Process for producing a gaba receptor modulator

Abstract

The present invention relates to processes of preparing Compound 1 or a pharmaceutically acceptable salt thereof. The present invention further relates to intermediate compounds useful in the process for producing Compound 1. The present invention also relates to processes for producing intermediate compounds useful in the process for producing Compound 1.

Description

PROCESS FOR PRODUCING A GABA RECEPTOR MODULATORCROSS REFERENCE TO RELATED APPLICATION

[0001] This PCT application claims the benefit of U.S. provisional application no. 63 / 690,444, filed on September 4, 2024, the entire contents of which is hereby incorporated by reference in its entirety.TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to processes for producing a GABA receptor modulator. The present invention further relates to intermediate compounds useful in the process for producing a GABA receptor modulator. The present invention also relates to processes for producing intermediate compounds useful in the process for producing a GABA receptor modulator.BACKGROUND

[0003] Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately -70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K+, Na+, Cf, organic anions) balance across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from -70 mV to -50 mV). This effect is mediated by postsynaptic nicotinic receptors which are stimulated by acetylcholine to increase membrane permeability to Na+ions. The reduced membrane potential stimulates neuronal excitability' in the form of a postsynaptic action potential.

[0004] In the case of the GABA receptor complex (GRC), the effect on brain excitability' is mediated by GABA, a neurotransmitter. GABA has a profound influence on overall brain excitability because up to 40% of the neurons in the brain utilize GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts wi th its recognition site on the GRC to facilitate the flow of chloride ions down an electrochemical gradient of the GRC into the cell. An intracellular increase in the levels of this anion causes hyperpolarization of the transmembrane potential, rendering the neuron less susceptible to161828748.1excitatory' inputs (i.e., reduced neuron excitability). In other words, the higher the chloride ion concentration in the neuron, the lower the brain excitability (the level of arousal).

[0005] It is well-documented that the GRC is responsible for the mediation of anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like GABA or facilitate the effects of GABA (e.g., the therapeutically useful barbiturates and benzodiazepines (BZs, such as Diazepam, i.e., (VALIUM®))) produce their therapeutically useful effects by interacting with specific regulatory sites on the GRC.

[0006] Accumulated evidence has now indicated that in addition to the benzodiazepine and barbiturate binding site, the GRC contains a distinct site for neuroactive steroids (Lan, N. C. et al.. Neurochem. Res. 16:347-356 (1991)).

[0007] Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3a-hydroxy -5 -reduced pregnan-20-one and 3a-21-dihydroxy-5- reduced pregnan-20-one, metabolites of hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, M. D. et al., Science 232: 1004-1007 (1986)1 Harrison. N. L. et al., J Pharmacol. Exp. Ther. 241 :346-353 (1987)).

[0008] The ovarian hormone progesterone and its metabolites have been demonstrated to have profound effects on brain excitability (Backstrom, T. et al., Acta Obstet. Gynecol.Scand. Suppl. 130: 19-24 (1985); Pfaff, D.W and McEwen, B. S„ Science 219:808-814 (1983); Gyermek et al., J Med Chem. 11 : 117 (1968); Lambert, J. et al.. Trends Pharmacol. Sci. 8:224-227 (1987)). The levels of progesterone and its metabolites vary with the phases of the menstrual cycle. It has been well documented that the levels of progesterone and its metabolites decrease prior to the onset of menses. The monthly recurrence of certain physical symptoms prior to the onset of menses has also been yvell documented. These symptoms, which have become associated with premenstrual syndrome (PMS), include stress, anxiety, and migraine headaches (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2ndedition, Chicago Yearbook, Chicago (1984)). Subjects with PMS have a monthly recurrence of symptoms that are present in premenses and absent in postmenses.

[0009] In a similar fashion, a reduction in progesterone has also been temporally correlated with an increase in seizure frequency in female epileptics, i.e., catamenial epilepsy (Laidlaw, J., Lancet, 1235-1237 (1956)). A more direct correlation has been observed with a reduction in progesterone metabolites (Rosciszeyvska et al., J. Neural. Neurosurg. Psych. 49:47-51 (1986)). In addition, for subjects with primary’ generalized petit mal epilepsy, the temporal incidence of seizures has been correlated yvith the incidence of the symptoms of premenstrual261828748.1syndrome (Backstrom, T. et al.. J. Psychosom. Obstet. Gynaecol. 2:8-20 (1983)). The steroid deoxycorticosterone has been found to be effective in treating subjects with epileptic spells correlated with their menstrual cycles (Aird, RB. and Gordan, G., J. Amer. Med. Soc. 145:715-719 (1951)).

[0010] A syndrome also related to low progesterone levels is postnatal depression (PND). Immediately after birth, progesterone levels decrease dramatically leading to the onset of PND. The symptoms of PND range from mild depression to psychosis requiring hospitalization. PND is also associated with severe anxiety and irritability. PND-associated depression is not amenable to treatment by classic antidepressants, and women experiencing PND show an increased incidence of PMS (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2ndedition. Chicago Yearbook, Chicago (1984)).

[0011] Collectively, these observations imply a crucial role for progesterone and deoxycorticosterone and more specifically their metabolites in the homeostatic regulation of brain excitability, which is manifested as an increase in seizure activity or symptoms associated with catamenial epilepsy, PMS, and PND. The correlation between reduced levels of progesterone and the symptoms associated with PMS, PND, and catamenial epilepsy (Backstrom, T. et al., J Psychosom. Obstet. Gynaecol. 2:8-20 (1983)): Dalton, K., Premenstrual Syndrome arid Progesterone Therapy, 2ndedition, Chicago Yearbook, Chicago (1984) has prompted the use of progesterone in their treatment (Mattson et al., "Medroxyprogesterone therapy of catamenial epilepsy," in Advances in Epileptology: XVthEpilepsy International Symposium, Raven Press, New York (1984), pp. 279-282, and Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2ndedition, Chicago Yearbook, Chicago (1984)). However, progesterone is not consistently effective in the treatment of the aforementioned syndromes. For example, no dose-response relationship exists for progesterone in the treatment of PMS (Maddocks et al., Obstet. Gynecol. 154:573-581 (1986); Dennerstein et al., Brit. Med J. 290: 16-17 (1986)).

[0012] New and improved synthetic processes to provide neuroactive steroids that act as modulating agents for brain excitability, as well as agents for the prevention and treatment of CNS-related diseases are needed. The processes and intermediates described herein are directed toward this end.361828748.1SUMMARY OF THE INVENTION

[0013] In one aspect, the invention includes a process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising:(iiic) contacting Compound 2with 4-cyanopyrazole or a salt thereof in the presence of cesium carbonate and a solvent to form Compound 1.

[0014] In another aspect, the invention includes a process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising(ia) contacting 3-amino- 1 H-pyrazole-4-carbonitrile or a salt thereof with a nitrite reagent in an aqueous solvent system to form a first reaction mixture;(iia) contacting the first reaction mixture with hypophosphorous acid to form 4- cyanopyrazole or salt thereof; and(iiia) contacting Compound 2461828748.1with 4-cyanopyrazole or a salt thereof in the presence of a base and a solvent to formCompound 1.

[0015] In another aspect, the invention includes a process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising:(ib) contacting Compound B, Compound B , wherein R2of Compound B is C 1-4O alkyl or phenyl, with Nfh’fbO to form 17 / -pyrazole-4-carboxamide,;(iib) contacting 177-pyrazole-4-carboxamide with a dehydrating reagent in the presence of a base and a solvent to form 4-cyanopyrazole; and(iiib) contacting Compound 2Compound 2 with 4-cyanopyrazole in the presence of a base and a solvent to form Compound 1.

[0016] In another aspect, the invention includes a process of preparing Compound 1561828748.1or a pharmaceutically acceptable salt thereof, comprising the steps of:(ivb) contacting Compound 3with molecular bromine to obtain Compound 2Compound 2; and(iiic) contacting Compound 2 with 4-cyanopyrazole or a salt thereof in the presence of a cesium carbonate base and a solvent to obtain Compound 1 or a pharmaceutically acceptable salt thereof.

[0017] In another aspect, the invention includes a process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising:(v) oxidizing Compound 4661828748.1in a reaction mixture comprising a ruthenium reagent, an oxidizing reagent, and a solvent to obtain Compound 3(iv) contacting Compound 3 with a brominating reagent to obtainCompound 2Compound 2; and(iii) contacting Compound 2 with 4-cyanopyrazole or a salt thereof in the presence of a base and a solvent to obtain Compound 1.

[0018] In another aspect, the invention includes a method of generating purified Compound1Compound 1, or a pharmaceutically acceptable salt thereof, comprising(xiii) mixing crude Compound 1 with an organic solvent to form a mixture;761828748.1(xiv) heating the mixture to dissolve the crude Compound 1; and(xv) adding a second organic solvent to the mixture to crystallize Compound 1 and obtaining the crystallized Compound 1, wherein the crystallized Compound 1 has an increased purity compared to the crude Compound 1. In some instances, the organic solvent of step (xiii) and the second organic solvent of step (xv) are the same.

[0019] In another aspect, the invention includes a process of preparing 4-cyanopyrazole4-cyanopyrazole or a pharmaceutically acceptable salt thereof, comprising the steps of:(ia-1) contacting hydrazine or a hydrate thereof with Compound A:Compound A , ^gj.^ pi jsQ1 4 a]] y l optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci-4 alkyl, and Ci-4 haloalkyl, to provide 3-amino-4-cyanopyrazole3-amino-4-cyanopyrazole .anc|(ia-2) contacting 3-amino-4-cyanopyrazole with a nitrite reagent in the presence of a solvent to provide a first reaction mixture; and(iia) contacting the first reaction mixture of step (ia-2) with hypophosphorous acid(H3PO2) to provide 4-cyanopyrazole or a salt thereof.

[0020] In another aspect, the invention includes a process of preparing 4-cyanopyrazole4-cyanopyrazole or a salt thereof, comprising the steps of:(ib) contacting Compound, wherein R2of Compound B is C 1-4861828748.1oN jT NH2alkyd or phenyl, with NH3»H2O to provide lH-pyrazole-4-carboxamide, HN ; and(iib) contacting lH-pyrazole-4-carboxamide with a dehydrating reagent in the presence of a base and a solvent to form 4-cyanopyrazole.

[0021] In one aspect, the invention includes a process of preparing Compound 1Compound 1 or a pharmaceutically acceptable salt thereof, comprising:(xiia) reducing Compound 8in the presence of hydrogen gas, a Pd / C catalyst, and a solvent to obtain Compound 7(ix) contacting Compound 7 with a reaction mixture comprising methyl aluminum bis(2,6-di-ter / -butj 1-4-methylphenoxide), methyl magnesium bromide, and a solvent (ixa), or contacting Compound 7 with a methylating agent in the presence of a solvent (ixb), to produce Compound 6, wherein the methylating agent is trimethylaluminum (AIMes):Compound 6 .961828748.1(viii) contacting Compound 6 with a reaction mixture comprising ethyl triphenyl phosphonium bromide, potassium / e / 7-butoxide. and a solvent, to produce Compound 5Compound 5 .(vii) reacting Compound 5 in a reaction mixture comprising 9- borabicyclo[3.3. l]nonane (9-BBN) and a solvent (viia). or reacting Compound 5 in a reaction mixture comprising BH3-THF and a solvent (viib), to obtain Compound 4;Compound 4(va) oxidizing Compound 4 in a reaction mixture comprising tetrabut l ammonium bromide, a phosphate buffer. NaBrCf. a catalytic amount of a ruthenium reagent, an oxidizing reagent, and a solvent to obtain Compound 3Compound 3(iva) contacting Compound 3 with a reaction mixture comprising molecular bromine and a catalytic amount of HBr to obtain Compound 21061828748.1(iiic) contacting Compound 2 with 4-cyanopyrazole in a reaction mixture comprising cesium carbonate and a solvent to provide Compound 1.

