WO2025240124A1

WO2025240124A1 - Processes for preparing enantiomeric compounds and related molecules

Info

Publication number: WO2025240124A1
Application number: PCT/US2025/027150
Authority: WO
Inventors: Joel Robert CALVIN; John Robert Rizzo
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 2024-05-14
Filing date: 2025-04-30
Publication date: 2025-11-20
Anticipated expiration: 2026-11-14

Abstract

The present disclosure relates to methods for preparing enantiomeric compounds (such as tricyclic heteroaryl carboxamide compounds) useful at least for treating certain immune-mediated diseases. Intermediates disclosed herein include, for example a compound of formula: The disclosure also relates to a solid form of a compound so prepared.

Description

PROCESSES FOR PREPARING ENANTIOMERIC COMPOUNDS AND RELATED MOLECULES Field [0001] The present disclosure relates to methods and intermediates for preparing enantiomeric compounds (such as tricyclic heteroaryl carboxamide compounds useful for treating certain immune-mediated diseases). This disclosure also relates to a solid form of a compound so prepared. Background [0002] Chirality plays an important role in pharmaceutical design. As compared to their non- chiral counterparts, chiral drugs can have higher potency, better pharmacokinetic and/or pharmacodynamic properties, and reduced side effects. Sometimes the desired chirality may be on a ring atom of a complex multi-ring structure. For example, WO2023/039278 discloses aryl hydrocarbon receptor (AHR) agonists having a chiral center on a ring atom of a cycloalkyl that is fused with a substituted pyridone. However, installing the chiral center on such a complex substrate is not trivial. For example, the ‘278 application relies on either a chiral starting material or chiral separation afterwards to reach its chiral product. These requirements undesirably limit the production scale and lead to inefficiency and high costs. There remains a need for a process that is amenable for large scale manufacturing, with good catalyst performance, enantiomer selectivity, purity, product stability, and route economics Summary [0003] Accordingly, the present disclosure provides, for example, various embodiments as presented below. [0004] In some embodiments, provided herein is a process for preparing a compound of first formula: or a compound of second formula: comprising contacting a compound of third formula: with a hydrogen source under asymmetric hydrogenation conditions to provide the compound of the first or second formula, wherein R⁰ is C_1-6 alkyl. [0005] In some embodiments, the process above provides the compound of the first formula: [0006] In some embodiments, the asymmetric hydrogenation conditions include presence of a transition metal-based asymmetric hydrogenation catalyst that includes a chiral ligand. [0007] In some embodiments, the hydrogen source is molecular hydrogen. In some embodiments, the transition metal-based asymmetric hydrogenation catalyst is an iridium (Ir) based catalyst, the Ir based catalyst including a bidentate chiral ligand coordinatively bonded to the Ir with a phosphorous and a nitrogen. [0008] In some embodiments, the hydrogen source includes an organic acid. In some embodiments, the hydrogen source is an azeotrope of formic acid and triethylamine. [0009] In some embodiments, the asymmetric hydrogenation conditions include presence of an asymmetric transfer hydrogenation catalyst. In some embodiments, the asymmetric transfer hydrogenation catalyst is a ruthenium (Ru) based catalyst, the Ru based catalyst including a diamine-based chiral ligand coordinatively bonded to the Ru. [0010] In some embodiments, the process further comprises contacting a compound of formula: with an acid under conditions sufficient to provide the compound of the third formula: [0011] In some embodiments, provided herein is a process, comprising contacting a compound of a formula of: with molecular hydrogen, at a pressure of about 400 to about 450 PSIg, in presence of bis(norbornadiene)rhodium(I) tetrafluoroborate at about 2 mol% to about 4 mol%, a chiral phosphine ligand, and an amine selected from triethylamine and N,N- diisopropylethylamine, in a protic medium, at a temperature of about 10 °C to about 50 °C, for greater than about 20 hrs., to provide a compound of the first formula: wherein R⁰ is C1-6 alkyl. [0012] In some embodiments, the process of any embodiments above, further comprising contacting the compound of the first or the second formula with an enantiomer of phenylethylamine having a chirality opposite to that of the compound of the first or the second formula to form a salt therebetween; isolating the salt; and contacting the isolated salt with an acid to recover the compound of the first or the second formula. [0013] In some embodiments, provided herein is a compound of the formula: or a salt thereof, wherein Q is O or NR⁰, and each occurrence of R⁰ is independently H or C1-6 alkyl. [0014] In some embodiments, provided herein is a process, comprising: contacting a compound of formula: with an acid under isomerization conditions to provide a compound of formula: contacting a product thereof with an organic hydrogen donor under asymmetric transfer hydrogenation conditions to provide a compound of formula: , wherein R⁰ is C1-6 alkyl. [0015] In some embodiments, provided herein is a process, comprising: forming a compound of fourth formula: from a compound of formula: contacting the compound of fourth formula with an enantiomer of phenylethylamine having a chirality opposite to that of the compound of the fourth formula to form a salt therebetween; isolating the salt; and contacting the isolated salt with an acid to recover the compound of the fourth formula. [0016] In some embodiments, provided herein is a process for preparing a compound of formula: , comprising: contacting a compound of formula: with hydrazine under conditions sufficient to provide a compound of formula: wherein the conditions include presence of a base. In some embodiments, the base is an organic base. In some embodiments, the base is an inorganic base. In some embodiments, the base is an inorganic base soluble in water, such as sodium hydroxide, carbonate, and the like. In some embodiments, the use of such bases avoids undesired cyclization with the neighboring carboxylic acid group. [0017] In some embodiments, provided herein is a process for preparing a compound of formula: comprising: contacting a compound of formula: with diphenylmethanone hydrazone under conditions suitable to provide a compound of formula: . [0018] In some embodiments, using organic hydrazones avoids undesired cyclization with the neighboring carboxylic acid group. [0019] In some embodiments, the conditions include presence of a palladium (Pd) based catalyst or a cuprous (Cu) based catalyst. [0020] In some embodiments, provided herein is a solid form having the formula: . [0021] In some embodiments, provided herein is a composition, comprising: a compound of formula: . [0022] In some embodiments, provided herein is a process, comprising: (1) forming a compound of formula: , wherein R⁰ is C1-6 alkyl; (2) forming a compound of formula: with phosphoryl chloride under conditions suitable, and followed by hydrolyzation to form a compound of formula: (4) forming a salt of formula: (5) forming a compound of formula: forming a compound of formula: ; (6) contacting a product of step (5) with an acid to form a compound of formula: (7) contacting the product of step (6) with 5-fluoropyrimidin-2-amineto provide a compound of formula: . [0023] In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation comprising a peak at diffraction angle 2-theta of 13.4° and one or more peaks at 8.2°, 10.0°, and 20.2°, with a tolerance for the diffraction angles of ± 0.2 degrees. [0024] In some embodiments, provided here is a process, comprising contacting a compound of a formula of: with molecular hydrogen under asymmetric hydrogenation conditions to provide a compound of the first formula: , wherein R⁰ is C1-6 alkyl. [0025] In some embodiments, the conditions include presence of a rhodium (Rh) based catalyst. [0026] In some embodiments, the Rh based catalyst is bis(norbornadiene)rhodium(I) tetrafluoroborate or a compound having CAS registry number of 36620-11-8. [0027] In some embodiments, the Rh based catalyst is present at about 0.2 mol% to about 0.4 mol%. [0028] In some embodiments, the conditions include presence of a chiral phosphine ligand. [0029] In some embodiments, the chiral phosphine ligand is (R)-1-[(S_P)-2- (diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine. [0030] In some embodiments, the conditions include the chiral phosphine ligand at a stoichiometric ratio of about 0.001:1 to about 0.005:1 relative to the compound of formula: . [0031] In some embodiments, provided here is a process, comprising contacting a compound of a formula of: with molecular hydrogen under asymmetric hydrogenation conditions to provide a compound of the first formula: , wherein: R⁰ is C_1-6 alkyl, the conditions include the presence of bis(norbornadiene)rhodium(I) tetrafluoroborate and the presence of a P-stereogenic C1-symmetric diphosphine ligand, the P-stereogenic C1-symmetric diphosphine ligand is (R)-1-[(SP)-2- (diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine at a stoichiometric ratio of about 0.002:1 to about 0.004:1 relative to the compound of formula: , and about 1.1:1 to about 1.3:1 relative to the bis(norbornadiene)rhodium(I) tetrafluoroborate, and the contacting is conducted at a temperature of about 20 °C to about 40 °C with the molecular hydrogen at a pressure at about 20 bar to about 30 bar in absence of an amine for a duration of about 2 hrs to about 4 hrs. Brief Description of the Figures [0032] Figure 1 is X-ray powder diffraction (XRPD) pattern of (S)-N-(5-fluoropyrimidin-2-yl)- 6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide. [0033] Figure 2 is Differential Scanning Calorimetry (DSC) curve of (S)-N-(5-fluoropyrimidin- 2-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide. [0034] Figure 3 is Thermogravimetric Analysis (TGA) curve of (S)-N-(5-fluoropyrimidin-2- yl)-6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide. [0035] Figure 4 is Dynamic Vapor Sorption (DVS) curve of (S)-N-(5-fluoropyrimidin-2-yl)-6- methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide. Detailed Description [0036] In some embodiments, provided herein is a process for preparing a compound of first formula: or a compound of second formula: comprising contacting a compound of third formula: with a hydrogen source under asymmetric hydrogenation conditions to provide the compound of the first or second formula, wherein R⁰ is C1-6 alkyl. [0037] In some embodiments, the asymmetric hydrogenation conditions include presence of a transition metal-based asymmetric hydrogenation catalyst that includes a chiral ligand. [0038] In some embodiments, the hydrogen source is molecular hydrogen. [0039] In some embodiments, the transition metal-based asymmetric hydrogenation catalyst is an iridium (Ir) based catalyst, the Ir based catalyst including a bidentate chiral ligand coordinatively bonded to the Ir with a phosphorous and a nitrogen. [0040] In some embodiments, the Ir based catalyst is (cyclooctadiene{I-7-((di-tert- butylphosphaneyl)oxy)-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine ĸN:ĸP}iridium(I) tetrakis(3,5-bis(trifluoromethyl)phenyl)borate or having a formula of: wherein BArF- is tetrakis(3,5-bis(trifluoromethyl)phenyl)borate. [0041] In some embodiments, the process above provides the compound of the first formula: [0042] In some embodiments, wherein the Ir based catalyst is present at about 0.5 mol% to about 1.5 mol%. [0043] In some embodiments, the process is conducted in a solvent of hexafluoro-propan-2-ol (HFIP). [0044] In some embodiments, the hydrogen source includes an organic acid. In some embodiments, the hydrogen source is an azeotrope of formic acid and triethylamine. [0045] In some embodiments, the asymmetric hydrogenation conditions include presence of an asymmetric transfer hydrogenation catalyst. [0046] In some embodiments, the asymmetric transfer hydrogenation catalyst is a ruthenium (Ru) based catalyst, the Ru based catalyst including a diamine-based chiral ligand coordinatively bonded to the Ru. [0047] In some embodiments, the Ru based catalyst is ([N-[(1R,2R)-2-(Amino-κN)-1,2- diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1- methylethyl)benzene]-ruthenium) or having a formula of: . [0048] In some embodiments, the process provides the compound of the first formula: [0049] In some embodiments, the asymmetric transfer hydrogenation catalyst is present at about 3 mol% to about 7 mol%. [0050] In some embodiments, the process is conducted at a temperature of less than about 50°C. [0051] In some embodiments, the process further comprises contacting a compound of formula: with an acid under conditions sufficient to provide the compound of the third formula: [0052] In some embodiments, provided herein is a process, comprising contacting a compound of a formula of: with molecular hydrogen, at a pressure of about 400 to about 450 PSIg, in presence of bis(norbornadiene)rhodium(I) tetrafluoroborate at about 2 mol% to about 4 mol%, a chiral phosphine ligand, and an amine selected from triethylamine and N,N-diisopropylethylamine, in a protic medium, at a temperature of about 10 °C to about 50 °C, for greater than about 20 hrs., to provide a compound of the first formula: wherein R⁰ is C_1-6 alkyl. [0053] In some embodiments, the process of any embodiments above, further comprising contacting the compound of the first or the second formula with an enantiomer of phenylethylamine having a chirality opposite to that of the compound of the first or the second formula to form a salt therebetween; isolating the salt; and contacting the isolated salt with an acid to recover the compound of the first or the second formula. [0054] In some embodiments, provided herein is a compound of the formula: or a salt thereof, wherein Q is O or NR⁰, and each occurrence of R⁰ is independently H or C_1-6 alkyl. [0055] In some embodiments, provided herein is a process, comprising: contacting a compound of formula: with an acid under isomerization conditions to provide a compound of formula: contacting a product thereof with an organic hydrogen donor under asymmetric transfer hydrogenation conditions to provide a compound of formula: , wherein R⁰ is C1-6 alkyl. [0056] In some embodiments, the process further comprises contacting the compound of formula: with a compound of formula: to form a salt therebetween; and isolating the salt. [0057] In some embodiments, the asymmetric transfer hydrogenation conditions include the presence of a ruthenium (Ru) based catalyst with a chiral diamine ligand. [0058] In some embodiments, the catalyst is of formula: [0059] In some embodiments, provided herein is a compound of the formula: or a salt thereof, wherein X is halo, provided that the compound is not: . [0060] In some embodiments, provided herein is a process, comprising: forming a compound of fourth formula: from a compound of formula: contacting the compound of fourth formula with an enantiomer of phenylethylamine having a chirality opposite to that of the compound of the fourth formula to form a salt therebetween; isolating the salt; and contacting the isolated salt with an acid to recover