was rinsed with toluene (0.5 L, 1 vol), and the rinse was added to the reaction vessel over 10 min. The contents of the reactor were stirred at 100°C for 1 h. A sample of the reaction mixture was taken and monitored by HPLC, which indicated 0.2% remaining III-A. [0216] The reaction mixture was cooled to rt over 6 h. The toluene was removed by distillation with a jacket temperature of 65°C. [0217] The contents of the reactor were cooled to rt. To the thick mixture was added water (5 L, 10 vol), over the course of 1 h while maintaining the temperature below 30°C. The mixture was allowed to age for 30 min. [0218] The solids were collected by filtration, and washed with water (2×5 L, 10 vol) and MeCN (4×2.5 L, 5 vol). The solids were dried on the filter for 2 h, before drying under full vacuum at 45°C for 16 h, yielding white solids (702 g, 82.6%), with an HPLC purity of 99.5% and a KF of 0.7%. [0219] The crude solids (700 g) were added to a cleaned 10 L jacketed reactor and suspended in MeCN (7 L, 10 vol). The slurry was heated to 80°C, where it was stirred for 1 h. The contents of the reactor were cooled to 20°C over 4 h, where they were stirred for 14 h. The solids were collected by filtration and washed with MeCN (3.5 L, 5 vol). The solids were dried on the filter for 2 h before drying in a vacuum oven overnight at 45°C. The isolated solids were 676 g of methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (V-A, 96.3% recovery, 79.5% overall yield) with an HPLC purity of 99.6% and a KF of 0.5%. [0220] ¹H NMR (CDCl₃, 300 MHz): δ (ppm): 8.30 (s, 1H), 7.59 (s, 1H), 4.55-4.50 (m, 2H), 4.35-4.30 (m, 2H), 4.15-4.05 (m, 8H), 3.72 (s, 3H). Example 9 Large Scale Synthesis of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3- dihydro-[1,4]dioxino[2,3-b]pyridine (VI)

[0221] Methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (V-A, 300.0 g, 0.817 mol; obtained via the process of Example 8), Bu₂S (900 mL, 3 vol) and MSA (600 mL, 2 vol) were charged to a 10 L jacket reactor. The mixture was heated to 70ºC and agitated for 19 h. LCMS indicated the completion of the reaction (V-A = 0.6%). The mixture was cooled to <10ºC, diluted with water (2.4 L) at ≤ 25ºC and extracted with n-heptane (3×1.2 L). [0222] The aqueous solution was cooled to 10ºC and neutralized with 28-30% NH₄OH (2.4 L) at ≤ 25ºC to afford 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro- [1,4]dioxino[2,3-b]pyridine (VI). [0223] The mixture stirred at rt for 1 h and extracted with DCM (2.4 L, 1.2 L and 1.2 L). The combined DCM extracts were washed with 1N NaOH (2.4 L), water (2.4 L) and added to another flask charged with (S)-tropic acid (VII, 135.7 g, 0.817 mol, 1.0 eq) and DCM (1.55 L). The mixture was stirred at rt (23ºC) for 20 h. Solids were collected by filtration, washed with DCM (600 mL) and dried in vacuum oven at 40ºC overnight to afford 360.2 g of (VI)•(VII) (yield, 92.8%) with 99.76% purity. LOD: 0.16%. [0224] ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 8.18 (d, J = 3 Hz, 1H), 7.65 (d, J = 3 Hz, 1H), 7.27-7.18 (m, 5H), 7.0-6.2 (br, 3H) 4.53-4.50 (m, 2H), 4.35-4.32 (m, 2H), 4.03 (br s, 4H), 3.90-3.92 (m, 1H), 3.60-3.50 (m, 6H). Example 10 Alternative Large Scale Synthesis of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI)

