Processes for preparing tetralin compounds

Abstract

Provided herein are processes, procedures, and useful intermediates for the preparation of compounds of Formula (I):

Description

Atty. Dkt. No.129802-0442 P0059-WO PROCESSES FOR PREPARING TETRALIN COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 649,995 filed on May 21, 2024; U.S. Provisional Patent Application No.63 / 746,502 filed on January 17, 2025; and U.S. Provisional Patent Application No. 63 / 775,196 filed on March 20, 2025; the entire contents of each of which are incorporated by reference herein. BACKGROUND

[0002] The following discussion is provided to aid the reader in understanding the disclosure and is not admitted to describe or constitute prior art thereto.

[0003] Hypoxia inducible factors (HIFs) are a family of transcription factors that modulate the cellular response to hypoxia. HIF is a heterodimer comprising an oxygen-regulated alpha subunit (of which there are 3 isoforms: HIF-1α, HIF-2α, and HIF-3α) that can heterodimerize with a constitutively expressed beta subunit. Under normal tissue oxygen saturation, HIF-2α protein is continuously degraded. In hypoxic tissue oxygen status, or in the case of VHL mutation or epigenetic silencing (pseudohypoxia), HIF-2α is stabilized and undergoes nuclear translocation. Upon dimerization with HIF-1β, HIF-2α mediates transcription of pro-tumorigenic genes associated with proliferation and angiogenesis.

[0004] The compound (5R,6S,8R)-3,5-trifluoro-8-((1S,2R)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile, designated herein as Compound (I), and having the structure: (Compound (I))has been identified as a potent and selective allosteric small molecule inhibitor that can prevent HIF-2α-dependent gene transcription and block tumor progression in preclinical models. The preparation of Compound (I) has been described in WO 2021 / 188769 and U.S. Patent No. 1Atty. Dkt. No.129802-0442 P0059-WO 12,145,901. Compuond (I) is a synthetically challenging compound to prepare due, in part, to the presence of multiple stereocenters. Accordingly, there is a need to provide improved processes to prepare Compound (I), for example, to reduce complexity and improve yields, purity, and scaling. The present disclosure addresses this need and provides related advantages as well. SUMMARY

[0005] In one aspect there is provided a process comprising: a) contacting a compound of Formula A: (Formula A); with an R5X reagent annd of Formula A1: (Formula A1), wherein:R1and R2are independently selected from -H, -F, -Cl, -Br, and -CN; R3is -H, -F or -Cl; R4is selected from -H, -F, -Cl, -C1-C3alkyl, and -S(O)2(C1-C3alkyl), wherein the -C1-C3 alkyl or -S(O)2(C1-C3 alkyl) is unsubstituted or substituted with 1-3 halogen; each R5is an alcohol protecting group; X is -Cl, -Br, -I, -OMs, -OTs, or -OTf; and the base is an amine, an amidine, a carbonate, a phosphate, a tetra alkyl ammonium salt, or a hydroxide salt; and 2Atty. Dkt. No.129802-0442 P0059-WO b) contacting the compound of Formula A1 with a deprotection agent to form a compound of Formula B: (Formula B).

[0006] In another aspect thcomprising contacting a compound of Formula B: (Formula B) with a hydrogen reagent in thet to form a compound of Formula C: (Formula C); wherein:R1and R2are independently selected from -H, -F, -Cl, -Br, and -CN; R3is -H, -F or -Cl; and R4is selected from -H, -F, -Cl, -C1-C3 alkyl, and -S(O)2(C1-C3 alkyl), wherein the -C1-C3 alkyl or -S(O)2(C1-C3 alkyl) is unsubstituted or substituted with 1-3 halogen.

[0007] Another aspect provides a process of preparing a compound of Formula A from a compound of Formula Z, the process comprising contacting a compound of Formula Z: 3Atty. Dkt. No.129802-0442 P0059-WO (Formula Z) with an oxidizing agent, thee y p epa g e co pound of Formula A: (Formula A); wherein:R1and R2are independently selected from -H, -F, -Cl, -Br, and -CN; R3is -H, -F or -Cl; and R4is selected from -H, -F, -Cl, -C1-C3alkyl, and -S(O)2(C1-C3alkyl), wherein the -C1-C3alkyl or -S(O)2(C1-C3 alkyl) is unsubstituted or substituted with 1-3 halogen.

[0008] Another aspect provides a process comprising one or more of steps a-g: a. contacting a compound of Formula W-1: (Formula W-1) wherein X is -Br, , d R6is an alcohol protecting group; with a compound of Formula V-1: 1) wherein Y, , , r -Bpin; and a group ten metal catalyst to form a compound of Formula X-1: 4Atty. Dkt. No.129802-0442 P0059-WO 1); b. contacting the d a hydrogen reagent to form a compound of Formula Y-1: (Formula Y-1); c. contacting the coa deprotection agent to form a compound of Formula Z-1: (Formula Z-1); d. contacting the coh an oxidizing agent to form a compound of Formula A-1: 1); e. contacting the nt and a base to form acompound of Formula A1-1: 1) wherein:R5is an alcohol protecting group; 5Atty. Dkt. No.129802-0442 P0059-WO X is -Cl, -Br, -I, -OMs, -OTs, or -OTf, and the base is an amine, an amidine, a carbonate, a phosphate, a tetra alkyl ammonium salt, or a hydroxide salt; f. contacting the compound of Formula A1-1 with an electrophilic fluorination agent to form a compound of Formula B-1: nd g. contacting th ent in the presence ofa chiral catalyst to form a compound of Formula C-1: 1).

[0009] Another aspect pro, , ,6Atty. Dkt. No.129802-0442 P0059-WO , , , , , aAtty. Dkt. No.129802-0442 P0059-WO

[0010] Another aspect provides a process of converting a compound of Formula A: B),R1and R2are independently selected from -H, -F, -Cl, -Br, and -CN; R3is -H, -F or -Cl; and R4is selected from -H, -F, -Cl, -C1-C3alkyl, and -S(O)2(C1-C3alkyl), wherein the -C1-C3alkyl or -S(O)2(C1-C3alkyl) is unsubstituted or substituted with 1-3 halogen.

[0011] Another aspect provides a process comprising converting a compound of Formula V: (Formula V) wherein Y is -B(OH)2, -B(O, 2, or -Bpin; R3is -H, -F or -Cl; and R4is selected from -H, -F, -Cl, -C1-C3alkyl, and -S(O)2(C1-C3alkyl), wherein the -C1-C3alkyl or -S(O)2(C1-C3 alkyl) is unsubstituted or substituted with 1-3 halogen; to a compound of Formula I: 8Atty. Dkt. No.129802-0442 P0059-WO (Formula I) wherein R1and R2are i-H, -F, -Cl, -Br, and -CN.

[0012] Another aspect provides a process comprising converting a compound of Formula A: (Formula A); wherein R1and R2from -H, -F, -Cl, -Br, and -CN; R3is -H, -F or -Cl; and R4is selected from -H, -F, -Cl, -C1-C3 alkyl, and -S(O)2(C1-C3 alkyl), wherein the -C1-C3 alkyl or -S(O)2(C1-C3alkyl) is unsubstituted or substituted with 1-3 halogen; to a compound of Formula I: (Formula I).

[0013] Another aspect provides a process for converting a compound of Formula A (Formula A);9Atty. Dkt. No.129802-0442 P0059-WO to a compound of Formula B (Formula B); the process comprising:means for converting said compound of Formula A to a compound of Formula A-1 (Formula A1); and means for convertiA1 to the compound of Formula B: (Formula B), wherein R1and R2are-H, -F, -Cl, -Br, and -CN; R3is -H, -F or -Cl; R4is selected from -H, -F, -Cl, -C1-C3 alkyl, and -S(O)2(C1-C3 alkyl), wherein the -C1-C3 alkyl or -S(O)2(C1-C3 alkyl) is unsubstituted or substituted with 1-3 halogen; and each R5is an alcohol protecting group.

[0014] Another aspect provides a pharmaceutical composition comprising a Compound (I) composition and one or more pharmaceutically acceptable excipients, wherein the Compound (I) composition comprises Compound (I): 10Atty. Dkt. No.129802-0442 P0059-WO )), and not more than 5 % wDETAILED DESCRIPTION

[0015] The present disclosure describes processes of preparing a compound of Formula I, and related compounds and compositions. The processes described herein relate to efficient processes that can be performed at any scale, for example, multigram or kilogram scale. Definitions

[0016] The terms “comprising,” “including,” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0017] The term “about” as used herein has its original meaning of approximately and is to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In general, the term “about” refers to the usual error range for the respective value readily known to the skilled person in this technical field. If the degree of approximation is not otherwise clear from the context, “about” means either within plus or minus 10% of the provided value, or rounded to the nearest significant figure, in all cases inclusive of the provided value. For example, about 50% includes a range of from 45% to 55%, while about 2.0 molar equivalents includes a range of from 1.8 to 2.2 molar equivalents. Accordingly, when referring to a range, “about” refers to each of the stated values + / - 10% of the stated value of each end of the range. For instance, a ratio of from about 1 to about 3 (weight / weight) includes a range of from 0.9 to 3.3. Where ranges are provided, they are inclusive of the boundary values.

[0018] The phrase “and / or” as used in the present disclosure will be understood to mean any one of the recited members individually or a combination of any two or more thereof¾for example, “A, B, and / or C” would mean “A, or B, or C”, “A and B”, “A and C”, “B and C”, or the combination of “A, B, and C.” 11Atty. Dkt. No.129802-0442 P0059-WO

[0019] The term “a” may be used to introduce claim elements and may encompass one or more elements. Thus, its construction is not limited to one unless the context is clear that one is intended. For example “a base” may include one or more bases including mixtures of two bases.

[0020] “Alkyl” is a linear or branched saturated monovalent hydrocarbon. For example, an alkyl group can have 1 to 8 carbon atoms (i.e., -C1-C8alkyl) or 1 to 6 carbon atoms (i.e., -C1-C6alkyl) or 1 to 4 carbon atoms (i.e., -C1-C4 alkyl) or 1 to 3 carbon atoms (i.e., -C1-C3 alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n- Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, - CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s- butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n- pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2- methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), and 2,3-dimethyl-2-butyl(-C(CH3)2CH(CH3)2). In some embodiments, the alkyl group is a -C1-C3 alkyl.

[0021] “Amine” as used herein refers to a compound with a molecular formula of R-NH2,R2NH, or R3N, and includes alkylamines (such as methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, dimethylamine, triethylamine (TEA), tributylamine (TBA), N,N-diisopropylethylamine (DIEA), and the like), and aryl amines (such as aniline, 1,4- benzenediamine, and the like).

[0022] “Amidine” as used herein refers to a compound with a molecular formula ofRC(=NR)NR2, including compounds such as acetamidine (CH3(=NH)NH2), diminazine, benzamidine, diazabicyclo[5.4.0]undec-7-ene (DBU) and the like.

[0023] “Carbonate” as used herein refers to a compound with a molecular formula of CO32-or a salt thereof (e.g., Na2CO3, CaCO3), and bicarbonates (i.e., HCO3-), and salts thereof (e.g., NaHCO3, KHCO3, and the like). 12Atty. Dkt. No.129802-0442 P0059-WO

[0024] “Phosphate” as used herein refers to a compound with a molecular formula of P(O)43-or a salt thereof, such as Na3PO4, Na2HPO4, NaH2PO4, K3PO4, K2HPO4, KH2PO4and the like.

[0025] “Tetra alkyl ammonium salt” or “quaternary alkylammonium salt” as used herein refers to an ionic compound with a cation having the molecular formula of NRxH(4-x)+, wherein x is 1, 2, 3 or 4, and a counter anion including, e.g., F-, Cl-, Br-, I-, and includes compounds such as tetra-n- butylammonium fluoride (TBAF), tetraethylammonium bromide, alkyl trimethylammonium chloride, and the like.

[0026] “Hydroxide salt” as used herein refers to ionic compounds with a formula of R(OH)n, with n being 1 or 2, wherein R is a cation including, e.g., sodium (Na), potassium (K), lithium (Li), calcium (Ca), magnesium (Mg), manganese (Mn) and the like. Examples of hydroxide salts include NaOH, KOH, LiOH, Ca(OH)2, Mg(OH)2, Mn(OH)2and the like.

[0027] “Phosphazene” as used herein refers to organophosphorus compounds having a double bond between a phosphorus(V) P and a nitrogen N atom. Examples include compounds with the molecular formula R-N=P(NR2)3, and (-N=P(X)2-)n, wherein X is a halogen, alkoxy, amide or other organic substituent group, and n is an integer (e.g., 1, 2, or 3). Exemplary phosphazene groups include compounds such as hexachlorocyclotriphosphazene, bis(triphenylphosphine)iminium chloride, and the like.

[0028] “Guanidine” as used herein refers to guanidine NH2C(=NH)NH2, and guanidine derivatives – i.e. compounds having a molecular formula (R1R2N)C(=NR3)NR4R5. Examples include arginine, creatine, triazabicyclodecene (TBD), tetramethylguanidine (TMG), 7-methyl- 1,5,7-trizabicyclo(4.4.0)dec-5-ene (MTBD), sulfadiazine, and the like.

[0029] “Halo” or “halogen” as used herein refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-I).

[0030] “Purity” refers to chemical purity independent of stereochemistry preference unless otherwise indicated.

[0031] As used herein “process byproduct” refers to a compound that is unintentionally produced during a chemical reaction and includes impurities, side products, or undesired stereoisomers generated during a reaction, process intermediate isolation, or process intermediate 13Atty. Dkt. No.129802-0442 P0059-WO storage, and the downstream impurities or side products they convert to as a result of subsequent chemical reactions.

[0032] As used herein, a “degradation product” refers to an impurity that is formed from the decomposition of a compound (e.g., a compound of Formula (I)) after isolation, during manufacture of a pharmaceutical composition comprising the compound, or during storage of a pharmaceutical composition comprising the compound.

[0033] As used herein, the phrase “substantially free of process byproducts” means that process byproducts are present in an amount that is below the reporting threshold for a particular detection method (e.g., high-performance liquid chromatography (HPLC)).

[0034] “Stereoisomer” and “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers. General methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0035] The compounds of the embodiments disclosed herein may contain one or more asymmetric centers and may thus give rise to stereoisomers including, e.g., enantiomers and diastereomers. Stereoisomeric forms may be defined, in terms of absolute stereochemistry, as(R)- or (S)-, and / or depicted using dashes ( ) and / or wedges ( ). The presentdisclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), or (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include, for example, chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When a stereochemical depiction (e.g., using dashes, , and / or wedges, ) is shown in a chemical structure, it is meant to indicate that the depicted stereoisomer is present and substantially free of one or more other stereoisomer(s) (e.g., enantiomers and / or diastereomers, when present). For example, a compound having an (R) 14Atty. Dkt. No.129802-0442 P0059-WO stereocenter can be substantially free of the opposite (S) enantiomer of the compound. An (S, S) compound having two stereocenters can be substantially free of other stereoisomers (e.g., (R, R), (S, R), and (R, S)) of the compound. A compound that is substantially free of other stereoisomers comprises 70% or more, e.g., 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, by weight of one stereoisomer of the compound.

[0036] A chemical bond to an asymmetric carbon that is depicted as a solid line ( )indicates that all possible stereoisomers at that carbon atom are included and may be present as a racemic or scalemic mixture of such compound(s).

[0037] As used herein, the term “racemic mixture” refers to a 1:1 mixture of enantiomers.

[0038] As used herein, the term “scalemic mixture” refers to a mixture of enantiomers that are at a ratio other than 1:1.

[0039] A compound having multiple stereoisomers but only indicating defined stereochemistry for a subset of the stereoisomers is understood to be substantially free of other stereoisomers for the stereocenters indicated. For example, a compound having five stereocenters but only indicating (R, S) stereochemistry for two of the stereocenters is understood to be substantially free of the (R, R), (S, R), and (S, S) isomers for the two indicated stereocenters. However, the compound may have a mixture of stereoisomers at the three undefined stereocenters.

[0040] Diastereomeric transformations are those that favor the formation of one diastereomer over another. The diastereomeric purity or diastereomeric excess (de) of such transformations is a measure of how selective the transformation is at the stereocenter effected by the transformation. In some embodiments, diastereomeric purity of the transformations according to this disclosure is least 60%, e.g., at least 65%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. 15Atty. Dkt. No.129802-0442 P0059-WO

[0041] The present disclosure includes all tautomers of compounds described herein, even if only one tautomer is expressly represented. “Tautomer” refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto tautomers.

[0042] “Catalyst” refers to a chemical reactant that increases the rate of a reaction without itself being consumed.

[0043] “Protecting group” refers to a moiety of a compound that masks or alters the properties of a functional moiety. The protecting group can be removed to restore the functional moiety to its original state. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See also Protective Groups in Organic Chemistry, Peter G. M. Wuts and Theodora W. Greene, 4th Ed., 2006. Protecting groups are often utilized to mask the reactivity of certain functional moieties, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. For example, an “alcohol protecting group” refers to a protecting group useful for masking alcohols, e.g., to render alcohols unreactive during intermediate steps of a synthetic process. Exemplary alcohol protecting groups include silyl groups (e.g., trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert- butyldimethylsilyl (TBS), and tert-butyldiphenylsilyl (TBDPS)), ether groups (e.g., methoxymethyl (MOM), methoxyethoxymethyl (MEM), benzyloxymethyl (BOM), and tetrahydropyranyl (THP)), alkyl groups (e.g., methyl, ethyl, isopropyl, or tert-butyl), trityl groups (e.g., trityl (Tr), 4-monomethoxytrityl (MMTr), and 4,4’-dimethoxytrityl (DMTr)), acyl groups (e.g., acetyl, benzoyl, pivaloyl), tert-butoxycarbanyl (Boc), or benzyl (e.g., benzyl, p- methoxybenzyl (PMB)) groups.

[0044] A “protecting agent” is a chemical reactant that is capable of effecting attachment of a protecting group. For example, the protecting agent tert-butyldimethylsilyl chloride may be used to install a tert-butyldimethylsilyl protecting group on an alcohol. A protecting group can subsequently be removed using a deprotecting agent, thereby restoring the functional moiety to its original form.

[0045] A “deprotecting agent” or, interchangeably, “deprotection agent” is a chemical reactant that is capable of effecting removal of a protecting group. For example, tetra(n-butyl)ammonium fluoride is capable of cleaving a tert-butyldimethylsilyl ether to form an alcohol. The deprotecting 16Atty. Dkt. No.129802-0442 P0059-WO agent used will depend on, for example, the identity of the protecting group that is to be removed, and the reactivity of other functional groups present on the molecule. Typical deprotecting agents include reducing agents, oxidizing agents, acids, Lewis acids, bases, electrophilic fluorination reagents, and enzymes. In general, silyl protecting groups can be removed under acid conditions, or by treatment with an electrophilic fluorination reagent; ether protecting groups can be removed under acidic conditions; alkyl protecting groups can be removed under reductive conditions, or by treatment with a Lewis acid; trityl protecting groups can be removed under acidic conditions, or by treatment with a Lewis acid; acyl protecting groups can be removed under reductive conditions, under basic conditions, or by treatment with an enzyme; tert-butoxycarbanyl (Boc) protecting groups can be removed under acidic conditions; and benzyl protecting groups can be removed under reductive conditions, or by treatment with a Lewis acid. Exemplary reducing agents include, but are not limited to, hydrogen, metal hydrides (e.g., diisobutylaluminum hydride (DIBAL), and lithium aluminum hydride (LAH)), or borohydrides (e.g., sodium borohydride). Exemplary bases include, but are not limited to, ammonia, methylamine, sodium methoxide, metal hydroxides (e.g., LiOH, NaOH, and KOH), and the like. Exemplary acids include, but are not limited to HCl, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and the like. Exemplary Lewis acids include, but are not limited to ZnCl2, ZnBr2, TiCl4, BF3, trimethylsilyl iodide (TMSI), and the like. Exemplary oxidizing agents include, but are not limited to dicyanodichloroquinone (DDQ), triethylenediamine (DABCO), poly(4-vinylpyridinium tribromide), hydrogen peroxide, and the like. Exemplary electrophilic fluorination reagents include, but are not limited to, quaternary ammonium fluoride reagents (e.g., tetra(n-butyl)ammonium fluoride (TBAF), and tris(dimethylamino)sulfur(trimethylsilyl)difluoride (TAS-F)), pyridinium fluoride, potassium fluoride, hydrofluoric acid, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SELECTFLUOR®), N-fluoro-N′-methyl-triethylenediamine bis(tetrafluoroborate) (SELECTFLUOR® II), N-fluorobenzenesulfonamide (NFSI), 1,1′-difluoro- 2,2′-bipyridinium bis(tetrafluoroborate) (Synfluor), 1-fluoropyridinium trifluoromethanesulfonate, and N-fluoropyridinium (NFPy) salts including, e.g., 1-fluoro-2,4,6- trimethylpyridinium tetrafluoroborate, 1-fluoro-2,3,4,5,6-pentachloropyridinium tetrafluoroborate, and 1-fluoro-2,6-dichloropyridinium tetrafluoroborate and the like. Exemplary enzymes include, but are not limited to, ester hydrolases, or lipases. 17Atty. Dkt. No.129802-0442 P0059-WO

[0046] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to 100% of the atom in question. For example, the compounds may incorporate radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C), or non-radioactive isotopes, such as deuterium (2H) or carbon-13 (13C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. In some embodiments, the compounds according to this disclosure are characterized by one or more deuterium atoms. PROCESSES

[0047] The present disclosure describes processes for preparing a compound of Formula I intermediates, and related compounds. The processes described herein relate to efficient processes that can be performed at any scale, for example, multigram or kilogram scale.

[0048] Provided herein is a process for forming a compound of Formula B from a compound of Formula A, the process comprising: a) contacting the compound of Formula A: (Formula A); with an R5X reagent annd of Formula A1: 1), wherein:R1and R2are independently selected from -H, -F, -Cl, -Br, and -CN; R3is -H, -F, or -Cl; 18Atty. Dkt. No.129802-0442 P0059-WO R4is selected from -H, -F, -Cl, -C1-C3alkyl, and -S(O)2(C1-C3alkyl), wherein the -C1-C3alkyl or -S(O)2(C1-C3alkyl) is unsubstituted or substituted with 1-3 halogen; each R5is an alcohol protecting group; X is -Cl, -Br, -I, -OMs, -OTs, or -OTf; and the base is an amine, an amidine, a carbonate, a phosphate, a tetra alkyl ammonium salt, or a hydroxide salt; and b) contacting the compound of Formula A1 with a deprotection agent to form the compound of Formula B: (Formula B).

[0049] In some embodimen, p g a compound of Formula B from a compound of Formula A is stereoselective on the tetralin portion of the molecule. In some embodiments, the process of forming a compound of Formula B from a compound of Formula A is not stereoselective on the indane portion of the molecule. In some embodiments, the compound of Formula B is a mixture of diastereomers. In some embodiments, the compound of Formula B is a mixture of two diastereomers. In some embodiments, the mixture of diastereomers comprise a compound of Formula Ba and a compound of Formula Bb: (Formula Bb).