the compound of the fourth formula. [0061] In some embodiments, the forming of the compound of the fourth formula includes: forming a compound of fifth formula: from the compound of the formula: converting the compound of the fifth formula into the compound of the fourth formula. [0062] In some embodiments, provided herein is a process for preparing a compound of formula: , comprising: contacting a compound of formula: with diphenylmethanone hydrazone under conditions suitable to provide a compound of formula: . [0063] In some embodiments, the conditions include presence of a palladium (Pd) based catalyst or a cuprous (Cu) based catalyst. [0064] In some embodiments, provided herein is a solid form having the formula: . [0065] In some embodiments, provided herein is a composition, comprising: a compound of formula: , and a compound of any one or more of: . [0066] In some embodiments, provided herein is a process, comprising: (1). forming a compound of formula: , wherein R⁰ is C1-6 alkyl; (2) forming a compound of formula: (3). contacting the compound of formula: with phosphoryl chloride under conditions suitable, and followed by hydrolyzation to form a compound of formula: (4). forming a salt of formula: (5). forming a compound of formula: forming a compound of formula: ; (6). contacting a product of step (5) with an acid to form a compound of formula: (7). contacting the product of step (6) with 5-fluoropyrimidin-2-amineto provide a compound of formula: . [0067] In some embodiments, provided herein is a crystalline form of a compound of the formula: . [0068] In some embodiments, the crystalline form is a crystalline anhydrate. [0069] In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation comprising a peak at diffraction angle 2-theta of 13.4° and one or more peaks at 8.2°, 10.1°, and 20.2°, with a tolerance for the diffraction angles of ± 0.2 degrees, wherein optionally: (a) the XRPD pattern further includes one or more peaks at 12.6°,15.4°, 16.5°, and 18.4°, with a tolerance for the diffraction angles of ± 0.2 degrees; (b) the XRPD pattern is substantially according to Figure 1; (c) the crystalline is further characterized by a differential scanning calorimetry (DSC) having an endothermic peak at about 285.3°C; (d) the crystalline is further characterized by a differential scanning calorimetry (DSC) having an endothermic onset at about 284.2°C; (e) the crystalline is further characterized by a thermogravimetric analysis (TGA) profile substantially according to Figure 3. [0070] In some embodiments, provided here is a process to prepare a compound of formula: wherein: ring B is a phenyl, or a 5-membered or 6-membered heteroaryl having 1 or 3 heteroatoms, wherein each heteroatom of the heteroaryl is independently selected from N, S, and O; R is H or C_1-6 alkyl; X is H, halo, C_1-6 alkyl optionally substituted with one or more halo, or a C_1-6 alkoxyl; Y is H, C_1-4 alkyl, or C_3-4 cycloalkyl, wherein the C_1-4 alkyl is a primary or secondary alkyl; and Z is CH or N, and wherein the process includes forming a compound of formula: according to an embodiment above. [0071] In some embodiments, provided here is a process for preparing a compound selected from Table 1: Table 1 wherein the process includes forming a compound of formula: according to an embodiment above. [0072] Additional embodiments include, for example: [0073] Embodiment 1. A process for preparing a compound of first formula: or a compound of second formula: comprising contacting a compound of third formula: with a hydrogen source under asymmetric hydrogenation conditions to provide the compound of the first or second formula, wherein R⁰ is C_1-6 alkyl. [0074] Embodiment 2. The process of embodiment 1, wherein the asymmetric hydrogenation conditions include presence of a transition metal based asymmetric hydrogenation catalyst that includes a chiral ligand. The transition metal may be, for example, Rh, Ru, Ir, and the like. [0075] Embodiment 3. The process of embodiment 1 or 2, wherein the hydrogen source is molecular hydrogen. [0076] Embodiment 4. The process of any one of embodiments 1-3, wherein the transition metal-based asymmetric hydrogenation catalyst is an iridium (Ir) based catalyst. [0077] Embodiment 5. The process of embodiment 4, wherein the Ir based catalyst includes a bidentate chiral ligand coordinatively bonded to the Ir with a phosphorous and a nitrogen. [0078] Embodiment 6. The process of embodiment 5, wherein the Ir based catalyst is selected from: , wherein BArF- is tetrakis(3,5-bis(trifluoromethyl)phenyl)borate, and COD is 1,5- cyclooctadiene. [0079] Embodiment 7. The process of embodiment 4 or 5, wherein the Ir based catalyst is (cyclooctadiene{(S)-7-((di-tert-butylphosphaneyl)oxy)-2-phenyl-6,7-dihydro-5H- cyclopenta[b]pyridine ĸN:ĸP}iridium(I) tetrakis(3,5-bis(trifluoromethyl)phenyl)borate or having a formula of: , wherein BArF- is tetrakis(3,5-bis(trifluoromethyl)phenyl)borate. [0080] Embodiment 8. The process of any one of embodiments 1-7, wherein the process provides the compound of the second formula: . [0081] Embodiment 9. The process of embodiment 4 or 5, wherein the Ir based catalyst is (cyclooctadiene{(R)-7-((di-tert-butylphosphaneyl)oxy)-2-phenyl-6,7-dihydro-5H- cyclopenta[b]pyridine ĸN:ĸP}iridium(I) tetrakis(3,5-bis(trifluoromethyl)phenyl)borate or having a formula of: wherein BArF- is tetrakis(3,5-bis(trifluoromethyl)phenyl)borate. [0082] Embodiment 10. The process of any one of embodiments 1-6 and 9, wherein the process provides the compound of the first formula: . [0083] Embodiment 11. The process of any of embodiments 7-10, wherein the Ir based catalyst is present at about 0.5 mol% to about 1.5 mol%. [0084] Embodiment 12. The process of embodiment 11, wherein the Ir based catalyst is present at a concentration of about 1 mol%. [0085] Embodiment 13. The process of any of embodiments 3-12, wherein the process is conducted in a solvent of hexafluoro-propan-2-ol (HFIP). [0086] Embodiment 14. The process of any of embodiments 3-13, wherein the molecular hydrogen is present at a pressure of about 400 to 500 PSIg. [0087] Embodiment 15. The process of any of embodiments 3-14 wherein the reaction time is greater than about 24 hrs. [0088] Embodiment 16. The process of embodiment 1 or 2, wherein the hydrogen source is an organic hydrogen donor. [0089] Embodiment 17. The process of embodiment 16, wherein the organic hydrogen donor includes an organic acid. [0090] Embodiment 18. The process of embodiment 16, wherein the organic hydrogen donor is an azeotrope of formic acid and triethylamine. [0091] Embodiment 19. The process of embodiment 18, wherein the formic acid and the triethylamine are present at a molar ratio of about 5 to about 2. [0092] Embodiment 20. The process of any one of embodiments 1 or 2, wherein the asymmetric hydrogenation conditions include presence of an asymmetric transfer hydrogenation catalyst. [0093] Embodiment 21. The process of embodiment 20, wherein the asymmetric transfer hydrogenation catalyst is a ruthenium (Ru) based catalyst. [0094] Embodiment 22. The process of embodiment 21, wherein the Ru based catalyst includes a diamine-based chiral ligand coordinatively bonded to the Ru. [0095] Embodiment 23. The process of embodiment 22, wherein the Ru based catalyst includes a ligand selected from N-Tosyl-1,2-diphenylethyl-1,2-diamine (TsDPEN), methanesulfonyl-1,2-diphenylethyl-1,2-diamine (MsDPEN), N-(2-aminocyclohexyl)-4- methylbenzenesulfonamide (TsDACH), and N-(2-amino-1,2-diphenylethyl)-2,4,6- triisopropylbenzenesulfonamide (TrisDPEN). [0096] Embodiment 24. The process of embodiment 22, wherein the asymmetric transfer hydrogenation catalyst is selected from: , , [0097] Embodiment 25. The process of embodiment 22, wherein the Ru based catalyst is ([N-[(1S,2S)-2-(Amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato- κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium) or having a formula of: . [0098] Embodiment 26. The process of any one of embodiments 1, 2, and 16-25, wherein the process provides the compound of the second formula: . [0099] Embodiment 27. The process of embodiment 22, wherein the Ru based catalyst is ([N-[(1R,2R)-2-(Amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato- κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium) or having a formula of: [0100] Embodiment 28. The process of any one of embodiments 1, 2, 16-24, and 27, wherein the process provides the compound of the first formula: . [0101] Embodiment 29. The process of any of embodiments 20-28, wherein the asymmetric transfer hydrogenation catalyst is present at about 3 mol% to about 7 mol%. [0102] Embodiment 30. The process of embodiment 25, wherein the asymmetric transfer hydrogenation catalyst is present at about 5 mol%. [0103] Embodiment 31. The process of any one of embodiments 20-27, wherein the process is conducted in a solvent of ethyl acetate. [0104] Embodiment 32. The process of any one of embodiments 20-28, wherein the process is conducted at a temperature of less than about 50°C. [0105] Embodiment 33. The process of any one of embodiments 1-32, further comprising contacting a compound of formula: with an acid under conditions sufficient to provide the compound of the third formula: . [0106] Embodiment 34. A process, comprising contacting a compound of a formula of: with molecular hydrogen under asymmetric hydrogenation conditions to provide a compound of the first formula: , wherein R⁰ is C1-6 alkyl. [0107] Embodiment 35. The process of embodiment 34, wherein the conditions include presence of a rhodium (Rh) based catalyst. [0108] Embodiment 36. The process of embodiment 35, wherein the Rh based catalyst is bis(norbornadiene)rhodium(I) tetrafluoroborate or a compound having CAS registry number of 36620-11-8. [0109] Embodiment 37. The process of embodiment 35 or 36, wherein the Rh based catalyst is present at about 2 mol% to about 4 mol%. [0110] Embodiment 38. The process of embodiment 35 or 36, wherein the Rh based catalyst is present at about 3 mol%. [0111] Embodiment 39. The process of any of embodiments 35-38, wherein the conditions include presence of a chiral phosphine ligand. [0112] Embodiment 40. The process of embodiment 39, wherein the chiral phosphine ligand is a P-chiral phosphine ligand. [0113] Embodiment 41. The process of embodiment 39, wherein the chiral phosphine ligand is a P-stereogenic C1-symmetric diphosphine ligand. [0114] Embodiment 42. The process of embodiment 39, wherein the chiral phosphine ligand is a ChenPhos ligand. [0115] Embodiment 43. The process of embodiment 42, wherein the ChenPhos ligand includes two cyclohexyl groups bonded to P. [0116] Embodiment 44. The process of embodiment 42, wherein the ChenPhos ligand is 1-(dicyclohexylphosphino)-1′-[(S)-[(1R)-2-[(1R)-1- (dimethylamino)ethyl]ferrocenyl]phenylphosphino]-Ferrocene. [0117] Embodiment 45. The process of embodiment 39, wherein the conditions include the chiral phosphine ligand at a stoichiometric ratio of about 0.01:1 to about 0.05:1 relative to the compound of formula: . In some instances, this stoichiometric ratio of about 0.02:1 to about 0.05:1. [0118] Embodiment 46. The process of embodiment 39, wherein the conditions include the chiral phosphine ligand at a stoichiometric ratio of about 1.2:1 to about 1:1 relative to the Rh based catalyst. [0119] Embodiment 47. The process of any of embodiments 34-46, wherein the conditions include contacting in a protic medium. [0120] Embodiment 48. The process of embodiment 47, wherein the process is conducted in methanol. [0121] Embodiment 49. The process of any one of embodiments 34-48, wherein the process is conducted at a temperature less than about 50°C. [0122] Embodiment 50. The process of any one of embodiments 34-49, wherein the conditions include contacting at a temperature of about 10 °C to about 50 °C. [0123] Embodiment 51. The process of any one of embodiments 34-50, wherein the conditions include molecular hydrogen at a pressure at about 0.5 MPa to about 2.5 MPa. [0124] Embodiment 52. The process of any of embodiments 34-50, wherein the conditions include molecular hydrogen at a pressure at about 1 MPa to about 2 MPa. [0125] Embodiment 53. The process of any of embodiments 34-50, wherein the molecular hydrogen is at a pressure of about 400 to about 450 PSIG. [0126] Embodiment 54. The process of any of embodiments 34-53, wherein the asymmetric hydrogenation conditions include presence of an amine. [0127] Embodiment 55. The process of embodiment 54, wherein the base is triethylamine. [0128] Embodiment 56. The process of embodiment 54, wherein the base is N,N- diisopropylethylamine. [0129] Embodiment 57. The process of any of embodiments 34-46, wherein the reaction time is greater than about 20 hrs. [0130] Embodiment 58. The process of any one of embodiments 1-57, further comprising: contacting the compound of the first or the second formula with an enantiomer of phenylethylamine having a chirality opposite to that of the compound of the first or the second formula to form a salt therebetween; isolating the salt; and contacting the isolated salt with an acid to recover the compound of the first or the second formula. [0131] Embodiment 59. The process of any one of embodiments 1-33, further comprising contacting a compound of formula: [0132] with an acid under isomerization conditions to provide the compound of third formula: . [0133] Embodiment 60. A compound of the formula: or a salt thereof, wherein Q is O or NR⁰, and each occurrence of R⁰ is independently H or C_1-6 alkyl. [0134] Embodiment 61. A compound of the formula: or a salt thereof, wherein Q is O or NR⁰, and each occurrence of R⁰ is independently H or C_1-6 alkyl. [0135] Embodiment 62. A process, comprising: contacting a compound of formula: with an acid under isomerization conditions to provide a compound of formula: contacting a product thereof with an organic hydrogen donor under asymmetric transfer hydrogenation conditions to provide a compound of formula: , wherein R⁰ is C1-6 alkyl. [0136] Embodiment 63. The process of embodiment 62, further comprising contacting the compound of formula: with a compound of formula: to form a salt therebetween; and isolating the salt. [0137] Embodiment 64. The process of embodiment 63, wherein the asymmetric transfer hydrogenation conditions include the presence of a ruthenium (Ru) based catalyst with a chiral diamine ligand. [0138] Embodiment 65. The process of embodiment 64, wherein the catalyst is of formula: . [0139] Embodiment 66. A compound of the formula: or a salt thereof, wherein Q is O or NR⁰, and each occurrence of R⁰ is independently H or C1-6 alkyl, and wherein X is halo. [0140] Embodiment 67. A process of preparing the compound of embodiment 66 or a salt thereof, comprising contacting a compound of formula: with phosphoryl halide, wherein Q is O or NR⁰, and each occurrence of R⁰ is independently H or C1-6 alkyl. [0141] Embodiment 68. A compound of the formula: or a salt thereof, wherein Q is O or NR⁰, and each occurrence of R⁰ is independently H or C_1-6 alkyl, and wherein X is halo. [0142] Embodiment 69. A process of preparing the compound of embodiment 68 or a salt thereof, comprising contacting a compound of formula: with phosphoryl halide, wherein Q is O or NR⁰, and each occurrence of R⁰ is independently H or C1-6 alkyl. [0143] Embodiment 70. A compound of the formula: or a salt thereof, wherein X is halo, provided that the compound is not: .