[0022] In another aspect, the invention includes a process of preparing Compound S-3bCompound S-3b or a pharmaceutically acceptable salt thereof, comprising:(S-3a) contacting Compound 2with an alkali metal acetate in the presence of an organic solvent to obtain Compound S3-a(S-3b) contacting Compound S-3a with a hydroxide base to obtain Compound S3- b

[0023] In another aspect, the invention includes a process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising:(S-3c) contacting Compound S-3b1161828748.1Compound S-3b with a compound of Formula (X)or a pharmaceutically acceptable salt thereof, wherein Z1is Ci-6 alkyl optionally substituted with one or more halo, or a 6-10 membered mono- or bi-cyclic aryl optionally substituted with methyl or halo, in the presence of a base and an organic solvent to obtain Compound 1 or a pharmaceutically acceptable salt thereof.

[0024] In another aspect, the invention includes a compound of Formula (X-l)or a salt thereof, wherein Z2is Ci-6 alkyl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from halo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from halo, C1-3 alkyl, or oxo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups (e.g.. 1-3 groups) independently selected methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from the group consisting of halo, C1-3 alkyl, and oxo.

[0025] In another aspect, the invention includes a method of preparing a compound of Formula (X-l)1261828748.1(X-l). or a salt thereof, whereinZ2is Ci-6 alkyl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from halo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups (e g., 1-3 groups) independently selected from halo, C1-3 alkyl, or oxo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with 1-3 groups independently selected from the group consisting of halo, C1-3 alkyl, and oxo, comprising:(S-4a) contacting Compound S-3bCompound S-3b with a compound of Formula (X-la)(X-la) wherein Z?is a leaving group in the presence of a nitrogen base and an organic solvent to form the compound of Formula (X-l).

[0026] In another aspect, the invention includes a process of preparing Compound 11361828748.1or a pharmaceutically acceptable salt thereof, comprising:(S-4b) contacting a compound of Formula (X-l)or a pharmaceutically acceptable salt thereof, whereinZ2is Ci-6 alkyl optionally substituted with one or more groups (e.g..l-3 groups) independently selected from halo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups (e.g.. 1-3 groups independently selected from halo, C1-3 alkyl, or oxo, a 3-10 membered mono- or bi-cyclic aryl) optionally substituted with one or more groups (e.g., 1-3 groups) independently selected methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups (e.g., 1-3 groups) independently- selected from the group consisting of halo, C1-3 alkyl, and oxo, with 4-cyanopyrazole in the presence of a base and an organic solvent to obtainCompound 1

[0027] In another aspect, the invention includes a process of preparing Compound 3 having the structure:1461828748.1comprising:(v) oxidizing Compound 4in a reaction mixture comprising a catalytic amount of a ruthenium reagent, an oxidizing reagent, and a solvent to obtain Compound 3.

[0028] In another aspect, the invention includes a process of preparing Compound 6 having the structure:comprising:(ixb) contacting Compound 7with a methylating agent in the presence of a solvent to obtain Compound 6. wherein the methylating agent is trimethylaluminum (AlMes).

[0029] In another aspect, the invention includes a process of preparing Compound 4 having the structure:1561828748.1comprising:(viib) reacting Compound 5Compound 5 with borane-THF (BH3-THF) in a solvent to obtain Compound 4.

[0030] In another aspect, the present invention provides a composition comprising 98.0%

[0031] In another aspect, the present invention provides a composition comprising 98.0% w / w or greater of Compound 4:

[0032] In another aspect, the invention includes a crystalline form of Compound 4, wherein the crystalline form is a methanol solvate of Compound 4.

[0033] In another aspect, the invention includes a composition comprising 95.0% w / w or greater of Compound 6:1661828748.1

[0034] In another aspect, the invention includes a composition comprising 99.0% w / w or greater of 4-cyanopyrazole4-cyanopyrazole

[0035] In another aspect, the invention includes a process of preparing Compound 3 having the structure:Compound 3 , comprising:(v) oxidizing Compound 4in a reaction mixture comprising a catalytic amount of a ruthenium reagent, an oxidizing agent, and a solvent to obtain Compound 3.

[0036] In yet another aspect, the invention includes a composition comprising 99.0% w / w or greater of Compound 1 having the following structure:BRIEF DESCRIPTION OF THE DRAWINGS

[0037] The following figures are presented as examples and are not intended to limit the scope of the invention.1761828748.1

[0038] Fig. 1 is the negative electrospray ion scanning spectrum of a purified reference standard of 4-cyanopyrazol.

[0039] Fig. 2 is the positive electrospray ion scanning spectrum of a purified reference standard of Compound 7.

[0040] Fig. 3 is a spectrum of a positive electrospray ionization scan of a purified reference standard of Compound 6.

[0041] Fig. 4 is a spectrum of a positive electrospray ionization scan of a purified reference standard of Compound 5.

[0042] Fig. 5 is a spectrum of a positive electrospray ionization scan of a purified reference standard of Compound 4 • MeOH.

[0043] Fig. 6 is a spectrum of a positive electrospray ionization scan of a purified reference standard of Compound 3.

[0044] Fig. 7 is a spectrum of a positive electrospray ionization scan of a purified reference standard of Compound 2.

[0045] Fig. 8 is a spectrum of a negative electrospray ionization scan of a purified reference standard of Compound 1.DETAILED DESCRIPTION OF THE INVENTION

[0046] I. DEFINITIONS

[0047] As used herein, the following definitions shall apply unless otherwise indicated.

[0048] As used herein. "Compound 1" refers to the compound having the formula (or structure):Compound 1.Compound 1 is also known as zuranolone, 3a-hy droxy-3P-methyl-21 -(4-cyanopyrazol- 1-yl)- 5p-19-norpregnan-20-one, and by its IUPAC name: l-(2-((3R,5R,8R,9R,10S,13S,14S,17S)- 3-hy droxy-3 J 3-dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2 -oxoethyl)- lH-pyrazole-4-carbonitrile (CAS Registry Number 1632051-40-1). Compound 1 was described in U.S. Patent No. 9,512,165 and PCT Application Publication No. WO 2014 / 169833, each of which are incorporated by reference in their entirety herein. Several crystalline forms of Compound 1 and methods of preparing said forms were described in1861828748.1U.S. Patent Application Publication No. US 2019 / 0177359 and PCT Application Publication No. WO 2018 / 039378. each of which are incorporated by reference in their entirety herein. Pharmaceutical compositions comprising Compound 1, methods of preparing said compositions, and micronization processes are disclosed in PCT Application Publication No. WO 2022 / 020363.

[0049] Compound 1 is a neuroactive steroid that has been shown to be a positive allosteric modulator of GABAA receptors that target synaptic and extrasynaptic GABA receptors. As a positive allosteric modulator of GABAA receptors. Compound 1 sen es as therapeutic agent to treat CNS related disorders, e.g., depression, postpartum depression and major depressive disorder and to treat neurological conditions, e.g., essential tremor, epilepsy, and Parkinson’s disease.

[0050] The terms "3-amino-4-cyanopyrazole" and "3-amino-17 / -pyrazole-4-carbonitrile" are used interchangeably herein to refer to a compound having Chemical Abstracts Service (CAS) Registry No. 16617-46-2. It will be appreciated that, as used herein, "3-amino-4- cyanopyrazole" and "3-amino-l 7 / -pyrazole-4-carbonitnle" encompass the corresponding N-H isomer referred to as "5-amino-4-cyanopyrazole" or "5-amino-l / / -pyrazole-4-carbonitrile". Thus, as used herein, the terms "3-amino-4-cyanopyrazole" and "3-amino-lE7-pyrazole-4- carbonitrile" encompass the structures3-amino-4-cyanopyrazoleanj 5-amino-4-cyanopyrazole

[0051] As used herein, the term "about", when referring to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, or within 5% of a stated value or of a stated limit of a range.

[0052] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version. Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books. Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J.. John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0053] As used herein, the term "hydroxyl" or "hydroxy" refers to an -OH moiety.

[0054] As used herein, the term "slurry" refers to a mixture comprising a liquid and a solid, wherein the solid is typically present as small particles.1961828748.1

[0055] It is noted that the use of the descriptors "first", "second", "third", or the like is used to differentiate separate elements (e.g., mixtures, solvents, reaction steps, processes, reagents, or the like) and may or may not refer to the relative order or relative chronology of the elements described.

[0056] As used herein, the term "solvent" refers to the liquid in which a solute is dissolved or slurried to form a solution.

[0057] As used herein, the term "neutralize" in acid-base chemistry refers to the act of adding an acid or a base to a mixture in order to change the pH to approximately 7 (for example, a pH of 6-8, 6.5-7.5, 6.8-7.2, or 6.9-7.1).

[0058] As used herein, the term "molar equivalent" refers to the ratio of the moles of one compound to the moles of another, typically the limiting reagent or reactant.

[0059] As used herein, the term "catalyst" refers to a substance that increases the rate of a chemical reaction without itself undergoing any permanent chemical change.

[0060] As used herein, the term "phase transfer catalyst" refers to a catalyst that is present in a biphasic mixture and facilitates the migration of a reactant from one phase into another phase where reaction occurs.

[0061] As used herein, the term "pharmaceutically acceptable" means approved or approvable by a regulatory' agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0062] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic maybe inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-I-carboxylic acid, glucoheptonic2061828748.1acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.

[0063] As used herein, the term "oxidizing reagent" refers to any substance that has the ability to oxidize (or accept electrons from) other substances. Examples of oxidizing reagents include without limitation O2, oxone, metal bromates (e.g., alkali metal bromates, e.g.. NaBrCE); metal periodates (e.g., alkali metal periodates, e.g., NalC ); metal chlorates (e.g., alkali metal chlorates, e.g., NaClCh or KCIO3); metal iodates (e.g., alkali metal iodates, e.g., NalCh or KICh); metal dichromates (e.g., alkali metal dichromates, e.g., potassium dichromate); pyridinium chlorochromate ("PCC"); pyridinium dichromate ("PDC"); Dess- Martin periodinane; Swem oxidation agents (i.e., oxalyl chloride and DMSO followed by an treatment with an organic base (e.g., EtsN)); Collins oxidation agents (i.e., chromium(VI) oxide with pyridine in di chloromethane); Jones oxidation agents (i.e., chromium tri oxide in aqueous sulfuric acid added to acetone reaction solution); and the like.

[0064] II. COMMONLY USED ABBREVIATIONS2161828748.12261828748.1

[0065] III. COMPOUNDS, COMPOSITIONS, AND METHODS OF SYNTHESES

[0066] In one aspect, the invention includes a process of preparing Compound 1Compound 1 or a pharmaceutically acceptable salt thereof, comprising:(iii) contacting Compound 2Compound 2 with 4-cyanopyrazole or a salt thereof in the presence of a base and a solvent to form Compound 1.In one embodiment, the base comprises a carbonate base or an alkylamine base (e.g.. NR3 wherein R is C1-6 alkyl, such as triethylamine). In another embodiment, the base comprises a metal carbonate base. In yet another embodiment, the base is an alkali metal carbonate base. In one embodiment, the metal carbonate base comprises cesium carbonate, potassium carbonate, sodium carbonate, or lithium carbonate. In a further embodiment, the base is cesium carbonate.

[0067] In some embodiments, about 1 molar equivalents (e.g., about 1.2 eq. or about 1.3 eq.) of the base is employed in step (iii).

[0068] In one embodiment of this aspect, the solvent comprises an organic solvent.