[0225] Methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (V-A, 300.0 g, 0.817 mol; obtained via the process of Example 8), Bu2S (900 mL, 3 vol) and MSA (600 mL, 2 vol) were charged to a 10 L jacketed reactor. The mixture was heated to 70ºC and agitated for 19 h. LCMS indicated the completion of the reaction (V-A = 0.5%). The mixture was cooled to <10ºC, diluted with water (2.4 L) at ≤25ºC and extracted with n-heptane (3×1.2 L). [0226] The aqueous solution was cooled to 10ºC and neutralized with 28-30% NH₄OH (2.4 L) at ≤25ºC. [0227] The mixture was stirred at rt for 20 min and then heated to 70ºC and stirred for 1 h. The mixture was cooled to 12ºC and stirred for 0.5 h. Solids were filtered and washed with water (600 mL). The free amine was then reslurried in water (2.4 L) at 70ºC for 18 h. The mixture was cooled to 12ºC and stirred for 0.5 h. Solids were filtered, washed with water (600 mL and dried in vacuum oven at 50ºC overnight to afford 216.1 g of to afford 7-((3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI, yield, 85.5%; LOD, 0.20%). [0228] A suspension of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3- dihydro-[1,4]dioxino[2,3-b]pyridine and (S)-tropic acid (121.9 g, 0.734 mol, 1.05 eq) in MeCN (4.32 L)/H₂O (43 mL) was stirred at rt (20ºC) for 21 h. The solids were collected by filtration, washed with MeCN (600 mL) and dried in vacuum oven a 40ºC overnight to afford 320.6 g of (VI)•(VII) (yield, 96.5%: overall yield, 82.6%) of with 99.66% purity. LOD: 0.14%. [0229] ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 8.18 (d, J = 3 Hz, 1H), 7.65 (d, J = 3 Hz, 1H), 7.27-7.18 (m, 5H), 7.0-6.2 (br, 3H) 4.53-4.50 (m, 2H), 4.35-4.32 (m, 2H), 4.03 (br s, 4H), 3.90-3.92 (m, 1H), 3.60-3.50 (m, 6H). Example 11 Large Scale Synthesis of (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)- 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I)