[0145] Embodiment 71. A process, comprising: forming a compound of fourth formula: from a compound of formula: contacting the compound of fourth formula with an enantiomer of phenylethylamine having a chirality opposite to that of the compound of the fourth formula to form a salt therebetween; isolating the salt; and contacting the isolated salt with an acid to recover the compound of the fourth formula. [0146] Embodiment 72. The process of embodiment 71, wherein the forming of the compound of the fourth formula includes: forming a compound of fifth formula: from the compound of the formula: converting the compound of the fifth formula into the compound of the fourth formula. [0148] Embodiment 73. A process for preparing a compound of formula: , comprising: contacting a compound of formula: with hydrazine under conditions sufficient to provide a compound of formula: wherein the conditions include presence of an inorganic base. [0149] Embodiment 74. The process of embodiment 73, further comprising contacting the compound of formula: with formic acid under conditions suitable to provide the compound of formula: . Embodiment 75. The process of embodiment 73 or 74, wherein the inorganic base is an inorganic hydroxide or carbonate. In some instances, the inorganic base is sodium carbonate. [0150] Embodiment 76. The process of embodiment 74 or 75, wherein the compound of formula: is contacted with the formic acid in situ. [0151] Embodiment 76A. The process of any of embodiments 73-76, wherein the conditions include the use of dimethoxyethane as the solvent. [0152] Embodiment 76B. The process of any of embodiments 73-76, wherein the conditions does not include the use of an organic amine. In some instances, by avoiding the use of organic amine, better yield and impurity control is achieved. [0153] Embodiment 77. A process for preparing a compound of formula: , comprising: contacting a compound of formula: with diphenylmethanone hydrazone under conditions suitable to provide a compound of formula: . [0154] Embodiment 78. The process of embodiment 77, wherein the conditions include presence of a palladium (Pd) based catalyst. [0155] Embodiment 79. The process of embodiment 78, wherein the Pd based catalyst is palladium acetate. [0156] Embodiment 80. The process of embodiment 77, wherein the conditions include presence of a cuprous (Cu) based catalyst. [0157] Embodiment 81. The process of embodiment 80, wherein the cuprous based catalyst is cuprous iodide. [0158] Embodiment 82. A compound, having the formula: , or a salt thereof. [0159] Embodiment 83. A process, comprising contacting a compound of formula: , with formic acid under conditions suitable to form a compound of formula: . [0160] Embodiment 84. A solid form having the formula: . [0161] Embodiment 85. The solid form of embodiment 84, wherein the solid form is a crystal. [0162] Embodiment 86. A composition, comprising: a compound of formula: , or a pharmaceutically acceptable salt of each thereof, and a compound of any one or more of: wherein: ring B is a phenyl, or a 5-membered or 6-membered heteroaryl having 1 or 3 heteroatoms, wherein each heteroatom of the heteroaryl is independently selected from N, S, and O; R is H or C_1-6 alkyl; X is H, halo, C1-6 alkyl optionally substituted with one or more halo, or a C1-6 alkoxyl; Y is H, C1-4 alkyl, or C3-4 cycloalkyl, wherein the C1-4 alkyl is a primary or secondary alkyl; and Z is CH or N. [0163] Embodiment 87. The composition of embodiment 86, wherein the compound of formula: is of formula: . Embodiment 88. A process, comprising: (1) forming a compound of formula: , wherein R⁰ is C_1-6 alkyl; (2) forming a compound of formula: according to any of embodiments 1-5, 9, 10, 16-24, 27, 28, and 34; (3) contacting the compound of formula: with phosphoryl chloride under conditions suitable, and followed by hydrolyzation to form a compound of formula: (4) forming a salt of formula: (5) forming a compound of formula: according to any of embodiments 77-81, or forming a compound of formula: according to embodiment 73 or 75; (6) contacting a product of step (5) with an acid to form a compound of formula: (7) contacting the product of step (6) with 5-fluoropyrimidin-2-amineto provide a compound of formula: . [0164] Embodiment 89. A process for preparing a compound of formula: comprising one or more steps of: forming a compound of formula: forming a compound of formula: according to any of embodiments 1-33; forming a salt of formula: forming a compound of formula: [0165] Embodiment 90. A crystalline form of a compound of the formula: . [0166] Embodiment 91. The crystalline form of embodiment 90, which is a crystalline anhydrate. [0167] Embodiment 92. The crystalline form of embodiment 90 or 91, characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation comprising a peak at diffraction angle 2-theta of 13.4° and one or more peaks at 8.2°, 10.1°, and 20.2°, with a tolerance for the diffraction angles of ± 0.2 degrees. [0168] Embodiment 93. The crystalline form of embodiment 92, wherein the XRPD pattern further includes one or more peaks at 12.6°,15.4°, 16.5°, and 18.4°, with a tolerance for the diffraction angles of ± 0.2 degrees. [0169] Embodiment 94. The crystalline form of embodiment 93, wherein the XRPD pattern is substantially according to Figure 1. [0170] Embodiment 95A. The crystalline form of any of embodiments 90-94, characterized by a differential scanning calorimetry (DSC) showing an endothermic peak at about 285.3°C. [0171] Embodiment 95. The crystalline form of any of embodiments 90-94, characterized by a differential scanning calorimetry (DSC) showing an endothermic onset at about 284.2°C. [0172] Embodiment 96. The crystalline form of any of embodiments 90-95, characterized by a thermogravimetric analysis (TGA) profile substantially according to Figure 3. [0173] In some embodiments, the catalyst loading, such as that of embodiment 34 may be reduced by selecting suitable conditions. [0174] Embodiment 97. The process of embodiment 35 or 36, wherein the Rh based catalyst is present at about 0.2 mol% to about 0.4 mol%. [0175] Embodiment 98. The process of embodiment 35 or 36, wherein the Rh based catalyst is present at about 0.3 mol%. [0176] Embodiment 99. The process of any of embodiments 35, 36, 97, and 98, wherein the conditions include presence of a chiral phosphine ligand. [0177] Embodiment 100. The process of embodiment 99, wherein the chiral phosphine ligand is a P-chiral phosphine ligand. [0178] Embodiment 101. The process of embodiment 99, wherein the chiral phosphine ligand is a P-stereogenic C1-symmetric diphosphine ligand. [0179] Embodiment 102. The process of embodiment 99, wherein the chiral phosphine ligand is a JosiPhos ligand. [0180] As compared to the ChenPhos ligand described in, for example, embodiment 42-44, the use of JosiPhos ligand allows avoidance of a base, such as DIPEA, thereby achieving better reaction stability. In some instances, the catalyst loading can be reduced. [0181] Embodiment 103. The process of embodiment 99, wherein the JosiPhos ligand includes two cyclohexyl groups bonded to P. [0182] Embodiment 104. The process of embodiment 103, wherein the JosiPhos ligand is (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine. [0183] Embodiment 105. The process of embodiment 99, wherein the JosiPhos ligand includes two phenyl groups bonded to P. [0184] Embodiment 106. The process of embodiment 105, wherein the JosiPhos ligand is (R)-1-[(SP)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine. [0185] Embodiment 107. The process of any of embodiments 99-106, wherein the conditions include the chiral phosphine ligand at a stoichiometric ratio of about 0.001:1 to about 0.005:1 relative to the compound of formula: . In some instances, this stoichiometric ratio is about 0.002:1 to about 0.004:1. [0186] Embodiment 108. The process of any of embodiments 99-106, wherein the conditions include the chiral phosphine ligand at a stoichiometric ratio of about 1.1:1 to about 1.3:1 relative to the Rh based catalyst. [0187] Embodiment 109. The process of any of embodiments 99-108, wherein the conditions include contacting in dioxane. [0188] Embodiment 110. The process of embodiment 109, wherein the process is conducted in a mixture of dioxane and methanol. [0189] Embodiment 111. The process of any one of embodiments 99-110, wherein the process is conducted at a temperature less than about 50°C. [0190] Embodiment 112. The process of any one of embodiments 99-111, wherein the conditions include contacting at a temperature of about 10 °C to about 50 °C. [0191] Embodiment 113. The process of any one of embodiments 99-112, wherein the conditions include molecular hydrogen at a pressure at about 20 bar to about 30 bar. [0192] Embodiment 114. The process of any of embodiments 99-113, wherein the asymmetric hydrogenation conditions does not include presence of a base. [0193] Embodiment 115. The process of any of embodiments 99-114, wherein the reaction time is about 2 hrs to about 4 hrs. [0194] Embodiment 116. The process of any one of embodiments 1-36 and 97-115, further comprising: contacting the compound of the first or the second formula with an enantiomer of phenylethylamine having a chirality opposite to that of the compound of the first or the second formula to form a salt therebetween; isolating the salt; and contacting the isolated salt with an acid to recover the compound of the first or the second formula. [0195] Embodiment 117. A process, comprising contacting a compound of a formula of: with molecular hydrogen under asymmetric hydrogenation conditions to provide a compound of the first formula: , wherein R⁰ is C_1-6 alkyl, and the conditions include the presence of bis(norbornadiene)rhodium(I) tetrafluoroborate and the presence of a P-stereogenic C1- symmetric diphosphine ligand. [0196] Embodiment 118. The process of embodiment 117, wherein: the P-stereogenic C1-symmetric diphosphine ligand is 1-(dicyclohexylphosphino)-1′-[(S)- [(1R)-2-[(1R)-1-(dimethylamino)ethyl]ferrocenyl]phenylphosphino]-Ferrocene at a stoichiometric ratio of about 0.02:1 to about 0.04:1 relative to the compound of formula: , and about 1.2:1 to about 1:1 relative to the bis(norbornadiene)rhodium(I) tetrafluoroborate, and the contacting is conducted in an alcoholic medium at a temperature of about 20 °C to about 40 °C with the molecular hydrogen at a pressure at about 1 MPa to about 2 MPa in presence of an amine for a duration greater than about 20 hrs. [0197] Embodiment 119. The process of embodiment 117, wherein: the P-stereogenic C1-symmetric diphosphine ligand is (R)-1-[(SP)-2- (diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine at a stoichiometric ratio of about 0.002:1 to about 0.004:1 relative to the compound of formula: , and about 1.1:1 to about 1.3:1 relative to the bis(norbornadiene)rhodium(I) tetrafluoroborate, and the contacting is conducted at a temperature of about 20 °C to about 40 °C with the molecular hydrogen at a pressure at about 20 bar to about 30 bar in absence of an amine for a duration of about 2 hrs to about 4 hrs. [0198] As used herein, the term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, straight, or branched chain hydrocarbon group containing one or more carbon atoms. [0199] As used herein, the term “aryl”, used alone or as part of a larger moiety, refers to an aromatic hydrocarbon group, having 6, 10, or 14 π-electrons shared in a cyclic array. Aryl can be monocyclic (having one ring), bicyclic (having two rings), or polycyclic (having two or more rings). Exemplary aryl includes phenyl, naphthyl, anthracenyl, and phenanthrenyl. [0200] As used herein, the term “chiral phosphine ligand” refers to a class of organophosphine compounds useful as ligands to metals to form metal complexes, where the chirality arises either from their carbon backbone or from the phosphorous. The term “P-chiral phosphine ligand” refers to a subset of “chiral phosphine ligand” where the chirality arises from a stereogenic phosphorous atom (P*). Examples of chiral phosphine ligands and P-chiral phosphine ligands are described in Imamoto, et. al., Proc. Jpn. Acad. Ser. B. Phys. Biol. Sci.2021, Nov 11; 97(9): 520–542. [0201] As used herein, the term “ChenPhos” refers to a class of chiral phosphine ligands, such as those described in Chen, W., et al., Angew. Chem. Int. Ed., 52: 8652-8656. For example, ChenPhos may have a structure of formula: wherein each occurrence of R is, independently, optionally substituted aryl or alkyl. Examples of suitable R group include cyclohexyl, phenyl, t-butyl, isopropyl, ethyl, 4-fluorophenyl (4- FC₆H₄), 4-trifluromethylphenyl (4-CF₃C₆H₄), 2-norbornyl, 2-furyl, o-anisidyl, 3,5- dimethylphenyl (3,5-(CH₃)₂C₆H₃), 3,5-di-trifluoromethylphenyl (3,5-(CF₃)₂C₆H₃), 3,5- dimethyl-4-methoxy-phenyl (3,5-(CH3)2-4-(CH3O)-C6H2), 1-naphthyl, among others. ChenPhos, along with others, is a subset of P-chiral phosphine ligands. [0202] As used herein, the term “JosiPhos” refers to a class of chiral diphosphine ligands, such as those described in H. U. Blaser, B. Pugin, F. Spindler, Helv. Chim. Acta 2021, 104, e2000192. For example, JosiPhos may have a general structure of formula: . wherein each occurrence of R and R’ is independently optionally substituted aryl or alkyl. Examples of suitable R and R’ groups include cyclohexyl, phenyl, t-butyl, xylyl, 3,5- bis(trifluoromethyl)phenyl, and p-trifluoromethylphenyl, among others. JosiPhos is also a subset of P-chiral phosphine ligands. [0203] As used herein, the term “cycloalkyl” refers to a saturated ring system containing at least three carbon atoms. Cycloalkyl can be monocyclic (having one ring), bicyclic (having two rings), or polycyclic (having two or more rings). Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. [0204] As used herein, the term “carbocycle” refers to a saturated or unsaturated ring system containing only carbons. Carbocycles include cycloalkyls and aryls and partially saturated rings. [0205] As used herein, the term “halo” refers to halogen as a substituent, and specifically chloro, fluoro, bromo, or iodo. [0206] As used herein, the term “heterocyclic” and “heterocycle” refers to an optionally substituted saturated ring system containing at least two carbon atoms and at least one heteroatom. Exemplary heteroatoms are oxygen, nitrogen, and sulfur. Exemplary heterocyclic rings (or heterocycles) include oxirane, aziridine, oxetane, oxolane, pyrrolidine, piperidine, and morpholine. Heterocycles can be monocycles (having one ring), bicycles (having two rings), or polycycles (having two or more rings) that may be, for example, fused with each other. [0207] As used herein, the term “heteroaryl” refers to groups having 5 to 10 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6, 10, or 14 π-electrons shared in a cyclic array, and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. The term “bicyclic heteroaryl” includes groups in which a heteroaryl ring is fused to one or more aryl, or heteroaryl rings. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, and quinoxalinyl. [0208] When there are two or more rings, the rings may be arranged separate from each other or connected with each other. When two rings are connected with each other, they may be connected in a “fuse” arrangement (or connection motif), a “spiro” arrangement, or a “bridge” arrangement. As used herein, the term “fuse” refers to an arrangement where the two rings are connected with each other, side-by-side, sharing two “bridgehead” atoms that are directly and immediately connected to each other. The “fuse” connection motif differs from “spiro” connection motif in that there is one and only one “bridgehead” atom in the “spiro” motif; and differs from “bridge” connection motif in that the two “bridgehead” atoms are not immediately connected to each other in the “bridge” motif. When a first ring is “fused with” a second ring, the "bridgehead” atoms are construed as belonging to both rings. Accordingly, if an embodiment provided here describes one such ring being a six-membered “carbocycle,” then the six ring atoms include two “bridgehead” atoms and four additional atoms. And all these six ring atoms are carbons in order to _{be a “carbocycle.” For example, the group} _{falls outside the scope of “a 5-membered} heteroaryl fused with a 6-membered carbocycle” because one bridgehead atom is not carbon. [0209] As used herein, the term “oxo” refers to the oxygen atom as a substituent connected to another atom by a double bond. It may be denoted as “=O”. The term oxo is the carbonyl group less the carbon atom. [0210] As used herein, the term “ortho-”, “meta-” and “para-” refers to the relative position between two substituents on a ring system. When two substituents are immediately adjacent to each other (i.e. directly bonded to two adjacent ring atoms), they are referred to as “ortho-” relative to each other. When they are separated by one other ring atom (in addition to the two ring atoms they are bonded to), they are referred to as “meta-” relative to each other. For a 6-membered ring system, when the two substituents are separated by two other ring atoms (in addition to the two ring atoms they are bonded to), they are referred to as “para-" relative to each other. For example, for the formula (A) below, A¹ and A², A² and A³, A³ and A⁴, A⁴ and A⁵, and A⁵ and A¹ are each considered ortho- relative to each other; A¹ and A³, A² and A⁴, A³ and A⁵, A⁴ and A¹, and A⁵ and A² of are each considered meta- relative to each other. For example, for the formula (B) below, A¹ and A², A² and A³, A³ and A⁴, A⁴ and A⁵, A⁵ and A⁶, and A⁶ and A¹ are each considered ortho- relative to each other; A¹ and A³, A² and A⁴, A³ and A⁵, A⁴ and A⁶, and A⁵ and A¹, and A⁶ and A² are each considered meta- relative to each other; A¹ and A⁴, A² and A⁵, and A³ and A⁶, are each considered para- relative to each other. (_{A) (B)} [0211] As used herein, represents a bond that is part of an aromatic system. It may be properly and alternatively represented as a single bond or double bond depending on how the aromatic system is depicted. For example, may be used to represent a 5-membered carbocycle fused with an aromatic system, such as a phenyl ring, at the two attachment points. The bond may be properly represented as a single bond (e.g. as part of ) or as a double bond (e.g. as part [0212] As used herein, the term “stereoisomer” refers to an isomer made up of the same atoms bonded by the same bonds but having different and non-interchangeable structures in the three- dimensional space. The term of stereoisomer includes “enantiomer” which refers to two stereoisomers that are mirror images of one another and are not superimposable over one another. A one-to-one mixture of a pair of enantiomers is referred to as a “racemic” mixture. The term of stereoisomer also includes “diastereoisomers” (or “diastereomer”) which refers to two stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry of a stereoisomer may be specified according to the Cahn- Ingold Prelog R S system, where the stereochemistry at each chiral center is designated as either R or S. When stereoisomers are resolved yet whose absolute configuration is unknown, those stereocenters are designated (+) or (−) depending on the direction (dextro- or laevorotary) that they rotate the plane of polarization at the wavelength of the sodium D line. Unless explicitly stated otherwise, “enantiomer 1” refers to the enantiomer that eludes out first from the column during chiral separation of a racemic mixture under a stated separation condition; and “enantiomer 2” refers to the enantiomer that eludes out the second during the same separation. Occasionally, the order of elution differs between a preparatory column (e.g. for separation) and an analytical column (e.g. for purity assessment). For clarity, the designation of “enantiomer 1” and “enantiomer 2” is based on preparatory column. Moreover, there may be multiple stereocenters and two separations may be necessary to fully resolve the stereoisomers. For example, a first separation results in two bands, the first band eluting out including “enantiomer 1/1” and “enantiomer 1/2", and the second band eluting out including “enantiomer 2/1” and “enantiomer 2/2". A subsequent separation (e.g. using the same or different column conditions) may be used to resolve between “enantiomer 1/1” (the first eluting band in the subsequent separation) and “enantiomer 1/2" (the second eluting band in the subsequent separation). [0213] As used herein, the term “immune-mediated disease” encompasses a group of autoimmune or inflammatory disorders in which immunological pathways play an important etiological and/or pathogenetic role. Such diseases are sometimes characterized by an alteration in cellular homeostasis. Immune-mediated diseases may be triggered by environmental factors, dietary habits, infectious agents, and genetic predisposition. Immune-mediated disease includes, for example, psoriasis, atopic dermatitis, ulcerative colitis, Crohn’s disease, graft-versus-host disease, rheumatoid arthritis, and multiple sclerosis. Immune-mediated diseases may be mediated by auto- antibodies, T cells, cytokines, complement, or others. [0214] As used herein, the term “asymmetric hydrogenation” refers to a spatial selective hydrogenation reaction of an unsaturated substrate molecule, such as alkene, that introduces chirality in the product. Asymmetric hydrogenation may utilize molecular hydrogen as the source of hydrogen atoms or may instead use an organic hydrogen donor. The term “organic hydrogen donor” refers to an organic compound that has active hydrogen atoms that is released during the hydrogenation reaction. [0215] The term “asymmetric transfer hydrogenation” refers to one subcategory of “asymmetric hydrogenation” where an organic hydrogen donor is used as the hydrogen source rather than molecular hydrogen. [0216] The term “transition metal-based” when used to characterize a compound, such as a catalyst, provides that the compound includes a transition metal ion. [0217] The term “PSIg” is an abbreviation of “Pounds per Square Inch Gauge”, and is a unit of pressure that measures the pressure above atmospheric pressure. [0218] The term “azeotrope” refers to a mixture of two or more fluidic components whose proportions are not altered during distillation. In other words, when an azeotrope is boiled, the vapor has the same proportions of constituents as the unboiled mixture. [0219] The term “CAS” refers to Chemical Abstract Services. CAS assigns an identification number to chemical substances in open literature, known as “CAS registry number”. [0220] The term “catalyst” refers to chemical substances that increase the rate of a chemical reaction without itself being consumed. As used herein, the term “catalyst” also incorporates precursor to the catalyst, or “pre-catalyst”, that is converted to the true catalyst in the reactor. [0221] The term “protic medium” refers to a medium that is capable of donating protons. Protic medium include, for example, water, methanol, ethanol, formic acid, among others. Certain abbreviations are as follows: “tBuOK” refers to potassium tert-butoxide; “DABCO” refers to triethylenediamine; “DCM” refers to dichloromethane; DIPEA refers to N,N-diisopropylethylamine; “DMA” refers to dimethylacetamide; “DMDACH” refers to trans- N,N′-dimethyl-1,2-diaminocyclohexane; “DME” refers to dimethyl ether; “DMF” refers to dimethylformamide; “DMSO” refers to dimethyl sulfoxide; “EtOH” refers to ethanol; “HPLC” refers to high-performance liquid chromatography; “hr/hrs” refers to hour or hours; Josiphos SL-J009-1” refers to (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert- butylphosphine; “Josiphos SL-J002-1” refers to (R)-1-[(S_P)-2- (diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; “LC/MS” refers to Liquid chromatography/mass spectrometry; “MeCN” refers to acetonitrile; “MeOH” refers to methanol; “MTBE” refers to methyl tert-butyl ether; “NMP” refers to N-methyl-2-pyrrolidone; “PhCl” refers to chlorobenzene; “TFA” refers to trifluoroacetic acid; and “THF” refers to tetrahydrofuran; Cp* refers to pentamethylcyclopentadienyl (η⁵-C(CH3)5). [0222] Moreover, (R,R)-Ms-DENEB refers to Chloro[N-[(1R,2R)-2-[(S)-[2-[[(1,2,3,4,5,6-η)-4- methylphenyl]methoxy]ethyl]amino-κN]-1,2- diphenylethyl]methanesulfonamidato-κN]ruthenium; (R,R)-TsDPEN RuCl (p-cymene) refers to [N-[(1R,2R)-2-(Amino-κN)-1,2-diphenylethyl]-4- methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1- methylethyl)benzene]ruthenium; Cp*(R,R)-TsDPEN IrCl refers to [N-[(1R,2R)-2-(Amino-κN)-1,2- diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5-η)- pentamethylcyclopentadienyl]iridium.