[0069] In one embodiment, the organic solvent comprises a ketone (e.g., acetone, MEK, MIBK), an ester (e.g., EtOAc, IPAC), a hydrocarbon (e.g., hexane, heptane, toluene), a halogenated solvent (e.g., DCM, CHCI3, dichloroethane, PhCFs), an alcohol (e.g., MeOH, EtOH, IPA, BuOH), an ether (e g., THF, MeTHF, CPME, MTBE, DME, dioxane), or a polar aprotic solvent (e.g., DMF, DMAc, NMP, NEP, MeCN, DMSO. sulfolane, DMPU, HMPA).

[0070] In another embodiment, the organic solvent comprises acetone, ethyl acetate, isopropyl acetate, hexane, heptane, dichloromethane, chloroform, methanol, ethanol,2361828748.1isopropyl alcohol, a butyl alcohol tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethylformamide, toluene, dimethylsulfoxide, or any combination thereof.

[0071] In a further embodiment, the organic solvent comprises ethyl acetate or acetone.

[0072] In one embodiment, the contacting step is performed at a temperature of from about 0 °C to about 80 °C. In another embodiment, the contacting step (iii) is performed at a temperature of from about 10 °C to about 60 °C. In another embodiment, the contacting step (iii) is performed at a temperature of from about 20 °C to about 50 °C. In one embodiment, the contacting step is performed at a temperature of from about 25 °C to about 45 °C. In one embodiment, the contacting step (iii) is performed at a temperature of from about 28 °C to about 45 °C.

[0073] In a further embodiment, the contacting step is performed at a temperature of from about 30 °C to about 40 °C.

[0074] In one embodiment, the contacting step (iii) is performed under mixing for at least about 1 hour. In another embodiment, the contacting step is performed under mixing for at least about 2 hours, at least 3 hours, at least 8 hours, at least 10 hours, at least 12 hours, or at least 14 hours. In another embodiment, the contacting step (iii) is performed under mixing for a period of from about 1 hour to about 24 hours (e g., from about 3 hours to about 8 hours or from 3 hours to about 24 hours).

[0075] In some embodiments, the process comprises:(iiic) contacting Compound 2Compound 2 with 4-cyanopyrazole or a salt thereof in the presence of a cesium carbonate base and a solvent to form Compound 1 or a pharmaceutically acceptable salt thereof. The solvent and reaction conditions (e.g., reaction temperature and time) are each independently as those described above for process (iii). In one embodiment, the solvent comprises an ester, such as ethyl acetate. In another embodiment, the solvent comprises ethyl acetate. In another embodiment, the contacting step is performed at a temperature of from about 30 °C to about 40 °C. In another embodiment, the contacting step is performed under mixing for at least 1 hour or at least about 2 hours. In yet another embodiment, the contacting step is performed2461828748.1under mixing for a period of from about 1 hour to about 24 hours. In yet another embodiment, the contacting step is performed under mixing for a period of from about 3 hour to about 24 hours.

[0076] In another aspect, the invention includes a process of preparing Compound 1Compound 1 or a pharmaceutically acceptable salt thereof, comprising:(ia) contacting 3-amino- 1 / 7-py razole-4-carbonilrile with a nitrite reagent in an aqueous solvent system to form a first reaction mixture;(iia) contacting the first reaction mixture with hypophosphorous acid to form 4- cyanopyrazole or a salt thereof; and(iiia) contacting Compound 2Compound 2 with 4-cyanopyrazole in the presence of a base and a solvent to form Compound 1.

[0077] Details of the step (iiia), including specific embodiments of the base, solvent, reaction temperature and time, are each and independently as described above for step (iii). In one embodiment, step (iiia) is as described above for step (iiic) wherein Compound 2 is contacted with 4-cyanopyrazole or a salt thereof in the presence of cesium carbonate and a solvent to form Compound 1.

[0078] In some embodiments, the nitrite reagent of step (ia) comprises sodium nitrite, tertbutyl nitrite, or amyl nitrite. In other embodiments, the nitrite reagent comprises sodium nitrite.

[0079] In some embodiments, step (ia) comprises contacting (e.g., reacting) 3-amino- l / 7- pyrazole-4-carbonitrile with sodium nitrite in an aqueous solvent system to form a first reaction mixture. In some implementations, step (ia) is performed under mixing.2561828748.1

[0080] In some embodiments, step (ia) further comprises step (ia-1 ) contacting hydrazine or a hydrate thereof (e.g.. hydrazine monohydrate) with Compound A having the structure, NC, ,CNOR1, wherein R1is Ci-4 alkyd optionally substituted with one or more substituents independently selected from the group consisting of halogen, unsubstituted Ci-4 alkyl, and Ci-4 haloalkyl. (e.g.. 2-(ethoxymethylene)malonodinitrile (EMM)) to provide 3-amino-4- cyanopyrazole. In one embodiment. R1is Ci-4 alkyl. In another embodiment, R1is methyl or ethyl. In yet another embodiment, Compound A is EMM.

[0081] In some embodiments, step (ia-1) further comprises combining water and Compound A (e.g., 2-(ethoxymethylene)malonodinitrile (EMM)) to form a mixture, and adjusting the temperature of the mixture (e.g.. cooling the mixture) to a temperature of from about -5 °C to about 5 °C (e.g., from about 0 °C to about 5 °C). In other embodiments, step (ia-1) further comprises adding hydrazine (e.g., hydrazine monohydrate) to the mixture, adjusting the temperature of the mixture (e.g., heating the mixture) to a temperature of from about 15 °C to about 30 °C (e.g., from about 20 °C to about 25 °C), and stirring the mixture at that temperature for a period of from about 4 hrs to about 8 hrs (e.g., from about 5 hrs to about 7 hrs, or about 6 hrs). And, in yet other embodiments, step (ia-1) further comprises adjusting the temperature of the mixture (e.g., cooling the mixture) to a temperature of from about -5 °C to about 5 °C (e.g., from about 0 °C to about 5 °C), agitating the mixture at that temperature for a period of from about 1 hr to about 3 hrs (e.g., about 2 hrs), and filtering the mixture to obtain 3-amino-4-cyanopyrazole as a solid.

[0082] In some embodiments, step (iia) further comprises step (iia-1) contacting 3-amino-4- cyanopyrazole with hypophosphorous acid and sodium nitrite in water. In other embodiments, step (iia-1) further comprises combining water and 3-amino-4-cyanopyrazole in water to form an aqueous mixture, to the aqueous mixture adding an aqueous solution of sodium nitrite (e.g., from about 1.0 to about 1.4 molar equiv., or about 1.2 molar equiv.) under stirring or agitation conditions, and to this mixture adding hypophosphorous acid (e.g., from about 4.0 molar equiv. to about 6.0 molar equiv. or about 5 molar equiv.) In yet other embodiments, the hypophosphorous acid has a concentration of from about 40% to about 60% (e g., from about 45% to about 55% or about 50%). In yet other embodiments, step (iia- 1) further comprises adding an alkali metal hydroxide to the resulting mixture to neutralize the pH of the mixture, and to the neutralized mixture, sodium chloride is added, and the mixture is extracted (1, 2, 3, 4. or 5 times) with ethyl acetate. In yet other embodiments, step2661828748.1(iia-1) further comprises combining organic layers and extracting such combined layers at low pH followed by washing with water to form a concentrated organic solution comprising 4-cyanopyrazole.

[0083] Details of the step (iiia), including specific embodiments of the base, solvent, reaction temperature and time, are each and independently as described above for processes (iii). In one embodiment, step (iiia) is as described above for step (iiic) wherein Compound 2 is contacted with 4-cyanopyrazole or a salt thereof in the presence of cesium carbonate and a solvent to form Compound 1. In one embodiment, the solvent comprises an ester. In one embodiment, the solvent comprises ethyl acetate. In another embodiment, the contacting step is performed at a temperature of from about 30 °C to about 40 °C. In another embodiment, the contacting step is performed under mixing for at least 1 hour or at least about 2 hours. In yet another embodiment, the contacting step is performed under mixing for a period of from about 1 hour to about 24 hours. In yet another embodiment, the contacting step is performed under mixing for a period of from about 3 hours to about 24 hours.

[0084] In another aspect, the invention includes a process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising:(ib) contacting Compound B, Compound B , wherein R2of Compound B is Ci-4O alkyd or phenyl, with NH ^HiO to form 177-pyrazole-4-carboxamide,(iib) contacting 17 / -pyrazole-4-carboxamide with a dehydrating reagent in the presence of a base and a solvent to form 4-cyanopyrazole, and(iiib) contacting Compound 22761828748.1Compound 2 with 4-cyanopyrazole in the presence of a base and a solvent to form Compound 1.

[0085] In some embodiments, R2of Compound B is Ci-4 alkyl. In some embodiments, R2of Compound B is methyl or ethyl. In some embodiments, R2of Compound B is ethyl, i.e.,Compound

[0086] In some embodiments, the NH.’FEO of step (ib) comprises a concentration of from about 20 to about 40 % of NHs (w / v) in water. In one embodiment, the NH3*H?O of step (ib) comprises a concentration of from about 20 to about 35 % of NH3(w / v) in water. And, in one embodiment, the NHs’fhO of step (ib) comprises a concentration of from about 20 to about 30 % of NH? (w / v) in water.

[0087] In some embodiments, about 3 volume equivalents to about 10 volume equivalents of NH3«H2O to Compound B are employed in step (ib). In some embodiments, about 10 volume equivalents of NPE’HiO to Compound B is employed in step (ib).

[0088] In some embodiments, the contacting step (ib) is performed at a temperature of from about 0 °C to about 200 °C. In one embodiment, the contacting step (ib) is performed at a temperature of from about 0 °C to about 80 °C. In another embodiment, the contacting step (ib) is performed at a temperature of from about 10 °C to about 60 °C. In one embodiment, the contacting step (ib) is performed at a temperature of from about 10 °C to about 40 °C. In one embodiment, the contacting step (ib) is performed at a temperature of from about 15 °C to about 35 °C. In another embodiment, the contacting step (ib) is performed at a temperature of from about 20 °C to about 30 °C. And, in one embodiment, the contacting step (ib) is performed at a temperature of from about 80 °C to about 150 °C.

[0089] In one embodiment, the contacting step (ib) is performed under mixing for about 1 hour to about 100 hours. In another embodiment, the contacting step (ib) is performed under mixing for about 50 hours to about 100 hours. In one embodiment, the contacting step (ib) is performed under mixing for about 60 hours to about 90 hours. And, in one embodiment, the contacting step (ib) is performed under mixing for about 65 hours to about 80 hours.2861828748.1

[0090] In some embodiments, the dehydrating reagent of step (iib) comprises POCI3. SOCI2. trifluoroacetic anhydride (TFAA), methyl-trimethyl-silyl-trifluoroacetamide (MSTFA), 2,2- dimethylpropanoyl chloride, oxalyl chloride, methyl N- (triethylammoniumsulfonyl)carbamate (Burgess Reagent), pyridine, or triethylamine (TEA), or any combination thereof. In one embodiment, the dehydrating reagent comprises POCI3. In another embodiment, the dehydrating reagent comprises SOCh. In one embodiment, the dehydrating reagent comprises TFAA. In one embodiment, the dehydrating reagent comprises MSTFA. In another embodiment, the dehydrating reagent comprises 2,2- dimethylpropanoyl chloride. In one embodiment, the dehydrating reagent comprises oxalyl chloride. In some embodiments, the dehydrating reagent comprises Burgess Reagent. In some embodiments, the dehydrating reagent comprises pyridine. In some embodiments, the dehydrating reagent comprises triethylamine.

[0091] In some embodiments, about 1 molar equivalent to about 5 molar equivalents of the dehydrating reagent to I H-pyrazole-4-carboxamide are employed.

[0092] In some embodiments of this aspect, the base of step (iib) comprises an amine base. In some embodiments, the base of step (iib) comprises EtsN, pyridine, N.N- diisopropylethylamine, N-methylmorpholine, lutidine, or picoline, or any combination thereof. In one embodiment, the base comprises EtsN. In another embodiment, the base comprises pyridine. In one embodiment, the base comprises N,N-diisopropylethylamine. In some embodiments, the base is N-methylmorpholine. In some embodiments, the base comprises lutidine. In some embodiments, the base comprises picoline.