(VI).(VII) [0230] To a 3 L round bottomed flask was added (VI)•(VII) (175.20 g; obtained from the process of Example 9), EDC•HCl (73.85 g, 0.525 eq), OxymaPure (20.99 g, 0.2 eq), and DMAc (700 mL, 2 vol). The contents of the flask were stirred at 20±5°C for 1 h. The remainder of the (VI)•(VII) (175.49 g) and EDC•HCl (74.18 g) was added, and the reaction mixture was allowed to stir for 4 h. An aliquot was sampled and analyzed by HPLC, which indicated 1.8% remaining 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3- b]pyridine (VI). To the flask was charged 2-MeTHF (700 mL, 2 vol), and the contents of the flask were passed through a 0.45 µm inline filter into a 10 L jacketed reactor. The flask was rinsed with DMAc (80 mL, 0.23 vol), and this solution was passed through the inline filter into the reactor. [0231] To the reactor was added EtOH (175 mL, 0.5 vol) and 2-MeTHF (1.05 L, 3 vol), and the mixture stirred at rt overnight. An aliquot was sampled and analyzed by HPLC, which indicated 0.1% 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro- [1,4]dioxino[2,3-b]pyridine (VI) remaining. [0232] To the reaction mixture was added water (4.2 L, 12 vol). The slurry was aged at rt for 30 min prior to collection of the solids by filtration. The solids were washed with water (3×1.4 L, 4 vol) and EtOH (1×1.4 L, 4 vol). The solids were dried on the filter for 2 h, yielding crude (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I) as a white solid (306.0 g, 90.9% yield) with an HPLC purity of 98.8%. [0233] To a cleaned 10 L jacketed reactor was added the crude (S)-1-(5-((2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3- hydroxy-2-phenylpropan-1-one (I) (300 g), EtOH (4.5 L, 15 vol), and water (300 mL, 1 vol). The contents of the reactor were heated to reflux (~78ºC), where they were stirred for 1 h. The contents of the reactor were cooled to 70ºC, where they were aged for 3 h. The contents of the reactor were cooled to 50ºC over 5 h, where they aged over the weekend. The contents of the reactor were cooled to 20ºC, where they were stirred for 1 h prior to filtration. The filter cake was rinsed with EtOH (900 mL, 3 vol). The solids were dried on the filter for 2 h before drying under full vacuum with a nitrogen bleed at 45ºC for 16 h. The isolated solids were 288.7 g of (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I, 96.2% recovery, 85.7% overall), with an HPLC purity of 99.8%. [0234] ¹H NMR (400 MHz, CDCl3) δ (ppm): 8.24 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.35-7.23 (m, 5H), 4.51-4.50 (m, 2H), 4.32-4.30 (m, 2H), 4.28-3.93 (m, 8H), 3.78-3.67 (m, 3H), 3.15-3.13 (m, 1H) ppm. Example 12 Alternative Large Scale Synthesis of (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7- yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan- 1-one (I) EDC (s) Oxymapure EtOH/DMAc (s) (VI).(VII) [0235] To a 2 L jacketed reactor was added (VI)•(VII) (150.01 g; obtained from the process of Example 10), EDC•HCl (63.49 g, 0.525 eq), OxymaPure^® (17.93 g, 0.2 eq), and DMAc (600 mL, 2 vol). The contents of the reactor were stirred at 20±5°C for 1 h. The remainder of the (VI)•(VII) (150.11 g) and EDC•HCl (63.85 g) was added, and the reaction mixture was allowed to stir for 3 h. An aliquot was sampled and analyzed by HPLC, which indicated 1.0% remaining 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3- b]pyridine (VI). To the reactor was charged 2-MeTHF (600 mL, 2 vol), and the contents of the flask were passed through a 0.45 µm inline filter into a 10 L jacketed reactor. The flask was rinsed with DMAc (60 mL, 0.2 vol), and this solution was passed through the inline filter into the reactor. [0236] To the reactor was added EtOH (150 mL, 0.5 vol) and 2-MeTHF (900 mL, 3 vol), and the mixture stirred at rt overnight. An aliquot was sampled and analyzed by HPLC, which showed 0.0% 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro- [1,4]dioxino[2,3-b]pyridine (VI) remaining. [0237] To the reaction mixture was added water (3.6 L, 12 vol). The slurry was aged at rt for 30 min prior to collection of the solids by filtration. The solids were washed with water (3×1.2 L, 4 vol) and EtOH (1×1.2 L, 4 vol). The solids were dried on the filter for 2 h prior to drying under full vacuum with a nitrogen bleed at 45ºC, yielding crude (S)-1-(5-((2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3- hydroxy-2-phenylpropan-1-one (I) as an off-white solid (248.7 g, 86.2% yield), with an HPLC purity of 98.8%. [0238] To a cleaned 10 L jacketed reactor was added the crude (S)-1-(5-((2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3- hydroxy-2-phenylpropan-1-one (I, 248.7 g), EtOH (3.75 L, 15 vol), and water (250 mL, 1 vol). The contents of the reactor were heated to reflux (~78ºC), where they were stirred for 1 h. The contents of the reactor were cooled to 70ºC, where they were aged for 3 h. The contents of the reactor were cooled to 50ºC over 5 h, where they aged overnight. The contents of the reactor were cooled to 20ºC, where they were stirred for 1 h prior to filtration. The filter cake was rinsed with EtOH (750 mL, 3 vol). The solids were dried on the filter for 2 h before drying under full vacuum with a nitrogen bleed at 45ºC for 16 h. The isolated solids were 237.75 g of (S)-1-(5- ((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I, 95.6% recovery, 82.4% overall), with an HPLC purity of 99.7%. [0239] ¹H NMR (400 MHz, CDCl3) δ (ppm): 8.24 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.35-7.23 (m, 5H), 4.51-4.50 (m, 2H), 4.32-4.30 (m, 2H), 4.28-3.93 (m, 8H), 3.78-3.67 (m, 3H), 3.15-3.13 (m, 1H) ppm. Example 13 Synthesis of (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H- pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one (II) Step 1: Methyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate (VIII-B)