[0050] In some embodiments, the compound of Formula B further comprises one or more process byproducts. In some embodiments, the one or more process byproducts are present in an amount of less than 10% a / a, such as less than 7% a / a, or less than 5% a / a, or less than 4% a / a, or 19Atty. Dkt. No.129802-0442 P0059-WO less than 3% a / a. In some embodiments, the one or more process byproducts are present in an amount of 0% a / a to 9.9% a / a, or 0% a / a to 8.9% a / a, or 0% a / a to 7.9% a / a, or 0% a / a to 6.9% a / a, or 0% a / a to 5.9% a / a, or 0% a / a to 4.9% a / a, or 0% a / a to 3.9% a / a, or 0% a / a to 2.9% a / a. In some embodiments, the one or more process byproducts comprise a compound of Formula Bc and / or a compound of Formula Bd: (Formula Bd).

[0051] with at least 80%, at least 77%, at least 75%, at least 72%, at least 70%, at least 65% or at least 50% diastereomeric purity. In some embodiments, the compound of Formula Ba has at least 80%, at least 77%, at least 75%, at least 72%, at least 70%, at least 65% or at least 50% diastereomeric purity. In some embodiments, the diastereomeric purity of the compound of Formula Ba is at least 55%, e.g., at least 60%, at least 65%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, the diastereomeric purity of the compound of Formula Ba is between about 55% to about 85%, such as 60%, 65%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, or 85%. In some embodiments, the compound of Formula Ba is present in an amount between about 65% and about 85%, or about 70% and about 80%, or about 70% and about 75%. In some embodiments, the compound of Formula Bb is present in an amount of between about 10% and about 30%, or about 15% and about 25%, or about 15% and about 23%. In some embodiments, the compound of Formula Bc is present in an amount between about 0% and about 10%, or about 0% and about 5%, or about 0% to about 3%. In some embodiments, the compound of Formula Bd is present in an amount between about 0% and about 10%, or about 0% and about 5%, or about 0% to about 3%. In some embodiments, 20Atty. Dkt. No.129802-0442 P0059-WO the compound of Formula Ba is present in an amount of about 70% to about 75% and the compound of Formula Bb is present in an amount of about 15% and about 23%. In some embodiments, the compound of Formula Ba is present in an amount of about 70% to about 80%, the compound of Formula Bb is present in an amount of about 15% to about 25%, the compound of Formula Bc is present in an amount of about 0% to about 5%, and the compound of Formula Bd is present in an amount of about 0% to about 5%.

[0052] In some embodiments, R5is a protecting group, such as an alcohol protecting group. In some embodiments, R5is a silyl group or an acyl group. In some embodiments, R5is a silyl group. In some embodiments, R5is an acyl group. In some embodiments, R5is acyl, benzoyl, or pivaloyl. In some embodiments R5is trimethylsilyl (TMS), triethyl silyl (TES), triisopropylsilyl, tert- butyldimethylsilyl (TBS or TBDMS), or tert-butyldiphenylsilyl (TBDPS).

[0053] In some embodiments, R5is tert-butyldimethylsilyl. In some embodiments, R5X is chlorotrimethylsilane, bromotrimethylsilane, trimethylsilyl iodide, tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), or an acyl halide (e.g., acetyl chloride, benzoyl chloride, pivaloyl chloride, and the like). In some embodiments, R5X is chlorotrimethylsilane, bromotrimethylsilane, trimethylsilyl iodide, tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf). In some embodiments, the R5X reagent is tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf).

[0054] In some embodiments, the deprotection agent is a desilylation agent. In some embodiments, the desilylation agent is a fluorination agent. In some embodiments, the fluorination agent is an electrophilic fluorination agent. Suitable electrophilic fluorination agents include 1- chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SELECTFLUOR®), N-fluoro-N′-methyl-triethylenediamine bis(tetrafluoroborate) (SELECTFLUOR® II), N-fluorobenzenesulfonamide (NFSI), 1,1′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) (Synfluor), 1-fluoropyridinium trifluoromethanesulfonate, and N- fluoropyridinium (NFPy) salts including, e.g., 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 1-fluoro-2,3,4,5,6-pentachloropyridinium tetrafluoroborate, and 1-fluoro-2,6- dichloropyridinium tetrafluoroborate. In some embodiments, the desilyation agent is 1- 21Atty. Dkt. No.129802-0442 P0059-WO chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SELECTFLUOR®).

[0055] In some embodiments, the process further comprises contacting the compound of Formula B with a hydrogen reagent in the presence of a chiral catalyst to form a compound of Formula C: (Formula C).

[0056] In some embodiments, p ula B is a mixture of diastereomers (e.g., a mixture of Formula Ba and Formula Bb). In some embodiments, the compound of Formula B further comprises one or more process byproducts (e.g., a compound of Formula Bc and / or a compound of Formula Bd). In some embodiments, the compound of Formula C is obtained in at least 75%, at least 70%, at least 65%, at least 60%, at least 55% or at least 50% yield. In some embodiments, the compound of Formula C is formed as a single isomer.

[0057] In some embodiments, the compound of Formula C further comprises one or more process byproducts. In some embodiments, the one or more process byproducts are diastereomers having structures of Formula Ca, Formula Cb, Formula Cc, and / or Formula Cd: (Formula Cb)22Atty. Dkt. No.129802-0442 P0059-WO (Formula Cd).

[0058] nt in an amount between about 0% a / a and about 15% a / a, or between about 0% a / a and about 10% a / a, or about 3% a / a to about 13% a / a. In some embodiments, the compound of Formula Cb is present in an amount of between about 0% a / a and about 15% a / a, or between about 0% a / a and about 10% a / a, or between about 0% a / a and about 5% a / a. In some embodiments, the compound of Formula Cc is present in an amount between about 0% a / a and about 10% a / a, or about 0% a / a and about 5% a / a, or about 0% a / a and about 3% a / a. In some embodiments, the compound of Formula Cd is present in an amount between about 0% a / a and about 10% a / a, or about 0% a / a and about 5% a / a, or about 0% a / a and about 3% a / a. In some embodiments, the Compound of Formula C is present in an amount between about 80% a / a to about 90% a / a, the compound of Formula Ca is present in an amount of about 3% a / a to about 13% a / a, the compound of Formula Cb is present in an amount of between about 0% a / a and about 5% a / a, the compound of Formula Cc is present in an amount of between about 0% a / a and about 3% a / a, and the compound of Formula Cd is present in an amount of between about 0% a / a and about 3% a / a. The amount of each compound can be determined using, for example, HPLC.

[0059] In some embodiments, the compounds of Formula Ca, Formula Cb, Formula Cc, and Formula Cd are the compounds a), and23Atty. Dkt. No.129802-0442 P0059-WO (Impurity 1c), and(Impurity 1d), respectively.diments, the process further comprises reducing the amount of the one or more process byproducts (e.g., a compound of Formula Ca, Formula Cb, Formula Cc, and / or Formula Cd) from the compound of Formula C. The reduced amount of the one or more diastereomers can be determined using, for example, HPLC. In some embodiments, the total amount of the one or more diastereomers is reduced to less than 3% a / a, or less than 2% a / a, or less than 1% a / a, or less than 0.5% a / a. In some embodiments, the amount of each of the one or more diastereomers is reduced to less than 3% a / a, less than 2% a / a, less than 1% a / a, or less than 0.5% a / a, respectively. In some embodiments, reducing the amount of the one or more diastereomers from the compound of Formula C comprises combining the compound of Formula C with one or more solvents to form a slurry; and filtering the precipitate from the slurry to form the compound of Formula C having reduced amounts of the one or more diastereomers. In some embodiments, the one or more solvents comprise water, an alcohol, acetone, toluene, or combinations thereof. In some embodiments, the one or more solvents comprise water, an alcohol, or a combination thereof. In some embodiments, the solution comprises water and ethanol.

[0061] In some embodiments, the compound of Formula C is formed with a diastereomeric purity of at least 60%, e.g., at least 65%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, the compound of Formula C is formed with a diastereomeric purity of between about 80% and about 100%, or about 85% 24Atty. Dkt. No.129802-0442 P0059-WO and about 100%, or about 90% and about 100%, or about 95% and about 100%, or about 98% and about 100%.

[0062] In some embodiments, a suitable chiral catalyst is a Noyori hydrogenation catalyst. In some embodiments, a suitable chiral catalyst is a chiral transition metal catalyst (e.g., a ruthenium, rhodium, or iridium chiral catalyst). In some embodiments, the chiral transition metal catalyst includes a transition metal center (e.g., ruthenium, rhodium, or iridium), and one or more chiral ligands. In some embodiments, the chiral catalyst is a chiral ruthenium catalyst. Exemplary chiral ruthenium catalysts include RuCl[Fsdpen](p-cymene), RuCl[Ts-DPEN](p-cymene), RuCl[(Ts- DPEN](mesitylene), chloro[N-[2-(4-methylbenzyloxy)ethyl]-N'-(p-toluenesulfonyl)-1,2- diphenylethylenediamine]ruthenium(II) (Ts-DENEB®), RuCl2[dm-segphos®][daipen], RuCl2[dm-segphos®][(dpen], RuCl2[(R)-xylbinap][diapen], RuCl2[xylbinap][dpen], and RuCl[daipena][xylbinap]. In some embodiments, the chiral ruthenium catalyst is selected from RuCl[(R,R)-Fsdpen](p-cymene), RuCl[(R,R)-Ts-DPEN](p-cymene), RuCl[(R,R)-Ts- DPEN](mesitylene), chloro[(R,R)-N-[2-(4-methylbenzyloxy)ethyl]-N'-(p-toluenesulfonyl)-1,2- diphenylethylenediamine]ruthenium(II) ((R,R)-Ts-DENEB®), RuCl2[(R)-dm-segphos®][(R)- daipen], RuCl2[(R)-dm-segphos®][(R,R)-dpen], RuCl2[(R)-xylbinap][(R)-diapen], RuCl2[(R)- xylbinap][(R)-dpen], and RuCl[(R)-daipena][(R)-xylbinap]. In some embodiments, the chiral ruthenium catalyst is RuCl[(R, R)-Ts-DPEN](mesitylene).

[0063] In some embodiments, suitable hydrogen reagents include hydrogen gas, formic acid, and hydrosilane. In some embodiments, the hydrogen reagent is formic acid.

[0064] In some embodiments, the compound of Formula B is contacted with a hydrogen reagent in the presence of a chiral catalyst and a base to form a compound of Formula C.

[0065] In some embodiments, suitable bases for the reaction to form Formula C from Formula B include an amine, an amidine, a carbonate, a phosphate, a tetraalkyl ammonium salt, and a hydroxide salt. Suitable amines include alkylamines (e.g., methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, dimethylamine, triethylamine (TEA), tributylamine(TBA), or N,N-diisopropylethylamine (DIEA)),and aryl amines (e.g., aniline, and 1,4-benzenediamine). Suitable amidines include acetamidine, diminazine, benzamidine, and diazabicyclo[5.4.0]undec-7-ene (DBU). Suitable carbonates include Na2CO3, and CaCO3, 25Atty. Dkt. No.129802-0442 P0059-WO NaHCO3, and KHCO3. Suitable phosphates include Na3PO4, Na2HPO4, NaH2PO4, K3PO4, K2HPO4, and KH2PO4. Suitable tetra alkyl ammonium salts, or quaternary alkylammonium salts include tetra-n-butylammonium fluoride (TBAF), tetraethylammonium bromide, and alkyl trimethylammonium chloride. Suitable hydroxide salts include NaOH, KOH, LiOH, Ca(OH)2, Mg(OH)2, and Mn(OH)2. In some embodiments, the base is an amine. In some embodiments, the base is triethylamine (TEA).

[0066] In some embodiments the process further comprises contacting the compound of Formula C with a fluorination agent to form a compound of Formula I: (Formula I).

[0067] In some embodimg for preparing Formula I from Formula C is a deoxyfluorination agent. Suitable deoxyfluorination agents include perfluoro-1-butanesulfonyl fluoride (PBSF), N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine (Ishikawa’s Reagent), nitrophenyl ester sulfuryl fluoride, benzenesulfonyl fluoride, diethylaminosulfur trifluoride (DAST), sulfur tetrafluoride, bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor®), 4-tert- butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead™), morpholinodifluorosulfinium tetrafluoroborate (XtalFluor-M®), N,N-diethylamino-S,S-difluorosulfinium tetrafluoroborate (XtalFluor-E®), pyridine-2-sulfonyl fluoride (PyFluor), PhenoFluor™, AlkylFluor™, morpholinosulfur trifluoride (morph-DAST), 4--(trifluoromethyl)benzenesulfonyl fluoride, N,N- diethyl-α,α-difluoro-3-methylbenzylamine (DFMBA), and tetramethylfluoroformamidinium hexafluorophosphate (TFFH). In some embodiments, the deoxyfluorination reagent is perfluoro- 1-butanesulfonyl fluoride (PBSF).

[0068] In some embodiments, the compound of Formula C is contacted with a deoxyfluorination reagent and a fluoride source to form a compound of Formula I. Suitable fluoride sources include triethylamine HF, pyridine HF (Py·HF), N,N-diisopropylethylamine trihydrofluoride (DIEA·3HF), 3,3-difluoro-1,2-diphenylcyclopropene tetra-n-butylammonium fluoride (TBAF), 26Atty. Dkt. No.129802-0442 P0059-WO and tetrabutylammonium bifluoride (TBABF). In some embodiments, the fluoride source is N,N- diisopropylethylamine trihydrofluoride (DIEA·3HF).

[0069] In some embodiments, a compound of Formula C is contacted with a fluorination agent (e.g., a deoxyfluorination agent) and a fluoride source in the presence of a base. Suitable bases for this step include an amine, an amidine, a phosphazene, and a guanidine. Suitable amines include alkylamines (e.g., methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, dimethylamine, triethylamine (TEA), tributylamine (TBA), or N,N-diisopropylethylamine (DIEA)),and aryl amines (e.g., aniline, and 1,4-benzenediamine). Suitableamidines include acetamidine, diminazine, benzamidine, and diazabicyclo[5.4.0]undec-7-ene (DBU). Suitable phosphazenes include hexachlorocyclotriphosphazene, and bis(triphenylphosphine)iminium chloride. Suitable guanidines include guanidine, and guanidine derivatives such as arginine, creatine and triazabicyclodecene (TBD), tetramethylguanidine (TMG), 7-methyl-1,5,7-trizabicyclo(4.4.0)dec-5-ene (MTBD), and sulfadiazine. In some embodiments, the base is an amine. In some embodiments, the amine is a tertiary amine, e.g., triethylamine, tributylamine, or N,N-diisopropylethylamine. In some embodiments, the base is N,N-diisopropylethylamine (DIEA).

[0070] In some embodiments, the compound of Formula I is prepared with low amounts of one or more process byproducts. The amount of process byproducts can be determined using, e.g., HPLC. In some embodiments, the amount of process byproducts is less than 20% a / a, or less than 15% a / a, or less than 10% a / a. In some embodiments, the one or more process byproducts comprise a compound of Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula If, or combinations thereof, wherein the compounds of Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie, and Formula If have the structures: (Formula Ib)27Atty. Dkt. No.129802-0442 P0059-WO Id) meess byproducts from the compound of Formula I. In some embodiments, reducing the amount of the one or more process byproducts from the compound of Formula I comprises combining the compound of Formula I with one or more solvents to form a slurry, and filtering the precipitate from the slurry to form the compound of Formula I with a reduced amount of the one or more process byproducts. In some embodiments, the solvent comprises acetonitrile, an alcohol, or a combination thereof. In some embodiments, the solvent comprises acetonitrile, 2-methyl-1- propanol, or a combination thereof. In some embodiments, the amount of process byproducts is less than 10% w / w, or less than 9% w / w, or less than 8% w / w, or less than 7% w / w, or less than 6% w / w, or less than 5% w / w, or less than 4% w / w, or less than 3% w / w, or less than 2% w / w, or less than 1% w / w. In some embodiments, the amount of process byproducts is 0% w / w to 9.9% w / w, or 0% w / w to 8.9% w / w, or 0% w / w to 7.9% w / w, or 0% w / w to 6.9% w / w, or 0% w / w to 5.9% w / w, or 0% w / w to 4.9% w / w, or 0% w / w to 3.9% w / w, or 0% w / w to 2.9% w / w, or 0% w / w to 1.9% w / w, or 0% w / w to 0.9% w / w. In some embodiments, the amount of each process byproduct is independently less than 5% w / w, or less than 4% w / w, or less than 3% w / w, or less than 2% w / w, or less than 1% w / w, or less than 0.5% w / w. In some embodiments, the amount of each process byproduct is independently 0% w / w to 4.9% w / w, or 0% w / w to 3.9% w / w, or 0% w / w to 2.9% w / w, or 0% w / w to 1.9% w / w, or 0% w / w to 0.9% w / w, or 0% w / w to 0.49% w / w. 28Atty. Dkt. No.129802-0442 P0059-WO In some embodiments, the compound of Formula I is substantially free of process byproducts. In some embodiments, the compound of Formula I is substantially free of process byproducts as determined by HPLC.

[0071] In some embodiments, R1is -F. In some embodiments R2is -CN. In some embodiments R3is -H. In some embodiments R4is -S(O)2CH3.

[0072] In some embodiments, the compound of Formula I is )).

[0073] In some embodimeor more process byproducts. In some embodiments, the one or more process byproducts comprise Impurity 2a, Impurity 2b, Impurity 3, Impurity 4, Impurity 5, Impurity 6, or combinations thereof: wherein Impurity 2a, Impurity 2b, Impurity 3, Impurity 4, Impurity 5, Impurity 6 have the structures: 2b) 4) me29Atty. Dkt. No.129802-0442 P0059-WO embodiments, the total amount of process byproducts is less than 10% w / w, or less than 9% w / w, or less than 8% w / w, or less than 7% w / w, or less than 6% w / w, or less than 5% w / w, or less than 4% w / w, or less than 3% w / w, or less than 2% w / w, or less than 1% w / w. In some embodiments, the total amount of process byproducts is 0% w / w to 9.9%w / w, or 0% w / w to 8.9% w / w, or 0% w / w to 7.9% w / w, or 0% w / w to 6.9% w / w, or 0% w / w to 5.9% w / w, or 0% w / w to 4.9% w / w, or 0% w / w to 3.9% w / w, or 0% w / w to 2.9% w / w, or 0% w / w to 1.9% w / w, or 0% w / w to 0.9% w / w. In some embodiments, the amount of each process byproduct is independently less than 5% w / w, or less than 4% w / w, or less than 3% w / w, or less than 2% w / w, or less than 1% w / w, or less than 0.5% w / w. In some embodiments, the amount of each process byproduct is independently 0% w / w to 4.9% w / w, or 0% w / w to 3.9% w / w, or 0% w / w to 2.9% w / w, or 0% w / w to 1.9% w / w, or 0% w / w to 0.9% w / w, or 0% w / w to 0.49% w / w. In some embodiments, Compound (I) is substantially free of process byproducts. In some embodiments, Compound (I) is substantially free of process byproducts as determined by HPLC.

[0074] Also provided herein is a process for forming a compound of Formula C from a compound of Formula B, the process comprising: contacting the compound of Formula B: B) with a hydrogen reagentrm a compound of Formula C: C); wherein:30Atty. Dkt. No.129802-0442 P0059-WO R1and R2are independently selected from -H, -F, -Cl, -Br, and -CN; R3is -H, -F or -Cl; and R4is selected from -H, -F, -Cl, -C1-C3 alkyl, and -S(O)2(C1-C3 alkyl), wherein the -C1-C3alkyl or -S(O)2(C1-C3alkyl) is unsubstituted or substituted with 1-3 halogen.

[0075] In some embodiments, a suitable chiral catalyst is a Noyori hydrogenation catalyst. In some embodiments, a suitable chiral catalyst includes a chiral transition metal catalysts (e.g., a ruthenium, rhodium, or iridium chiral catalyst). In some embodiments, the chiral transition metal catalyst includes a transition metal center (e.g., ruthenium, rhodium, or iridium), and one or more chiral ligands. In some embodiments, the chiral catalyst is a chiral ruthenium catalyst. In some embodiments suitable chiral ruthenium catalysts include RuCl[Fsdpen](p-cymene), RuCl[Ts- DPEN](p-cymene), RuCl[Ts-DPEN](mesitylene), chloro[N-[2-(4-methylbenzyloxy)ethyl]-N'-(p- toluenesulfonyl)-1,2-diphenylethylenediamine]ruthenium(II) (Ts-DENEB®), RuCl2[dm- segphos®][daipen], RuCl2[dm-segphos®][dpen], RuCl2[xylbinap][diapen], RuCl2[xylbinap][dpen], and RuCl[daipena][xylbinap]. In some embodiments suitable chiral ruthenium catalysts include RuCl[(R,R)-Fsdpen](p-cymene), RuCl[(R,R)-Ts-DPEN](p-cymene), RuCl[(R,R)-Ts-DPEN](mesitylene), chloro[(R,R)-N-[2-(4-methylbenzyloxy)ethyl]-N'-(p- toluenesulfonyl)-1,2-diphenylethylenediamine]ruthenium(II) ((R,R)-Ts-DENEB®), RuCl2[(R)- dm-segphos®][(R)-daipen], RuCl2[(R)-dm-segphos®][(R,R)-dpen], RuCl2[(R)-xylbinap][(R)- diapen], RuCl2[(R)-xylbinap][(R)-dpen], and RuCl[(R)-daipena][(R)-xylbinap]. In some embodiments, the chiral ruthenium catalyst is RuCl[(R,R)-Ts-DPEN](mesitylene).

[0076] Suitable hydrogen reagents include hydrogen gas, formic acid, and hydrosilane. In some embodiments, the hydrogen reagent is formic acid.

[0077] In some embodiments, the compound of Formula B is contacted with a hydrogen reagent in the presence of a chiral catalyst and a base to form a compound of Formula C.

[0078] In some embodiments, suitable bases include an amine, an amidine, a carbonate, a phosphate, a tetraalkyl ammonium salt, and a hydroxide salt. Suitable amines include alkylamines (e.g., methylamine, ethylamine, propylamine, isopopylamine, butylamine, isobutylamine, dimethylamine, triethylamine (TEA), tributylamine (TBA), and N,N-diisopropylethylamine (DIEA)), and aryl amines (e.g., aniline and 1,4,benzenediamine). Suitable amidines include 31Atty. Dkt. No.129802-0442 P0059-WO acetamidine, diminazine, benzamidine, and diazabicyclo[5.4.0]undec-7-ene (DBU). Suitable carbonates include Na2CO3, and CaCO3, NaHCO3, and KHCO3. Suitable phosphates include Na3PO4, Na2HPO4, NaH2PO4, K3PO4, K2HPO4, and KH2PO4. Suitable tetra alkyl ammonium salts, or quaternary alkylammonium salts include tetra-n-butylammonium fluoride (TBAF), tetraethylammonium bromide, and alkyl trimethylammonium chloride. Suitable hydroxide salts include NaOH, KOH, LiOH, Ca(OH)2, Mg(OH)2, and Mn(OH)2. In some embodiments, the base is an amine. In some embodiments, the base is triethylamine.