Preparation of (S)-N-(5-Fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H- cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide Scheme A [0223] In Step 1, cyclopentane-1,3-dione in toluene is reacted with N,N-dimethylformamide dimethyl acetal at a suitable temperature (for example, about 30-40 °C) to give intermediate compound 2. [0224] In Step 2, intermediate compound 2 is reacted with methyl 2-cyanoacetate in the presence of toluene, and a solvent such as DCM, and at a suitable temperature (for example, about 25-35 °C) to give compound 3. [0225] In Step 3, compound 3 is contacted with acetic acid in the presence of toluene under suitable conditions (for example, at a temperature of about 110 °C) to allow for intramolecular cyclization, giving compound 4. [0226] Step 4 depicts a Wittig reaction in which compound 4 is contacted with methyltriphenylphosphonium bromide, and a strong base such as potassium tert-butoxide in a solvent such as toluene, and at a suitable temperature (for example, at about 35-45 °C) to give compound 5. [0227] Step 5 shows conversion of compound 5 to compound 6 by contacting compound 5 with a rhodium catalyst such as bis(norbornadiene)rhodium(I) tetrafluoroborate, and a ChenPhos phosphine ligand, such as 1-(dicyclohexylphosphino)-1′-[(S)-[(1R)-2-[(1R)-1- (dimethylamino)ethyl]ferrocenyl]phenylphosphino]ferrocene under suitable conditions, (for example, temperature of about 20-30 °C, in presence of an amine such as DIPEA), in a solvent such as MeOH. Alternatively, the phosphine ligand may be a JosiPhos ligand, such as (R)-1-[(S_P)-2- (dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine, or (R)-1-[(S_P)-2- (diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine, under suitable conditions, (for example, temperature of about 20-30 °C in absence of any amine), in a solvent such as dioxane. [0228] Step 6 depicts a chlorination reaction, in which compound 6 is contacted with PhCl and POCl3 under suitable conditions, such as a temperature of about 80-100 °C to give compound 7. [0229] Step 7 depicts a hydrolysis reaction in which compound 7 is contacted with a base such as KOH, in solvents such as MeOH and H₂O and at a temperature of about 25 °C to give compound 8. [0230] Step 8 depicts chiral purification of compound 8 by reacting compound 8 with (S)-(-)-1- phenylethylamine, in the presence of MeCN, and MeOH and at a suitable temperature of about 20- 60 °C. The reaction mixture is filtered to give compound 9. [0231] In Step 9, the (S)-(-)-1-phenylethylamine in compound 9 is removed by contacting compound 9 with H₂O, and an acid such as HCl at a suitable temperature (for example, about 20-30 °C) to give a chiral pure compound 10. [0232] In Step 10, the chiral pure compound 10 is contacted with hydrazine in the presence of a solution made of KCl, DIPEA, and NMP at a suitable temperature (for example, about 110-125 °C) to allow for substitution giving compound 11. Alternatively, the chiral pure compound 10 is contacted with hydrazine in the presence of sodium carbonate in dimethoxyethane (DME) at a suitable temperature (for example, about 70-9 °C) to provide the compound 11. [0233] Step 11 depicts an intramolecular cyclization reaction in which compound 11 is converted to compound 12 by contacting compound 11 with formic acid, under suitable conditions, for example at a temperature of about 90-100 °C. [0234] Step 12 depicts an amide coupling reaction in which compound 12 is reacted with 5- fluoropyrimidin-2-amine in the presence of a solvent such as MeCN, a base such as pyridine, and a coupling agent such as bis(2-oxo-3-oxazolidinyl)phosphinic chloride, under suitable conditions, such as a temperature of about 15-25 °C., to give compound 13. [0235] Step 13 depicts crystallization of compound 13 by contacting compound 12 with a mixture of MeOH and methoxybenzene at a temperature of about 50 to 70 °C, then seeding with 1% seed, adding MTBE, and cooling to give the crystallized compound 13A. Scheme B [0236] Alternatively, compound 13 can be prepared using Scheme B. Scheme B is similar to Scheme A but differs on Step 5 and 5a. Steps 1 through 4 of Scheme B are as described in Scheme A. [0237] In Step 5, compound 5 is contacted with an acid (such as TFA) in a solvent (such as DCM) at 0 °C to give compound 5a. [0238] Compound 5a is converted to compound 6 by contacting compound 5a with asymmetric transfer hydrogenation ruthenium catalysts such as (R,R)-TsDPEN RuCl (p-cymene) (CAS Registry No.192139-92-7) or (R,R)-Ms-DENEB RuCl (CAS Registry No.1333981-86-4), or (Cp*) (R,R)-TsDPEN IrCl in the presence of a hydrogen source (such as formic acid and triethylamine combination, or formic acid and DABCO combination), and a solvent (such as ethyl acetate, or DCM) at a temperature of about 30 °C. One skilled in the art will recognize that there are many other asymmetric transfer hydrogenation catalysts, ligand, hydrogen source, and solvent combinations that may be used to perform this transformation. [0239] Alternatively, an iridium catalyst may be used instead along with molecular hydrogen as the hydrogen source. For example, compound 5 may be contacted with as an iridium catalyst including a bidentate chiral ligand coordinatively bonded to the Ir with a phosphorous and a nitrogen, in presence of a base (such as DIPEA), under hydrogen atmosphere, in a suitable solvent (such as HFIP), to form compound 6. [0240] In Step 10, the chiral pure compound 10 is contacted with hydrazine in the presence of a base (such as NaOH, DIPEA, KF, Na₂CO₃, or K₂CO₃) in a solvent (such as dioxane, NMP, DME or H2O) at a suitable temperature (for example, about 80-135 °C) to give compound 11. [0241] All the other steps on Scheme B are substantially the same as the steps of Scheme A.