(VIII-B) [0240] K₂CO₃ (90 g, 648 mmol) and DMSO (750 mL, 15 vol) were charged into a reaction vessel. A yellow solution of pyridine-2-sulfonamide (VIII-A, 52.6 g, 316 mmol) in DMSO (100 mL, 2 vol) was then charged into the reaction vessel in NLT 5 min. The container was then rinsed with DMSO (50 mL, 1 vol) and the solution charged into the reaction vessel. The reaction mixture was heated to 85-90°C, at which point a light slurry was formed. [0241] A solution of methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A, 70.8 g, 316 mmol) in DMSO (100 mL, 2 vol) was charged into the reaction vessel, keeping the temperature at 85-90°C. The container was rinsed with DMSO (50 mL, 1 vol) and the solution charged into the reaction vessel. Complete conversion was observed after 1 h and 20 min, as assessed by UPLC analysis of the reaction mixture. [0242] The reaction mixture was cooled to 20-25°C and quenched with water (500 mL), maintaining a temperature of 20-30°C. The resulting solution was stirred for 3 h at a temperature of 20-25°C and then filtered through a fritted funnel. The filter cake was washed with water (2x250 mL; 2x5 vol) to remove residual inorganic salts. The solid was dried in a vacuum over at 40-45°C for 16 h to afford 53 g of methyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate (VIII-B, 54.2% yield) with a UPLCMS purity of >99%. [0243] ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.81-8.70 (m, 1H), 8.18-8.06 (m, 1H), 8.01-7.92 (m, 1H), 7.77-7.65 (m, 1H), 4.23 (br s, 4H), 4.00 (br s, 4H), 3.59 (s, 3H). Step 2: 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX)

[0244] Methyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate (VIII-B, 15 g, 48.5 mmol) and MeOH (118 mL, 2909 mmol) were charged into a reaction vessel. The suspension was stirred at rt for 5 min and a 3M solution of aqueous potassium hydroxide (64.7 mL, 194 mmol) was charged into the reaction vessel. [0245] The resulting solution was heated to reflux (approximately 75°C) and maintained at that temperature for 23 h. The solution was then concentrated under reduced pressure and extracted with DCM (4x65 mL). The combined extracts were concentrated under reduced pressure and the resulting light brown solid was slurried with MTBE. The resulting slurry was concentrated under reduced pressure and dried at rt to afford 6.18 g of 2-(pyridin-2-ylsulfonyl)- 1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX, 50.7% yield), which was carried onto the next step without further purification. [0246] ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.78-8.72 (m, 1H), 8.16-8.08 (m, 1H), 7.95 (dt, J = 7.8 Hz), 1H, 7.70 (ddd, J = 7.4, 4.7, 1.2 Hz, 1H), 4.15 (s, 4H), 3.50 (s, 4H), 3.32 (br s, 1H). Alternative Step 2a: 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole dihydrobromide (X)

[0247] Methyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate (VIII-B, 4.13 g, 13.35 mmol) was charged into a reaction vessel and HBr in acetic acid was added (33 wt%; 19.87 mL, 113 mmol). The resulting solution was stirred at 20-25°C for 5 min. The solution was then heated to 45-50°C over 30 min and stirred at that temperature for approximately 3 h. [0248] The solution was cooled to 20-25°C and EtOAc (40 mL) was added to the reaction mixture slowly. The resulting solution was stirred at rt for 2 h and then the solids filtered. The filter cake was washed with additional EtOAc (2x10 mL) and rinsed with IPA (2x10 mL). The resulting brown solid was allowed to dry on the filter under suction overnight to afford 5.5 g of 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole dihydrobromide (X, 100% yield). [0249] ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 10.15-9.90 (br s, 1H), 8.80-8.70 (m, 1H), 8.16-8.06 (m, 1H), 8.00-7.90 (m, 1H), 7.75-7.20 (m, 1H), 7.25-6.35 (br s, 1H), 4.20 (s, 4H), 3.90 (s, 4H). Alternative Step 2b: 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX)