[0079] In some embodiments, the compound of Formula B is prepared by a process comprising: a. contacting a compound of Formula A: (Formula A); with an R5X reagenpound of Formula A1: 1), wherein:each R5is an alcohol protecting group; X is -Cl, -Br, -I, -OMs, -OTs, or -OTf; and the base is an amine, an amidine, a carbonate, a phosphate, a tetra alkyl ammonium salt, or a hydroxide salt; and b. contacting the compound of Formula A1 with a fluorination agent thereby preparing the compound of Formula B.

[0080] In some embodiments, R5is a silyl group or an acyl group. In some embodiments, R5is a silyl group. In some embodiments, R5is an acyl group. In some embodiments, R5is acyl, benzoyl, or pivaloyl. In some embodiments R5is trimethylsilyl (TMS), triethyl silyl (TES), 32Atty. Dkt. No.129802-0442 P0059-WO triisopropylsilyl, tert-butyldimethylsilyl (TBS or TBDMS), or tert-butyldiphenylsilyl (TBDPS). In some embodiments, R5is tert-butyldimethylsilyl. In some embodiments, R5X is chlorotrimethylsilane, bromotrimethylsilane, trimethylsilyl iodide, tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), or an acyl halide (e.g., acetyl chloride, benzoyl chloride, pivaloyl chloride, and the like). In some embodiments, R5X is chlorotrimethylsilane, bromotrimethylsilane, trimethylsilyl iodide, or tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf). In some embodiments, the R5X reagent is tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf).

[0081] In some embodiments, the fluorination agent is an electrophilic fluorination agent. Suitable electrophilic fluorination agents include 1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SELECTFLUOR®), N-fluoro-N′-methyl- triethylenediamine bis(tetrafluoroborate) (SELECTFLUOR® II), N-fluorobenzenesulfonamide (NFSI), 1,1′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) (Synfluor), 1-fluoropyridinium trifluoromethanesulfonate, and N-fluoropyridinium (NFPy) salts including, e.g., 1-fluoro-2,4,6- trimethylpyridinium tetrafluoroborate, 1-fluoro-2,3,4,5,6-pentachloropyridinium tetrafluoroborate, and 1-fluoro-2,6-dichloropyridinium tetrafluoroborate. In some embodiments, the electrophilic fluorination agent is 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SELECTFLUOR®).

[0082] In some embodiments, the process of preparing a compound of Formula C from a compound of Formula B further comprises contacting the compound of Formula C with a fluorination agent to form a compound of Formula I: (Formula I).

[0083] In some embodiments, the fluorination agent is a deoxyfluorination agent. Suitable deoxyfluorination reagents include perfluoro-1-butanesulfonyl fluoride (PBSF), nitrophenyl ester sulfuryl fluoride, benzenesulfonyl fluoride, diethylaminosulfur trifluoride (DAST), sulfur 33Atty. Dkt. No.129802-0442 P0059-WO tetrafluoride, bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor®), 4-tert-butyl-2,6- dimethylphenylsulfur trifluoride (Fluolead™), morpholinodifluorosulfinium tetrafluoroborate (XtalFluor-M®), N,N-diethylamino-S,S-difluorosulfinium tetrafluoroborate (XtalFluor-E®), pyridine-2-sulfonyl fluoride (PyFluor), PhenoFluor™, AlkylFluor™, morpholinosulfur trifluoride (morph-DAST), 4-(trifluoromethyl)benzenesulfonyl fluoride, N,N-diethyl-α,α-difluoro-3- methylbenzylamine (DFMBA), tetramethylfluoroformamidinium hexafluorophosphate (TFFH), and 3,3-difluoro-1,2-diphenylcyclopropene. In some embodiments, the deoxyfluorination reagent is perfluoro-1-butanesulfonyl fluoride (PBSF).

[0084] In particular embodiments, a compound of Formula C is contacted with a fluorination reagent (e.g., a deoxyfluorination reagent) and a fluoride source to form a compound of Formula I. Suitable fluoride sources include triethylamine HF, pyridine HF (Py·HF), N,N- diisopropylethylamine trihydrofluoride (DIEA·3HF), tetra-n-butylammonium fluoride (TBAF) or tetrabutylammonium bifluoride (TBABF). In some embodiments, the fluoride source is N,N- diisopropylethylamine trihydrofluoride (DIEA·3HF).

[0085] In particular embodiments, the compound of Formula C is contacted with a fluorination agent (e.g., a deoxyfluorination agent) and a fluoride source in the presence of a base. In particular embodiments the base is an amine, amidine, a phosphazene, and a guanidine. Suitable amines include alkylamines (e.g., methylamine, ethylamine, propylamine, isopopylamine, butylamine, isobutylamine, dimethylamine, triethylamine (TEA), tributylamine (TBA), and N,N- diisopropylethylamine (DIEA)), aryl amines (e.g., aniline and 1,4,benzenediamine). Suitable amidines include acetamidine, diminazine, benzamidine, and diazabicyclo[5.4.0]undec-7-ene (DBU). Suitable phosphazenes include hexachlorocyclotriphosphazene, and bis(triphenylphosphine)iminium chloride. Suitable guanidines include guanidine, and guanidine derivatives (e.g., arginine, creatine and triazabicyclodecene (TBD), tetramethylguanidine (TMG), 7-methyl-1,5,7-trizabicyclo(4.4.0)dec-5-ene (MTBD), and sulfadiazine). In some embodiments, the base is an amine. In some embodiments, the amine is a tertiary amine, e.g., triethylamine, tributylamine, or N,N-diisopropylethylamine. In some embodiments, the base is N,N- diisopropylethylamine (DIEA). 34Atty. Dkt. No.129802-0442 P0059-WO

[0086] In particular embodiments, R1is -F. In particular embodiments, R2is CN. In particular embodiments, R3is -H. In particular embodiments, R4is -S(O)2CH3.

[0087] In particular embodiments, the compound of Formula I is Compound (I): I)).

[0088] Also provided isA: (Formula A); wherein:R1and R2are independently selected from -H, -F, -Cl, -Br, and -CN; R3is -H, -F or -Cl; and R4is selected from -H, -F, -Cl, -C1-C3alkyl, and -S(O)2(C1-C3alkyl), wherein the -C1-C3alkyl or -S(O)2(C1-C3alkyl) is unsubstituted or substituted with 1-3 halogen; said process comprising contacting a compound of Formula Z: (Formula Z)with an oxidizing agent thereby preparing the compound of Formula A.

[0089] Suitable oxidizing agents include chromate salt (e.g., CrO3and H2SO4, pyridinium chlorochromate (PCC), and pyridinium dichromate (PDC)), sodium hypochlorite, a hypervalent 35Atty. Dkt. No.129802-0442 P0059-WO iodine compound (e.g., Dess-Martin periodinane (DMP), 2-iodoxybenzoic acid (IBX), and 1- acetoxy-5-bromo-1,2-benziodoxol-3(1H)-one (ABBX)), N-tert-butylbenzenesulfinimidoyl chloride, tetrapropylammonium perruthenate, and 2-hydroxy-2-azaadamantane (AXADOL®). In some embodiments, the oxidizing agent is sodium hypochlorite.

[0090] In particular embodiments, the compound of Formula Z is contacted with an oxidizing agent (e.g., sodium hypochlorite) in the presence of a catalyst. In some embodiments, the catalyst is TEMPO.

[0091] In some embodiments, the compound of Formula Z is substantially free of process byproducts. In some embodiments, the process byproducts comprise a compound of Formula 8, having the structure: (Formula 8).

[0092] In some embodimen, p yp uct of Formula 8 is Impurity 8: (Impurity 8).

[0093] In some embodiments, the process comprises preparing a compound of Formula Z from a compound of Formula X, the process comprising: a. contacting the compound of Formula X: (Formula X) wherein R6is ana co o protect ng group; with a catalyst and a hydrogen reagent to form the compound of Formula Y: 36Atty. Dkt. No.129802-0442 P0059-WO (Formula Y); and b. contacting Y with a deprotection agent thereby preparingthe compound of Formula Z.

[0094] In particular embodiments, the catalyst is a palladium-based or platinum-based hydrogenation catalyst. In some embodiments, the catalyst is palladium on carbon or platinum on carbon. In some embodiments, the catalyst is palladium on carbon.

[0095] In particular embodiments, the hydrogen reagent is hydrogen gas, formic acid, or hydrosilane. In some embodiments, the hydrogen reagent is hydrogen gas.

[0096] In some embodiments, the compound of Formula X comprises low levels of Suzuki coupling catalyst. In some embodiments, the level of Suzuki coupling catalyst is measured by detecting a transition metal and / or related degradants (e.g., phosphorous from catalyst ligand). In some embodiments, the level of Suzuki coupling catalyst is measured using elemental analysis. In some embodiments, the compound of Formula X comprises less than 1000 parts per million (ppm), or less than 900 ppm, or less than 800 ppm, or less than 750 ppm, or less than 700 ppm, or less than 600 ppm, or less than 650 ppm, or less than 500 ppm, or less than 450 ppm, or less than 400 ppm, or less than 350 ppm, or less than 300 ppm, or less than 250 ppm, or less than 200 ppm, or less than 150 ppm, or less than 100 ppm, or less than 50 ppm, or less than 25 ppm of Suzuki cross coupling catalyst. In some embodiments, the compound of Formula X comprises 0 to 999 ppm, or 0 to 899 ppm, or 0 to 799 ppm, or 0 to 749 ppm, or 0 to 699 ppm, or 0 to 649 ppm, or 0 to 599 ppm, or 0 to 549 ppm, or 0 to 499 ppm, or 0 to 449 ppm, or 0 to 399 ppm, or 0 to 349 ppm, or 0 to 299 ppm, or 0 to 249 ppm, or 0 to 199 ppm, or 0 to 149 ppm, or 0 to 99 ppm, or 0 to 49 ppm, or 0 to 24 ppm of Suzuki cross coupling catalyst. In some embodiments, the Suzuki coupling catalyst comprises a suitable group ten metal catalyst. Suitable group ten metal catalysts include nickel catalysts, palladium catalysts, and platinum catalysts. In some embodiments, the group ten metal catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is Pd(cod)Cl2, Pd(dppe)Cl2, Pd(dppp)Cl2, Pd(dppf)Cl2, Pd(PPh3)2Cl2, and Pd(PPh3)4. In some embodiments, the 37Atty. Dkt. No.129802-0442 P0059-WO palladium catalyst is Pd(dppf)Cl2. In some embodiments, the compound of Formula X comprises less than 1000 parts per million (ppm), or less than 900 ppm, or less than 800 ppm, or less than 750 ppm, or less than 700 ppm, or less than 600 ppm, or less than 650 ppm, or less than 500 ppm, or less than 450 ppm, or less than 400 ppm, or less than 350 ppm, or less than 300 ppm, or less than 250 ppm, or less than 200 ppm, or less than 150 ppm, or less than 100 ppm, or less than 50 ppm, or less than 25 ppm of palladium. In some embodiments, the compound of Formula X comprises 0 to 999 ppm, or 0 to 899 ppm, or 0 to 799 ppm, or 0 to 749 ppm, or 0 to 699 ppm, or 0 to 649 ppm, or 0 to 599 ppm, or 0 to 549 ppm, or 0 to 499 ppm, or 0 to 449 ppm, or 0 to 399 ppm, or 0 to 349 ppm, or 0 to 299 ppm, or 0 to 249 ppm, or 0 to 199 ppm, or 0 to 149 ppm, or 0 to 99 ppm, or 0 to 49 ppm, or 0 to 24 ppm of palladium.

[0097] In particular embodiments, the process further comprises contacting the compound of Formula X with a catalyst and a hydrogen reagent and an acid additive to form the compound of Formula Y. Suitable acid additives include phosphoric acid, citric acid, tartaric acid, oxalic acid, benzoic acid, formic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, and the like. In some embodiments, the acid additive is tartaric acid (e.g., L-tartaric acid).

[0098] In some embodiments, step a further comprises reducing the amount of process byproducts (e.g., a compound of Formula 8, a compound of Formula 9, or combination thereof) from the compound of Formula Y. In some embodiments, reducing the amount of process byproducts from the compound of Formula Y comprises combining the compound of Formula Y with one or more solvents to form a slurry; and filtering the precipitate from the slurry to prepare the compound of Formula Z having reduced process byproducts. In some embodiments, the one or more solvents comprise water, an alcohol, toluene, or combinations thereof. In some embodiments, the one or more solvents comprise water and ethanol. In some embodiments, the compound of Formula Y comprises less than 5% process byproducts, or less than 4% process byproducts, or less than 3% process byproducts, or less than 1% process byproducts. In some embodiments, the compound of Formula X comprises 0 to 4.9%, or 0 to 3.9%, or 0 to 2.9%, or 0 to 1.9%, or 0 to 0.9% process byproducts. In some embodiments, the compound of Formula Y is substantially free of process byproducts. In some embodiments, the compound of Formula Y is substantially free of process byproducts as determined by HPLC. In some embodiments, the 38Atty. Dkt. No.129802-0442 P0059-WO process byproducts comprise a compound of Formula 9 . In someembodiments, the compound of Formula 9 is Impurit In someembodiments, the process byproducts comprise a compound of Formu (Formula 8). In some embodiments, the compound of F8: (Impurity 8).odiments, step b further comprises reducing the presence of process byproducts (e.g., a compound of Formula 8) from the compound of Formula Z. In some embodiments, reducing the presence of process byproducts comprises combining the compound of Formula Z with a solvent to form a slurry; and filtering the precipitate from the slurry to prepare the compound of Formula Z having reduced process byproducts. In some embodiments, the solvent is an alcohol, anisole, or a combination thereof. In some embodiments, the solvent is anisole. In some embodiments, the slurry is heated to a temperature of at least 25 °C, or at least 30 °C, or at least 35 °C, or at least 40 °C, or at least 45 °C, or at least 50 °C. In certain such embodiments, the slurry may be cooled to a temperature between 17 °C about 25°C, such as 18 °C, 19 °C, 20 °C, 21 °C, 22 °C, 23 °C, or 24 °C prior to filtering. In some embodiments, the compound of Formula Z comprises less than 5% process byproducts, or less than 4% process byproducts, or less than 3% process byproducts, or less than 1% process byproducts. In some embodiments, the compound of Formula Z comprises 0 to 4.9%, or 0 to 3.9%, or 0 to 2.9%, or 0 to 1.9%, or 0 to 0.9% process byproducts. In some embodiments, the compound of Formula Z is 39Atty. Dkt. No.129802-0442 P0059-WO substantially free of process byproducts. In some embodiments, the compound of Formula Z is substantially free of process byproducts as determined by HPLC. In some embodiments, the process byproducts comprise compound of Formula 8: meembodiments, the compound of Formula 8 is Impurit .

[0100] In some embodiments, the process comprisf Formula X from a compound of Formula W, the process comprising: contacting the compound of Formula W: (Formula W) wherein X is -with a compound of Formula V: (Formula V), wherein Y is -B(OH)2, , (OEt)2, or -Bpin; and a group ten metal catalyst thereby preparing the compound of Formula X.

[0101] Suitable group ten metal catalysts include nickel catalysts, palladium catalysts, and platinum catalysts. In some embodiments, the group ten metal catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is Pd(cod)Cl2, Pd(dppe)Cl2, Pd(dppp)Cl2, Pd(dppf)Cl2, Pd(PPh3)2Cl2, and Pd(PPh3)4. In some embodiments, the palladium catalyst is Pd(dppf)Cl2. 40Atty. Dkt. No.129802-0442 P0059-WO

[0102] In particular embodiments, R6is trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), triphenylsilyl (TPS), tert-butyldimethylsilyl (TBS), methoxymethyl (MOM), tetrahydropyranyl (THP), pivaloyl (Piv), tert-butoxycarbanyl (Boc), or trityl (Tr), acetyl, benzoyl. In some embodiments, R6is pivaloyl (Piv).

[0103] In some embodiments, the process further comprises reducing the presence of Suzuki cross coupling catalyst from the compound of Formula X. The level of Suzuki coupling catalyst can be measured by detecting a transition metal and / or related degradants (e.g., ligand). In some embodiments, the level of Suzuki coupling catalyst is measured using elemental analysis. Without wishing to be bound by theory, reducing residual Suzuki cross coupling catalyst improves the robustness of subsequent processes (e.g., converting a compound of Formula X to a compound of Formula Y). In some embodiments, reducing the presence of Suzuki cross coupling catalyst comprises filtering a solution comprising the compound of Formula X through a suitable filter. In some embodiments, the filter comprises diatomite, activated carbon, or a combination thereof. In some embodiments, the compound of Formula X comprises less than 1000 parts per million (ppm), or less than 900 ppm, or less than 800 ppm, or less than 750 ppm, or less than 700 ppm, or less than 600 ppm, or less than 650 ppm, or less than 500 ppm, or less than 450 ppm, or less than 400 ppm, or less than 350 ppm, or less than 300 ppm, or less than 250 ppm, or less than 200 ppm, or less than 150 ppm, or less than 100 ppm, or less than 50 ppm, or less than 25 ppm of Suzuki cross coupling catalyst. In some embodiments, the compound of Formula X comprises 0 to 999 ppm, or 0 to 899 ppm, or 0 to 799 ppm, or 0 to 699 ppm, or 0 to 599 ppm, or 0 to 499 ppm, or 0 to 399 ppm, or 0 to 299 ppm, or 0 to 199 ppm, or 0 to 99 ppm, or 0 to 49 ppm, or 0 to 24 ppm of Suzuki cross coupling catalyst. In some embodiments, the compound of Formula X is substantially free of Suzuki cross coupling catalyst as determined by elemental analysis. In some embodiments, the Suzuki cross coupling catalyst comprises a suitable group ten metal catalyst. Suitable group ten metal catalysts include nickel catalysts, palladium catalysts, and platinum catalysts. In some embodiments, the group ten metal catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is Pd(cod)Cl2, Pd(dppe)Cl2, Pd(dppp)Cl2, Pd(dppf)Cl2, Pd(PPh3)2Cl2, and Pd(PPh3)4. In some embodiments, the palladium catalyst is Pd(dppf)Cl2. In some embodiments, the compound of Formula X comprises less than 1000 parts per million (ppm), or less than 900 ppm, or less than 800 ppm, or less than 750 ppm, or less than 700 ppm, or less than 600 ppm, or 41Atty. Dkt. No.129802-0442 P0059-WO less than 650 ppm, or less than 500 ppm, or less than 450 ppm, or less than 400 ppm, or less than 350 ppm, or less than 300 ppm, or less than 250 ppm, or less than 200 ppm, or less than 150 ppm, or less than 100 ppm, or less than 50 ppm, or less than 25 ppm of palladium. In some embodiments, the compound of Formula X comprises 0 to 999 ppm, or 0 to 899 ppm, or 0 to 799 ppm, or 0 to 749 ppm, or 0 to 699 ppm, or 0 to 649 ppm, or 0 to 599 ppm, or 0 to 549 ppm, or 0 to 499 ppm, or 0 to 449 ppm, or 0 to 399 ppm, or 0 to 349 ppm, or 0 to 299 ppm, or 0 to 249 ppm, or 0 to 199 ppm, or 0 to 149 ppm, or 0 to 99 ppm, or 0 to 49 ppm, or 0 to 24 ppm of palladium.

[0104] In one aspect, this disclosure is directed to a process comprising one or more of steps a-g: a. contacting a compound of Formula W-1: (Formula W-1) with a compound-1: 1) and a group tend of Formula X-1 1); b. contactng t e compound o ormu a ( - ) 42Atty. Dkt. No.129802-0442 P0059-WO (Formula X-1) with a catalyst and a hydund of Formula Y-1: 1); c. c1) with a deprotection agen); d. c1) with an oxidizing agentto orm a compound o ormua -: 43Atty. Dkt. No.129802-0442 P0059-WO (Formula A-1); e. cmula A-1 (Formula A-1) with an R5X reagent andFormula A1-1: 1); f.1) with an electrophilic flua B-1: nd g.contactng te compound o ormua -: 44Atty. Dkt. No.129802-0442 P0059-WO 1), with a hydrogen reagentompound of Formula C-1: 1); wherein for each of theY, when present, have the meanings provided elsewhere herein.

[0105] In particular embodiments, the processes comprises one or more, two or more, three or more, five or more, or six or more of steps a-g. In some embodiments the process comprises steps a-g. In some embodiments the process comprises two or more of steps a-g, and the steps are performed separately or sequentially. In some embodiments, the process comprises two or more of steps a-g, and the two or more steps are sequential.

[0106] In some embodiments, the process for preparing a compound of Formula C-1 further comprises contacting the compound of Formula C-1 with a fluorination agent to form Compound (I): )).

[0107] In some embod ments, t e compound o ormu a s formed directly from the compounds of Formula V and Formula W. In some embodiments, compound of Formula Y is formed directly from the compound of Formula X. In some embodiments, compound of Formula Z if formed directly from the compound of Formula Y. In some embodiments, the compound of 45Atty. Dkt. No.129802-0442 P0059-WO Formula A is formed directly from the compound of Formula Z. In some embodiments, the compound of Formula A1 is formed directly from the compound of Formula A. In some embodiments, the compound of Formula B is formed directly from the compound of Formula A1. In some embodiments, the compound of Formula C is formed directly from the compound of Formula B. In some embodiments the compound of Formula I is formed directly from the compound of Formula C.

[0108] In one aspect, this disclosure is directed to compounds that are useful intermediates in the preparation of Compound (I). In some embodiments, the intermediates include one or more of the compounds: , ,46Atty. Dkt. No.129802-0442 P0059-WO ,

[0109] In some embodiments, the intermediates are selected from the compounds ,47Atty. Dkt. No.129802-0442 P0059-WO PivO PivO O O .PivO PivO O O .