Scheme C [0242] Scheme C uses a process similar to steps 10, 11, and 12 of Schemes A and B. Instead of inorganic hydrazine, Scheme C uses an organic hydrazone, such as diphenylmethanone hydrazone. Compound 10 is contacted with the organic hydrazone, a palladium catalyst such as palladium acetate, a diphosphine ligand such as Josiphos SL-J009-1 (CAS registry No.158923-11-6), in the presence of a base such as sodium tert-butoxide, in solvents such as methyl tetrahydrofuran, and DME, and at a temperature of about 80 °C to give compound 11. [0243] Alternatively, Compound 10 can be contacted with an organic hydrazone such as diphenylmethanone hydrazone, a cuprous catalyst such as cuprous iodide (CuI), a ligand such as DMDACH, in the presence of a base such as potassium carbonate, in solvents such as methyl tetrahydrofuran or DMA, and at a temperature of about 90 °C to give compound 11. [0244] While Schemes A-C illustrate the process using compound 13 as the final product as an example, a person skilled in the art understands that other compounds, such as compounds of Table 1, can be prepared following the same procedures. Preparation of (5S)-2-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3- carboxylic acid Step 1 (E)-2-(2-Cyano-3-methoxy-3-oxoprop-1-en-1-yl)-3-oxocyclopent-1-en-1-olate dimethylammonium [0245] To a solution of cyclopentane-1,3-dione (79.1 kg, 806 mol) in toluene (237.3L, 3 V) was added DMF-DMA (N,N-dimethylformamide dimethyl acetal) (115 kg, 965 mol) at 0 -10 °C. The reaction mixture was stirred at 30-40 °C for 15 hrs. Toluene (158.2 L), DCM (158.2 L) and methyl 2-cyanoacetate (96.36 kg, 972 mol) were charged into a reactor at 0 -10 °C. The reaction mixture was stirred at 25-35 °C for 15 hrs. After cooling, the reaction mixture was filtered and washed with toluene (316 L). The cake was dried at 45-55 °C under vacuum to give the title compound as a brown-yellow solid (193 kg, assay 94.4%, 94.9% assay yield of two steps: 99.6% HPLC purity). LC/MS: calculated 252.11 (C12H16N2O4), observed [M+H]⁺ = 208.06 (without dimethyl amine counter ion).¹H NMR (DMSO-d6): δ ppm 2.10-2.30 (m, 4 H), 2.55 (s, 6 H), 3.65 (s, 3 H), 7.62 (s, 1 H), 7.97 - 8.38 (brs, 1 H). Step 2 Methyl 2,5-dioxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [0246] Acetic acid (520 kg, 8,659 mol) was added to a solution of (E)-2-(2-cyano-3-methoxy- 3-oxoprop-1-en-1-yl)-3-oxocyclopent-1-en-1-olate dimethylammonium (182 kg, 722 mol) in toluene (9100 L, 50 V) at 0 -10 °C. The reaction mixture was stirred at 105-115 °C for 18 hrs. After cooling, the reaction mixture was filtered and washed with toluene (728 L, 4 V). The cake was dried at 45-55 °C under vacuum to give the title compound as a brown solid (108.5 kg, assay: 90.0%, assay yield: 65.3%, 95.6% HPLC purity). LC/MS: calculated 207.05 (C₁₀H₉NO₄), observed [M+H]⁺ = 208.06.¹H NMR (DMSO-d6): ppm 2.45-2.65 (m, 2 H), 2.90-3.10 (m, 2 H), 3.75 (s, 3 H), 8.06 (s, 1 H), 12.90 (brs, 1 H). Step 3 Methyl 5-methylene-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [0247] To a solution of Ph₃PCH₃Br (646 kg, 1,809 mol) and tBuOK (solid, 195kg, 1,738 mol) in toluene (300 L, 40 V) was added methyl 2,5-dioxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine- 3-carboxylate (75 kg, 347 mol.) at 20-30 °C. The reaction mixture was stirred at 35-45 °C for 24 hrs. After cooling, diatomaceous earth (150kg, 2.0X) was charged into the reactor, and the slurry filtered. The filter cake with absolute EtOH (50V) was filtered and dispersed with NaH2PO4/Na2HPO4 buffer (8V, pH: 6.2-6.8) and 5% citric acid solution (5V). The mixture was extracted with DCM (20V), concentrated under vacuum, filtered, and crystalized with DCM/n- heptane (2V/8V) to give the title compound as a brown solid (31.7 kg, assay: 81.7%, assay yield: 34.1%, 76.0% HPLC purity). LC/MS: calculated 205.07 (C11H11NO3), observed [M+H]⁺ = 206.08. ¹H NMR (DMSO-d6): ppm 2.66 - 2.74 (m, 2 H), 2.82 - 2.88 (m, 2 H), 3.74 (s, 3 H), 4.70-4.85 (m, 1 H), 5.10-5.25 (m, 1 H), 8.20 (s, 1 H), 12.49 (brs, 1 H). Step 4A Methyl (S)-5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [0248] A mixture of bis(norbornadiene)rhodium(I) tetrafluoroborate (Rh(NBD)₂BF₄) (1.1 kg, 2.9 mol) and 1-(dicyclohexylphosphino)-1′-[(S)-[(1R)-2-[(1R)-1- (dimethylamino)ethyl]ferrocenyl]phenylphosphino]ferrocene (CAS: 952586-19-5, 2.29 kg, 3.0 mol) in MeOH (92.8 L, 4V) under N₂ atmosphere was charged into a reactor and stirred at 20-30 °C for 1-3 hrs. MeOH (325 L, 14V) and methyl 5-methylene-2-oxo-2,5,6,7-tetrahydro-1H- cyclopenta[b]pyridine-3-carboxylate (23.2 kg, 111 mol) were charged into the reactor, and swapped with H₂ three times. The reaction mixture was stirred at 5-15 °C under 2.8-3.2 MPa H₂ for 40-55 hrs. The reaction mixture was filtered to give the title compound as a MeOH solution (131.6 kg, assay: 1.3%, assay yield: 84.7%, 71.7% HPLC purity, 91.4% chiral purity). LC/MS: calculated 207.09 (C11H13NO3), observed [M+H]⁺ = 208.10.¹H NMR (DMSO-d6): ppm 1.15 (d, J=6.78 Hz, 3 H), 1.49-1.61 (m, 1 H), 2.19-2.32 (m, 1 H), 2.70-2.80 (m, 2 H), 2.97-3.05 (m, 1 H), 3.71 (s, 3 H) 7.95 (s, 1 H) 12.23 (brs, 1 H). Step 4B (alternative method) Methyl (S)-5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [0249] A mixture of bis(norbornadiene)rhodium(I) tetrafluoroborate (Rh(NBD)2BF4) (0.44 kg, 1.29 mol) and (R)-1-[(S_P)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (CAS 155830-69-60.76 kg, 1.4 mol in MeOH (165 L, 2V) and dioxane (1063 L, 13V) under N₂ atmosphere was charged into a reactor and stirred at 20-30 °C for 1-3 hrs. Methyl 5-methylene-2- oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (80.0 kg, 389 mol) were charged into the reactor, and swapped with H₂ three times. The reaction mixture was stirred at 20-305 °C under 2.8-3.2 MPa H2 for 10-20 hrs. The reaction mixture was filtered to give the title compound as a dioxane/MeOH solution (1294.2 kg, assay: 5.1%, assay yield: 81.9%, 79.4% HPLC purity, 84,3% chiral purity). LC/MS: calculated 207.09 (C₁₁H₁₃NO₃), observed [M+H]⁺ = 208.10.¹H NMR (DMSO-d6): ppm 1.15 (d, J=6.78 Hz, 3 H), 1.49-1.61 (m, 1 H), 2.19-2.32 (m, 1 H), 2.70-2.80 (m, 2 H), 2.97-3.05 (m, 1 H), 3.71 (s, 3 H) 7.95 (s, 1 H) 12.23 (brs, 1 H). Step 5 (S)-2-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid [0250] To a solution of methyl (S)-5-methyl-2-oxo-2,5,6,7-tetrahydro-1H- cyclopenta[b]pyridine-3-carboxylate (38.6 kg, 186 mol) in PhCl (5 V) was added POCl3 (86 kg, 561 mol) at 20-30 °C. The reaction mixture was stirred at 85-99 °C for 40-50 hrs. The mixture was diluted with 2-MeTHF and quenched with H2O at 20-30 °C, then charged with 30% wt. KOH and stirred at 20-30 °C for 24 hrs. The reaction solution was diluted with 10V H2O and 25V 2-MeTHF, pH adjusted to 2.0 with concentrated HCl then filtered with 2X diatomaceous earth. The organic phase was separated and swapped with acetone (5V*3). The mixture solution (acetone) was decolored at 20-30 °C for 8-16 hrs., through CUNO filter. (S)-2-chloro-5-methyl-6,7-dihydro-5H- cyclopenta[b]pyridine-3-carboxylic acid solution in acetone was obtained (34.4 kg, 87.3% assay yield, 90.3% HPLC purity, 93.6% chiral purity). LC/MS: calculated 211.04 (C₁₀H₁₀ClNO₂), observed [M+H]⁺ = 212.05.¹H NMR (DMSO-d6): δ ppm 1.26 (d, J=6.78 Hz, 3 H) 1.57-1.70 (m, 1 H) 2.29 -2.40 (m, 1 H) 2.87-2.95 (m, 2 H) 3.18-3.24 (m, 1 H) 7.99 (s, 1 H). Purification of (S)-2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3- carboxylic acid (S)-1-Phenylethan-1-amine (S)-2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3- carboxylate [0251] To a solution of (5S)-2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3- carboxylic acid (34.4 kg, 163 mol) in MeCN (10V)/MeOH (1V) was added (S)-(-)-1- phenylethylamine (22.5 kg, 186 mol) at 20-55 °C. The reaction mixture was stirred at 20-30 °C for 4-12 hrs. The mixture was filtered and dried to provide [(1S)-1-phenylethyl]ammonium (5S)-2- chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate as a white solid (42.3 kg, 68.3% assay yield, 100% HPLC purity, 99% chiral purity). LC/MS: calculated 211.04 (C10H10ClNO2), observed [M+H]⁺ = 212.05.¹H NMR (DMSO-d6): ppm 1.22 (d, J=6.78 Hz, 3 H) 1.47 (d, J=6.78 Hz, 3 H) 1.50-1.68 (m, 1 H) 2.23-2.38 (m, 1 H) 2.77-2.87 (m, 2 H) 3.10-3.20 (m, 1 H) 4.33 (q, J=6.69 Hz, 1 H) 7.30-7.43 (m, 3 H) 7.45-7.51 (m, 2 H) 7.55 (s, 1 H) Step 2 (S)-2-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid [0252] To a solution of [(1S)-1-phenylethyl]ammonium (5S)-2-chloro-5-methyl-6,7-dihydro- 5H-cyclopenta[b]pyridine-3-carboxylate (42.3 kg, 127.7 mol) in H2O (11 V) was added 1.0M HCl at 20-30 °C. The reaction mixture was stirred at 20-30 °C for 3 hrs., filtered, and dried to give the title compound as a white solid (23.9 kg, 98.6% assay, 90.3% assay yield, 99.8% HPLC purity, 99.0% chiral purity). LC/MS: calculated 211.04 (C10H10ClNO2), observed [M+H]⁺ = 212.05.