[0250] 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole dihydrobromide (X, 1 g, 2.421 mmol) was charged into a reaction vessel and diluted with water (12.5 mL). DCM (7.5 mL) was added to the reaction vessel, followed by IPA (3 mL). The resulting solution was stirred for 5 min and the solid then filtered. [0251] The filtrate was washed with DCM (1 mL) and then rinsed with water (1 mL). The resulting layers were separated and the aqueous layer extracted with DCM (5 mL). The aqueous layer was then basified with 2.5M NaOH (3 mL) to a pH of 14. The aqueous layer was then extracted with DCM (3x5 mL). The organic layers were combined and concentrated under reduced pressure to afford 0.58 g of 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4- c]pyrrole (IX, 95% yield), which was used in the next step without further purification. [0252] ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.78-8.72 (m, 1H), 8.16-8.08 (m, 1H), 7.95 (dt, J = 7.8 Hz), 1H, 7.70 (ddd, J = 7.4, 4.7, 1.2 Hz, 1H), 4.15 (s, 4H), 3.50 (s, 4H), 3.32 (br s, 1H). Step 3: (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4- c]pyrrol-2-yl]ethan-1-one (II)

[0253] 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX, 0.5 g, 1.990 mmol) was charged into a reaction vessel with (R)-2-hydroxy-2-phenylacetic acid (0.318 g, 2.089 mmol) and HOBt (0.096 g, 0.497 mmol). DMSO (4 mL, 8 vol) was then added to the reaction vessel. [0254] A thin suspension of EDC (0.115 g, 2.388 mmol) in degassed DMSO (2 mL, 4 vol) was added to the reaction vessel. The container was rinsed with degassed DMSO (1 mL, 2 vol) and added to the reaction vessel. The resulting solution was stirred at 20-25°C overnight. [0255] After stirring overnight, analysis by UPLCMS showed that approx.50% pyrrolidine (IX) was converted to product. Additional EDC (0.34 g) were charged and the resulting mixture was stirred at rt for 2 h, at which time UPLCMS analysis showed complete conversion to product. [0256] Water (35 mL) was slowly added to the reaction mixture over 1 h and the resulting solution was stirred for 16 h. The resulting solid was filtered through a funnel and the filter cake was washed with water (2x3 mL, 1x6 vol) and then rinsed with EtOH (6 mL, 12 vol). The solid was dried under air aspirator suction for 30 min and then in a vacuum oven at 40-45°C for 5 h to afford 0.61 g of (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H- pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one (II, 80% yield). [0257] ¹H NMR (400 MHz, DMSO- d₆) δ (ppm): 8.71 (d, J = 4.4 Hz, 1H), 8.12-8.05 (m, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.68 (dd, J = 7.6, 4.4 Hz, 1H), 7.40-7.25 (m, 5H), 5.65 (d, J = 6.2 Hz, 1H), 5.18 (d, J = 6.2 Hz, 1H), 4.30-3.90 (m, 8H). [0258] All patents and publications cited herein are fully incorporated by reference herein in their entirety. [0259] Any composition disclosed herein may comprise, consist of, or consist essentially of any of the compounds or components disclosed herein. In accordance with the present disclosure, the phrases “consist essentially of,” “consists essentially of,” “consisting essentially of,” and the like limit the scope of a claim to the specified materials or steps and those materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. [0260] The reagents and conditions described herein are intended to be exemplary and not limiting. As one of skill in the art would appreciate, various analogs may be prepared by modifying the synthetic reactions such as using different starting materials, different reagents, and different reaction conditions (e.g., temperature, solvent, concentration, etc.). [0261] The present disclosure enables one of skill in the relevant art to make and use the inventions provided herein in accordance with multiple and varied embodiments. Various alterations, modifications, and improvements of the present disclosure that readily occur to those skilled in the art, including certain alterations, modifications, substitutions, and improvements are also part of this disclosure. Accordingly, the foregoing description and drawings are by way of example to illustrate the discoveries provided herein. [0262] As used herein, the term "about" refers to the cited value being within the errors arising from the standard deviation found in their respective testing measurements, and if those errors cannot be determined, then "about" refers to within 10% of the cited value. [0263] Unless expressly stated to the contrary, use of the term “a” is intended to include “at least one” or “one or more.” For example, “a compound” is intended to include “at least one compound” or “one or more compounds.” [0264] Any ranges given either in absolute terms or in approximate terms are intended to encompass both, and any definitions used herein are intended to be clarifying and not limiting. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass any and all subranges (including all fractional and whole values) subsumed therein. [0265] Furthermore, the invention encompasses any and all possible combinations of some or all of the various embodiments described herein. It should also be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the invention and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims.