[0093] In some instances, step (iib) comprises contacting 17 / -pyrazole-4-carboxamide with TFAA in the presence of EtsN. In other instances, step (iib)comprises contacting 1H- pyrazole-4-carboxamide with 2,2-dimethylpropanoyl chloride in the presence of pyridine.

[0094] In some instances, step (iib) comprises contacting Uf-pyrazole-4-carboxamide with POCI3 in the presence of EtsN. In other instances, step (iib) comprises contacting \ H- pyrazole-4-carboxamide with POCI3 in the presence of pyridine. And, in some instances, step (iib) comprises contacting 177-pyrazole-4-carboxamide with POCI3 in the presence of N,N- diisopropylethylamine.

[0095] In some embodiments of this aspect, the solvent of step (iib) comprises an organic solvent. In one embodiment, the organic solvent comprises a ketone (e.g., acetone, MEK, MIBK), an ester (e g., EtOAc, IPAC), a hy drocarbon (e.g., hexane, heptane, toluene), a halogenated solvent (e.g., DCM. CHCI3, dichloroethane, PI1CF3), an ether (e.g., THF, MeTHF, CPME, MTBE, DME, dioxane), or a polar aprotic solvent (e.g., DMF, DMAc, NMP,2961828748.1NEP, MeCN, DMSO, sulfolane, DMPU. HMPA).

[0096] In one embodiment, the organic solvent of step (iib) comprises acetone, ethyl acetate, hexane, heptane, dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, dimethylformamide, toluene, dimethylsulfoxide, or any combination thereof. In another embodiment, the organic solvent of step (iib) comprises dimethylformamide, tetrahydrofuran, toluene, acetonitrile, or dichloromethane, or any combination thereof. In one embodiment, the organic solvent of step (iib) comprises toluene.

[0097] In some embodiments, step (iib) comprises contacting l / 7-pyrazole-4-carboxamide with POCh in the presence of a base and a solvent to form 4-cyanopyrazole, wherein the base comprises EhN and wherein the solvent comprises toluene.

[0098] In some embodiments, the contacting step (iib) is performed at a temperature of from about 0 °C to about 150 °C. In one embodiment, the contacting step (iib) is performed at a temperature of from about 15 °C to about 35 °C. In another embodiment, the contacting step (iib) is performed at a temperature of from about 20 °C to about 30 °C. In one embodiment, the contacting step (iib) is performed at a temperature of from about 50 °C to about 150 °C. In another embodiment, the contacting step (iib) is performed at a temperature of from about 80 °C to about 120 °C. In one embodiment, the contacting step (iib) is performed at a temperature of from about 60 °C to about 100 °C. And, in one embodiment, the contacting step (iib) is performed at a temperature of from about 70 °C to about 90 °C.

[0099] In one embodiment, the contacting step (iib) is performed under mixing for at least 1 hour. In some embodiments, the contacting step is performed under mixing for about 1 hour to about 20 hours. In another embodiment, the contacting step (iib) is performed under mixing for about 4 hours to about 20 hours. In one embodiment, the contacting step (iib) is performed under mixing for about 2 hours to about 10 hours. In one embodiment, the contacting step (iib) is performed under mixing for about 4 hours to about 8 hours. In another embodiment, the contacting step (iib) is performed under mixing for about 10 hours to about 20 hours. In one embodiment, the contacting step (iib) is performed under mixing for about 10 hours to about 14 hours. And, in one embodiment, the contacting step (iib) is performed under mixing for about 14 hours to about 18 hours.

[0100] In some embodiments, step (iib) further comprises purifying 4-cyanopyrazole, wherein the purifying 4-cyanopyrazole comprises crystallizing 4-cyanopyrazole in a solvent comprising dichloromethane, ethyl acetate, and / or heptane. In some embodiments, the crystallization step comprises:(iib- 1 ) dissolving crude 4-cyanopyrazole in a mixture of di chloromethane, ethyl3061828748.1acetate, and heptane at a temperature of about 20 °C to about 40 °C to form a solution of 4- cyanopyrazole;(iib-2) cooling the solution of 4-cyanopyrazole to a temperature of from about -10 °C to about 10 °C; and(iib-3) collecting cry stallized 4-cyanopyrazole.

[0101] In some embodiments, step (iib-2) comprises cooling the solution of 4-cyanopyrazole to a temperature of from about -5 °C to about 5 °C.

[0102] Details of the step (iiib), including but not limited to specific embodiments of the base, solvent, and reaction conditions (e.g., reach on temperature and time), are each and independently as described above for processes (iii). In one embodiment, step (iiib) is as described above for step (iiic) wherein Compound 2 is contacted with 4-cyanopyrazole or a salt thereof in the presence of cesium carbonate and a solvent to form Compound 1. In one embodiment, the solvent comprises an ester. In another embodiment, the solvent comprises ethyl acetate. In another embodiment, the contacting step is performed at a temperature of from about 30 °C to about 40 °C. In another embodiment, the contacting step is performed under mixing for at least 1 hour or at least about 2 hours. In yet another embodiment, the contacting step is performed under mixing for a period of from about 1 hour to about 24 hours. In yet another embodiment, the contacting step is performed under mixing for a period of from about 3 hours to about 24 hours.

[0103] The processes (iiia), (iiib), and (iiic) which employ CS2CO3 as the base afford better reaction kinetics than, for example, K2CO3. Such better reaction kinetics in turn allow the reaction to proceed at lower temperatures. For example, processes employing employ CS2CO3 can be performed at a temperature of from about 30 °C to about 40 °C while the process employing K2CO3 generally is performed at a higher temperature, e.g., at a temperature of about 40 °C to about 50 °C. Further, the processes (ilia), (iiib), and (iiic), employing CS2CO3 as the base, allows use of ethyl acetate as the solvent. Such use of ethyl acetate allows a phase separation from an aqueous phase during reaction, and such phase separation spares a separate phase separation and makes the processes shorter and more convenient. Further, the processes (iiia), (iiib), and (iiic) which employ CS2CO3 as the base afford a high purity' and yield of Compound 1.

[0104] In one aspect of the invention, substantially pure Compound 1 comprises less than 1.0 %w / w of any impurities. In some embodiments, substantially pure Compound 1 comprises less than 0.7 %w / w. 0.5 %w / w, 0.3 %w / w, 0.2 %w / w, or 0.1 %w / w, of any impurities.3161828748.1

[0105] In some embodiments, the impurities include:structurally related byproducts. In some embodiments, substantially pure Compound 1 comprises no more than 1.0 %w / w, 0.7 %w / w, 0.5 %w / w, 0.3 %w / w, 0.2 %w / w, or 0.1 %w / w, of any of impurity 1 and impurity 2.

[0106] A further aspect of the invention provides a composition comprising 99.0% w / w or greater of Compound 1. In one embodiment, the composition comprises 99.3% w / w or greater of Compound 1. In another embodiment, the composition comprising 99.5 % w / w or greater of Compound 1. In another embodiment, the composition comprising 99.7% w / w or greater of Compound 1. In another embodiment, the composition comprising 99.8% w / w or greater of Compound 1. In another embodiment, the composition comprising 99.9% w / w or greater of Compound 1. In some embodiments, the compositions comprise at least 1 kg (e.g., at least 5 kg or at least 10 kg) of Compound 3.

[0107] In some embodiments, such substantially pure Compound 1 is prepared employing the process (iiic) described above. In some embodiments, such substantially pure Compound 1 is prepared employing the processes (ia), (iia) and (iiia) described above. In some embodiments, such substantially pure Compound 1 is prepared employing the processes (ib), (iib) and (iiib) described above. In some embodiments, such substantially pure Compound 1 is prepared employing the processes (ic), (iic) and (iiic) described above. In certain embodiments, Compound 2 is prepared by any method described below.

[0108] In one embodiment, Compound 2 is prepared employing a process comprising:(iv) contacting Compound 3Compound 3 with a brominating reagent to obtain Compound 2.3261828748.1

[0109] In some embodiments, the brominating reagent of step (iv) comprises molecular bromine, N-bromosuccinimide, dibromo-dimethyl-hydantoin. tribromotriazinone, dibromohydantoin, N-bromosaccharin, or tribromocyanuric acid. In one embodiment, the brominating reagent comprises molecular bromine.

[0110] In one embodiment, from at least about 0.8 to about 1.5 molar equivalents, from at least about 0.8 to about 1.2 molar equivalents, at least about 0.8 molar equivalents, at least about 0.9 molar equivalents, or about 1 molar equivalent of brominating reagent is employed. [OH l] In another embodiment. Compound 3 is contacted with the brominating reagent in the presence of a solvent and a catalytic amount of a protic acid.

[0112] In some embodiments, the protic acid comprises HBr. In a further embodiment, the HBr is added as an aqueous solution. In still a further embodiment, the aqueous HBr is about a 48% aqueous solution.

[0113] In one embodiment, the solvent of step (iv) comprises an alcohol solvent. In some embodiments, the solvent comprises methanol, ethanol, isopropanol, tert-butanol, or any combination thereof. In a further embodiment, the solvent comprises methanol.

[0114] In one embodiment, contacting Compound 3 with the brominating agent is performed for at least one hour, at least 3 hours, at least 5 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 24 hours, from about 1 to about 24 hours, or from about 1 hour to about 12hours.

[0115] In one embodiment, contacting Compound 3 with the brominating agent in step (iv) is performed at a temperature of from about -25 °C to about 25 °C, from about -10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, or from about -5 °C to about 5 °C.

[0116] In one embodiment, contacting Compound 3 with the brominating agent in step (iv) comprises adding the brominating agent to Compound 3; and mixing (e.g., agitating) Compound 3 and the brominating agent. In some embodiments, the brominating reagent is added to a mixture of Compound 3, the protic acid, and a solvent; and mixing (e.g., agitating) the brominating reagent and the mixture of Compound 3, the protic acid, and solvent.

[0117] In some embodiments, the brominating agent is molecular bromine. In some embodiments, the protic acid comprises HBr. In some embodiments, the solvent comprises methanol. In some embodiments, the molecular bromine is added to a mixture of Compound 3, the protic acid, and a solvent comprising methanol. In some embodiments, the molecular bromine is added to a mixture of Compound 3, HBr, and a solvent comprising methanol. In3361828748.1some embodiments, the molecular bromine is added to a mixture of Compound 3, HBr, and a solvent comprising methanol.

[0118] In some embodiments, adding molecular bromine to a mixture of Compound 3, HBr, and a solvent comprising methanol comprises:(iv-a) adding molecular bromine (e.g., from at least about 0.8 to about 1.2 molar equivalents, at least about 0.8 molar equivalents, at least about 0.9 molar equivalents, or at least about 1 molar equivalents) to a reaction mixture comprising Compound 3 over a period of time sufficient to maintain the reaction mixture at a temperature of from about -25 °C to about 25 °C (e.g., from about -10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about -5 °C to about 5 °C); and(iv-b) agitating a mixture resulting from step (iv-a) (e.g., for at least one hour (e.g., from 1 to 3 hrs, from 1 to 2 hrs)) at a temperature of from about -25 °C to about 25 °C (e.g., from about -10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about -5 °C to about 5 °C).

[0119] In one embodiment, adding the molecular bromine to a mixture of Compound 3.HBr, and a solvent comprising methanol comprises:(iv-a) adding from about 0.45 to about 0.55 molar equivalents of molecular bromine to a reaction mixture comprising Compound 3 over a period of time sufficient to maintain the reaction mixture at a temperature of from about -25 °C to about 25 °C (e.g., from about - 10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about -5 °C to about 5 °C); and(iv-b) agitating a mixture resulting from step (iv-a) for at least one hour (e.g., from 1 to 3 hrs, from 1 to 2 hrs) at a temperature of from about -25 °C to about 25 °C (e.g., from about -10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about -5 °C to about 5 °C).