[0111] In some embodiments, the intermediate is the compou .COMPOSITIONS

[0112] The process according to this disclosure is useful for the preparation of Compound (I) compositions containing low amounts of process byproducts. The phrase “Compound (I) composition” refers to a composition comprising a plurality of Compound (I) molecules. In some embodiments, the compositions further comprise a plurality of process byproduct molecules, wherein the plurality of process byproduct molecules are present in an amount of not more than 10 % w / w of the Compound (I) composition. The process utilizes stereoselective approaches and purification methods that allow for the control of potential process byproducts. Without wishing 48Atty. Dkt. No.129802-0442 P0059-WO to be bound by theory, purification of intermediate steps aids in preventing the downstream chemistry of byproducts that are unintentionally produced during certain chemical transformations. In some embodiments, the Compound (I) compositions according to this disclosure comprise, consist of, or consist essentially of Compound (I) and not more than 10% w / w, or not more than 9% w / w, or not more than 8% w / w, or not more than 7% w / w, or not more than 6% w / w, or not more than 5% w / w, or not more than 4% w / w process byproducts, or no more than 3% w / w process byproducts, or not more than 2.5% w / w, or not more than 2% w / w, or not more than 1.5% w / w process byproducts as determined by HPLC. In some embodiments, the Compound (I) compositions according to this disclosure comprise, consist of, or consist essentially of Compound (I) and 0 to 9.9% w / w, or 0 to 8.9% w / w, or 0 to 7.9% w / w, or 0 to 6.9% w / w, or 0 to 5.9% w / w, or 0 to 4.9% w / w, or 0 to 3.9% w / w, or 0 to 2.9% w / w, or 0 to 2.4% w / w, or 0 to 1.9% w / w, or 0 to 1.4% w / w process byproducts as determined by HPLC. The process byproduct content can be determined as described in the examples. In some embodiments, the Compound (I) compositions according to this disclosure are substantially free of process byproducts. In some embodiments, the Compound (I) compositions according to this disclosure are substantially free of process byproducts as determined by HPLC. In some embodiments, the one or more process byproducts comprise, consist of, or consist essentially of a compound selected from , , ,49Atty. Dkt. No.129802-0442 P0059-WO Inlly,

[0113] In some embodiments, the Compound (I) compositions prepared using the process according to this disclosure are useful in the manufacture of a pharmaceutical composition comprising the Compound (I) composition and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is intended for oral 50Atty. Dkt. No.129802-0442 P0059-WO administration. In some embodiments, the pharmaceutical composition is a capsule. In other embodiments, the pharmaceutical composition is a tablet.

[0114] In some embodiments, this disclosure provides a pharmaceutical composition comprising a Compound (I) composition, and one or more pharmaceutically acceptable excipients, wherein the Compound (I) composition is substantially free of one or more process byproducts as determined by HPLC. As described above, the phrase “Compound (I) composition” refers to a composition comprising a plurality of Compound (I) molecules. In some embodiments, the Compound (I) composition further comprise a plurality of process byproduct molecules, wherein the plurality of process byproduct molecules are present in an amount of not more than 10 % w / w of the Compound (I) composition. In some embodiments, the pharmaceutical composition comprises a Compound (I) composition, and one or more pharmaceutically acceptable excipients, wherein the Compound (I) composition comprises, consists of, or consists essentially of Compound (I) and not more than 10% w / w, or not more than 9% w / w, or not more than 8% w / w, or not more than 7% w / w, or not more than 6% w / w, or not more than 5% w / w, or not more than 4% w / w, or not more than 3% w / w, or not more than 2.5% w / w, or not more than 2% w / w, or not more than 1.5% w / w process byproducts as determined by HPLC. In some embodiments, the pharmaceutical composition comprises a Compound (I) composition, and one or more pharmaceutically acceptable excipients, wherein the Compound (I) composition comprises, consists of, or consists essentially of Compound (I) and 0 to 9.9% w / w, or 0 to 8.9% w / w, or 0 to 7.9% w / w, or 0 to 6.9% w / w, or 0 to 5.9% w / w, or 0 to 4.9% w / w, or 0 to 3.9% w / w, or 0 to 2.9% w / w, or 0 to 2.4% w / w, or 0 to 1.9% w / w, or 0 to 1.4% w / w process byproducts as determined by HPLC. The process byproduct content can be determined as described in the examples. In some embodiments, the one or more process byproducts comprise, consist of, or consist essentially of a compound selected from ,51Atty. Dkt. No.129802-0442 P0059-WO , , orist,52Atty. Dkt. No.129802-0442 P0059-WO

[0115] The pharmaceutical compositions according to this disclosure comprise one or more pharmaceutically acceptable excipients. Exemplary excipients include, but are not limited to, fillers, binders, lubricants, disintegrants, glidants, and / or and polymers. In some embodiments, the one or more excipients include one or more fillers, one or more disintegrants, and one or more lubricants. In some embodiments, the one or more excipients further comprise one or more polymers. The pharmaceutical composition may further comprise a coating.

[0116] The one or more binders can include a dry binder or a wet binder, optionally one or more in the group of starch, pregelatinized starch, sodium alginate, gelatin, polyvinylpyrrolidone (PVP), microcrystalline cellulose (MCC), hydroxypropyl methylcellulose (HPMC), a polymethacrylate, sodium carboxymethylcellulose, polyethylene glycol (PEG).

[0117] The one or more fillers can include, but are not limited to, one or more in the group of a pharmaceutically acceptable polymer, a mineral, a metal salt, a sugar, and a starch, optionally one or more in the group of lactose, MCC, silicified microcrystalline cellulose, starch, a natural starch, a modified starch, calcium phosphate, calcium carbonate, sucrose, maltodextrin, mannitol, sorbitol, and sodium chloride, optionally one or more in the group of MCC, mannitol, and lactose, optionally selected from one or both of MCC and mannitol.

[0118] The one or more disintegrants can include, but are not limited to, one or more in the group of crospovidone, croscarmellose calcium, croscarmellose sodium, and sodium starch glycolate, for example croscarmellose sodium.

[0119] The one or more lubricants can include, but are not limited to, one or more in the group of calcium stearate, magnesium stearate, talc, and liquid paraffin, for example magnesium stearate.

[0120] The one or more glidants can include, but are not limited to, one or more in the group of fumed silica, magnesium carbonate, magnesium stearate, silicon dioxide, and talc, for example silicon dioxide.

[0121] The one or more polymers can include, but are not limited to: a) cellulose-based polymers, including cellulose esters and cellulose ethers (e.g., cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), 53Atty. Dkt. No.129802-0442 P0059-WO hydroxyethyl cellulose (HEC), and carboxymethyl cellulose (CMC)); b) polymethacrylates; c) pyrrolidones (e.g., polyvinyl pyrrolidine (PVP) or polyvinyl pyrrolidine and vinyl acetate (PVP / VA) copolymer); and d) polyethylene glycols (PEG). In some embodiments, the one or more polymers comprise HPMCAS.

[0122] In some embodiments, the pharmaceutical composition according to this disclosure comprise a Compound (I) composition and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients comprise HPMCAS, microcrystalline cellulose, mannitol, croscarmellose sodium, magnesium stearate, or combinations thereof. In some embodiments, the pharmaceutical composition further comprises a coating (e.g., Opadry® AMB II). EXAMPLES

[0123] The following examples are put forth to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use what is disclosed in the present disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Additional compounds within the scope of this disclosure may be made using methods based on those illustrated in these examples, or based on other methods known in the art. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental errors and deviations should be accounted for.

[0124] All reactions were performed using a Teflon-coated magnetic stir bar or mechanical stirring, depending on the scale. NMR spectra were recorded on a Bruker 300 or 400 MHz NMR instrument and are referenced to the residual proton signal of the deuterated solvent for1H spectra, and to the carbon multiplet of the deuterated solvent for13C spectra. The chemical shifts are reported in ppm and the spectroscopic data are reported as follows: multiplicity, number of protons and coupling constant. Analytical HPLC was performed on an Agilent HPLC system with UV detector or an equivalent HPLC system. LCMS data was collected on an Agilent infinity series LCMS with UV detection or an equivalent system using a binary solvent system. The HPLC was equipped with a GL Sciences Inertsil ODS-3 (150mm×4.6mm, 3.0 µm) column, XBridge C18, 150 mm x 4.6 mm, 3.5μm column, XBridge BEH C18, 75 mm x 4.6 mm, 2.5 μm column, or ACE Excel 3 C18-PFP, 150 mm x 4.6 mm, 3 μm column. 54Atty. Dkt. No.129802-0442 P0059-WO

[0125] Unless indicated otherwise, temperature is in degrees Celsius (° C), and pressure is at or near atmospheric. Standard abbreviations are used, including the following: rt or r.t.=room temperature; min=minute(s); h or hr=hour(s); ng=nanogram; μg=microgram; mg=milligram; g=gram; kg=kilogram; μl or μL=microliter; ml or mL=milliliter; l or L=liter(s); V or v = volumes; μM=micromolar; mM=millimolar; M=molar; mol=mole; mmol=millimole; aq.=aqueous; calcd=calculated; sat. or satd. = saturated; eq. or equiv. = equivalent(s); d.r. = diastereomeric ratio; ee = enantiomeric excess; psi = pounds per square inch; MHz=megahertz; Hz=hertz; ppm=parts per million; cat. = catalyst; ESI MS = electrospray ionization mass spectrometry; MW = molecular weight; HRMS = high resolution mass spectrometry; m / z = mass-to-charge ratio; NMR=nuclear magnetic resonance; Q-NMR = quantitative nuclear magnetic resonance; s = singlet; m = multiplet; d = doublet; dd = doublet of doublets; ddd = doublet of doublet of doublets; t = triplet; dt = doublet of triplets; NMT = no more than; TLC = thin layer chromatography; LCMS = liquid chromatography-mass spectrometry; LCAP = liquid chromatography area percent; HPLC = high- performance liquid chromatography; IPC = ion pair chromatography; % a / a or %-a / a or a% = area percent; % w / w or %-w / w or wt% = weight percent; IY = isolated yield; PE = petroleum ether; DMSO = dimethyl sulfoxide; DCM of CH2Cl2 = dichloromethane; DMF = dimethylformamide; DMA = dimethylacetamide; MeOH = methanol; EtOH = ethanol; iBuOH = 2-methyl-1-propanol; n-BuOH = n-butanol; PE = polyethylene; EA = ethyl acetate; AcOH or CH3COOH = acetic acid; DMAc = dimethylacetamide; THF = tetrahydrofuran; Me-THF = 2-methyltetrahydrofuran; MTBE = methyl tert-butyl ether; MeCN = acetonitrile; PhMe = toluene; DMAP = 4- dimethylaminopyridine; HCO2H or HCOOH = formic acid; m-CPBA = meta- chloroperoxybenzoic acid; PPA = polyphosphoric acid; IPA = isopropyl alcohol; ACVA = 4,4- azobis(4-cyanovaleric acid); MsOH = methanesulfonic acid; PivCl = pivaloyl chloride; DIEA = N,N-diisopropylethylamine; DIEA•3HF = N,N-diisopropylethylamine trihydrofluoride; Et3N or TEA = triethylamine; HCOOH / Et3N = formic acid triethylamine complex; (COCl)2= oxalyl chloride; DAST = diethylaminosulfur trifluoride; DIAD = diisopropyl azodicarboxylate; DBDMH = 1,3-dibromo-5,5-dimethylhydantoin; PBSF or C4F9SO2F= perfluoro-1-butanesulfonyl fluoride; TBAF = 3,3-difluoro-1,2-diphenylcyclopropene tetra-n-butylammonium fluoride; TsOH•H2O = p-toluenesufonic acid monohydrate; MsCl = methanesulfonyl chloride; Tf2O = trifluoromethanesulfonic anhydride; TfOH = trifluoromethanesulfonic acid; TBSOTf = 55Atty. Dkt. No.129802-0442 P0059-WO trifluoromethanesulfonic acid tert-butyldimethylsilyl ester; TEMPO = (2,2,6,6- tetramethylpiperidin-1-yl)oxyl; AlCl3= aluminum chloride; NaIO4= sodium periodate; NaSMe = sodium thiomethoxide; Na2CO3 = sodium carbonate; K2CO3 = potassium carbonate; NaHCO3 = sodium bicarbonate; Na2S2O3= sodium thiosulfate; NaOCl = sodium hypochlorite; Na4EDTA = tetrasodium N,N′-(ethane-1,2-diyl)bis[N-(carboxylatomethyl)glycinate]; Zn(CN)2= zinc cyanide; t-BuOK = potassium tert-butoxide; AcOK = potassium acetate; iPrMgCl = isopropylmagnesium; iPrMgCl•LiCl = isopropylmagnesium chloride lithium chloride complex; nBuLi = n-butyllithium; LiHMDS = lithium bis(trimethylsilyl)amide; LiOH = lithium hydroxide; LiOH•H2O = lithium hydroxide hydrate; KBr = potassium bromide; K3PO4 = tripotassium pohosphate; PPh3 = triphenyl phosphine; B2(pin)2 = bis(pinacolato)diboron; PMHS = polymethylhydrosiloxane; Pd / C = palladium on carbon; Pd(OH)2 / C = palladium hydroxide on carbon; Pd(dppf)Cl2•DCM = 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex; Pd(DPEPhos)Cl2 = dichloro[bis(2-diphenylphosphino)phenyl)ether]palladium(II); RuCl[(R,R)- Tsdpen](mesitylene) or RuCl[(R,R)-TsDPEN](mesitylene) = [N-[(1R,2R)-2-(Amino-κN)-1,2- diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro [(1,2,3,4,5,6-η)-1,3,5- trimethylbenzene]-ruthenium; Cu(OTf)2 = copper(II) trifluoromethanesulfonate; CuCl = copper(I) chloride; ZnCl2 = zinc chloride; K4[Fe(CN)6]•3H2O = potassium hexacyanoferrate (II) trihydrate; RuCl(p-cymene)[(S,S)-MsDpen] = [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; RuCl[(R, R)-Tsdpen](mesitylene) = [N-[(1R,2R)-2-(amino-κN)-1,2- diphenylethyl]-4- methylbenzenesulfonamidato-κN]chloro [(1,2,3,4,5,6-η)-1,3,5-trimethylbenzene]-ruthenium. Example 1: Synthesis of (5R,6S,8R)-3,5-trifluoro-8-((1S,2R)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (Compound (I)) 56Atty. Dkt. No.129802-0442 P0059-WOStep 1: Preparation of (R)-5-cyano-7-fluoro-4-(7-mesyl-1-oxo-4-indanyl)-1,2-dihydro-1- naphthyl 2,2-dimethylpropionate (Intermediate X)

[0126] Anhydrous potassium phosphate (47.55 kg, 224.0 mol, 1.20 equiv.), water (395.65 kg, 5 V) and toluene (688.70 kg, 10 V) were charged to a nitrogen flushed, dry, and clean jacketed vessel. The batch was sparged with nitrogen for 30 min. (R)-5-cyano-7-fluoro-4- (trifluoromesyloxy)-1,2-dihydro-1-naphthyl 2,2-dimethylpropionate (81.99 kg, 187.8 mol, 1.00 equiv.), 7-mesyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-indanon(72.00 kg, 207.3 mol, 1.20 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.076 kg, 1.32 mol, 0.0070 equiv.) were charged to the vessel. The batch temperature 57Atty. Dkt. No.129802-0442 P0059-WO was increased to 27 °C, and the mixture was agitated for 12 h. The mixture was then filtered through a pad of diatomite (40.0 kg), and the filter cake was washed with toluene (139.35 kg, 2 V). The biphasic filtrate was allowed to separate, and the aqueous layer was discarded. N-acetyl- L-cysteine (3.08 kg, 18.9 mol, 0.10 equiv.) and water (159.6 kg, 2 V) were added to the vessel, and the mixture was stirred for 8 h at 60 °C. After cooling, the mixture was then filtered through a pad of diatomite (40.0 kg), and the filter cake was washed with toluene (137.60 kg, 2 V). The aqueous layer was discarded. The organic layer was then washed with water (789.70 kg, 10 V) and filtered through a pad of diatomite (23.75 kg) and activated carbon (60.0 kg). The filter cake was washed with dichloromethane (527.85 kg, 5 V). The filtrate was then vacuum distilled to approximately 396−554 L. The vessel temperature was adjusted to 50 °C. n-Heptane (338.55 kg, 6 V) was charged to the vessel, and the batch was agitated for 2 h. The contents were cooled to 20 °C and held for 6 h. The slurry was filtered, and the filter cake was washed with n-heptane / toluene (1:1, 242.85 kg, 4 V). The solids were vacuum-dried at 45 °C for 19 h to obtain (R)-5-cyano-7- fluoro-4-(7-mesyl-1-oxo-4-indanyl)-1,2-dihydro-1-naphthyl 2,2-dimethylpropionate (72.77 kg, 77.7%, 98.9a%, 98.6wt%) as a white solid.

[0127] 1H NMR (400 MHz, DMSO-d6) δ 8.05 (m, 1H), 7.92 (d, J = 7.8 Hz, 1H, major rotamer), 7.85 – 7.69 (m, 2H), 7.63 (dd, J = 8.7, 2.8 Hz, minor rotamer), 6.51 (t, J = 4.7 Hz, minor rotamer), 6.47 – 6.39 (m, 1H, major rotamer), 6.00 – 5.86 (m, 1H), 3.42 (s, 3H), 3.16 (dt, J = 19.9, 8.2 Hz, minor rotamer), 2.92 – 2.68 (m, 5H), 2.68 – 2.56 (m, 1H, major rotamer), 1.18 (s, 3H, minor rotamer), 1.09 (s, 6H, major rotamer). HRMS (ESI) m / z: calcd for C26H25FNO5S [M + H]+, 482.1432; found, 482.1465. Step 2: Preparation of (1R,4R)-5-cyano-7-fluoro-4-(7-mesyl-1-oxo-4-indanyl)-1,2,3,4- tetrahydro-1-naphthyl 2,2-dimethylpropionate (Intermediate Y)

[00128] (R)-5-cyano-7-fluoro-4-(7-mesyl-1-oxo-4-indanyl)-1,2-dihydro-1-naphthyl 2,2- dimethylpropionate (72.76 kg, 98.4 wt% 148.7 mol, 1.00 equiv.), 10% palladium / carbon wet (3.58 58Atty. Dkt. No.129802-0442 P0059-WO kg, 0.05% w / w), 10% palladium hydroxide / carbon (3.58 kg, 0.05% w / w), tartaric acid (22.44 kg, 149.5 mol, 1.00 equiv.), toluene (311.2 kg, 5 V), dichloromethane (478.75 kg, 5 V) and water (72.30 kg, 1 V) were charged to two hydrogenation vessels under nitrogen. Vessel was sealed, and the head space was purged with nitrogen and then purged with hydrogen (× 3). The batch was hydrogenated at 30 °C and 2.0 MPa hydrogen for 35 h. The batch was cooled to 20 °C, the head space was purged with nitrogen (× 5), and the reaction mixture was filtered. The filter cake was washed with toluene (251.05 kg, 4 V) (IPC: 88.6a% Intermediate Y; 7.6a% Impurity 9; 0.9a% Impurity 8). The combined organic phase was washed with aqueous sodium chloride solution (17.6 wt%, 610 kg, 7 V). The batch was then vacuum distilled to approximately 501−644 L keeping jacket temperature no more than 60 °C. After cooling, ethanol (565.1 kg, 10 V) was charged to vessel. The batch was then vacuum distilled to approximately 358−429 L. After cooling to 25 °C, ethanol (566.2 kg, 10 V) was charged to vessel. The batch was then vacuum distilled to approximately 358−429 L keeping jacket temperature no more than 60 °C. After cooling to 25 °C, ethanol (546.6 kg, 10 V) was charged to vessel. The batch was then vacuum distilled to approximately 358−429 L keeping jacket temperature no more than 60 °C. After cooling to 25 °C, ethanol (282.95 kg, 5 V) was charged to vessel. The contents were cooled to 20 °C and held for 8 h. The slurry was filtered, and the filter cake was washed with ethanol (170.00 kg, 3.0 V). The solids were vacuum-dried at 45 °C for 18 h. (1R,4R)-5-cyano-7-fluoro-4-(7-mesyl-1-oxo-4- indanyl)-1,2,3,4-tetrahydro-1-naphthyl 2,2-dimethylpropionate (59.09 kg, 80.9%, 99.1a%, 98.4wt%) was obtained as a white solid.

[0129] 1H NMR (400 MHz, Chloroform-d) δ 8.02 (d, J = 7.9 Hz, 1H), 7.40 – 7.29 (m, 2H), 6.96 (d, J = 7.9 Hz, 1H), 5.96 (dd, J = 8.8, 5.5 Hz, 1H), 4.72 (dd, J = 6.5, 3.9 Hz, 1H), 3.63 – 3.48 (m, 1H), 3.45 (s, 3H), 3.32 – 3.06 (br, 1H), 3.01 – 2.80 (m, 2H), 2.46 – 2.30 (m, 1H), 2.19 – 2.05 (m, 1H), 2.01 – 1.89 (m, 1H), 1.88 – 1.72 (m, 1H), 1.28 (s, 9H). HRMS (ESI) m / z: calcd for C26H27FNO5S [M + H]+, 484.1594; found, 484.1612. Step 3: Preparation of (5R,8R)-3-fluoro-5-hydroxy-8-(7-mesyl-1-oxo-4-indanyl)-5,6,7,8- tetrahydro-1-naphthonitrile (Intermediate Z) 59Atty. Dkt. No.129802-0442 P0059-WO

[0130] Lithium hydroxide hydrate (8.27 kg, 197.1 mol, 1.60 equiv.), water (236.85 kg, 4 V) and methanol (94.00 kg, 2 V) were charged to a nitrogen flushed, dry, and clean jacketed vessel. The mixture was agitated for ca. 30 min until it became a clear solution. The batch temperature was cooled to 20 °C. Methanol (652.25 kg, 14 V) and (1R,4R)-5-cyano-7-fluoro-4-(7-mesyl-1- oxo-4-indanyl)-1,2,3,4-tetrahydro-1-naphthyl 2,2-dimethylpropionate (58.98 kg, 98.4 wt%, 120.0 mol, 1.0 equiv.) was charged to the vessel. The batch temperature was increased to 30 °C, and the mixture was agitated for 17 h. Water (708.60 kg, 12 V) was charged to the vessel over 3 h. The contents were cooled to 20 °C and held for 6 h. The slurry was filtered, and the filter cake was washed with water (117.9 kg, 2 V). The solids were vacuum-dried at 50 °C for 38 h to give crude (5R,8R)-3-fluoro-5-hydroxy-8-(7-mesyl-1-oxo-4-indanyl)-5,6,7,8-tetrahydro-1-naphthonitrile (42.12 kg, 98.0a%). The crude product and anisole (467.95 kg, 8 V) were charged to a nitrogen flushed, dry, and clean jacketed vessel. The batch temperature was increased to 50 °C over 1 h, and the mixture was agitated for 6 h. The batch temperature was then cooled to 20 °C over 1 h, and the mixture was agitated for 6 h. The slurry was filtered, and the filter cake was washed with anisole (116.80 kg, 2 V). The solids were vacuum-dried at 50 °C for 18 h. The desired product (39.43 kg, 79.5%, 98.1a%, 96.7wt%) was obtained as an off white solid.