Claims

CLAIMS 1. A process for preparing a compound according to formula (III-Y):

Scheme A1 wherein R12 is -CR2R3-(C6-C10 aryl), where the C6-C10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C₁-C₆ alkyl; and R4 is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or -OSO2R7, wherein each R7 is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or C6-C10 aryl, where C6-C10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R9 is a suitable silyl protecting group selected from the group consisting of trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), or dimethylisopropylsilyl (DMIPS); and R10 is C₁-C₆ alkyl.

2. The process according to claim 1 comprising reacting an azomethine precursor according to formula (III-W1) with an electron-poor alkyne according to formula (III-X) according to Step 1^A1’ Scheme A1’, wherein Step 1^A1’ is performed in the presence of an acid: Scheme A1’

wherein R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or -OSO2R7, wherein each R7 is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁- C6 haloalkoxy, or C6-C10 aryl, where C6-C10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R9 is a suitable silyl protecting group selected from the group consisting of trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), or dimethylisopropylsilyl (DMIPS); and R10 is C₁-C₆ alkyl.

3. The process according to any of the preceding claims wherein R5 and R6 are each chloro.

4. The process according to any of the preceding claims, wherein the acid is selected from the group consisting of TFA, TMSOTf, TMSI, TMSOTf in combination with CsF, or TMSI in combination with any one of CsF, LiF, ZnCl2 or a combination thereof.

5. The process according to any of the preceding claims further comprising a Step 2^A2 transforming the compound of formula (III-Y) into a compound of formula (III-Z) according to Scheme A2: Scheme A2

wherein R1 is selected from the group consisting of C₁-C₆ alkoxycarbonyl (e.g. tert- butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e. Cbz), C6-C10 aryloxy (e.g. phenoxycarbonyl), C₁-C₆ alkylcarbonyl (e.g. acetyl), haloalkylcarbonyl (e.g. trifluoroacetyl), and -SO2-(C6-C10 aryl) (e.g. tosyl).

6. The process according to claim 5, wherein R1 is –C(O)(C₁-C₆ alkoxy), such as - C(O)OCH₃.

7. The process according to any one of claims 5-6 further comprising a Step 3^A3 reacting the compound of formula (III-Z) with a compound of formula (IV-Y) into a compound of formula (V-Z) according to Scheme A3: Scheme A3

(IV-Y) (III-Z) (V-Z) wherein R11 is C6-C10 aryl, 6-10 membered heteroaryl comprising 1-3 O, N, S, wherein aryl and heteroaryl are each optionally substituted with one or more substituents selected from -R13 and - OR13; each R13 is independently -H, -C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, -F, -Cl, -Br, -I, -CN, -NO2; or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring; wherein the reaction is performed in the presence of a base.

8. The process according to claim 7, wherein R11 is selected from the group consisting of 2- pyridyl, 3-pyridyl, 4-pyridyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl.