[0120] In one embodiment, adding the molecular bromine to a mixture of Compound 3, HBr, and a solvent comprising methanol comprises:(iv-a) adding at least about 1 molar equivalents of molecular bromine to a reaction mixture comprising Compound 3 over a period of time sufficient to maintain the reaction mixture at a temperature of from about -25 °C to about 25 °C (e.g., from about -10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about - 5 °C to about 5 °C); and(iv-b) agitating a mixture resulting from step (iv-a) for at least one hour (e.g., from 1 to 3 hrs, from 1 to 2 hrs) at a temperature of from about -25 °C to about 25 °C (e.g., from3461828748.1about -10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about -5 °C to about 5 °C).

[0121] In one embodiment, adding the molecular bromine to a mixture of Compound 3, HBr, and a solvent comprising methanol comprises:(iv-a) adding from about 0.45 to about 0.55 molar equivalents of molecular bromine to a reaction mixture comprising Compound 3 over a period of time sufficient to maintain the reaction mixture at a temperature of from about -25 °C to about 25 °C (e.g., from about - 10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about -5 °C to about 5 °C);(iv-b) agitating a mixture resulting from step (iv-a) for at least one hour (e g., from 1 to 3 hrs, from 1 to 2 hrs) at a temperature of from about -25 °C to about 25 °C (e.g., from about -10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about -5 °C to about 5 °C);(iv-c) adding from about 0.45 to about 0.55 molar equivalents of molecular bromine to a mixture resulting from step (iv-b) over a period of time sufficient to maintain the mixture at a temperature of from about -25 °C to about 25 °C (e.g., from about -10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about -5 °C to about 5 °C); and(iv-d) agitating a mixture resulting from step (iv-c) for at least one hour at a temperature of from about -25 °C to about 25 °C (e.g., from about -10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about -5 °C to about 5 °C).

[0122] In some embodiments, the process further comprises isolating Compound 2 from the reaction mixture resulting from the agitating step(s). In some embodiments, the isolation step comprises adding water to the reaction mixture from the agitation steps and filtrating out Compound 2.

[0123] In another, Compound 2 is prepared employing a process comprising:(iva) contacting Compound 33561828748.1with a reaction mixture comprising molecular bromine and a catalytic amount of HBr to obtain Compound 2.

[0124] Details of step (iva), including but not limited to reaction conditions (e.g., reaction temperature and time), and isolation of Compound 2 are as described above for step (v).

[0125] In one aspect of the invention, Compound 3 is prepared employing a process comprising:(v) oxidizing Compound 4Compound 4 in a reaction mixture comprising a ruthenium reagent, an oxidizing reagent, and a solvent, to obtain Compound 3

[0126] In one embodiment, the ruthenium reagent comprises RuCl? or any hydrate thereof, ruthenium tetroxide, or tetrapropylammonium perruthenate (TPAP). In some embodiments, the ruthenium reagent comprises RuCh or any hydrate thereof.

[0127] In one embodiment, the solvent comprises a mixture of an organic solvent and water. In some embodiments, the organic solvent is a non-water miscible organic solvent.

[0128] In one embodiment, the organic solvent comprises a ketone (e.g., MEK, MIBK), an ester (e.g., EtOAc, IPAC), a hydrocarbon (e.g., hexane, heptane, toluene), a halogenated solvent (e.g., DCM, CHCh, dichloroethane, PhCFs), or an ether (e.g., THF, MeTHF, CPME, MTBE. DME, dioxane), or any combination thereof. In some embodiments, the organic solvent comprises an ether, an ester, a hydrocarbon, or any combination thereof. In some embodiments, the organic solvent comprises an ether.

[0129] In a further embodiment, the organic solvent comprises methyl tert-butyl ether (MTBE), ethyl acetate, isopropyl acetate, diethyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dimethyl ether, toluene, hexane, and heptane. In some embodiments, the organic solvent comprises MTBE.

[0130] In one embodiment, the ruthenium reagent is present in a catalytic amount in the reaction mixture of step (v).

[0131] In another embodiment, the reaction mixture of step (v) further comprises a phase3661828748.1transfer catalyst, and a buffer.

[0132] In a further embodiment, the phase transfer catalyst comprises a quaternary ammonium ion. In still a further embodiment, the phase transfer catalyst is tetrabutylammonium bromide.

[0133] In one embodiment, the buffer comprises a phosphate buffer.

[0134] In one embodiment, the oxidizing reagents comprises without limitation O2, oxone. metal bromates (e.g.. alkali metal bromates, e.g., NaBrCh); metal periodates (e.g., alkali metal periodates, e.g., NalCh); metal chlorates (e.g., alkali metal chlorates, e g., NaClCE or KCIO3); metal iodates (e.g., alkali metal iodates, e.g., NalOs or KIO3); metal dichromates (e.g., alkali metal dichromates, e.g., potassium dichromate); pyridinium chlorochromate ("PCC"); pyridinium dichromate ("PDC"); Dess-Martin periodinane; Swem oxidation agents (i.e., oxalyl chloride and DMSO followed by an treatment with an organic base (e.g., EtsN)); Collins oxidation agents (i.e., chromium(VI) oxide with pyridine in di chloromethane); Jones oxidation agents (i.e., chromium trioxide in aqueous sulfuric acid added to acetone reaction solution); or permanganates. In some embodiments, the oxidizing reagent comprises O2. oxone, a metal bromate, a metal periodate, a metal chlorate, a metal iodate, metal dichromate, pyridinium chlorochromate, pyridinium dichromate, Dess-Martin periodinane, oxalyl chloride and DMSO, chromium(VI) oxide with pyridine in di chloromethane, or chromium trioxide in aqueous sulfuric acid.3. In some embodiments, the oxidizing reagent comprises O2. oxone, a metal bromate, a metal periodate, a metal chlorate, a metal iodate, or a metal dichromate. In some embodiments, the oxidizing reagent comprises a metal bromate. In some embodiments, the oxidizing reagent comprises NalCh, NaClCE, NalCh, NaBrCh, KIO4, KCIO3, KIO3, or KBrOs. In some embodiments, the oxidizing reagent comprises NaBrOs or KBrCh. In some embodiments, the oxidizing reagent comprises NaBrOs.

[0135] In another embodiment, the oxidation step (v) compnses mixing (e.g., agitating) Compound 4 with the reaction mixture comprising the ruthenium reagent, oxidizing reagent, and solvent for at least 2 hours, at least 3 hours, at least 5 hours, at least 7 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, from about 2 hours to about 24 hours, from about 3 hours to about 24 hours, from about 5 hours to about 24 hours, from about 7 hours to about 24 hours, or from about 10 hours to about 24 hours.

[0136] In one embodiment, the mixing (e.g., agitating) of Compound 4 with the reaction mixture comprising the ruthenium reagent, oxidizing reagent, and solvent is performed at a temperature of from about 30 °C to about 60 °C or from about 40 °C to about 50 °C.

[0137] In another embodiment, the process further comprises (vi) crystallizing the3761828748.1Compound 3 isolated from step (v). In some embodiments, the cry stallization employs a solvent comprising an ether and / or a hydrocarbon. In some embodiments, the ether comprises MTBE. In some embodiments, the hydrocarbon comprises a heptane, such as n- heptane.

[0138] In one embodiment, Compound 3 is prepared employing a process comprising: (va) oxidizing Compound 4in a reaction mixture comprising tetrabutylammonium bromide, a phosphate buffer, NaBrCh. a catalytic amount of a ruthenium reagent, an oxidizing reagent, and a solvent to obtain Compound 3.

[0139] Details of step (va), including but not limited to the ruthenium reagent, oxidizing reagent, solvent, solvent, and reaction conditions (e.g., reaction temperature and time), and the details of crystallization of Compound 3, are each independently as described above for step (v).

[0140] One aspect of the present invention provides a substantially pure Compound 3, wherein Compound 3 comprises no more than 2.0 %w / w (e.g., no more than 1.0 %w / w, 0.5 %w / w, no more than 0.4 %w / w, no more than 0.3%w / w, no more than 0.2%w / w, or no more than 0. 1 %w / w) of any impurities. In another aspect, the invention provides a composition comprising a substantially pure Compound 3 comprising no more than 2.0 %w / w (e.g., no more than 1.0 %w / w, 0.5 %w / w, no more than 0.4 %w / w, no more than 0.3%w / w, no more than 0.2%w / w. or no more than 0. l%w / w) of any impurities.

[0141] A further aspect of the invention provides a composition comprising 98.0% w / w or greater (e.g., 99.0 %w / w or greater, 99.5% w / w or greater, 99.6 %w / w or greater, 99.7 %w / w or greater, 99.8 %w / w or greater, or 99.9 %w / w or greater) of Compound 3. In some embodiments, the composition comprises 98.0% w / w or greater of Compound 3. In some embodiments, the composition comprising 99.0 % w / w or greater of Compound 3. In some embodiments, the composition comprising 99.5% w / w or greater of Compound 3. In some embodiments, the compositions comprise at least 1 kg (e.g., at least 5 kg or at least 10 keg) of Compound 3.3861828748.1

[0142] In some embodiments, such substantially pure Compound 3 is prepared employing the processes (v) or (va) described above.

[0143] The processes comprising step (v) or (va), which employ a ruthenium reagent for preparing Compound 3, advantageously avoid the use of a heavy metal agent, such as pyridinium chlorochromate (PCC), to oxidize Compound 4. Such PCC generally employs a stoichiometric amount, and its byproducts includes Cr salts (e.g., CrCh) which are difficult to remove and very toxic. The use of PCC typically leads to the presence of genotoxic (or potentially genotoxic) impurities or method artifacts that are difficult to remove via purification. As opposed to PCC, the ruthenium reagent employed in step (v) and (va) is typically used in a catalytic amount, and allows a biphasic reaction (i.e., in a solvent comprising water and non-water miscible organic solvent) where a byproduct such as NaBr is readily removed from the reaction mixture. These processes further allow a large quantity of Compound 3 of high purity, which may advantageously result in a high quality of, e.g., drug substance made via Compound 3 with less purification steps.

[0144] In another aspect of the invention, Compound 4 is prepared employing a process comprising:(vii) contacting Compound 5Compound 5 with a reaction mixture comprising a boron reducing agent and a solvent, to obtain Compound 4.

[0145] In some embodiments, the boron reducing agent comprises 9- borabicyclo[3.3.1]nonane (9-BBN), borane-THF (BH3-THF), pinacolborane, disiamylborane, thexylborane (thexyl-Blty), disiamylborane, catecholborane, borane-DMS (dimethylsulfide) (BH3-DMS), BH3*Me2S, BFs’EtzO, NaBH, a borane amine complex, or any combination thereof. In some embodiments, the boron reducing agent comprises 9- borabicyclo[3.3.1]nonane (9-BBN), BH3-THF, or thexyl-BFE. In some embodiments, the boron reducing agent comprises 9-borabicyclo[3.3.1]nonane (9-BBN). In some embodiments, the boron reducing agent comprises BH3-THF. In some embodiments, the boron reducing agent comprises thexyl-BFh.3961828748.1

[0146] In one embodiment, about 1 molar equivalent to about 10 molar equivalents of the boron reducing agent to Compound 5 is employed. In some embodiments, 1 molar equivalent to about 5 molar equivalents of the boron reducing agent are employed. In some embodiments, 1 molar equivalent to about 3 molar equivalents of the boron reducing agent are employed.