[0131] 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 7.8 Hz, 1H), 7.72 (dd, J = 9.8, 2.8 Hz, 1H), 7.68 (dd, J = 8.1, 2.8 Hz, 1H), 6.97 (s, 1H), 4.75 – 4.59 (m, 2H), 3.40 (s, 3H), 3.32 (br, 2H), 2.84 (t, J = 5.9 Hz, 2H), 2.35 – 2.19 (m, 1H), 1.95 – 1.79 (m, 2H), 1.66 – 1.47 (m, 1H). HRMS (ESI) m / z: calcd for C21H19FNO4S [M + H]+, 400.1019; found, 400.1031 Step 4: Preparation of (R)-3-fluoro-8-(7-mesyl-1-oxo-4-indanyl)-5-oxo-5,6,7,8-tetrahydro-1- naphthonitrile (Intermediate A) 60Atty. Dkt. No.129802-0442 P0059-WO

[0132] (5R,8R)-3-fluoro-5-hydroxy-8-(7-mesyl-1-oxo-4-indanyl)-5,6,7,8-tetrahydro-1- naphthonitrile (39.35 kg, 96.7 wt%, 95.26 mol, 1.00 equiv.), 2,2,6,6-tetramethylpiperidin-1-oxyl (0.782 kg, 4.76 mol, 0.050 equiv.) and dichloromethane (506.75 kg, 10 V) were charged to a nitrogen flushed, dry, and clean jacketed vessel. The batch temperature was cooled to 20 °C, and the mixture was agitated for 30 min. Aqueous sodium bicarbonate solution (8.5 wt%, 412.2 kg, 10 V) and potassium bromide (4.56 kg, 38.19 mol, 0.40 equiv.) were charged to the vessel. The batch temperature was then cooled to 5 °C, and the mixture was agitated for 1 h. Aqueous sodium hypochlorite solution (49.49 kg, 1.25 equiv.) was charged to the vessel over 2 h, and the mixture was agitated for 2.5 h. Upon reaction completion, aqueous sodium hydrogen sulfite solution (9.4 wt%, 211 kg, 5 V) was charged to the vessel over 1.5 h. The batch temperature was adjusted to 25 °C, and the mixture was agitated for 0.5 h. The aqueous layer was discarded. The organic layer was then washed with aqueous sodium chloride solution (11.4 wt%, 225 kg, 5 V) and vacuum distilled to approximately 152−190 L keeping jacket temperature at no more than 40 °C. After cooling to 25 °C, ethanol (151.50 kg, 5 V) was charged to vessel. The batch was then vacuum distilled to approximately 152−190 L, keeping jacket temperature at no more than 60 °C. After cooling to 25 °C, ethanol (151.05 kg, 5 V) was charged to vessel. The batch was then vacuum distilled to approximately 152−190 L keeping jacket temperature at no more than 60 °C. The slurry temperature was cooled to 25 °C, filtered, and the filter cake was washed with ethanol (59.95 kg, 2 V). The solids were vacuum-dried at 50 °C for 10 h. (R)-3-fluoro-8-(7-mesyl-1-oxo-4-indanyl)- 5-oxo-5,6,7,8-tetrahydro-1-naphthonitrile (37.87 kg, 98.3%, 99.7a%, 98.3wt%) was obtained as a white solid.

[0133] 1H NMR (400 MHz, DMSO-d6) δ 8.23 (dd, J = 8.1, 2.9 Hz, 1H), 8.06 (dd, J = 8.8, 2.9 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 5.02 (dd, J = 5.6, 2.6 Hz, 1H), 3.44 (s, 3H), 3.38 (t, J = 5.9 Hz, 2H), 2.99 – 2.80 (m, 2H), 2.77 – 2.63 (m, 1H), 2.65 – 2.51 (m, 2H), 2.27 – 2.16 (m, 1H). HRMS (ESI) m / z: calcd for C21H17FNO4S [M + H]+, 398.0862; found, 398.0883. 61Atty. Dkt. No.129802-0442 P0059-WO Step 5: Preparation of 8-[2-fluoro-7-mesyl-1-oxo-4-indanyl]-3,6-difluoro-5-oxo-5,6,7,8- tetrahydro-1-naphthonitrile (Intermediate B)

[0134] (R)-3-fluoro-8-(7-mesyl-1-oxo-4-indanyl)-5-oxo-5,6,7,8-tetrahydro-1-naphthonitrile (37.78 kg, 98.3 wt%, 93.45 mol, 1.00 equiv.), triethylamine (43.10 kg, 468.92 mol, 4.50 equiv.) and dichloromethane (993.0 kg, 20 V) were charged to a nitrogen flushed, dry, and clean jacketed vessel 1. The batch temperature was cooled to 25 °C. Trifluoromethanesulfonic acid tert- butyldimethylsilyl ester (87.85 kg, 365.49 mol, 3.50 equiv.) was charged to vessel 1 over 2.5 h, and the mixture was agitated for 15 h. Upon reaction completion, aqueous sodium bicarbonate solution (5 wt%, 198.75 kg, 5 V) was charged to the vessel over 3 h. The aqueous layer was discarded. The organic layer was then washed with aqueous sodium chloride solution (16.7 wt%, 225.35 kg, 5 V) and vacuum distilled to approximately 113−151 L keeping jacket temperature no more than 50 °C. After cooling to 25 °C, acetonitrile (596.40 kg, 20 V) was charged to vessel 1. The batch was vacuum distilled to approximately 340−415 L keeping jacket temperature no more than 50 °C. The resulting solution of the protected intermediate in acetonitrile was cooled to 25 °C. 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (76.30 kg, 215.38 mol, 2.27 equiv.) and acetonitrile (298.7 kg, 10 V) were charged to a nitrogen flushed, dry, and clean jacketed vessel 2. The batch temperature was cooled to 20 °C. The (R)-5-[(tert- butyl)bis(methyl)siloxy]-8-{3-[(tert-butyl)bis(methyl)siloxy]-4-mesyl-1H-inden-7-yl}-3-fluoro- 62Atty. Dkt. No.129802-0442 P0059-WO 7,8-dihydro-1-naphthonitrileacetonitrile solution in vessel 1 was charged to vessel 2 over 3 h. The mixture was agitated for 6 h. The batch was then vacuum distilled to approximately 151−227 L keeping jacket temperature no more than 55 °C. After cooling to 25 °C, ethyl acetate (510.50 kg, 15 V) was charged to vessel 2. The batch was washed with aqueous hydrochloric acid solution (0.6 N, 197.90 kg, 5 V), aqueous sodium bicarbonate solution (5 wt%, 197.70 kg, 5 V) and aqueous sodium chloride solution (16.7 wt%, 226.70 kg, 5 V). Acetonitrile (30.7 kg, 1 V) was charged to the organic layer. The mixture was polish filtered and vacuum distilled to approximately 227−302 L keeping jacket temperature no more than 55 °C. After cooling to 25 °C, ethanol (298.00 kg, 10 V) was charged to vessel. The batch was then vacuum distilled to approximately 302−378 L keeping jacket temperature no more than 55 °C. After cooling to 25 °C, ethanol (298.40 kg, 10 V) was charged to vessel. The batch was then vacuum distilled to approximately 302−378 L keeping jacket temperature no more than 55 °C. The batch temperature was then cooled to 25 °C, and the mixture was agitated for 6 h. The slurry was filtered, and the filter cake was washed with ethanol (59.50 kg, 2 V). The solids were vacuum-dried at 50 °C for 18 h. 8-[2-fluoro-7-mesyl-1-oxo-4- indanyl]-3,6-difluoro-5-oxo-5,6,7,8-tetrahydro-1-naphthonitrile as a mixture of diastereomers (36.90 kg, major diastereomer 76.4a%, minor isomer (1) 19.4a%, minor isomer (2) 2.79%) was obtained as a white solid.

[0135] 1H NMR (400 MHz, DMSO-d6) δ 8.30 (dd, J = 8.1, 2.9 Hz, 1H), 8.12 (dd, J = 8.6, 2.8 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 5.89 – 5.62 (m, 1H), 5.64 – 5.36 (m, 1H), 5.24 – 5.13 (m, 1H), 4.09 – 3.90 (m, 1H), 3.46 (s, 3H), 3.37 – 3.22 (m, 1H), 2.99 – 2.81 (m, 1H), 2.74 – 2.58 (m, 1H). HRMS (ESI) m / z: calcd for C21H15F3NO4S [M + H]+, 434.0674; found, 434.0690. Step 6: Preparation of (5S,6S,8R)-8-[(1S,2R)-2-fluoro-1-hydroxy-7-mesyl-4-indanyl]-3,6- difluoro-5-hydroxy-5,6,7,8-tetrahydro-1-naphthonitrile (Intermediate C)63Atty. Dkt. No.129802-0442 P0059-WO

[0136] The mixture of diastereomers from Step 5 (36.81 kg, 84.9 mol, 1.00 equiv.), RuCl[(R, R)-Tsdpen](mesitylene) (2.26 kg, 3.6 mol, 0.04 equiv.) and acetonitrile (582.4 kg, 20 V) were charged to a nitrogen flushed, dry, and clean jacketed vessel. The batch temperature was set to 20 °C, and the mixture was agitated for 30 min. Phosphoric acid / potassium phosphate tribasic buffer solution (pH 8.0, 77.55 kg, 2 V) was charged to the vessel. Formic acid triethylamine complex (5:2, 28.73 kg, 332.3 mol, 3.90 equiv.) was then charged to the vessel over 2.5 h, and the mixture was agitated for 14 h. The batch temperature was adjusted to 30 °C, and the mixture was agitated for 4 h. Upon reaction completion (IPC: 82.8a% Intermediate C), the batch temperature was cooled to 25 °C. Aqueous citric acid solution (22 wt%, 444 kg, 10 V) was charged to the vessel, and the mixture was agitated for 1 h. Ethyl acetate (330.50 kg, 10 V) and aqueous sodium chloride solution (16.7 wt%, 226.70 kg, 5 V) were charged to the vessel. The batch was agitated for 30 min. The aqueous layer was discarded. The organic layer was then washed with aqueous sodium chloride solution (16.7 wt%, 218 kg, 5 V) and vacuum distilled to approximately 147−221 L keeping jacket temperature no more than 60 °C. After cooling to 25 °C, ethanol (301.65 kg, 10 V) was charged to vessel. The batch was then vacuum distilled to approximately 147−221 L keeping jacket temperature no more than 60 °C. After cooling to 25 °C, ethanol (288.95 kg, 10 V) was charged to vessel. The batch was then vacuum distilled to approximately 147−221 L keeping jacket temperature no more than 60 °C. The vessel temperature was adjusted to 50 °C. Water (165.2 kg, 4.5 V) was charged to vessel dropwise over 2 h, and the batch was agitated for 14 h. The contents were cooled to 20 °C and held for 4 h. The slurry was filtered, and the filter cake was washed with water (73.75 kg, 2 V). The solids were vacuum-dried at 50 °C for 15 h to give crude (5S,6S,8R)- 8-[(1S,2R)-2-fluoro-1-hydroxy-7-mesyl-4-indanyl]-3,6-difluoro-5-hydroxy-5,6,7,8-tetrahydro-1- naphthonitrile (29.31 kg, 98.3a%). The crude product and ethanol (116.25 kg, 4V) were charged to a nitrogen flushed, dry, and clean jacketed vessel. The batch temperature was increased to 50 °C over 30 min, and the mixture was agitated for 8 h. The batch temperature was then cooled to 20 °C, and the mixture was agitated for 4 h. The slurry was filtered, and the filter cake was washed with ethanol (27.90 kg, 1 V). The solids were vacuum-dried at 50 °C for 15 h. The desired product (27.34 kg, 63.9% over 2 steps, 99.6a%, 94.6wt%) was obtained as a single isomer as an off white solid. 64Atty. Dkt. No.129802-0442 P0059-WO

[0137] 1H NMR (400 MHz, DMSO-d6) δ 7.83 (dd, J = 8.1, 2.8 Hz, 1H), 7.76 (dd, J = 9.6, 2.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 6.57 (s, 1H), 6.40 (d, J = 6.9 Hz, 1H), 6.00 – 5.86 (m, 1H), 5.52 (dt, J = 10.9, 5.6 Hz, 1H), 5.32 (d, J = 53.6 Hz, 1H), 4.83 – 4.69 (m, 2H), 4.57 (d, J = 50.4 Hz, 1H), 3.36 (s, 3H), 3.28 (s, 1H), 2.44 (m, 1H), 2.19 – 2.07 (m, 1H). HRMS (ESI) m / z: calcd for C21H19F3NNaO4S [M + Na]+, 460.0801; found, 460.0824. Step 7: Preparation of crude (5R,6S,8R)-3,5-trifluoro-8-((1S,2R)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (Compound (I))

[0138] (5S,6S,8R)-8-[(1S,2R)-2-fluoro-1-hydroxy-7-mesyl-4-indanyl]-3,6-difluoro-5- hydroxy-5,6,7,8-tetrahydro-1-naphthonitrile (26.83 kg, 94.6 wt%, 58.02 mol, 1.00 equiv.) and dichloromethane (711.75 kg, 20 V) were charged to a nitrogen flushed, dry, and clean jacketed vessel 1. The batch was vacuum distilled to approximately 214−268 L keeping jacket temperature no more than 40 °C. After cooling to 25 °C, dichloromethane (71.7 kg, 2 V) was charged to vessel 1 followed by N,N-diisopropylethylamine (95.15 kg, 695.42 mol, 12.0 equiv.) over 2 h. The batch temperature was cooled to 10 °C, and the mixture was agitated for 20 min. N,N- diisopropylethylamine trihydrofluoride (46.42 kg, 231.81 mol, 4.00 equiv.) was charged to the vessel 1 over 2 h, and the mixture was agitated for 1 h. Perfluoro-1-butanesulfonyl fluoride (73.60 kg, 231.81 mol 4.00 equiv.) was charged to vessel 1 over 2 h, and the mixture was agitated for 12 h. The batch temperature was then increased to 20 °C, and the mixture was agitated for 13 h. Aqueous sodium bicarbonate solution (5 wt%, 559 kg, 20 V) was charged to vessel 2. The batch temperature was cooled to 20 °C. The reaction mixture in vessel 1 was charged to vessel 2 over 4 h. Acetonitrile (106.30 kg, 4 V) was charged to vessel 1 and then transferred to vessel 2. The biphasic mixture was allowed to separate. The aqueous layer was extracted with dichloromethane (178.05 kg, 5 V). The combined organic layer was washed with aqueous sodium bicarbonate 65Atty. Dkt. No.129802-0442 P0059-WO solution (5 wt%, 278 kg, 10 V), aqueous hydrochloric acid solution (1 N, 295 kg × 2, 10 V × 2) and aqueous sodium chloride solution (16.7 wt%, 321 kg, 10 V). The batch was polish filtered and vacuum distilled to approximately 161−214 L keeping jacket temperature no more than 40 °C. After cooling to 25 °C, methanol (211.10 kg, 10 V) was charged to the vessel. The batch was then vacuum distilled to approximately 214−268 L keeping jacket temperature no more than 60 °C. After cooling to 25 °C, methanol (205.20 kg, 10 V) was charged to the vessel. The batch was then vacuum distilled to approximately 214−268 L keeping jacket temperature no more than 60 °C. After cooling to 25 °C, methanol (211.20 kg, 10 V) was charged to the vessel. The batch was then vacuum distilled to approximately 214−268 L keeping jacket temperature no more than 60 °C. The batch temperature was then cooled to 10 °C, and the mixture was agitated for 6 h. The slurry was filtered, and the filter cake was washed with methanol (42.85 kg, 2 V). The solids were vacuum- dried at 50 °C for 16 h. Crude Compound (I) (21.57 kg, 81.3%, 96.2 a%, 96.1 wt%) was obtained as a white solid. Step 8: Purification of Compound (I)

[0139] p . g, . , . , . q . acetonitrile (251.5 kg, 15 V) were charged to a nitrogen flushed, dry, and clean jacketed vessel. The batch temperature was increased to 25 °C, and the mixture was agitated for ca.30 min until it became a clear solution. The mixture was polish filtered and atmospheric distillated to approximately 64−85 L keeping jacket temperature no more than 130 °C. The batch temperature was then cooled to 80 °C, and the mixture was agitated for 2 h.2-Methyl-1-propanol (170.40 kg, 10 V) was charged to vessel over 2 h. The batch was then atmospheric distilled to approximately 64−85 L keeping jacket temperature no more than 130 °C. The batch temperature was then cooled to 108 °C, and the mixture was agitated for 2 h. The batch temperature was then cooled to 25 °C, and the mixture was agitated for 2 h. 2-Methyl-1-propanol (170.40 kg, 10 V) was charged to vessel over 2 h, and the mixture was agitated for 2 h. Acetonitrile (8.18 kg) was charged to the vessel to reach the desired 66Atty. Dkt. No.129802-0442 P0059-WO acetonitrile content of the liquid phase at 4% v / v (determined by GC analysis, target 3−5%v / v). The batch temperature was increased to 80 °C, and the mixture was agitated for 2 h. The batch temperature was then cooled to 25°C, and the mixture was agitated for 2 h. The slurry was filtered, and the filter cake was washed with 2-methyl-1-propanol (85.2 kg, 5 V). The solids were vacuum- dried at 50 °C for 18 h. Compound (I) (19.22 kg, 92.7%, 98.7 a%, 99.0 wt%) was obtained as a white solid. Example 2: Previous Synthetic Route to Compound (I)

[0140] A previous route to prepare Compound (I) is shown in the scheme below. The previous route was performed on a milligram or gram scale. The process described herein reduces the number of steps required to prepare Compound (I) and can be completed on a multi-kilogram scale. 67Atty. Dkt. No.129802-0442 P0059-WO68Atty. Dkt. No.129802-0442 P0059-WO Example 3: Preparation of Intermediate VStep 169Atty. Dkt. No.129802-0442 P0059-WO

[0141] To a reactor under N2atmosphere was added N, N-dimethylacetamide (389 kg, 1.5V) followed by benzyl triethylammonium chloride (228.1 kg, 1.10 equiv.) and sodium bicarbonate (155.2 kg, 2 equiv.) while maintaining the pot temperature at 20±5 °C. Vacuum / N2 refilling cycles was repeated 3 times before charging 2-bromo-4-fluoroiodobenzene (Compound 3-1, 273.1 kg, 1.00 equiv.), palladium acetate (1.648 kg, 0.008 equiv.), 3-butene-1-ol (79.8 kg, 1.20 equiv.) and N, N-dimethylacetamide (129 kg, 0.5V) as rinse. The reaction temperature was increased to 50±10 °C in 3±1 hours and was agitated at 50±10 °C for 2 hours. Then the temperature was adjusted to 62.5±2.5 °C in 2±1 hours followed by at least 3 hours agitation. The reaction progress was monitored by HPLC and temperature was adjusted to 20±5 °C upon reaction completion. The reactor contents were agitated for at least 1 hour after adding methyl tert-butyl ether (5V) and water (8.5 V). The organic phase was separated, and the aqueous phase was back extracted with methyl tert-butyl ether (3V). Organic phases were combined and washed with 2% sodium sulfate aqueous solution (4V), concentrated to 2.5V at no more than 35 °C. This solution was diluted with N, N-dimethylacetamide (1.5V) and dichloromethane (1.5V), and concentrated to 3V at no more than 35 °C. The resulted solution (21.2% w / w Compound 3-2, 72% assay yield) was taken to next step without further purification. Step 2

[0142] To a reactor under N2 atmosphere was added N, N-dimethylacetamide (655 kg, 4.4V) followed by Compound 3-2 (157.7 kg, 1 equiv.) in N, N-dimethylacetamide (586 kg, 3.6V) at 25±5 °C. A solution of 22% oxone (1 equiv.) in water (1816.9 kg, 9V) was added dropwise controlling the temperature at 25±5 °C and was agitated for at least 2 hours. The reaction mixture was quenched with 4 % sodium bisulfite aqueous solution (3V) after adjusting temperature to 10±5 °C. Then, 1N HCl aqueous solution (13V) and methyl tert-butyl ether (7V) was charged, agitated for no less than 1 hour and the organic phase was separated. The aqueous phase was back extracted with methyl tert-butyl ether (5V) and the combined organic phases were washed with 70Atty. Dkt. No.129802-0442 P0059-WO 5% NaCl aqueous solution followed by 6% NaOH aqueous solution (3.5V). The aqueous phase was collected, treated with 7% HCl aqueous solution (2.6V) and the resulting slurry was filtered. The obtained cake was rinsed with water (2V) and re-slurried with n-heptane (4V) for no less than 2 hours at 15±5 °C. The final solid was collected via filtration, rinsed with n-heptane (1V) followed by drying for at least 12hours in a vacuum oven at 40±5 °C, which provided Compound 3-3 (174 kg, 90.0% LCAP, 89% assay yield).

[0143] 1H-NMR: (300 MHz, DMSO-d6) δ 12.09 (s, 1H), 7.52 (dd, 1H, J = 8.4, 2.7 Hz), 7.37 (dd, 1H, J = 8.7, 6.3 Hz), 7.20 (td, 1H, J = 8.4, 2.7 Hz), 2.72-2.66 (m, 2H), 2.25 (t, 2H, J = 7.2 Hz), 1.82-1.72 (m, 2H). HPLC: 98.89%. LCMS: MS-1=259.0 / 260.9. Step 3 [o a eac o u e 2 a osp e e was a e o pou - . g, equiv.), dichloromethane (2784 kg, 6V) and N,N-dimethylformamide (1.09 kg, 0.01 equiv.). Oxalyl chloride (217.1 kg, 1.3 equiv.) was charged dropwise over 10 hours keeping the reaction temperature at 15±5 °C and was agitated for at least another 2 hours. After confirming reaction completion via HPLC, the rection mixture was charged dropwise to a solution of aluminum chloride (212.2 kg, 1.2 equiv.) in dichloromethane (2550 kg, 5.5V) over 10 hours keeping reaction temperature at 10±5 °C. The resulting mixture was agitated for at least 2 hours and upon reaction completion, was charged to water (8V) keeping the temperature at 5±5 °C. The organic phase was separated, the aqueous phase was back extracted with dichloromethane (5V), and the combined organic phase was washed with water (5V) and 5% sodium bicarbonate aqueous solution (5V). The organic phase was concentrated to 4.5V keeping the pot temperature no more than 40 °C, diluted with isopropanol (3V) and concentrated to 4.5V keeping the pot temperature no more than 50 °C. Then, the pot temperature was adjusted to 25±5 °C, charged water (7V) and agitated for at least 1 hour. The final solid was collected via filtration, rinsed with n-heptane (1V) followed by 71Atty. Dkt. No.129802-0442 P0059-WO drying for at least 12hours in a vacuum oven at 45±5 °C, which provided Compound 3-5 (324.3 kg, 98.1% LCAP, 99% assay yield).