9. A process for preparing a compound of formula (V-Z) comprising the steps of: a. reacting an azomethine precursor of formula (III-W) with an electron-poor alkyne of formula (III-X) according to Scheme A1, wherein the reaction is performed in the presence of an acid and in a first non-polar solvent: Scheme A1

(III-W) (III-X) (III-Y) , wherein R12 is -CR2R3-(C6-C10 aryl), where the C6-C10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C₁-C₆ alkyl; and R4 is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or -OSO₂R7, wherein each R7 is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or C6-C10 aryl, where C6-C10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R9 is a suitable silyl protecting group selected from the group consisting of trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), or dimethylisopropylsilyl (DMIPS); and R10 is C₁-C₆ alkyl; b. transforming the compound of formula (III-Y) into a compound of formula (III-Z) according to Scheme A2 by reacting with R1-Cl in a second non-polar solvent: Scheme A2

, wherein R11 is C6-C10 aryl, 6-10 membered heteroaryl comprising 1-3 O, N, S, wherein aryl and heteroaryl are each optionally substituted with one or more substituents selected from -R13 and - OR13; each R13 is independently -H, -C₁-C₆ alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, -F, -Cl, -Br, -I, -CN, -NO2; or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring.

10. A compound of formula (III-Y) or a salt thereof:

(III-Y) wherein R12 is -CR2R3-(C₆-C₁₀ aryl), where the C₆-C₁₀ aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C₁-C₆ alkyl; and R4 is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or -OSO2R7, wherein each R7 is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or C₆-C₁₀ aryl, where C₆-C₁₀ aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy.

11. The compound according to claim 10, wherein R12 is benzyl, i.e. a compound of formula (III-B):

(III-B) (1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate).

12. A compound of formula (III) or a salt thereof:

wherein R1 is -C(O)(C₁-C₆ alkyl), -C(O)(C₁-C₆ haloalkyl), -C(O)(C₁-C₆alkoxy), -C(O)(benzyloxy), -C(O)(ph enoxy), or –S(O)₂(tolyl).

13. The compound according to claim 12, wherein the compound is of formula (III-A):

(III-A) (methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate), or a salt thereof.

14. A compound of formula (V-Z):

(V-Z) wherein R1 is –C(O)(C₁-C₆ alkyl), –C(O)(C₁-C₆ haloalkyl), –C(O)(C1- C₆alkoxy), -C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)₂(tolyl); and R11 is R11 is C₆-C₁₀ aryl, 6-10 membered heteroaryl comprising 1-3 O, N, S, wherein aryl and heteroaryl are each optionally substituted with one or more substituents selected from -R13 and - OR13; each R13 is independently -H, -C₁-C₆ alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, -F, -Cl, -Br, -I, -CN, -NO₂; or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring.

15. The compound according to claim 14, wherein the compound is of formula (V):

wherein R1 is –C(O)(C₁-C₆ alkyl).

16. The compound according to claim 14, wherein the compound is of formula (VIII):

wherein R1 is –C(O)(C₁-C₆ alkyl).

17. Use of a compound according to any one of claims 14-16 for preparing a compound according to formula (I) or (II).

18. A process for preparing a compound according to formula (I):

Scheme G2

; e. performing a coupling reaction of the compound of formula (VI) and a compound of formula (VII) according to Scheme G3 or performing a coupling reaction from the salt of formula (VI) ^(VII) according to Scheme G3’ using a coupling reagent and an additive in a second suitable solvent to afford the compound of formula (I): Scheme G3 coupling reagent, additive (^{VI) (VII) (I)} or Scheme G3’

19. A compound of formula (VI) ^(VII):

. 20. Use of the compound according to claim 19 for preparing Etavopivat (I). 21. A process for preparing a compound according to formula (II):

comprising the steps of: a. reacting a compound of formula (III-D) with a compound of formula (III-C) according to Scheme B1’ Step 1^B1’ in the presence of a first acid in a first non-polar solvent: Scheme B1’ 1

.