¹H NMR (DMSO-d6): δ ppm 1.26 (d, J=6.78 Hz, 3 H) 1.57-1.70 (m, 1 H) 2.29 -2.40 (m, 1 H) 2.87- 2.95 (m, 2 H) 3.18-3.24 (m, 1 H) 7.99 (s, 1 H) Preparation of (S)-6-Methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3- a]pyridine-4-carboxylic acid Method 1: Use of Inorganic Hydrazine [0253] To a solution of (S)-2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3- carboxylic acid (23.5 kg, 111 mol) in NMP (8 V) was added KCl (17.6 kg, 236 mol), DIPEA (30 kg, 232 mol), and 80% wt. hydrazine hydrate (68.0 kg, 1,360 mol) at 15-25 °C. The reaction mixture was stirred at 90-100 °C for 24 hrs., then cooled to 15-25 °C. Formic acid (165 L) was charged into the reactor and stirred at 90-100 °C for 5 hrs. Acetone (34V) was charged into the reactor and stirred at 5-15 °C. The product was precipitated and filtered. The wet cake was slurried with H2O (20V), filtered, crystalized with formic acid/THF (2V/13V), filtered, and dried to give the title compound as a white solid (9.2 kg, 96.8% assay, 36.9% assay yield, 99.2% HPLC purity). LC/MS: calculated 217.09 (C₁₁H₁₁NO₃), observed [M+H]⁺ = 218.09.¹H NMR (DMSO-d6): ppm 1.28 (d, J=6.78 Hz, 3 H) 1.80 (ddt, J=12.99, 9.16, 6.74, 6.74 Hz, 1 H) 2.51 - 2.57 (m, 1 H) 3.13 - 3.22 (m, 1 H) 3.23 - 3.29 (m, 1 H) 3.30 - 3.38 (m, 1 H) 8.00 (s, 1 H) 9.33 (s, 1 H). [0254] Alternatively, the reaction was carried out in the presence of NaOH as a base, and DME as a solvent. (S)-2-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (1 g, 4.72 mmol), NaOH (0.37 g, 9.4 mmol), DME (5V), and 80% wt. hydrazine hydrate (6.0 g, 94 mmol) were added together at 15 to 25 °C. The temperature was raised to 75-85 °C., and the reaction mixture stirred for 72 hrs. at this temperature, then cooled to 40-50 °C. The reaction gave the hydrazine intermediate that was used in the next step allowing intramolecular cyclization to give (S)-6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid. [0255] In a further alternative method, Na₂CO₃ was used as a base, in DME (5V) as the solvent. (S)-2-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (5 g, 23.6 mmol), Na₂CO₃ (5 g, 47.2 mmol), DME (5V), and 80% wt. hydrazine hydrate (30 g, 480 mmol) were added together at 15 to 25 °C. The temperature was raised to 75-85 °C., and the reaction mixture stirred for 72 hrs., at this temperature, then cooled to 40-50 °C. The reaction gave the hydrazine intermediate that was used in the next step allowing intramolecular cyclization to give (S)-6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid. Method 2: Use of organic hydrazone [0256] 2-MeTHF (5 V), Pd(OAc)₂ (0.26 g, 1.2 mmol), Josiphos SL-J009-1 (CAS registry No. 158923-11-6, 1.11 g, 1.2 mmol), were mixed together at 20-30 °C., under nitrogen atmosphere, and stirred for 0.5 hrs. 2-MeTHF (15V) was then added. A mixture of (S)-2-chloro-5-methyl-6,7- dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (5 g, 23.6 mmol), diphenylmethanone hydrazone (6.9 g, 35.4 mmol), t-BuONa (5.4 g, 56.6 mmol), was added and stirred at 75-85 °C for 16-18 hrs., then cooled to 40-50 °C. The temperature of the mixture was then adjusted to 15-25 °C for 3-5 hrs., and the mixture filtered and washed with 2-MeTHF (2V x2). The wet cake was charged with 2-MeTHF (15 V), and stirred at 40-50 °C for 1-3 hrs., cooled to 15-25°C., and stirred for 3-5 hrs. The reaction was filtered and washed with 2-MeTHF (2V x2). The wet cake was dried for 16 hrs. at 45-55 °C to give the hydrazone intermediate, (S)-2-(2- (diphenylmethylene)hydrazineyl)-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid), which undergoes intramolecular cyclization under suitable conditions such as presence of formic acid at 100 °C to give (S)-6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3- a]pyridine-4-carboxylic acid. [0257] Alternatively, a cuprous catalyst can be used instead of the palladium catalyst to give the hydrazone intermediate, (S)-2-(2-(diphenylmethylene)hydrazineyl)-5-methyl-6,7-dihydro-5H- cyclopenta[b]pyridine-3-carboxylic acid) . In this reaction, DMA (15 V), CuI (7.2 mg, 0.038 mmol.), K₂CO₃ (78.8 mg, 0.57 mmol), (S)-2-chloro-5-methyl-6,7-dihydro-5H- cyclopenta[b]pyridine-3-carboxylic acid (40 mg, 0.19 mmol), diphenylmethanone hydrazone (74.2 mg, 3.8 mmol), and DMDACH (10.8 mg, 0.076 mmol) are added together at 20-30 °C under nitrogen atmosphere. The temperature is adjusted to 85-95 °C., and the mixture stirred at this temperature for 16-18 hrs., then cooled to 40-50 °C to give the hydrazone intermediate which is used in the next step allowing intramolecular cyclization to give (S)-6-methyl-7,8-dihydro-6H- cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid. Preparation of (S)-N-(5-Fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H cyclopenta[e][1,2,4]triazolo[4,3- a]pyridine-4-carboxamide (S)-N-(5-Fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H cyclopenta[e][1,2,4]triazolo[4,3- a]pyridine-4-carboxamide [0258] To a solution of (S)-6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3- a]pyridine-4-carboxylic acid (8 kg, 36.8 mol) and 5-fluoropyrimidin-2-amine (4.9 kg, 43.3 mol) in MeCN (110kg, 15V) was added pyridine (9.6 kg, 121 mol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (15.6 kg, 61.3 mol) at 20-30 °C under N₂ atmosphere. The mixture was stirred at 55-65 °C for 10 hrs. H2O (30V) was charged into the mixture and stirred at 15-25 °C for 8 hrs. The reaction mixture was filtered to give the title compound as a brown solid (11.7kg, 94.9% assay, 86.7% assay yield, 99.4% HPLC purity, 100% chiral purity). LC/MS: calculated 312.11 (C₁₅H₁₃FN₆O), observed [M+H]⁺ = 313.12.¹H NMR (DMSO-d6): ppm 1.33 (d, J=7.03 Hz, 3 H) 1.80 - 1.89 (m, 1 H) 2.52 - 2.62 (m, 1 H) 3.16 - 3.45 (m, 3 H) 8.24 (s, 1 H) 8.87 (s, 2 H) 9.50 (s, 1 H) 12.47 (s, 1 H). Crystallization of (S)-N-(5-fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H- cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide. [0259] (S)-N-(5-Fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H- cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide (10.3 kg, 33 mol) was dissolved into MeOH/methoxybenzene (4V/8V) at 50-70 °C and the mixture solution was decolored at 50-70 °C for 8-16 hrs., through CUNO. The mixture was then washed with MeOH/methoxybenzene (1V/2V).1% seed was charged into the reactor at 45-55 °C and stirred for 1-3 hrs., and then MTBE (15V) was charged into the reactor over 8 hrs., at 45-55 °C. The mixture in the reactor was cooled to 5-15 °C., over 5 hrs., and stirred at 5-15 °C for 3-6 hrs. The mixture was then filtered and dried to give the crystal of ((S)-N-(5-fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H- cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide) as a yellow powder (9.5 kg, 99.9% assay, 92.9% assay yield, >99% HPLC purity, 100% chiral purity). LC/MS: calculated 312.11 (C₁₅H₁₃FN₆O), observed [M+H]⁺ = 313.12.¹H NMR (DMSO-d6): ppm 1.33 (d, J=7.03 Hz, 3 H) 1.80 - 1.89 (m, 1 H) 2.52 - 2.62 (m, 1 H) 3.16 - 3.45 (m, 3 H) 8.24 (s, 1 H) 8.87 (s, 2 H) 9.50 (s, 1 H) 12.47 (s, 1 H). XRPD of (S)-N-(5-fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H- cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide [0260] The received product was characterized with XRPD on a Bruker D8 Advance X-ray powder diffractometer, equipped with a CuKα (1.54060Å) source and a LynxEye detector, operating at 40 kV and 40 mA. The sample was placed on the monocrystalline silicon plate and tested under the following instrument parameters: [0261] The XRPD for the product is illustrated in Figure 1, and as diffraction peaks (2-theta values) as described in Table 2, and in particular comprising a peak at diffraction angle 2-theta of 13.4°, and one or more peaks at diffraction angle 2-theta of 10.1°, 20.2°, 8.3°, 15.4°, 12.6°,18.4°, and 16.5°, with a tolerance for the diffraction angles of ± 0.2 degrees. Table 2. XRPD peaks of crystalline (S)-N-(5-fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro- 6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide [0262] It is well known in the crystallographic art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See, e.g. The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in the crystallography art that for any given crystal form the angular peak positions may vary slightly. For example, peak positions can shift due to a variation in the temperature at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the present case, a peak position variability of ± 0.22θ° is presumed to take into account these potential variations without hindering the unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks. Thermal analysis of (S)-N-(5-fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H- cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide [0263] The received product was further characterized with thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The DSC is illustrated in Figure 2, and demonstrates an endotherm having an onset temperature at 284.2°C and peaking at 285.3°C when scanned at a rate of 50°C/min. The TGA is illustrated in Figure 3, and shows a weight loss of about 0.21% between 45°C and 200°C. The DSC instrument parameters are listed as follows: [0264] The TGA instrument parameters are listed as follows: Dynamic Vapor Sorption (DVS) analysis of (S)-N-(5-fluoropyrimidin-2-yl)-6-methyl- 7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide [0265] The received product was further characterized with DVS. The result isotherm plot is illustrated in Figure 4, which shows a 0.80% weight gain from 0% RH to 95%RH, and a 0.79% weight loss from 95%RH to 0% RH. [0266] The DVS is conducted by transferring about 10-20 mg of sample into a DVS and record the weight change with respect to the atmospheric humidity at 25°C. [0267] The DVS instrument parameters are listed as follows:

Claims

What is Claimed is: 1. A process for preparing a compound of first formula: or a compound of second formula: comprising contacting a compound of third formula: with a hydrogen source under asymmetric hydrogenation conditions to provide the compound of the first or second formula, wherein R⁰ is C_1-6 alkyl.

2. The process of claim 1, wherein the asymmetric hydrogenation conditions include presence of a transition metal-based asymmetric hydrogenation catalyst that includes a chiral ligand.

3. The process of claim 1 or 2, wherein the hydrogen source is molecular hydrogen.

4. The process of claim 2 or 3, wherein the transition metal-based asymmetric hydrogenation catalyst is an iridium (Ir) based catalyst, the Ir based catalyst including a bidentate chiral ligand coordinatively bonded to the Ir with a phosphorous and a nitrogen.

5. The process of claim 4, wherein the Ir based catalyst is (cyclooctadiene{I-7-((di-tert- butylphosphaneyl)oxy)-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine ĸN:ĸP}iridium(I) tetrakis(3,5-bis(trifluoromethyl)phenyl)borate or having a formula of: wherein BArF- is tetrakis(3,5-bis(trifluoromethyl)phenyl)borate.

6. The process of any one of claims 1-5, wherein the process provides the compound of the first formula: .

7. The process of any of claims 4-6, wherein the Ir based catalyst is present at about 0.5 mol% to about 1.5 mol%.

8. The process of any of claims 3-7, wherein the process is conducted in a solvent of hexafluoro-propan-2-ol (HFIP).

9. The process of claim 1 or 2, wherein the hydrogen source includes an organic acid.

10. The process of claim 9, wherein the hydrogen source is an azeotrope of formic acid and triethylamine.

11. The process of any one of claims 1 or 2, wherein the asymmetric hydrogenation conditions include presence of an asymmetric transfer hydrogenation catalyst.

12. The process of claim 11, wherein the asymmetric transfer hydrogenation catalyst is a ruthenium (Ru) based catalyst, the Ru based catalyst including a diamine-based chiral ligand coordinatively bonded to the Ru.

13. The process of claim 12, wherein the Ru based catalyst is ([N-[(1R,2R)-2-(Amino-κN)- 1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1- methylethyl)benzene]-ruthenium) or having a formula of: .

14. The process of any one of claims 1, 2, and 9-13, wherein the process provides the compound of the second formula: .

15. The process of any of claims 11-14, wherein the asymmetric transfer hydrogenation catalyst is present at about 3 mol% to about 7 mol%.

16. The process of any one of claims 11-15, wherein the process is conducted at a temperature of less than about 50°C.

17. The process of any one of claims 1-16, further comprising contacting a compound of formula: sufficient to provide the compound of the third formula: .

18. A process, comprising contacting a compound of a formula of: with molecular hydrogen, at a pressure of about 400 to about 450 PSIg, in presence of bis(norbornadiene)rhodium(I) tetrafluoroborate at about 2 mol% to about 4 mol%, a chiral phosphine ligand, and an amine selected from triethylamine and N,N-diisopropylethylamine, in a protic medium, at a temperature of about 10 °C to about 50 °C, for greater than about 20 hrs., to provide a compound of the first formula: , wherein R⁰ is C_1-6 alkyl.

19. The process of any one of claims 1-18, further comprising: contacting the compound of the first or the second formula with an enantiomer of phenylethylamine having a chirality opposite to that of the compound of the first or the second formula to form a salt therebetween; isolating the salt; and contacting the isolated salt with an acid to recover the compound of the first or the second formula.

20. A compound of the formula: or a salt thereof, wherein Q is O or NR⁰, and each occurrence of R⁰ is independently H or C_1-6 alkyl.

21. A process, comprising: contacting a compound of formula: with an acid under isomerization conditions to provide a compound of formula: contacting a product thereof with an organic hydrogen donor under asymmetric transfer hydrogenation conditions to provide a compound of formula: , wherein R⁰ is C1-6 alkyl.

22. The process of claim 21, further comprising contacting the compound of formula: to form a salt therebetween; and isolating the salt.

23. The process of claim 22, wherein the asymmetric transfer hydrogenation conditions include the presence of a ruthenium (Ru) based catalyst with a chiral diamine ligand.

24. The process of claim 23, wherein the catalyst is of formula: .

25. A compound of the formula: X is halo, provided that the compound is not: .

26. A process, comprising: forming a compound of fourth formula: from a compound of formula: contacting the compound of fourth formula with an enantiomer of phenylethylamine having a chirality opposite to that of the compound of the fourth formula to form a salt therebetween; isolating the salt; and contacting the isolated salt with an acid to recover the compound of the fourth formula.

27. The process of claim 26, wherein the forming of the compound of the fourth formula includes: forming a compound of fifth formula: converting the compound of the fifth formula into the compound of the fourth formula.

28. A process for preparing a compound of formula: , comprising: contacting a compound of formula: with diphenylmethanone hydrazone under conditions suitable to provide a compound of formula: .

29. The process of claim 28, wherein the conditions include presence of a palladium (Pd) based catalyst or a cuprous (Cu) based catalyst.

30. A solid form having the formula: .

31. A composition, comprising: a compound of formula: , and a compound of any one or more of: .

32. A process, comprising: (1) forming a compound of formula: , wherein R⁰ is C_1-6 alkyl; (2) forming a compound of formula: (3) contacting the compound of formula: with phosphoryl chloride under conditions suitable, and followed by hydrolyzation to form a compound of formula: (4) forming a salt of formula: (5) forming a compound of formula: forming a compound of formula: ; (6) contacting a product of step (5) with an acid to form a compound of formula: (7) contacting the product of step (6) with 5-fluoropyrimidin-2-amineto provide a compound of formula: . 34. The crystalline form of claim 33, which is a crystalline anhydrate. 35. The crystalline form of claim 33 or 34, characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation comprising a peak at diffraction angle 2-theta of 13.4° and one or more peaks at 8.2°, 10.1°, and 20.2°, with a tolerance for the diffraction angles of ± 0.2 degrees, wherein optionally: (a) the XRPD pattern further includes one or more peaks at 12.6°,15.4°, 16.5°, and 18.4°, with a tolerance for the diffraction angles of ± 0.2 degrees; (b) the XRPD pattern is substantially according to Figure 1; and (c) the crystalline is further characterized by a differential scanning calorimetry (DSC) having an endothermic onset at about 284.2°C; 36. A process, comprising contacting a compound of a formula of: with molecular hydrogen under asymmetric hydrogenation conditions to provide a compound of the first formula: , wherein R⁰ is C_1-6 alkyl. 37. The process of claim 36, wherein the conditions include presence of a rhodium (Rh) based catalyst. 38. The process of claim 37, wherein the Rh based catalyst is present at about 0.2 mol% to about 0.4 mol%. 39. The process of claim 37 or 38, wherein the conditions include presence of a chiral phosphine ligand. 40. A process, comprising contacting a compound of a formula of: with molecular hydrogen under asymmetric hydrogenation conditions to provide a compound of the first formula: , wherein: R⁰ is C1-6 alkyl, the conditions include the presence of bis(norbornadiene)rhodium(I) tetrafluoroborate and the presence of a P-stereogenic C1-symmetric diphosphine ligand, the P-stereogenic C1-symmetric diphosphine ligand is (R)-1-[(S_P)-2- (diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine at a stoichiometric ratio of about 0.002:1 to about 0.004:1 relative to the compound of formula: , and about 1.1:1 to about 1.3:1 relative to the bis(norbornadiene)rhodium(I) tetrafluoroborate, and the contacting is conducted at a temperature of about 20 °C to about 40 °C with the molecular hydrogen at a pressure at about 20 bar to about 30 bar in absence of an amine for a duration of about 2 hrs to about 4 hrs.