[0147] In some embodiments, the solvent of step (vii) comprises an organic solvent. In some embodiments, the organic solvent of step (vii) comprises a hydrocarbon (e.g., hexane, heptane, toluene), a halogenated solvent (e.g., DCM, CHCh, dichloroethane, PhCFs), and an ether (e.g., THF, 2-MeTHF, CPME, MTBE, DME, dioxane). In other embodiments, the organic solvent of step (vii) comprises hexane, heptane, toluene, DCM, CHCE, dichloroethane, PhCFs, THF, 2-MeTHF. CPME. MTBE, DME, or dioxane, or any combination thereof. In some embodiments, the organic solvent of step (vii) comprises an ether. In some embodiments, the organic solvent of step (vii) comprises tetrahydrofuran (THF) or 2-MeTHF. In some embodiments, the organic solvent of step (vii) comprises tetrahydrofuran (THF).

[0148] In some embodiments, the process (vii) further comprises step (vii-a) adding aqueous sodium hydroxide to the reaction mixture of step (vii), followed by aqueous hydrogen peroxide. In some embodiments, step (vii-a) may comprise adding from about 1% (w / w) to about 50% (w / w) aqueous sodium hydroxide (e.g., from about 1% (w / w) to about 20% (w / w), from about 5% to about 15% (w / w), or about 10% (w / w) aqueous sodium hydroxide) to the reaction mixture of step (vii), followed by about 1% (w / w) to about 50% (w / w) of aqueous hydrogen peroxide (e.g., from about 10% (w / w) to about 50% (w / w), from about 20% (w / w) to about 40% (w / w), from about 25% (w / w) to about 35% (w / w), or about 30% (w / w)) of aqueous hydrogen peroxide.

[0149] In one embodiment, Compound 4 is prepared by a process comprising: (viia) reacting Compound 5:Compound 5 in a reaction mixture comprising 9-borabicyclo[3.3.1]nonane (9-BBN) and a solvent to obtainCompound 4.4061828748.1

[0150] The details of step (viia), including but not limited to the solvent and reaction conditions (e.g., reaction temperature and time), are each and independently as described above for step (vii). In some embodiments, 1 molar equivalent to about 3 molar equivalents of the boron reducing agent to Compound 5 are employed. In some embodiments, the process (viia) further comprises step (viia-a) adding aqueous sodium hydroxide to the reaction mixture of step (viia), followed by aqueous hydrogen peroxide. The amounts of the aqueous sodium hydroxide and the aqueous hydrogen peroxide for step (viia-a) are each independently as those for step (vii-a) described above.

[0151] In another embodiment, Compound 4 is prepared by a process comprising: (viib) reacting Compound 5:Compound 5 with borane-THF (BH3-THF) in a solvent to obtain Compound 4.

[0152] The details of step (viib), including but not limited to the solvent and reaction conditions (e.g., reaction temperature and time), are each and independently as described above for step (vii). In some embodiments, 1 molar equivalent to about 3 molar equivalents of the boron reducing agent to Compound 5 are employed. In some embodiments, the process (viib) further comprises step (viib-a) adding aqueous sodium hydroxide to the reaction mixture of step (viib), followed by aqueous hydrogen peroxide. The amounts of the aqueous sodium hydroxide and the aqueous hydrogen peroxide for step (viib-a) are each independently as those for step (vii-a) described above.

[0153] One aspect of the present invention provides a substantially pure Compound 4, wherein Compound 4 comprises no more than 2.0 %w / w (e.g., no more than 1.0 %w / w, no more than 0.5 %w / w, no more than 0.4 %w / w, no more than 0.3 %w / w, no more than 0.2 %w / w, or no more than 0. 1 %w / w) of any impurities. Another aspect of the present invention provides a composition comprising a substantially pure Compound 4 comprising no more than 2.0 %w / w (e.g., no more than 1.0 %w / w, no more than 0.5 %w / w, no more than 0.4 %w / w, no more than 0.3 %w / w, no more than 0.2 %w / w, or no more than 0. 1 %w / w) of any impurities.

[0154] In a further aspect of the invention provides a composition comprising 98.0 %w / w or4161828748.1greater (e.g., 99.0 %w / w or greater, 99.5 % w / w or greater, 99.6 %w / w or greater, 99.7 %w / w or greater, 99.8 %w / w or greater, or 99.9 %w / w or greater) of Compound 4. In some embodiments, the composition comprises 98.0 %w / w or greater of Compound 4. In some embodiments, the composition comprising 99.0 %w / w or greater of Compound 4. In some embodiments, the composition comprising 99.5 %w / w or greater of Compound 4. In some embodiments, the compositions comprise at least 1 kg (e.g.. at least 5 kg or at least 10 keg) of Compound 4.

[0155] In another aspect, the invention provides Compound 4 with a high selectivity (e.g., at least about 98% diastereomeric excess (de), at least about 99% de, or exclusively a single diastereomer). In yet another aspect, the invention provides a composition comprising Compound 4 with high selectivity (e.g., at least about 98% diastereomeric excess (de), at least about 99% de, or exclusively a single diastereomer).

[0156] In some embodiments, Compound 4 with such substantial purities and high selectivity7is prepared employing the processes (vii) and (viib) described above. In some embodiments, Compound 4 with such substantial purities and high selectivity is prepared employing the process (viib) described above. In some embodiments, Compound 4 with such substantial purities and high selectivity7is prepared employing the processes (vii) and (viib) described above, wherein the solvent comprises THF.

[0157] The processes comprising steps (vii) and (viib) that employ BH3-THF as the boron reagent for preparing Compound 4 involve fewer reagents and simpler processes than the processes employing 9-BBN, and advantageously afford Compound 4 substantially free (e.g., no more than 2.0 %w / w, no more than 1.0 %w / w, no more than 0.5 %w / w, no more than 0.4 %w / w, no more than 0.3 %w / w, no more than 0.2 %w / w. or no more than 0. 1 %w / w) of any impurities (e.g., Compound 5). Further, the processes (vii) and (viib) disclosed herein also advantageously afford Compound 4 with high selectivity (e.g., at least about 98% diastereomeric excess (de), at least about 99% de, at least about 99. 5% de, at least about 99.9 % de, or exclusively a single diastereomer). These processes further allow a large quantity7of Compound 4 of high purity, which may advantageously result in a high quality7of, e.g.. drug substance made via Compound 4 with fewer purification steps.

[0158] In another aspect, the invention includes a crystalline form of Compound 4, wherein the crystalline form is a methanol solvate of Compound 4. In one embodiment, the methanol solvate of Compound 4 is a mono-MeOH solvate.

[0159] In some embodiments, the methanol solvate of Compound 4 are characterized by one or more peaks corresponding to 2-theta values measured in degrees in an X-ray powder4261828748.1diffraction pattern. In one embodiment, the methanol solvate of Compound 4 characterized by one or more peaks corresponding to 2-theta values measured in degrees of 6.2 ± 0.2, 12.3 ± 0.2, 12.4 ± 0.2, 15.4 ± 0.2, and 16.3 ± 0.2 in an X-ray powder diffraction pattern. In another embodiment, the methanol solvate of Compound 4 is further characterized by one or more peaks corresponding to 2-theta values measured in degrees of 18. 1 ± 0.2, 18.2 ± 0.2, and 18.4 ± 0.2 in an X-ray powder diffraction pattern. In another embodiment, the methanol solvate of Compound 4 is further characterized by one or more peaks corresponding to 2- theta values measured in degrees of 13.4 ± 0.2, 17.4 ± 0.2, 18.7 ± 0.2, and 19.2 ± 0.2 in an X- ray powder diffraction pattern. In another embodiment, the methanol solvate of Compound 4 is further characterized by one or more peaks corresponding to 2-theta values measured in degrees of 21.8 ± 0.2 in an X-ray powder diffraction pattern.

[0160] In other embodiments, the methanol solvate of Compound 4 are characterized by a single crystal structure in an orthorhombic cry stal system. In one embodiment, the cry stal system is P2(l)2(l)2(l) space group. In another embodiment, the cry stal system is P2(l)2(l)2(l) space group with a = TA ±0.2 A, b = 9.8 ±0.2 A, c = 28.5±0.2 A, a = 90°, = 90°, / = 90°. In yet another embodiment, the cry stal system is P2(l)2(l)2(l) space group with a = 7.4 ±0.1 A, 6 = 9.8 ±0.1 A, c = 28.5±0.1 A, a = 90°, = 90°, y= 90 .

[0161] Compound 5 can be prepared by olefmation of Compound 6. In one embodiment, Compound 5 is prepared by employing a process comprising:(viii) contacting Compound 6Compound 6 with a reaction mixture comprising ethyl triphenyl phosphonium bromide, a base, and a solvent, to obtain Compound 5.

[0162] In one embodiment, the base of step (viii) comprises an alkyl lithium, a metal alkoxide, a metal amylate, a metal hydride, or a metal dialkylamide. In some embodiments, the base comprises a metal alkoxide (e.g., sodium / lithium / potassium methoxide), a metal amide (e.g., LDA, LHMDS, NaHMDS, or KHMDS), or a metal hydride (e.g., sodium / lithium / potassium hydride). In one embodiment, the base of step (viii) comprises n- butyl lithium, tert-buty l lithium, sodium or potassium methoxide, sodium or potassium4361828748.1ethoxide, sodium or potassium / c / 7-butoxide. sodium hydride, or lithium diisopropylamide. In one embodiment, the base comprises potassium / m-butoxide. In one embodiment, the base comprises tert-butyl lithium, sodium or potassium methoxide, sodium or potassium ethoxide, sodium or potassium ter t-butoxi de, sodium hydride, or lithium diisopropylamide. In one embodiment, the base comprises potassium tert-butoxide.

[0163] In one embodiment, the solvent of step (viii) is an organic solvent.

[0164] In one embodiment, the organic solvent comprises an ester (e.g., EtOAc, IPAC), a hydrocarbon (e.g., hexane, heptane, toluene), a halogenated solvent (e g., DCM, CHCh, dichloroethane, PhCFs), an alcohol (e.g., MeOH, EtOH, IPA, BuOH), an ether (e.g., THF, 2- MeTHF, CPME, MTBE, DME, dioxane), or a polar aprotic solvent (e.g., DMF. DMAc, NMP, NEP, MeCN. DMSO, sulfolane, DMPU. HMPA).

[0165] In another embodiment, the organic solvent comprises acetonitrile, dichloromethane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, hexane, heptane, cy clohexane, pyridine, or 1,4-di oxane, or any combination thereof. In another embodiment, the organic solvent comprises an ether. In yet another embodiment, the organic solvent comprises tetrahydrofuran (THF) or 2-MeTHF. In yet another embodiment, the organic solvent comprises tetrahydrofuran (THF).

[0166] In one embodiment, the reaction mixture of step (viii) is maintained at a temperature of from about 10 °C to about 30 °C. In another embodiment, the reaction mixture of step (viii) is maintained at a temperature of from about 15 °C to about 25 °C.

[0167] In some embodiments, the contacting of step (vii) comprises agitating or mixing for at least 3 hours, or at least 5 hours, or at least 8 hours. In other embodiments, the contacting of step (vii) comprises agitating or mixing for about 3 hours to about 24 hours, for about for about 3 hours to about 18 hours, for about 3 hours to about 12 hours, for about 3 hours to about 10 hours, for about 5 hours to about 24 hours, for about 5 hours to about 18 hours, for about 5 hours to about 12 hours, for about 5 hours to about 10 hours, for about 8 hours to about 24 hours, for about 8 hours to about 16 hours, for about 8 hours to about 12 hours, or for about 8 hours to about 10 hours.

[0168] In yet another embodiment, the reaction mixture of step (viii) is agitated at a temperature of from about 15 °C to about 25 °C for at least 8 hours (e.g., 8 to 10 hrs).