[0145] 1H-NMR: (300 MHz, DMSO-d6) δ 7.89 (dd, 1H, J = 7.8, 2.7 Hz), 7.61 (dd, 1H, J = 8.7, 2.7 Hz), 2.91 (t, 2H, J = 6.0 Hz), 2.65-2.60 (m, 2H), 2.12-2.03 (m, 2H). HPLC: 99.78%. LCMS: MS+1=242.9 / 245.0. Step 4

[0146] To a react(295.5 kg, 1 equiv.), 1- butanol (1197 kg, 5V), potassium acetate (118.3 kg, 1 equiv.) and potassium hexacyanoferrate (II) aqueous solution (14.8%, 1733 kg, 5V). The reactor contents were sparged with N2 before and after charging dichloro[bis(2-(diphenylphosphino) phenyl) ether] palladium (II) (7.075 kg, 0.008 equiv.). The reaction temperature was adjusted to 90±5 °C in 1.5 hours, and agitated until completion of reaction. Ethyl acetate (10V) and 10% sodium bicarbonate aqueous solution (2V) was charged to the reaction mixture after cooling down to 20±5 °C. The organic phase was separated, the aqueous phase was back extracted with ethyl acetate (4V), and the combined organic phase was washed with 10% sodium chloride aqueous solution (5V) twice. The organic phase was filtered through activated carbon, concentrated to 3.5V keeping the pot temperature no more than 45 °C, diluted with n-heptane (5V) and agitated for 1 hour at 80±5 °C. The reactor contents were concentrated to 3.5V keeping the pot temperature no more than 45 °C and this process was repeated till reaching target ethyl acetate level. Then, the contents were cooled to 0±5 °C, agitated for at least 5 hours and isolated via filtration. The final solid was collected after n-heptane (2V) rinse and drying for at least 12hours in a vacuum oven at 45±5 °C, which provided Compound 3-6 (197.0 kg, 98.8% LCAP, 90.6% assay yield). 72Atty. Dkt. No.129802-0442 P0059-WO

[0147] 1H-NMR: (300 MHz, DMSO-d6) δ 8.13 (dd, 1H, J = 8.1, 2.7 Hz), 7.87 (dd, 1H, J = 8.7, 2.7 Hz), 3.09 (t, 2H, J = 5.7 Hz), 2.70-2.66 (m, 2H), 2.17-2.08 (m, 2H). HPLC: 99.17%. LCMS: MS+1=190.7. Step 5

[0148] To a rete (1678 kg, 9V) and formic acid (104.0 kg, 2 equiv.). The reactor temperature was adjusted to 10±5 °C and triethyl amine (114.6 kg, 1 equiv.) was charged dropwise over 1 hour. Compound 3-6 (214.3 kg, 1 equiv.) and RuCl[(R, R)-Ts-DPEN] (p-cymene) (3.60 kg, 0.005 eq) was added, then the temperature was adjusted to 25±5 °C in 2 to 3 hours and was agitated until reaction completion. Water (5V) was charged dropwise, agitated for 1 hour and the organic phase was separated. The aqueous phase was back extracted with isopropyl acetate (5V), and the combined organic phase was washed with 20% sodium chloride aqueous solution (5V). The organic phase was concentrated to 3.5V keeping the pot temperature no more than 50 °C, diluted with isopropyl acetate (5V) and concentrated to 3.5V keeping the pot temperature no more than 50 °C. Then, isopropyl acetate (5V) was charged, agitated for 0.5 hours and the resulted solution was taken to next step without further purification (97.8% LCAP, 13.2% w / w solution of Compound 3-7).

[0149] 1H-NMR: (300 MHz, DMSO-d6) δ 7.65 (dd, 1H, J = 8.4, 2.7 Hz), 7.54 (dd, 1H, J = 9.9, 2.7 Hz), 5.54 (d, 1H, J = 6.0 Hz), 4.60-4.54 (m, 1H), 2.89-2.72 (m, 2H), 2.00-1.90 (m, 2H), 1.79- 1.74 (m, 2H). HPLC: 99.49%. GCMS: MS=191. Chiral purity: 98.18%ee at Rt = 4.684 min (Lux Cellulose-3, 100 x 4.6 mm, 3 μm, eluting isocratically with 100% n-Hexane MeOH: EtOH (950:25:25) over 10 min, flow rate 1.0 mL / min). 73Atty. Dkt. No.129802-0442 P0059-WO Step 6

[0150] To a reactor under N2 atmosphere was added isopropyl acetate solution of Compound 3-7 (1 equiv.) from the previous step, isopropyl acetate (371 kg, 2V), triethyl amine (287.5 kg, 2.5 equiv.) and 4-dimethyl pyridine (13.62 kg, 0.10 equiv.) at 20±5 °C. The reactor contents were cooled to 5±5 °C, pivaloyl chloride (176.9 kg, 1.3 equiv.) was charged dropwise over 3 hours, the mixture warmed to 20±5 °C and agitated for at least 10 hours. Upon completion of the reaction, water (5V) was added to the reactor at 5±5 °C and the layers were separated. The aqueous phase was back extracted with isopropyl acetate (5V), and the combined organic phase was washed with 10% citric acid aqueous solution (5V), 5% sodium bicarbonate aqueous solution (10V) and 10% sodium chloride aqueous solution (6V). The organic phase was concentrated to 3.5V keeping the pot temperature no more than 50 °C, diluted with n-heptane (5V) and concentrated to 3.5V keeping pot temperature no more than 50 °C. Then, n-heptane (5V) was charged, the mixture agitated for 0.5 hours and the resulting solution was filtered through a pad of silica gel (0.25% w / w). The filtrate was concentrated to 2.5V keeping the pot temperature no more than 40 °C and the process was repeated two times with acetonitrile (5V). Then, the mixture was diluted with acetonitrile (5V) and was taken to next step without further purification (97.7% LCAP, 21.9% w / w solution of Compound 3-8, > 98% assay yield, aliquot sample was purified to collect characterization data).

[0151] 1H-NMR: (300 MHz, DMSO-d6) δ 7.80 (dd, 1H, J = 8.4, 2.7 Hz), 7.41 (dd, 1H, J = 9.6, 2.7 Hz), 5.83-5.81 (m,1H), 2.92-2.90 (m, 2H), 2.83-2.81 (m, 1H), 1.99-1.94 (m, 1H), 1.90-1.82 (m, 2H), 1.15 (s, 9H). HPLC: 99.45%. GCMS: MS=275.1. Chiral purity: 98.17%ee at Rt=1.913 min (Lux Cellulose-3, 100 x 4.6 mm, 3 μm, eluting isocratically with 5% MeOH: EtOH (1:1) and 95% n-Hexane over 5min, flow rate 1.0 mL / min). 74Atty. Dkt. No.129802-0442 P0059-WO Step 7

[0152] To a reactolution of Compound 3-8 (96.12 kg, 1 equiv.), acetonitrile (382 kg, 5V), water (965 kg, 10V), 1,3-dibromo-5,5- dimethylhydantoin (170.0 kg, 1.7 equiv.) and 4,4-(diazene-1,2-diyl)bis(4-cyanopentanoic acid) (4.8 kg, 0.05 equiv.). The reactor temperature was adjusted to 55±5 °C over 2±1 hours and the contents were agitated for 2 hours. Once the completion of reaction was confirmed via HPLC analysis, the reaction mixture was cooled to 5±5 °C, quenched by adding 10% sodium sulfite aqueous solution (8V) and the pH was adjusted to 7-8 by charging 7% sodium bicarbonate aqueous solution (18V). The reaction temperature was adjusted to 20±5 °C after charging methyl tert-butyl ether (10V), agitated for 1 hour and the organic phase was separated. The aqueous phase was back extracted with methyl tert-butyl ether (5V), and the combined organic phase was washed with water (5V). It was concentrated to 3.5V keeping the pot temperature no more than 45 °C, diluted with isopropanol (5V) and concentrated to 3.5V keeping the pot temperature no more than 45 °C. Concentration was repeated with n-heptane (5V), diluted with n-heptane (5V) and was agitated for 2 hours at 20±5 °C. The final solid was collected after filtration, n-heptane (2V) rinse followed by drying for at least 12 hours in a vacuum oven at 45±5 °C, which provided Compound 3-9 (77.96 kg, 97.1% LCAP, 77% assay yield).

[0153] 1H-NMR: (300 MHz, DMSO-d6) δ 8.04 (dd, 1H, J = 8.4, 2.7 Hz), 7.59 (ddd, 1H, J = 9.0, 2.7, 0.6 Hz), 6.05 (dd, 1H, J = 7.8, 3.9 Hz), 2.82-2.77 (m, 2H), 2.51-2.50 (m, 1H), 2.20-2.18 (m, 1H), 1.19 (s, 9H). HPLC: 99.63%. LCMS: MS+23=312.1. Chiral purity: 99.76%ee at Rt = 8.306 min (Lux Cellulose-4, 150 x 4.6 mm, 3 μm, eluting with 0.05% H3PO4in water-MeCN gradient over 13.1 min. Gradient information: 0.0-8.0 min, ramped from 50% MeCN to 65% MeCN; 8.0-10.0 min, ramped from 65% MeCN to 90% MeCN; 10.0-13.1 min, held at 90% MeCN; then 13.0-13.1 min, ramped from 90% MeCN to 50% MeCN; post time over 5.0 min, flow rate 1.0 mL / min). 75Atty. Dkt. No.129802-0442 P0059-WO Step 8

[0154] To a reacethane (2458 kg, 20V), Compound 3-9 (93.0 kg, 1 equiv.) and the pot temperature was adjusted to −50±5 °C. The reactor contents were agitated and lithium bis(trimethylsilyl)amide (274.0 kg, 0.99 equiv., 1.0 M in THF) was added dropwise over 4 hours keeping the pot temperature at −50±5 °C. Once the completion of reaction was confirmed via HPLC analysis, the reaction mixture was further cooled to −70±5 °C, quenched by adding trifluoromethanesulfonic anhydride (108.8 kg, 1.20 equiv.) and was agitated for another hour. The reactor temperature was adjusted to 20±5 °C, and pH was adjusted to 3-4 by charging to a 2% citric acid aqueous solution (8V) at 0±10 °C. The organic phase was separated, washed with 5% sodium chloride aqueous solution (10V) twice and was concentrated to 2.5V keeping pot temperature no more than 35 °C. The resulting mixture was diluted with ethanol (5V) and concentrated to 2.5V keeping the pot temperature no more than 35 °C. The reactor temperature was adjusted to 3±3 °C, ethanol / water (2:3) solution (0.8V) was charged dropwise and agitated for 2 hours at 3±3 °C. Then additional ethanol / water (2:3) solution (6.2V) was charged dropwise and agitated for 3 hours at 3±3 °C. The final solid was collected after filtration, rinsed with pre-cooled (<10 °C) ethanol / water (2:3) solution followed by drying for at least 12 hours in a vacuum oven at 30±5 °C, which provided Intermediate V (122.4 kg, 98.5% LCAP, 89.5% assay yield).

[0155] 1H-NMR: (300 MHz, DMSO-d6) δ 8.05 (dd, 1H, J = 8.4, 2.7 Hz), 7.76 (dd, 1H, J = 8.4, 2.7 Hz), 6.62 (t, 1H, J = 4.8 Hz), 5.86 (t, 1H, J = 3.9 Hz), 2.86 (t, 1H, J = 3.9 Hz), 1.04 (s, 9H). HPLC: 99.95%. LCMS: MS+23=444.0. Chiral purity: 99.44%ee at Rt = 8.602 min (CHIRALCEL OJ-3R, 100 x 4.6 mm, 3 μm, eluting with 0.1% H3PO4in water-MeCN: MeOH (1: 1) gradient over 17.1 min. Gradient information: 0.0-11.0 min, ramped from 55% MeCN: MeOH (1: 1) to 65% 76Atty. Dkt. No.129802-0442 P0059-WO MeCN: MeOH (1: 1); 11.0-14.0 min, ramped from 65% MeCN: MeOH (1: 1) to 95% MeCN: MeOH (1: 1); 14.0-17.0 min, held at 95% MeCN: MeOH (1: 1); then 17.0-17.1 min, ramped from 95% MeCN: MeOH (1: 1) to 55% MeCN: MeOH (1: 1); post time over 3.0 min, flow rate 1.0 mL / min). Example 3a: Alternative preparation of Intermediate 3-6 Step 1[ ] -nec - ott e equ ppe w t a mec an ca st rrer was sparge w t 2 e ore addition of iPrMgCl·LiCl (1.36 M in THF, 1.05 eq.3.68 L). The solution temperature was lowered to -3 °C before 1-bromo-2-chloro-4-fluorobenzene (1.01 kg, 1.0 eq.) was added to the Grignard solution dropwise at -3 °C - 0 °C for 0.5 h. The resultant solution was allowed to warm to rt and stirred for 1 h.

[0157] To a separate reactor equipped with a mechanical stirrer was added CuBr·DMS (0.03 equiv, 29.4 g). The reactor was evacuated and backfilled with N23 times.2-Me-THF (4 L, 4 V, KF = 367 ppm) and dimethyl cyclopropane-1,1-dicarboxylate (1.05 kg, 1.3 eq. KF=524 ppm, QNMR= 93.50%) was charged. The resultant suspension was stirred and cooled to -5 °C.

[0158] The resultant Grignard solution (Compound 3a-1’) was transferred via peristaltic pump to the suspension at a temperature between -7 °C and -5 °C over 2 hours to afford an orange solution. The mixture was allowed to warm up to room temperature and was stirred for 1 hour. HPLC showed no starting material left with 80% as the LCAP of product. The reaction mixture was quenched with NH4Cl aq (8 L, 8 V) to afford a clear organic layer with a blue aqueous layer. The layers were separated and the resulting aqueous layer was further extracted with MTBE (4 V × 2). The combined organic layer was wash with brine. The solvent was concentrated under 77Atty. Dkt. No.129802-0442 P0059-WO reduced pressure to afford the crude 3a-2 (1.67 kg, LCAP: 85.2%, assay yield: 80.6%) as a yellow oil, which was used as the starting material for the following step without further purification.

[0159] 1H-NMR: (300 MHz, DMSO-d6, ppm) δ 7.42 - 7.35 (m, 2H), 7.18 (td, 1H), 3.66 (s, 6H), 3.55 (t, 1H), 2.69 (dd, 2H), 2.12 - 1.98 (m, 2H). HPLC: 80.32%. HRMS: MW+1 = 289.0763. Step 2. g, y . g, 1 eq.) from the previous step, was added HCl (6 M in H2O, 2 V, 2.2 L) and CH3COOH (4.8 V, 5.3 L). The resultant mixture was refluxed at 105±5 °C for 36 hours until HPLC analysis indicated complete consumption of Compound 3a-2 (HPLC: 2.1% of Compound 3a-2). After reaction completion, the mixture was cooled down and MTBE (3.5 V, 3.9 L) and water (1.5 V, 1.7 L) was added. The layers were separated and the aqueous layer was extracted with MTBE (3.5 V, 3.9 L) once. The combined organic layers were washed with 5% Na2SO4 aq (5 V × 2, 11.1 L). A 6% NaOH aqueous solution (9 V, 10 L) was charged to the organic phase to adjust pH to 11 and the resulting layers were separated. The aqueous layer was extracted with MTBE (5 V, 5.5 L) once; 7% HCl aq (7 V, 7.8 L) was charged to the aqueous phase to adjust the pH of system to between 4 and 5. MTBE (8 V, 8.9 L) was charged to the aqueous phase, the mixture was agitated, and the layers separated. The organic phase was collected and the MTBE was evaporated under vacuum. n-Heptane (5 V, 5.6 L) was charged to the crude material and concentrated to 2 V at 40 °C. This step was repeated 3 times. The solvent was concentrated under reduced pressure at 40 °C to afford the Compound 3a-3 as a brown oil (752.6 g, LCAP: 97.9% , Q-NMR: 91.1% , IY = 82.5%), which was used directly in the next step without further purification.

[0161] 1H-NMR: (300 MHz, DMSO-d6, ppm) δ 12.10 (s, 1H), 7.43 – 7.33 (m, 2H), 7.17 (td, 1H), 2.69 (dd, 2H), 2.25 (t, 2H), 1.86 - 1.70 (m, 2H). HPLC: 97.11%. HRMS: MW+1 = 217.0443. 78Atty. Dkt. No.129802-0442 P0059-WO Step 3

[0162] wt%, 1.0 eq.) from the previous step was sparged with N2before addition of DCM (5 V, 3.4 L) and DMF (5 g, 0.02 equiv.). The solution was stirred for 5 min before oxalyl chloride (482.5 g, 1.2 equiv.) was added dropwise over 30 min at 20±5 °C. The mixture was further stirred for 2 h at rt. An aliquot was withdrawn from the solution of the chloride intermediate and quenched with anhydrous MeOH to ensure full conversion.

[0163] To a separate round bottom flask with mechanical agitation was added AlCl3 (2 equiv., 838 g), the flask was degassed and sparged with N23 times. DCM (5 V, 3.4 L) was added, and the resultant suspension was stirred and cooled to 0±5 °C. The resultant chloride solution was transferred via peristaltic pump to the AlCl3 suspension over 1 hour. During addition, the internal temperature was maintained at 0±5 °C. After addition, the mixture was allowed to come to room temperature and was stirred for 12 hours at which time HPLC analysis indicated reaction completion.

[0164] The reaction was quenched with H2O (8 V, 5.5 L) at 5 ± 5 °C and the layers were separated. The water phase was extracted with DCM (5 V, 3.4 L), and the organic layers were combined. The DCM solution was charged with 30 wt% activated carbon and the mixture was stirred for 3 h. The mixture was filtered and the resulting cake was washed with DCM (10 V, 6.85 L). The filtrate was concentrated to 3 V, charged with EtOH (10 V, 6.84 L), and then concentrated to 6 V. This process was repeated 2 times to swap out the DCM. The EtOH solution was cooled to 0-5 °C. Water (3.4 L, 5 V) was added dropwise to the EtOH solution over 1 h and the mixture stirred at 20 ± 5 °C for 1 h. The solution was filtered and the cake was washed with water (4 V). The cake was collected and dried under vacuum to afford 581.4 g of Compound 3a-4 afforded with 100% of HPLC purity as an off white solid. (KF: 456 ppm, Q-NMR: 96.11%, IY=89.1%). 79Atty. Dkt. No.129802-0442 P0059-WO

[0165] 1H-NMR: (300 MHz, DMSO-d6, ppm) δ 7.78 (dd, 1H), 7.59 (dd, 1H), 2.99- 2.88 (m, 2H), 2.64 (dd, 2H), 2.16 - 2.01 (m, 2H). HPLC: 99.5%. HRMS: MW + 1 = 199.0376. Step 4

[0166] To a round bottom flask with mechanical agitation was added Compound 3a-4 (50.0 g, 1.0 eq.), DMAP (15.4 g, 0.5 eq), NiCl2(dppf) (5.16 g, 0.03 eq.), and Zn(CN)2 (16.3 g, 0.55 eq.). The flask was sparged with N2 and degassed 3 times, and DMAc (250 mL, 5 V) was charged. The reaction mixture was bubbled with N2for 20 min and then was heated to 120±5 °C. PMHS (0.75 g, 0.05 eq.) was added to the reaction mixture. The reaction mixture was further stirred until HPLC indicated complete consumption of Compound 3a-4.

[0167] The mixture was allowed to cool down to room temperature and was diluted with toluene (10 V, 500 mL) following by being filtration through Celite® (50 wt%). The cake was washed with toluene (2 V × 5, 500 mL). The filtrate was diluted with toluene (20 V, 1 L) and washed with a Na4EDTA aqueous solution (2.5 eq., 20 V, 1 L, pH = 12-13). The layers were separated and the organic phase collected. The aqueous phase was extracted with toluene (10 V, 500 mL) and the organic phases combined, which were subsequently washed with brine (10 V, 500 mL). Activated charcoal (50.0 g, 100 wt%) was added to the organic phase, and the resulting mixture was stirred at 25±2 °C for 16 h. The mixture was filtered and the resulting cake washed with toluene (2 V × 2, 200 mL). The organic phase was concentrated to 2-3 V under vacuum and n-heptane (5 V, 250 mL) was added. This cycle was repeated 3 times with the final n-heptane addition of 7.5 V, 375 mL. The mixture was heated to 50±2 °C and stirred for 1 hour and then cooled to 0±2 °C. The mixture was filtered and washed with pre-cooled n-heptane (1 V, 50 mL), and the filter cake was collected. Crude Compound 3-6 and softened water (20 V, 1 L) was added in a bottle, the mixture was stirred at 40±2 °C for 2 hours. The mixture was filtered and wash with softened water (2 V, 100 mL). The filter cake was dried under vacuum to afford 42 g off-white 80Atty. Dkt. No.129802-0442 P0059-WO solid of Compound 3-6 with 98.2% of HPLC purity (Q-NMR: 93.26 wt%, IY = 85%, KF = 0.12 wt%).

[0168] 1H-NMR: (300 MHz, DMSO-d6, ppm) δ 8.16 (dd, 1H), 7.90 (dd, 1H), 3.10 (m, 2H), 2.68 (m, 2H), 2.16 (m, 2H). HPLC: 98.29%. HRMS: MS+1=190.

[0169] Through a number of optimization experiments, it was determined that this reaction could alternatively be performed with 1 mol% NiCl2(dppf), 0.05 equivalents PMHS, 0.55 equivalents Zn(CN)2, and 0.5 equivalents DMAP at 100°C in 5 V DMAc (99.8% LCAP). Example 4: Preparation of Intermediate WStep 1

[0170] To a reactor under N2atmosphere was added N,N-dimethyl acetamide (1864 kg, 14V), Compound 4-1 (142.6 kg, 1.0 equiv.) and the pot temperature was adjusted to 0±5 °C. The reactor contents were agitated and 20% sodium methanethiolate aqueous solution (242.2 kg, 1.12 equiv.) 81Atty. Dkt. No.129802-0442 P0059-WO was added. The mixture was further agitated for 4 hours while keeping the pot temperature at 0±5 °C. Once the completion of reaction was confirmed via HPLC analysis, the reaction mixture was cooled to −5±5 °C, quenched by adding water (33V) over 6 hours and agitated for another 6 hours. The resulting slurry was filtered, rinsed with water (1.5V) and the wet cake obtained was taken to next step without drying to yield Compound 4-2 (193 kg wet cake with 73.3% w / w, 97.7% LCAP, 88% assay yield).

[0171] 1H-NMR: (300 MHz, DMSO-d6) δ 7.79 (dd, 1H, J = 13.5, 8.7 Hz), 7.16 (dd, 1H, J = 16.2, 8.7 Hz), 2.97-2.93 (m, 2H), 2.67-2.63 (m, 2H), 2.44 (s, 3H). HPLC: 97.01%. LCMS: MS+1=256.9 / 258.9. Step 2

[0172] To a reactor under N2 atmosphere was added dichloromethane (3014 kg, 16V), Compound 4-2 from the previous step (141.5 kg, 1.0 equiv.), and the pot temperature was adjusted to 5±5 °C. The reactor contents were agitated, ruthenium (III) chloride (0.623 kg, 0.005 equiv.) aqueous suspension (0.10V) was added followed by 8% sodium periodate aqueous solution (318.53 kg, 2.7 equiv.) dropwise over 2 hours keeping the pot temperature at 5±5 °C. Then the reaction mixture was agitated for 10 hours at 20±5 °C. Once the completion of reaction was confirmed via HPLC analysis, the organic phase was separated. The aqueous phase collected was back extracted with dichloromethane (5V), and the organic phase was separated. The combined organic phase was washed with 5% sodium hydrogen sulfite aqueous solution (5V), concentrated to 3.5V while keeping the pot temperature no more than 40 °C. The reactor contents were diluted with ethanol (5V) and concentrated to 3.5V keeping the pot temperature no more than 40 °C. The reactor contents were agitated for 1 hour at 45±5 °C, then water (5V) was added at 25±5 °C and 82Atty. Dkt. No.129802-0442 P0059-WO agitated for 3 hours at 5±5 °C. The resulting slurry was filtered, rinsed with water (1V) and dried for 12 hours at 45±5 °C to afford Compound 4-3 (157.0 kg, 99.2% LCAP, 98% assay yield).