[0169] In one aspect, the invention includes Compound 54461828748.1Compound 5 wherein the E to Z ratio is from about 1:99 to about 10:90. In one embodiment, the E to Z ratio is from about 1:99 to about 6:94. In one embodiment, the E to Z ratio is from about 2:98 to about 6:94. And. in one embodiment, the E to Z ratio is from about 3:97 to about 5:95. In some embodiments. Compound 5 with such E to Z ratio is prepared by a process employing step (viii) as described above.

[0170] Compound 6 can be prepared by methylating Compound 7. In some embodiments, Compound 6 is prepared by a process comprising:(ix) contacting Compound 7Compound 7 with a methylating reagent in the presence of a solvent to obtain Compound 6. In some embodiments, the methylating reagent comprises a reaction mixture comprising an organoaluminum reagent and an organometallic methyl nucleophile. In certain embodiments, the organoaluminum reagent comprises a sterically hindered phenol. In one embodiment, the organoaluminum reagent comprises a sterically hindered phenol (e.g., 2.4.6-tri- / e / 7-butyl phenol or 2.6-di-to7-butyl-4-methylphenol). In another embodiment, the organoaluminum reagent comprises a bis(2.6-di- / -butyl-4-melhylphenoxide) (MAD reagent). In certain embodiments, the organometallic methyl nucleophile comprises MeMgX, wherein X is Cl, Br, or I, or MeLi. In other embodiments, the organoaluminum reagent comprises trimethyl aluminum (Me? Al).

[0171] In one embodiment, Compound 6 is prepared by a process comprising: (ixa) contacting Compound 74561828748.1with a reaction mixture comprising methyl aluminum bis(2.6-di- / m-butyl-4- methylphenoxide) (MAD reagent), methyl magnesium bromide, and a solvent, to obtain Compound 6.

[0172] In one embodiment, the MAD reagent of step (ix) or (ixa) is formed by contacting trimethyl aluminum with 2,6-di-to7-butyl-4-methylphenol (BHT) in the reaction mixture (i.e., in situ).

[0173] In one embodiment, in .s fa-formed MAD reagent is added to Compound 7 to form a mixture of MAD reagent and Compound 7, and the methyl magnesium bromide is reacted with the mixture of MAD reagent and Compound 7. In one embodiment, the methyl magnesium bromide is added to the mixture of MAD reagent and Compound 7. In one embodiment, the mixture of MAD reagent and Compound 7 is added to the methyl magnesium bromide.

[0174] In another embodiment, the solvent of step (ix) and (ixa) each independently comprises DCM. toluene, tetrahydrofuran, 2-methyltetrahydrofuran, a hexane, a heptane, 1,4- dioxane, pyridine, or cyclohexane, or any combination thereof. In another embodiment, the solvent of step (ix) and (ixa) each independently comprises DCM, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, a hexane, a heptane, 1,4-dioxane, or cyclohexane, or any combination thereof. In certain embodiments, the solvent comprises DCM, toluene, or 2- methyltetrahydrofuran, or any combination thereof. In other embodiments, the solvent comprises a mixture of toluene and 2-methyltetrahydrofuran.

[0175] In one embodiment, the process (ix) further comprises (xi) cry stallizing Compound 6 from a reaction mixture resulting from step (ix). In one embodiment, the process (ixa) further comprises (xia) crystallizing Compound 6 from a reaction mixture resulting from step (ixa). In certain embodiments, the crystallization of steps (xi) and (xia) each and independently employ a solvent comprising methyl / e / V-butyl ether and a hexane.

[0176] In another aspect, the invention provides a process for preparing Compound 6, wherein the process comprises:(ixb) contacting Compound 74661828748.1with a methylating reagent in the presence of a solvent to obtain Compound 6, wherein the methylating reagent is trimethylaluminum (AlMe?).

[0177] In some embodiments, about 3 molar equivalents to about 4 molar equivalents of trimethylaluminum (AlMes) to Compound 7 is employed in step (ixb).

[0178] In some embodiments, the solvent of step (ixb) comprises an organic solvent. In one embodiment, the organic solvent comprises ethyl acetate, isopropyl acetate, a hexane, a heptane, dichloromethane, chloroform, tetrahydrofuran. 2-methyltetrahydrofuran, acetonitrile, dimethylformamide, or toluene, or any combination thereof In another embodiment, the organic solvent comprises dichloromethane, a hexane, or a heptane, or any combination thereof. In one embodiment, the organic solvent comprises a mixture of dichloromethane, a hexane, and a heptane. In another embodiment, the organic solvent comprises a mixture of di chloromethane and a heptane. And, in one embodiment, the organic solvent comprises a mixture of di chloromethane and a heptane in a ratio of from about 5 : 1 to about 1:5 (e.g., from about 2.5: 1 to about 1:2.5, from about 1.5:1 to about 1: 1.5, or about 1: 1).

[0179] In some embodiments, the contacting step (ixb) is performed at a temperature of from about -50 °C to about 50 °C. In one embodiment, the temperature is from about -50 °C to about 0 °C. In one embodiment, the temperature is from about -40 °C to about -10 °C. In one embodiment, the temperature is from about -35 °C to about -15 °C. In one embodiment, the temperature is from about -30 °C to about -10 °C. In one embodiment, the temperature is from about -25 °C to about -15 °C.

[0180] In some embodiments, step (ixb) further comprises separating Compound 6 from the mixture resulting from the contacting Compound 7 with the trimethylaluminum in the presence of a solvent by employing a biphasic solvent system comprising water and the solvent. In one embodiment, the solvent comprises dichloromethane and a heptane. In some embodiments, the solvent comprises a 1 : 1 v / v mixture of dichloromethane and a heptane.

[0181] In some embodiments, the process (ixb) further comprises(xib) cry stallizing Compound 6 from a reaction mixture resulting from step (ixb).4761828748.1

[0182] In one embodiment, the crystallization of steps (xib) employs a solvent comprising methyl tert-butyl ether and a hexane.

[0183] Another aspect of the present invention provides a composition comprising a substantially pure Compound 6 comprising no more than 5.0 %w / w (e.g., no more than 4.0 %w / w, no more than 3.0 %w / w, no more than 2.0 %w / w, no more than 1.0 %w / w, no more than 0.5 %w / w, no more than 0.4 %w / w. no more than 0.3 %w / w. no more than 0.2 %w / w, or no more than 0. l%w / w, or no more than 0.7%w / w) of any impurities. Another aspect of the present invention provides a composition comprising a substantially pure Compound 6 comprising no more than 5.0 %w / w (e.g., no more than 4.0 %w / w, no more than 3.0 %w / w, no more than 2.0 %w / w, no more than 1.0 %w / w, no more than 0.5 %w / w, no more than 0.4 %w / w, no more than 0.3%w / w, no more than 0.2 %w / w, or no more than 0.1%w / w, or no more than 0.7 %w / w) of any impurities.

[0184] In a further aspect of the invention provides a composition comprising 95.0% w / w or greater (e.g., 98.0 %w / w or greater, 99.0% w / w or greater, 99.3 %w / w or greater, or99.7 %w / w or greater) of Compound 6. In some embodiments, the composition comprises 95.0% w / w or greater of Compound 6. In some embodiments, the composition comprising 98.0 % w / w or greater of Compound 6. In some embodiments, the composition comprising 99.0% w / w or greater of Compound 6. In some embodiments, the composition comprising 99.3% w / w or greater of Compound 6. In some embodiments, the compositions comprise at least 1 kg (e.g.. at least 5 kg or at least 10 kg) of Compound 6.

[0185] In one embodiment. Compound 6 with such substantial purities is prepared employing the process (ixb) described above.

[0186] The process (ixb) disclosed herein for preparing Compound 6 is much simpler and uses fewer reagents than, for example, the processes employing a MAD reagent like in step (ixa). Further the process (ixb) advantageously can be performed at a higher temperature than that for a process employing, e.g., MAD reagent which employs a cryogenic condition. The process (ixb) affords Compound 6 substantially free (e.g., no more than 5.0%w / w (e.g., no more than 4.0 %w / w, no more than 3.0 %w / w, no more than 2.0 %w / w, no more than 1.0 %w / w, no more than 0.5 %w / w, no more than 0.4 %w / w, no more than 0.3%w / w. no more than 0.2%w / w, or no more than 0. l%w / w, or no more than 0.7%w / w)) of any impurities (e.g., Compound 7). This process further allows a large quantity of Compound 6 of high purity, which may advantageously result in a high quality of, e.g., drug substance made via Compound 6 with less purification steps.

[0187] Compound 7 can be prepared by reducing Compound 8. In one embodiment.4861828748.1Compound 7 is prepared employing a process comprising:(xii) reducing Compound 8Compound 8 in presence of a solvent to obtain Compound 7.

[0188] In some embodiments, the reduction of process (xii) is performed in the presence of a metal catalyst and a source of hydrogen.

[0189] In some embodiments, the catalyst comprises a palladium catalyst, an iridium catalyst, a nickel catalyst, a platinum catalyst, a rhodium catalyst, or any combination thereof.

[0190] In some embodiments, the palladium catalyst comprises a palladium on carbon catalyst.

[0191] In some embodiments, the source of hydrogen comprises a silane, molecular hydrogen, or formic acid or a salt thereof. In one embodiment, the source of hydrogen comprises a silane or molecular hydrogen. In another embodiment, the source of hydrogen comprises molecular hydrogen.

[0192] In one embodiment, the solvent for process (xii) comprises an ester (e.g., EtOAc, IPAC), a hydrocarbon (e.g., hexane, heptane, toluene), an alcohol (e.g., MeOH, EtOH, IPA, BuOH), or an ether (e.g.. THF, MeTHF, CPME, MTBE. DME, dioxane). In some embodiments, the solvent comprises an ester (e.g., EtOAc, IPAC), or an alcohol (e.g., MeOH, EtOH, IPA, or BuOH). In some embodiments, the solvent comprises EtOAc, IPAC, MeOH, EtOH, IPA, BuOH, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, a hexane, a heptane, 1,4-di oxane, pyridine, or cyclohexane, or any combination thereof. In some embodiments, the solvent comprises tetrahydrofuran or 2-methyltetrahydrofuran.

[0193] In one embodiment, the process further comprises adding an acid catalyst to the reaction mixture of step (xii).

[0194] In some embodiments, the acid catalyst comprises HC1, HBr, p-toluenesulfonic acid, acetic acid, citric acid, nitric acid, or sulfuric acid. In one embodiment, the acid catalyst comprises HBr.

[0195] In some embodiments, the acid is provided in a catalytic amount.

[0196] In some embodiments, Compound 7 is prepared by a process comprising: (xiia) reducing Compound 84961828748.1Compound 8 in presence of hydrogen gas, a Pd / C catalyst, and a solvent to obtain Compound 7.

[0197] The details of step (xiia), including but not limited to the solvent and reaction conditions, are each and independently as described above for step (xii).

[0198] In another aspect, the invention includes a method of generating purified Compound1Compound 1, or a pharmaceutically acceptable salt thereof, comprising:(xiii) mixing crude Compound 1 with an organic solvent to form a mixture;(xiv) heating the mixture to dissolve the crude Compound 1; and(xv) adding a second organic solvent to the mixture to crystallize Compound 1 and obtaining the cry stallized Compound 1, wherein the cry stallized Compound 1 has an increased purity compared to the crude Compound 1. or alternatively cooling the mixture in step xiv to crystallize Compound 1 and obtaining the crystallized Compound 1. wherein the crystallized Compound 1 has an increased purity compared to the crude Compound 1.

[0199] In a further embodiment, step (xiv) comprises adding a second organic solvent to the mixture to cry stallize Compound 1 and obtaining the crystallized Compound 1, wherein the crystallized Compound 1 has an increased purity compared to the crude Compound 1.

[0200] In one embodiment, the solvent in step (xiii) comprises an ester. In a further embodiment, the ester comprises ethyl acetate.