[0173] 1H-NMR: (300 MHz, DMSO-d6) δ 8.19 (d, 1H, J = 8.1 Hz), 7.88 (d, 1H, J = 8.1 Hz), 3.43 (s, 3H), 3.11-3.08 (m, 2H), 2.84-2.80 (m, 2H). HPLC: 98.08%. LCMS: MS+1=288.9 / 290.9. Step 3

[0174] To a reactor under N2 atmosphere was added toluene (1227 kg, 9V), 1,4-dioxane (486 kg, 3V), Compound 4-3 from the previous step (156.8 kg, 1.0 equiv.), bis(pinacolato)diboron (164.9 kg, 1.2 equiv.) and potassium acetate (160.0 kg, 3.0 equiv.). The reactor contents were agitated and sparged with N2 until the oxygen concentration reach less than 500 ppm. Bis(triphenylphosphine)Palladium (II) chloride (3.137 kg, 0.008 equiv.) was charged, the mixture sparged with N2for another 0.5 hours and then agitated for at least 6 hours after adjusting the pot temperature to 90±5 °C over 2 hours. Once the completion of reaction was confirmed via HPLC analysis, the temperature was adjusted to 20±5 °C, the mixture diluted with dichloromethane (5V) and filtered. The filtrate was concentrated to 3.5V keeping the pot temperature no more than 50 °C. The reactor contents were diluted with toluene (5V) and concentrated to 3.5V while keeping the pot temperature no more than 50 °C. n-Heptane (12V) was charged dropwise to the reactor contents at 20±5 °C, the mixture agitated for 1 hour, then agitated for 3 hours at 0±5 °C. The resulting slurry was filtered, rinsed with n-heptane (1V) and dried for 12 hours at 45±5 °C to afford Intermediate W (187.7 kg, 98.7% LCAP, 90% assay yield). 83Atty. Dkt. No.129802-0442 P0059-WO

[0175] 1H-NMR: (300 MHz, DMSO-d6) δ 8.16 (d, 1H, J = 7.8 Hz), 7.98 (d, 1H, J = 7.5 Hz), 3.44 (s, 3H), 3.35-3.31 (m, 2H), 2.77-2.73 (m, 2H), 1.35 (s, 12H). HPLC: 99.41%. LCMS (boronic acid derivative): MS+1=255. Example 5: Alternative Preparation of Intermediate A84Atty. Dkt. No.129802-0442 P0059-WO F O S NaSCH3(1.12 eq.) O Triethoxymethane (2.0 eq.) (20% aqueous solution)TsOH•H2O (0.05 eq.)

[0176] To a stirred solution of i-PrMgCl·LiCl (1.3 M, 550 mL, 1.05 eq.) was added Compound 5-1 (200.0 g, 1.0 eq.) dropwise over 10 mins and stirred at -10±5oC for 0.5 h under nitrogen atmosphere in vessel A. 85Atty. Dkt. No.129802-0442 P0059-WO

[0177] In vessel B, Compound 5-2 (118.0 g, 1.3 eq.) and dry THF (600 mL, 3 v) were added under N2atmosphere and cooled to -10 ± 5oC. CuCl (13.2 g, 0.2 eq.) was added and stirred at - 10±5oC for 0.5 h. Then, the solution in vessel A was added dropwise to B over 30 mins at -10 ± 5oC. The reaction was allowed to warm to room temperature and stirred for 16 h when 87.15% of Compound 5-3 was observed in HPLC. The reaction was quenched with aqueous HCl (1 M, 2 L, 10 v) at 0±5oC. Then extracted with ethyl acetate (2×2 L, 10 v), the organic phase was combined and washed with brine (2×2 L, 10 v). The organic phase was concentrated and the residue was applied onto a silica gel column with ethyl acetate / PE (0%-20%).150.0 g of Compound 5-3 was obtained as a yellow oil (IY = 82.0%).

[0178] 1H-NMR (300 MHz, DMSO-d6, ppm) δ 7.86 (m, 1H), 7.77 (m, 1H), 7.46 (m, 1H), 5.25 (s, 2H), 2.12 (s, 3H). HPLC: 97.26%. LCMS: MS+1=275. Step 2 [0] o a roun o om as w a s r ar was a e ( m , v), ompound 5- 3 (120 g, 1.0 eq.) and RuCl(p-cymene)[(S,S)-MsDpen] (1.21 g, 0.5 mol%) under N2atmosphere and the system was cooled to 0±5oC. After 5 mins, a mixture of Et3N (108 mL, 1.5 eq.) / formic acid (60 mL, 3.0 eq.) was added dropwise to the system over 5 min at 0±5oC. The reaction was heated to 40oC and stirred for 16 h, at which point 75.7% of Compound 5-4 and 16.0% of Compound 5-4’ showed on HPLC. The reaction was cooled down to room temperature and quenched with 5 wt% aqueous solution of NaHCO3(2.4 L, 10 v) at 5±5oC. The mixture was next extracted with ethyl acetate (2×2.4 L, 10 v) and washed with brine (2×2.4 L, 10 v). The organic phase was collected and the solvent removed.115.0 g mixture of Compound 5-4 and Compound 5-4’ obtained as a brown oil (IY = 81.9%).

[0180] 1H-NMR: (300 MHz, DMSO-d6, ppm) δ 7.63 (d, 1H), 7.55 (d, 1H), 7.33 (t, 1H), 5.89 (s, 1H), 5.05 (t, 1H), 4.09 (t, 2H), 2.00 (s, 3H). HPLC: 97.36%. LCMS: MS+1=277. ee: 85.36%. 86Atty. Dkt. No.129802-0442 P0059-WO Step 3 [0H (805 mL, 7 v) was added K2CO3(28.8 g, 0.5 eq.). The reaction was stirred at rt for 16 h, at which point 91.6% of Compound 5-5 showed on HPLC. The system was poured into ice water (1.15 L, 10 v). Then the aqueous layer was extracted with ethyl acetate (2 × 1.15 L, 10 V) and the combined organic layers were washed with brine (2 × 1.15 L, 10 v). The organic phase was collected and the solvent removed.89.2 g of Compound 5-5 obtained as a brown oil (IY = 90.5%).

[0182] 1H-NMR: (300 MHz, DMSO-d6, ppm) δ 7.59 (m, 1H), 7.48 (m, 1H), 7.29 (t, 1H), 5.51 (d, 1H), 4.82 (m, 2H), 3.47 (m, 1H), 3.28 (m, 1H). HPLC: 97.09%. LCMS: Ms-1=233.0 ee: 84.89%. Step 3a

[0183] To a round bottom flask with a stir bar was added toluene (445 mL, 5 v) and Compound 5-5 (89.0 g, 1.0 eq.) and the mixture stirred at 25oC for 10 mins.1,2-Diaminocyclohexane (43.4 g, 1.0 eq.) was added and stirred at 25oC for 10 mins. n-Heptane (133.5 mL, 1.5 v) was added over 5 mins and stirred at 25oC for 16 h. The reaction mixture was stirred at 0±5oC for 1 h and filtered while maintaining the temperature at 5-10oC. The cake was washed with toluene / n- heptane=1:1 (178 mL, 2 x 2 v) and was dried under reduced pressure.100.5 g of Compound 5-5’ was obtained as an off-white solid (HPLC: 98.18%, IY = 79.4%). 87Atty. Dkt. No.129802-0442 P0059-WO

[0184] 1H-NMR: (300 MHz, DMSO-d6, ppm) δ 7.58 (m, 1H), 7.47 (m, 1H), 7.22 (m, 1H), 6.05 (s, 1H), 5.31 (s, 1H), 3.51 (m, 1H), 3.29 (m, 1H), 2.03 (m, 2H), 1.72 (m, 2H), 1.68 (m, 2H), 1.59 (m, 3H), 1.41 (m, 2H), 1.12 (m, 2H). HPLC: 96.65%. LCMS: Ms-1=233. Step 3b [0018as added HCl aqueous solution (1 L, 1 M, 10 v) slowly at rt. The reaction system was stirred at rt for 1 h. The system was separated and collecting the organic phase. Then the aqueous phase was extracted with EA (2×1 L, 20 v). The combined organic layers were washed with brine (2×1 L, 20 v) and concentrated under reduced pressure. 68.2 g of Compound 5-5’’ obtained as a brown oil (IY = 92.6%).

[0186] 1H-NMR: (400 MHz, DMSO-d6, ppm) δ 7.59 (m, 1H), 7.48 (m, 1H), 7.29 (t, 1H), 5.51 (d, 1H), 4.82 (m, 2H), 3.47 (m, 1H), 3.28 (m, 1H). HPLC: 98.80%. LCMS: Ms-1=233. ee: 97.93%. Step 4

[0187] To a round bottom flask with N2 atmosphere was added Compound 5-5’’ (60 g, 1.0 eq.), DCM (600 mL, 10 v), and TEA (92 mL, 2.5 eq.), and the resulting mixture was cooled to 0±5oC. MsCl (48 mL, 2.3 eq.) was added dropwise over 30 mins. Then the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for 16 h, at which point 91.3% of Compound 5-6 showed on HPLC. The reaction mixture was diluted with DCM (600 mL, 10 v) and quenched with aqueous CH3COOH (10 wt%, 600 mL, 10 v). The aqueous layer was extracted 88Atty. Dkt. No.129802-0442 P0059-WO with DCM (2×600 mL, 10 v). The combined organic layer was washed with brine (2×600 mL, 10 v) and concentrated under reduced pressure. The residue was applied onto a silica gel column with DCM / PE (0%-70%).87.3 g of Compound 5-6 obtained as a white solid (IY = 88.5%).

[0188] 1H-NMR: (400 MHz, DMSO-d6, ppm) δ 7.72 (m, 2H), 7.45 (m, 1H), 6.07 (t, 1H), 4.56 (m, 2H), 3.17 (d, 6H). HPLC: 97.70%. ee: 99.10%. Step 5, 3.0 eq.), 2-methyl-2-butanol (2.4 L, 30 V), t-BuOK (57.5 g, 2.5 eq.), the resulting mixture was heated to 80 - 85oC and stirred for 1 h. Compound 5-6 (80.0 g, 1.0 eq.) was added at 80 - 85oC and stirred for 16 h, at which point 85.14% Compound 5-7 was detected in HPLC. The system was allowed to cool down to room temperature and quenched with AcOH (5% aq., 2 L, 25 v, pH = 6-7) at 5±5oC. The organic layer was combined and washed with H2O (800 mL, 10 v) and brine (800 mL, 10 v, pH = 6-7). The system was charged with H2O (2.4 L, 30 v) and concentrated under reduced pressure. Next, the mixture was cooled down to 30oC, IPA (800 mL) was added and stirred at rt for 16 h. The mixture was filtered and the cake was washed with H2O / IPA (160 mL, 2 v×2, 1:1). After drying, 48.3 g Compound 5-7 was obtained as a white solid (HPLC: 99.20%, IY = 70.2%).

[0190] 1H-NMR: (300 MHz, DMSO-d6, ppm) δ 7.61 (m, 1H), 7.23 (m, 1H), 7.17 (m, 1H), 3.73 (s, 3H), 3.17 (t, 3H), 3.11 (t, 1H), 2.28 (m, 1H), 1.75 (m, 1H). HPLC: 99.20%. LCMS: MS+1=331. ee: 100.0%. 89Atty. Dkt. No.129802-0442 P0059-WO Step 6

[0191] Compoundp 1. Step 7

[0192] To a round bottom flask was added compound 4-2 (100 g, 1.0 eq.) and ethane-1,2-diol (2000 mL, 20 V) at 25 °C. Triethoxymethane (115.8 g, 2.0 eq.) was added followed by addition of TsOH٠H2O (3.71 g, 0.05 eq.) at 25 °C. The resulting mixture was heated to 40 °C and stirred for 16 hours.

[0193] The reaction solution was cooled to 25 °C and H2O (2.0 L, 20 V) was added to the reaction and the resulting mixture stirred for 30 minutes. Thes solution was extracted with DCM 1000 mL × 2 (10 V × 2). The combined organic phase was concentrated under reduced pressure at 35 ~ 40 °C. The residue was applied onto a silica gel column with PE / THF = 10:1 to afford compound 5-8 (51 g, IY = 43.5%).

[0194] 1H NMR (300 MHz, DMSO-d6) δ 7.53 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 4.22 – 4.10 (m, 2H), 4.05 – 3.94 (m, 2H), 2.77 (t, J = 7.0 Hz, 2H), 2.41 (s, 3H), 2.16 (t, J = 7.0 Hz, 2H). HPLC: 98.09 %, LCMS: MS+1 = 301. 90Atty. Dkt. No.129802-0442 P0059-WO Steps 8A and 8B

[0195] p - . g, . q. y HF (200 mL, 10 v) under N2atmosphere and the reaction was cooled to -78±5oC. After 5 mins, n-BuLi (2.5 M in hexanes, 31 mL, 1.2 eq.) was added toto the system dropwise over 20 min and stirred at -78±5oC for 0.5 h. Then MeMgCl (3.0 M in THF, 26 mL, 1.2 eq.) was added dropwise to the system at -75±5oC over 20 min and then the reaction was allowed to warm to room temperature naturally. After that, ZnCl2 (0.7 M in THF, 93 mL, 1.0 eq.) was added dropwise to the system over 30 min and stirred at 20±5oC for 30 min. The mixture of Compound 5-7 (22.0 g, 1.0 eq.) / Cu(OTf)2 (2.34 g, 0.1 eq.) and dry THF (100 mL, 5 v) was added dropwise to the system over 30 min at 20±5oC. The reaction mixture was stirred at rt for 5 h, at which time 54.0% of INT-2 was detected in HPLC. The reaction mixture was diluted with EA (200 mL, 10 v) and quenched with aqueous solution of NH4Cl (200 mL, 10 v). The aqueous layer was extracted with EA (2 × 200 mL, 10 v). The combined organic layers were washed with brine (2 × 200 mL, 10 v) and concentrated under reduced pressure. The residue was applied onto a silica gel column with THF / PE (0%-50%).17.2 g of Compound 5-9 was obtained as a white solid (HPLC: 97.99%, IY = 46.4%).

[0196] 1H-NMR: (300 MHz, DMSO-d6, ppm) δ 7.59 (m, 1H), 7.46 (m, 1H), 7.29 (m, 2H), 7.08 (m, 1H), 4.38 (t, 1H), 4.17 (t, 2H), 3.99 (m, 2H), 3.63 (s, 6H), 3.28 (m, 1H), 2.80 (m, 1H), 2.61 91Atty. Dkt. No.129802-0442 P0059-WO (m, 1H), 2.53 (t, 2H), 2.39 (m, 3H), 2.10 (m, 2H). HPLC: 97.99%. LCMS: MS+1=553. ee: 99.25%. Step 9, 0 mL, 10 v) under N2 atmosphere and the system cooled to 0±5oC. Next, m-CPBA (14.1 g, 3.0 eq.) was charged to the system. Then ice bath was removed and the reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with aqueous Na2S2O3 (150 mL, 10 v). The aqueous layer was extracted with DCM (2×150 mL, 10 v). The combined organic layer was washed with brine (2×150 mL, 10 v) and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (150 mL, 10 v) and HCl (1 M, 150 mL, 10 v), and stirred at rt for 2 h. at which point 86.4% of INT-2-1 showed on HPLC. The aqueous layer was extracted with DCM (2×150 mL, 10 v). The combined organic layer was washed with brine (3×150 mL, 10 v) and concentrated under reduced pressure. The residue was applied onto a silica gel column with THF / PE (0%-30%).12.1 g of Compound 5-10 was obtained as a light-yellow solid (HPLC: 98.19, IY = 80.4%).

[0198] 1H-NMR: (300 MHz, DMSO-d6, ppm) δ 7.98 (m, 1H), 7.63 (m, 1H), 7.55 (m, 1H), 7.35 (m, 1H), 7.29 (m, 1H), 4.61 (m, 1H), 3.66 (d, 6H), 3.38 (s, 3H), 3.27 (m, 1H), 3.18 (m, 1H), 2.97 (m, 1H), 2.74 (m, 2H), 2.56 (m, 2H). HPLC: 98.19%. LCMS: MS+1=541. 92Atty. Dkt. No.129802-0442 P0059-WO Step 10 [001150 mL, 15 v) under N2atmosphere and the system was heated to 120±5oC and stirred for 16 h, at which point 76.5% of Compound 5-11 showed on HPLC. The reaction mixture was quenched with ice water (300 mL, 30 v). The aqueous layer was extracted with EA (2×100 mL, 10 v). The combined organic layer was washed with brine (3×100 mL, 10 v) and concentrated under reduced pressure. The residue was applied onto a silica gel column with THF / PE (0%-40%).5.3 g of Compound 5- 11 was obtained as a brown solid and further purified through reverse phase column. 4.0 g of Compound 5-11 was obtained as a yellow solid.

[0200] 1H NMR: (300 MHz, DMSO-d6) δ 8.00 (dd, J = 8.0, 2.7 Hz, 1H), 7.90 – 7.77 (m, 2H), 7.13 (d, J = 7.9 Hz, 1H), 4.83 (d, J = 3.9 Hz, 1H), 3.44 (s, 3H), 3.43 – 3.34 (m, 2H), 2.89 (t, J = 5.6 Hz, 2H), 2.67 (ddd, J = 18.0, 12.2, 5.1 Hz, 1H), 2.50 – 2.44 (m, 2H), 2.19 (d, J = 13.1 Hz, 1H). HPLC: 99.07%. LCMS: MS+1=451. Step 11

[0201] To a solution of Compound 5-11 (2.5 g, 1.0 eq.) in n-BuOH (5 v) was added AcOK (0.55 g, 1.0 eq.), and K4[Fe(CN)6]٠3H2O (1.18 g, 0.5 eq.) under N2 atmosphere, followed by addition of Pd(DPEPhos)Cl2(0.40 g, 0.1 eq.) and H2O (5 v). N2was bubbled through the mixture 93Atty. Dkt. No.129802-0442 P0059-WO over 5 mins. The reaction was heated to 90±5oC for 16 h, at which point 81.7% of Intermediate A showed on HPLC. The reaction mixture was quenched with ice water (50 mL, 20 v). The aqueous layer was extracted with EA (2×25 mL, 10 v). The combined organic layer was washed with brine (3×25 mL, 10 v) and concentrated under reduced pressure. The residue was applied onto a silica gel column with THF / PE (0%-50%).1.3 g of Intermediate A was obtained as a light-yellow solid (HPLC: 99.16%, IY = 58.7%).

[0202] 1H-NMR: (400 MHz, DMSO-d6, ppm) δ 8.24 (m, 1H), 8.07 (m, 1H), 7.83 (m, 1H), 7.18 (m, 1H), 5.75 (s, 1H), 3.43 (s, 3H), 3.31 (t, 2H), 2.90 (m, 2H), 2.74 (m, 1H), 2.68 (m, 2H), 2.24 (d, 1H). HPLC: 99.16%.LCMS: MS+1=398. ee: 98.19%. Example 6: Alternative Synthesis of Intermediate A

[0203] An analogous protocol to Example 5, using 2-chloro-4-fluoro-1-iodobenzene in place of 2-bromo-4-fluoro-1-iodobenzene in step 1 can be used to prepare Intermediate A. Characterization of the resulting intermediates is provided in Table 1 below:

[0204] Table 1 Intermediate Characterization d, %. d, ), S:94Atty. Dkt. No.129802-0442 P0059-WO 1H-NMR: (300 MHz, DMSO-d6, ppm) δ 7.59 (dd, 1H), 7.35 (dq, 33 d, 6 d, d, e: = ), .1 ), ), ), d, m, S: 5 t, H-95Atty. Dkt. No.129802-0442 P0059-WO Example 7: Control of Process Impurities

[0205] Compound (I) contains five stereocenters at C-5, C-6, C-8, C-1’ and C-2’ carbon centers, as depicted below:

[0206] Theoretically, 32 stpound (I) are possible. Based on inherent stereo-selectivity of the synthetic route, the probabilities of stereoisomer impurity formation derived from less than perfect selectivity are assessed, and appropriate controls are put in place. The following discussion refers to the process described in Example 1, and process byproducts identified in Table 2 below.

[0207] Compound (I) prepared using the process described herein has high enantiomeric purity and therefore has low levels of its enantiomer. In addition, the C-8 center chiral purity reported for the product of Step 4, Intermediate A, is extremely high and does not change in the subsequent steps. Thus, half of the 32 stereoisomers are effectively controlled.

[0208] The C-5 chiral center is formed in Steps 6 and 7. The C-5 epimer originating byproduct, Impurity 1a, is monitored in the Step 6 product and its resulting byproduct, Impurity 2a, is controlled in Step 8. The C-6 chiral center is formed in Step 5 in high stereo selectivity derived from control by C-8 chiral center. The C-6 epimer is formed in Steps 5 and 6. The originating byproduct, Impurity 1b, is monitored in the Step 6 product and the resulting byproduct, Impurity 2b, is controlled in Step 8. The stereocenters C-1’ and C-2’ are formed in Step 6. In typical step 6 lab scale runs, the C-1’ epimer (Impurity 1c) is not observed while the C-2’ epimer (Impurity 1d) is formed at low levels and purged to below 0.15%.

[0209] Next, the 6 stereoisomers derived from two chiral centers among C-5, C-6, C-1’, C-2’ being epimeric are considered. Due to the inherent stereochemical selectivity for the formation of each of the stereocenters, these isomers are considered not likely to form at significant levels and purging effects in steps 6, 7 and 8 isolations will likely reduce their levels even further. 96Atty. Dkt. No.129802-0442 P0059-WO

[0210] The remaining 5 stereoisomers derived from three or four of the chiral centers among C-5, C-6, C-1’, C-2’ being epimeric are considered. Due to the inherent stereochemical selectivity for the formation of each of the stereocenters, these isomers are considered not likely to form at significant levels and purging effects in steps 6, 7 and 8 isolations will likely reduce their levels even further.

[0211] The process byproducts identified in Table 2 below have been confirmed via independent synthesis and characterization. Table 2 provides a summary of the identified process byproducts, and acceptable levels of each process byproduct in the final product. Acceptable levels are not reported for process byproducts not observed in the final product. Total process byproducts are determined as the summation of individual process byproducts that are at or above the reporting threshold. Process byproducts without acceptable levels reported, as well as any process byproducts not identified in Table 2 are controlled to not more than (NMT) 0.15 % w / w as determined by HPLC. The total process byproduct content of the final product is controlled to NMT 4.0 %w / w. An exemplary HPLC method used to measure process byproducts is summarized in Table 3 below. Table 2: Potential and Observed Drug Product Process Byproducts Compound Structural Formula HPLC Relative Acceptable Code Name Retention levels (% w / w97Atty. Dkt. No.129802-0442 P0059-WO Compound Structural Formula HPLC Relative Acceptable Code Name Retention levels (% w / w # *98Atty. Dkt. No.129802-0442 P0059-WO Compound Structural Formula HPLC Relative Acceptable Code Name Retention levels (% w / w # * 8d. Table 3: Assay and Impurities by HPLC Parameter Setting m99Atty. Dkt. No.129802-0442 P0059-WO Table 3: Assay and Impurities by HPLC Parameter Setting 0.0 85 15ep ese a ve a c a a ys s us g e e o esc e a e of Compound (I) compositions that were prepared as described in Example 1 is presented in Table 4. Table 4: Batch Analyses of Compound (I) Drug Substance Process Byproducts by Batch 1 Batch 2 HPLC (% w / w)Example 8: Pharmaceutical Compositions

[0213] A spray dried dispersion (SDD) comprising Compound (I) (prepared using the process described herein) is useful in the manufacture of tablets having low process byproduct content. Exemplary spray dried dispersions are summarized in Table 5. The dispersions are prepared by dissolving Compound (I) and a pharmaceutically acceptable polymer in acetone. The solution was fed to a nozzle and atomized into droplets that were rapidly dried into particles by a hot nitrogen 100Atty. Dkt. No.129802-0442 P0059-WO gas stream. The particles were collected by a cyclone that separated them from the drying gas exhaust. Table 5: SDD Compositions Dispersion polymer Dispersion Polymer Loading Compound (I) Loading (wt%) (wt%)

[0214] The five SDD compositions were manufactured with high yields. After spray drying, the SDDs were secondary dried in the vacuum tray dryer at 40 °C for approximately 22 hours. A manufacturing summary is provided in Table 6 below. Table 6: Manufacturing Summary for SDD Compositions 25 / 75 25 / 75 25 / 75 25 / 75 40 / 60 Compound Compound Compound Compound Compound S-101Atty. Dkt. No.129802-0442 P0059-WO Calculated Dry Yield80% 91% 92% 92% 95%reparat on o ab ets

[0215] Tablets containing the 25 / 75 Compound (I) / HPMCAS-M spray dried dispersion were investigated. Tablets were prepared by blending the SDD with intragranular excipients (e.g., microcrystalline cellulose, silicified microcrystalline cellulose, MCC-DCP (75 percent microcrystalline cellulose and 25 percent anhydrous dibasic calcium phosphate, produced using spray-dried co-processing), mannitol, lactose, croscarmellose sodium and magnesium stearate), de-lumping, lubrication, roller compaction and milling, blending with extra-granular excipients (e.g., microcrystalline cellulose and magnesium stearate), lubrication, compression and packaging. In some instances, a further coating process may be performed prior to packaging. The tablets are summarized in Table 7. Table 7: Tablets Containing SDDs of Compound (I) Prototype Prototype Prototype Prototype Prototype 1 2 3 4 5102Atty. Dkt. No.129802-0442 P0059-WO Lactose MonohydrateFiller 13.0 13.0 --- --- ---

[0216] Content of degradation products in the tablet formulations can be determined using high-performance liquid chromatography (HPLC). An exemplary method is summarized in Table 7. Identity is established by comparing the retention time and UV spectrum for the main peak in the drug product sample preparation to that of the Compound (I) reference standard preparation. The assay (% label claim) and degradation products (% w / w, relative to label claim) are determined against the external Compound (I) reference standard. Total degradation products are determined as the summation of individual degradation products that are at or above the reporting threshold. Individual degradation products are controlled to no more than (NMT) 0.2 % w / w. The total degradation products are controlled to NMT 2.5 % w / w. Content of process byproducts in the tablet formulation are also determined using HPLC, the content of which is reported as % w / w, relative to the label claim. Total process byproducts are controlled during release of the active 103Atty. Dkt. No.129802-0442 P0059-WO pharmaceutical ingredient (see Example 7). The relative retention times (RRT) for each observed process byproduct of tablet Prototype 5 using the HPLC method of Table 8 are summarized in Table 9. Table 8: Identification, Assay, and Process Byproducts by HPLC Parameter Setting Column Advanced Materials Technology Halo C8 27 µm 46 x 150 mmTable 9: Relative Retention Time (RTT) for Observed Process Byproducts Compound Code Name Structural Formula HPLC RTT104Atty. Dkt. No.129802-0442 P0059-WO Compound Code Name Structural Formula HPLC RTT

[0217] Particular embodiments of this disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Upon reading the foregoing, description, variations of the disclosed embodiments may become apparent to individuals working in the art, and it is expected that those skilled artisans may employ such variations as appropriate. 105Atty. Dkt. No.129802-0442 P0059-WO Accordingly, it is intended that the disclosure be practiced otherwise than as specifically described herein, and that the disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context. 106

Claims

Atty. Dkt. No.129802-0442 P0059-WO CLAIMS What is claimed is:

1. A process comprising: a) contacting a compound of Formula A: (Formula A); with an R5X reagent annd of Formula A1: 1), wherein:R1and R2are independently selected from -H, -F, -Cl, -Br, and -CN; R3is -H, -F or -Cl; R4is selected from -H, -F, -Cl, -C1-C3alkyl, and -S(O)2(C1-C3alkyl), wherein the -C1-C3 alkyl or -S(O)2(C1-C3 alkyl) is unsubstituted or substituted with 1-3 halogen; each R5is an alcohol protecting group; X is -Cl, -Br, -I, -OMs, -OTs, or -OTf; and the base is an amine, an amidine, a carbonate, a phosphate, a tetra alkyl ammonium salt, or a hydroxide salt; and b) contacting the compound of Formula A1 with a deprotection agent to form a compound of Formula B: 107Atty. Dkt. No.129802-0442 P0059-WO (Formula B).

2. The process of claim 1,.

3. The process of claim 1 or 2, wherein the R5X reagent is TBSOTf.

4. The process of any of claims 1-3, wherein the deprotection agent is a fluorination agent.

5. The process of any one of claim 4, wherein the fluorination agent is an electrophilic fluorination agent.

6. The process of any one of claim 5, wherein the electrophilic fluorination agent is selected from 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SELECTFLUOR®), N-fluoro-N′-methyl-triethylenediamine bis(tetrafluoroborate) (SELECTFLUOR® II), N-fluorobenzenesulfonamide (NFSI), 1,1′-difluoro-2,2′- bipyridinium bis(tetrafluoroborate) (Synfluor), 1-fluoropyridinium trifluoromethanesulfonate, and N-fluoropyridinium (NFPy) salts including 1-fluoro-2,4,6- trimethylpyridinium tetrafluoroborate, 1-fluoro-2,3,4,5,6-pentachloropyridinium tetrafluoroborate, and 1-fluoro-2,6-dichloropyridinium tetrafluoroborate.

7. The process of any one of claims claim 1-6, further comprising contacting the compound of Formula B with a hydrogen reagent in the presence of a chiral ruthenium catalyst to form a compound of Formula C: ).

8. The process of claim 7,s selected from RuCl[(R,R)-Fsdpen](p-cymene), RuCl[(R,R)-Ts-DPEN](p-cymene), RuCl[(R,R)-Ts- 108Atty. Dkt. No.129802-0442 P0059-WO DPEN](mesitylene), chloro[(R,R)-N-[2-(4-methylbenzyloxy)ethyl]-N'-(p- toluenesulfonyl)-1,2-diphenylethylenediamine]ruthenium(II) ((R,R)-Ts-DENEB®), RuCl2[(R)-dm-segphos®][(R)-daipen], RuCl2[(R)-dm-segphos®][(R,R)-dpen], RuCl2[(R)-xylbinap][(R)-diapen], RuCl2[(R)-xylbinap][(R)-dpen], and RuCl[(R)- daipena][(R)-xylbinap].

9. The process of claim 7 or 8, wherein the hydrogen reagent is hydrogen gas, formic acid, or hydrosilane.

10. The process of any one of claims 7-9, wherein the compound of Formula B is contacted with a hydrogen reagent in the presence of a chiral ruthenium catalyst and a base.

11. The process of any one of claims 6-10 wherein the compound of Formula C is formed with a diastereomeric purity of at least about 90%.

12. The process of claim 10, wherein the base is an amine, an amidine, a carbonate, a phosphate, a tetra alkyl ammonium salt, or a hydroxide salt.

13. The process of any one of claims 7-12, further comprising contacting the compound of Formula C with a fluorination agent to form a compound of Formula I: (Formula I).

14. The process of claim 1, gent is a deoxyfluorination agent.

15. The process of claim 14, wherein the deoxyfluorination agent is selected from perfluoro- 1-butanesulfonyl fluoride (PBSF), N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine (Ishikawa’s Reagent), nitrophenyl ester sulfuryl fluoride, benzenesulfonyl fluoride, diethylaminosulfur trifluoride (DAST), sulfur tetrafluoride, bis(2- methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor®), 4-tert-butyl-2,6- dimethylphenylsulfur trifluoride (Fluolead™), morpholinodifluorosulfinium tetrafluoroborate (XtalFluor-M®), N,N-diethylamino-S,S-difluorosulfinium 109Atty. Dkt. No.129802-0442 P0059-WO tetrafluoroborate (XtalFluor-E®), pyridine-2-sulfonyl fluoride (PyFluor), PhenoFluor™, AlkylFluor™, morpholinosulfur trifluoride (morph-DAST), 4- (trifluoromethyl)benzenesulfonyl fluoride, N,N-diethyl-α,α-difluoro-3- methylbenzylamine (DFMBA), and tetramethylfluoroformamidinium hexafluorophosphate (TFFH).

16. The process of claim 14 or 15, wherein the compound of Formula C is contacted with a deoxyfluorination agent and a fluoride source.

17. The process of claim 16, wherein the fluoride source is triethylamine HF, pyridine HF (Py·HF), N,N-diisopropylethylamine trihydrofluoride (DIEA·3HF), 3,3-difluoro-1,2- diphenylcyclopropene tetra-n-butylammonium fluoride (TBAF) or tetrabutylammonium bifluoride (TBABF).

18. The process of claim 16 or 17, wherein the compound of Formula C is contacted with a deoxyfluorination agent in the presence of a base.

19. The process of claim 18, wherein the base is an amine, amidine, phosphazene, or a guanidine.

20. The process of any one of claims 1-19, wherein R1is -F.

21. The process of any one of claims 1-20, wherein R2is -CN.

22. The process of any one of claims 1-21, wherein R3is -H.

23. The process of any one of claims 1-22, wherein R4is -S(O)2CH3.

24. The process of any one of claims 13-23, wherein the compound of Formula I is Compound (I): )).

25. A process comprising contacting a compound of Formula B: 110Atty. Dkt. No.129802-0442 P0059-WO (Formula B) with a hydrogen reagent ruthenium catalyst to form a compoundof Formula C: (Formula C); wherein:R1and R2are independently selected from -H, -F, -Cl, -Br, and -CN; R3is -H, -F or -Cl; and R4is selected from -H, -F, -Cl, -C1-C3 alkyl, and -S(O)2(C1-C3 alkyl), wherein the -C1-C3 alkyl or -S(O)2(C1-C3 alkyl) is unsubstituted or substituted with 1-3 halogen.

26. The process of claim 25, wherein the chiral ruthenium catalyst is selected from RuCl[(R,R)-Fsdpen](p-cymene), RuCl[(R,R)-Ts-DPEN](p-cymene), RuCl[(R,R)-Ts- DPEN](mesitylene), chloro[(R,R)-N-[2-(4-methylbenzyloxy)ethyl]-N'-(p- toluenesulfonyl)-1,2-diphenylethylenediamine]ruthenium(II) ((R,R)-Ts-DENEB®), RuCl2[(R)-dm-segphos®][(R)-daipen], RuCl2[(R)-dm-segphos®][(R,R)-dpen], RuCl2[(R)-xylbinap][(R)-diapen], RuCl2[(R)-xylbinap][(R)-dpen], and RuCl[(R)- daipena][(R)-xylbinap].

27. The process of claim 25 or 26, wherein the hydrogen reagent is hydrogen gas, formic acid, or hydrosilane.

28. The process of any one of claims 25-27, wherein the compound of Formula B is contacted with a hydrogen reagent in the presence of a chiral ruthenium catalyst and a base. 111Atty. Dkt. No.129802-0442 P0059-WO 29. The process of claim 28, wherein the base is an amine, an amidine, a carbonate, a phosphate, a tetra alkyl ammonium salt, or a hydroxide salt.

30. The process of any one of claims 25-29, wherein the compound of Formula B is prepared by a process comprising: a. contacting a compound of Formula A: (Formula A); with an R5X reagent and of Formula A1: (Formula A1), wherein:each R5is an alcohol protecting group; X is -Cl, -Br, -I, -OMs, -OTs, or -OTf; and the base is an amine, an amidine, a carbonate, a phosphate, a tetra alkyl ammonium salt, or a hydroxide salt; and b. contacting the compound of Formula A1 with a fluorination agent thereby preparing the compound of Formula B.

31. The process of claim 30, wherein R5is a silyl group.

32. The process of claim 30 or 31, wherein the R5X reagent is tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf).

33. The process of any one of claims 30-32, wherein the fluorination agent is an electrophilic fluorination agent. 112Atty. Dkt. No.129802-0442 P0059-WO 34. The process of claim 33, wherein the electrophilic fluorination agent is selected from 1- chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SELECTFLUOR®), N-fluoro-N′-methyl-triethylenediamine bis(tetrafluoroborate) (SELECTFLUOR® II), N-fluorobenzenesulfonamide (NFSI), 1,1′-difluoro-2,2′- bipyridinium bis(tetrafluoroborate) (Synfluor), 1-fluoropyridinium trifluoromethanesulfonate, and N-fluoropyridinium (NFPy) salts including, 1-fluoro- 2,4,6-trimethylpyridinium tetrafluoroborate, 1-fluoro-2,3,4,5,6-pentachloropyridinium tetrafluoroborate, and 1-fluoro-2,6-dichloropyridinium tetrafluoroborate.

35. The process of any one of claims 25-34, further comprising contacting the compound of Formula C with a fluorination agent to form a compound of Formula I: (Formula I).

36. The process of claim 35, w ere n e uor na on agent is a deoxyfluorination agent.

37. The process of claim 36, wherein the deoxyfluorination agent is selected from perfluoro- 1-butanesulfonyl fluoride (PBSF), nitrophenyl ester sulfuryl fluoride, benzenesulfonyl fluoride, diethylaminosulfur trifluoride (DAST), sulfur tetrafluoride, bis(2- methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor®), 4-tert-butyl-2,6- dimethylphenylsulfur trifluoride (Fluolead™), morpholinodifluorosulfinium tetrafluoroborate (XtalFluor-M®), N,N-diethylamino-S,S-difluorosulfinium tetrafluoroborate (XtalFluor-E®), pyridine-2-sulfonyl fluoride (PyFluor), PhenoFluor™, AlkylFluor™, morpholinosulfur trifluoride (morph-DAST), 4- (trifluoromethyl)benzenesulfonyl fluoride, N,N-diethyl-α,α-difluoro-3- methylbenzylamine (DFMBA), tetramethylfluoroformamidinium hexafluorophosphate (TFFH), and 3,3-difluoro-1,2-diphenylcyclopropene. 113Atty. Dkt. No.129802-0442 P0059-WO 38. The process of any one of claims 35-37, wherein the compound of Formula C is contacted with a deoxyfluorination reagent and a fluoride source.

39. The process of claim 38, wherein the fluoride source is triethylamine HF, pyridine HF (Py·HF), N,N-diisopropylethylamine trihydrofluoride (DIEA·3HF), tetra-n- butylammonium fluoride (TBAF) or tetrabutylammonium bifluoride (TBABF).

40. The process of claim 38 or 39, wherein the compound of Formula C is contacted with a fluorination agent and a fluoride source in the presence of a base.

41. The process of claim 40, wherein the base is an amine, amidine, phosphazene, or a guanidine.

42. The process of any one of claims 25-41, wherein R1is -F.

43. The process of any one of claims 25-42, wherein R2is -CN.

44. The process of any one of claims 25-43, wherein R3is -H.

45. The process of any one of claims 25-44, wherein R4is -S(O)2CH3.

46. The process of any one of claims 25-45, wherein the compound of Formula I is Compound (I): )).

47. A process of prepar(Formula A); wherein:R1and R2are independently selected from -H, -F, -Cl, -Br, and -CN; 114Atty. Dkt. No.129802-0442 P0059-WO R3is -H, -F or -Cl; and R4is selected from -H, -F, -Cl, -C1-C3alkyl, and -S(O)2(C1-C3alkyl), wherein the -C1-C3 alkyl or -S(O)2(C1-C3 alkyl) is unsubstituted or substituted with 1-3 halogen; said process comprising contacting a compound of Formula Z: (Formula Z) with an oxidizing agompound of Formula A.

48. The process of claim 47, wherein the oxidizing agent is selected from a chromate salt including CrO3 and H2SO4, pyridinium chlorochromate (PCC), and pyridinium dichromate (PDC), sodium hypochlorite, and a hypervalent iodine compound, including Dess-Martin periodinane (DMP), 2-iodoxybenzoic acid (IBX), and 1-acetoxy-5-bromo-1,2- benziodoxol-3(1H)-one (ABBX), N-tert-butylbenzenesulfinimidoyl chloride, tetrapropylammonium perruthenate, and 2-hydroxy-2-azaadamantane (AXADOL®.

49. The process of claim 48, wherein the compound of Formula Z is contacted with sodium hypochlorite in the presence of a catalyst.

50. The process of claim 49, wherein the catalyst is (2,2,6,6-tetramethylpiperidine-1-yl)oxyl (TEMPO).

51. The process of any one of claims 47-50, wherein the compound of Formula Z is prepared by a process comprising: a. contacting a compound of Formula X: (Formula X)115Atty. Dkt. No.129802-0442 P0059-WO wherein R6is an alcohol protecting group; with a catalyst and a hydrogen reagent to form the compound of Formula Y: (Formula Y); and b. contacting Y with a deprotection agent thereby preparingthe compound of Formula Z.

52. The process of claim 51, wherein the catalyst is palladium on carbon.

53. The process of claim 51 or 52, wherein the hydrogen reagent is hydrogen gas, formic acid, or hydrosilane.

54. The process of any one of claims 51-53, wherein step a) further comprises an acid additive.

55. The process of claim 54, wherein the acid additive is selected from phosphoric acid, citric acid, tartaric acid, oxalic acid, benzoic acid, formic acid, hydrochloric acid, sulfuric acid, trifluoracetic acid, or methanesulfonic acid.

56. The process of any one of claims 51-55, wherein the compound of Formula X is prepared by a process comprising contacting a compound of Formula W: (Formula W)wherein X is -Br, -I, or -OTf; with a compound of Formula V: (Formula V)116Atty. Dkt. No.129802-0442 P0059-WO wherein Y is -B(OH)2, -B(OMe)2, -B(OEt)2, or -Bpin; and a group ten metal catalyst thereby preparing the compound of Formula X.

57. The process of claim 56, wherein the group ten metal catalyst is Pd(cod)Cl2, Pd(dppe)Cl2, Pd(dppp)Cl2, Pd(dppf)Cl2, Pd(PPh3)2Cl2, or Pd(PPh3)4.

58. The process of any one of claims 51-57, wherein R6is trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), triphenylsilyl (TPS), tert-butyldimethylsilyl (TBS), methoxymethyl (MOM), tetrahydropyranyl (THP), pivaloyl (Piv), tert-butoxycarbanyl (Boc), trityl (Tr), acetyl, or benzoyl.

59. A process comprising one or more steps selected from the steps: a. contacting a compound of Formula W-1: (Formula W-1) wherein X is- , - , - ; and R6is an alcohol protecting group; with a compound of Formula V-1: 1) wherein Y- 2, - 2, - 2, or –Bpin, BF3-; and a group ten metal catalyst to form a compound of Formula X-1: 1);117Atty. Dkt. No.129802-0442 P0059-WO b. contacting the compound of Formula (X-1) with a catalyst and a hydrogen reagent to form a compound of Formula Y-1: 1); c. contacting theon agent to form a compound of Formula Z-1: (Formula Z-1); d. contacting theith an oxidizing agent to form a compound of Formula A-1: (Formula A-1); e. contacting the compound of Formula A-1 with an R5X reagent and a base to form a compound of Formula A1-1: -1) wherein:R5is an alcohol protecting group; X is -Cl, -Br, -I, -OMs, -OTs, or -OTf, and 118Atty. Dkt. No.129802-0442 P0059-WO the base is an amine, an amidine, a carbonate, a phosphate, a tetra alkyl ammonium salt, or a hydroxide salt; f. contacting the compound of Formula A1-1 with an electrophilic fluorination agent to form a compound of Formula B-1: (Formula B-1); and g. contacting theh a hydrogen reagent in the presence of a chiral ruthenium catalyst to form a compound of Formula C-1: 1).

60. The process of claim 59,of steps a-g.

61. The process of claim 59, wherein the process comprises three or more of steps a-g.

62. The process of claim 59, wherein the process comprises four or more of steps a-g.

63. The process of claim 59, wherein the process comprises five or more of steps a-g.

64. The process of claim 59, wherein the process comprises six or more of steps a-g.

65. The process of claim 59, wherein the process comprises steps a-g.

66. The process of any one of claims 60-65, wherein the steps are sequential.

67. The process of any one of claims 59-66, wherein step g further comprises contacting the compound of Formula C-1 with a fluorination agent to form Compound (I): 119Atty. Dkt. No.129802-0442 P0059-WO I)).

68. A compound selectMe,120Atty. Dkt. No.129802-0442 P0059-WO , , 69.A pharmaceutical composition comprising a Compound (I) composition and one or more pharmaceutically acceptable excipients, wherein the Compound (I) composition comprises Compound (I): )),121Atty. Dkt. No.129802-0442 P0059-WO and not more than 5 % w / w process byproducts.

70. The pharmaceutical composition of claim 69, wherein the Compound (I) composition comprises no more than 4% w / w process byproducts.

71. The pharmaceutical composition of any one of claims 69-70, wherein the process byproducts comprise one or more compounds selected fro ,, 72.y , cess byproducts are detected by high-performance liquid chromatography.

73. The pharmaceutical composition of any one of claims 69-72, wherein the pharmaceutical composition is a tablet. 122

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