[0201] In some embodiments, the second solvent of step (xv) comprises a hexane or a heptane. In one embodiment, the second solvent of step (xv) comprise n-heptane. In another embodiment, the volume of n-heptane added in step (xv) is about equal to the volume of the mixture in step (xiv).

[0202] The use of n-heptane in step (xv) advantageously affords purified Compound 1 in a5061828748.1higher yield as compared to other solvents, such as ethyl acetate.

[0203] In one embodiment, the process further comprises (xxx) micronizing the Compound 1 having an increased purity (e.g., using a jet mill) to produce particles of purified Compound 1 having a particle size distribution defined by a Ds>o of about 1 pm to about 100 pm. In some embodiments, Compound 1 has a particle size distribution defined by a D90 of about 1 pm to about 20 pm. In some embodiments, Compound 1 has a particle size distribution defined by a D90 of about 1 pm to about 10 pm. In some embodiments, Compound 1 has a particle size distribution defined by a D90 of about 1 pm to about 5 pm. In some embodiments, Compound 1 has a particle size distribution defined by a D90 of less than or equal to about 11 pm. The particle size distributions can be determined by any suitable method known in the art. Examples of suitable techniques include dynamic light scattering (DLS).

[0204] Another aspect of the present invention provides a process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising the steps of:(xiia) reducing Compound 8Compound 8 in presence of hydrogen gas, a Pd / C catalyst, and a solvent to obtain Compound 7Compound 7(ixa-b) contacting Compound 7 with a reaction mixture comprising methyl aluminum bis(2,6-di-Zert-butyl-4-methylphenoxide), methyl magnesium bromide, and a solvent (ixa), or5161828748.1contacting Compound 7 with trimethylaluminum (AIMes) in the presence of a solvent (ixb). to produce Compound 6Compound 6(viii) contacting Compound 6 with a reaction mixture comprising ethyl triphenyl phosphonium bromide, potassium / e / 7-butoxide. and a solvent, to produce Compound 5Compound 5(viia) reacting Compound 5 in a reaction mixture comprising 9- borabicyclo[3.3. l]nonane (9-BBN) and a solvent (viia). or reacting Compound 5 in a reaction mixture comprising BH3-THF and a solvent (viib), to obtain Compound 4;Compound 4(va) oxidizing Compound 4 in a reaction mixture comprising tetrabutyl ammonium bromide, a phosphate buffer. NaBrCh. a catalytic amount of a ruthenium reagent, an oxidizing agent, and a solvent to obtain Compound 3Compound 3(iva) contacting Compound 3 with a reaction mixture comprising molecular5261828748.1bromine and a catalytic amount of HBr to obtain Compound 2(iiic) contacting Compound 2 with 4-cyanopyrazole in a reaction mixture comprising cesium carbonate and a solvent to provide Compound 1.

[0205] The details of steps (xiia), (ixa), (ixb), (viii). (viia), (viib) (va), (iva), and (iiic) are each independently as described above for each respective step.

[0206] In some embodiments, step (ix) is step (ixa) where Compound 7 is contacted with the reaction mixture comprising methyl aluminum bis(2.6-di- / c / 7-butyl-4-methylpheno.\ide). methyl magnesium bromide to produce Compound 6.

[0207] In other embodiments, step (ix) is step (ixb) where Compound 7 is contacted with trimethylaluminum (AlMes) in the presence of a solvent, to produce Compound 6.

[0208] In some embodiments, step (vii) is step (viia) where Compound 5 is contacted with the reaction mixture comprising 9-borabicyclo[3.3.1]nonane (9-BBN) to obtain Compound 4.

[0209] In other embodiments, step (vii) is step (viib) where Compound 5 is contacted with BH3 THF to obtain Compound 4.

[0210] In yet other embodiments, step (ix) is step (ixa) where Compound 7 is contacted with the reaction mixture comprising methyl aluminum bis(2,6-di-tert-butyl-4-methylphenoxide). methyl magnesium bromide to produce Compound 6; and step (vii) is step (viia) where Compound 5 is contacted with the reaction mixture comprising 9-borabicyclo[3.3.1]nonane (9-BBN) to obtain Compound 4.

[0211] In yet other embodiments, step (ix) is step (ixb) where Compound 7 is contacted with the reaction mixture comprising methyl aluminum bis(2,6-di-te / 7-butyl-4-methylphenoxide). methyl magnesium bromide to produce Compound 6; and step (vii) is step (viib) where Compound 5 is contacted with BH3 THF to obtain Compound 4.

[0212] In yet other embodiments, step (ix) is step (ixb) where Compound 7 is contacted with trimethylaluminum (AlMes) in the presence of a solvent, to produce Compound 6; and step (vii) is step (viia) where Compound 5 is contacted with the reaction mixture comprising 9- borabicyclo[3.3.1]nonane (9-BBN) to obtain Compound 4.5361828748.1

[0213] In yet other embodiments, step (ix) is step (ixa) where Compound 7 is contacted with trimethylaluminum (AlMes) in the presence of a solvent, to produce Compound 6; and step (vii) is step (viib) where Compound 5 is contacted with BHvTHF to obtain Compound 4.

[0214] In some embodiments, the process further comprises recrystallization of Compound 1 employing a solvent system comprising ethyl acetate and a heptane (e.g., n-heptane). In one embodiment, the recrystallization comprises:(xiii-a-1) mixing crude Compound (1) with ethyl acetate at a temperature of from about 70 °C to about 77 °C to form a mixture;(xv-a-1) adding a volume of heptane to the mixture of step (xiii-a-1) while keeping the temperature of the mixture from about 70 °C to about 77 °C;(xv-d-1) slowly cooling the mixture to a temperature of from about 30 °C to about 35 °C and agitating the mixture (e.g., for from about 1 to about 24 hours) to produce a slurry comprising solid Compound 1; and(xv-e-1) obtaining the solid Compound 1 by filtration.; and

[0215] In some embodiments, the process further comprises: (xxx) micronizing Compound 1 (e.g.. using a jet mill) to produce purified Compound 1 having a particle size distribution defined by a D90 of less than about 100 pm (e.g., less than about 75 pm, less than about 50 pm, less than about 40 pm, less than about 30 pm, less than about 20 pm, or less than or equal to about 11 pm).

[0216] In another aspect, the present invention provides a process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising:(xiia) reducing Compound 8in presence of hydrogen gas, a Pd / C catalyst, and a solvent to obtain Compound 75461828748.1(ixb) contacting Compound 7 with trimethylaluminum ( AIMcs) in the presence of a solvent to obtain Compound 6Compound 6(viii) contacting Compound 6 with a reaction mixture comprising ethyl triphenyl phosphonium bromide, potassium / e / 7-butoxide, and a solvent, to produce Compound 5Compound 5(viib) reacting Compound 5 in a reaction mixture comprising borane-THF (BH3- THF) and a solvent;(viib-a) adding aqueous sodium hydroxide to the reaction mixture, followed by adding hydrogen peroxide to the reaction mixture to obtain Compound 4(va) oxidizing Compound 4 in a reaction mixture comprising tetrabutylammonium bromide, a phosphate buffer. NaBrCti. a catalytic amount of a ruthenium reagent, an oxidizing agent, and a solvent to obtain Compound 35561828748.1Compound 3(iva) contacting Compound 3 with a reaction mixture comprising molecular bromine and a catalytic amount of HBr to obtain Compound 2Compound 2(iiic) contacting Compound 2 with 4-cyanopyrazole in a reaction mixture comprising cesium carbonate and a solvent to provide Compound 1.

[0217] The details of steps (xiia), (ixb), (viii), (viib), (viib-a), (va), (iva), and (iiic) are each independently as described above for each respective step.

[0218] In some embodiments, the process further comprises recry stallization of Compound 1 employing a solvent system comprising ethyl acetate and a heptane (e.g., n-heptane). In one embodiment, the recrystallization comprises:(xiii-a-1) mixing crude Compound (1) with ethyl acetate at a temperature of from about 70 °C to about 77 °C to form a mixture;(xv-a-1) adding a volume of heptane to the mixture of step (xiii-a-1) while keeping the temperature of the mixture from about 70 °C to about 77 °C;(xv-d-1) slowly cooling the mixture to a temperature of from about 30 °C to about 35 °C and agitating the mixture (e.g., for from about 1 to about 24 hours) to produce a slurry’ comprising solid Compound 1; and(xv-e-1) obtaining the solid Compound 1 by filtration.

[0219] In some embodiments, the process further comprises: (xxx) micronizing Compound 1 (e.g., using a jet mill) to produce purified Compound 1 having a particle size distribution defined by a D90 of less than about 100 pm (e.g., less than about 75 pm, less than about 50 pm, less than about 40 pm, less than about 30 pm. less than about 20 pm. or less than or equal to about 11 pm).5661828748.1

[0220] In one aspect, the invention includes a process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising the steps of:(ivb) contacting Compound 3with molecular bromine to obtain Compound 2Compound 2; and(iiic) contacting Compound 2 with 4-cyanopyrazole or a salt thereof in the presence of a cesium carbonate base and a solvent to obtain Compound 1 or a pharmaceutically acceptable salt thereof.

[0221] The details of steps of (ivb) and (iiic) are each and independently as described above for each respective step.

[0222] In one embodiment, Compound 3 is contacted with molecular bromine in the presence of a solvent and a catalytic amount of a protic acid. In another embodiment, the protic acid is HBr. In a further embodiment, the HBr is added as an aqueous solution. In still a further embodiment, the aqueous HBr is about a 48% aqueous solution.

[0223] In one embodiment, the solvent of step (ivb) comprises an alcohol.

[0224] In a further embodiment, the solvent of step (ivb) comprises methanol, ethanol, isopropanol, or tert-butanol. In a further embodiment, the solvent of step (ivb) comprises methanol.5761828748.1

[0225] In some embodiments, the contacting of step (ivb) comprises: (ivb-a) adding the molecular bromine to a reaction mixture comprising Compound 3 over a period time sufficient to maintain the reaction mixture at a temperature of from about -25 °C to about 25 °C. In other embodiments, the contacting of step (iv) further comprises: (ivb-b) mixing (e.g., agitating) a mixture resulting from step (ivb-a) at a temperature of from about -25 °C to about 25 °C.

[0226] In some embodiments, the molecular bromine is added to a mixture of Compound 3, HBr, and methanol. In a further embodiment, the addition of the molecular bromine to the mixture of Compound 3, HBr, and methanol comprise:(ivb-a) adding at least about 1 molar equivalents of molecular bromine to a reaction mixture comprising Compound 3 over a period of time sufficient to maintain the reaction mixture at a temperature of from about -25 °C to about 25 °C (e.g., from about -10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about - 5 °C to about 5 °C); and(ivb-b) agitating a mixture resulting from step (ivb-a) for at least one hour (e.g., from 1 to 3 hrs, from 1 to 2 hrs) at a temperature of from about -25 °C to about 25 °C (e.g., from about -10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about -5 °C to about 5 °C).

[0227] In one embodiment, the molecular bromine is added in multiple portions to a mixture of Compound 3. HBr, and methanol. In one embodiment, step (ivb) optionally comprises performing steps (ivb-a) and (ivb-b) in two aliquots of at least 0.5 molar equivalents per aliquot. In a further embodiment, the addition of the molecular bromine in multiple portions to the mixture of Compound 3, HBr, and methanol comprise:(ivb-a) adding from about 0.45 to about 0.55 molar equivalents of molecular bromine to a reaction mixture comprising Compound 3 over a period of time sufficient to maintain the reaction mixture at a temperature of from about -25 °C to about 25 °C (e.g., from about - 10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about -5 °C to about 5 °C);(ivb-b) agitating a mixture resulting from step (ivb-a) for at least one hour (e.g., from 1 to 3 hrs, from 1 to 2 hrs) at a temperature of from about -25 °C to about 25 °C (e.g., from about -10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about -5 °C to about 5 °C);(ivb-c) adding from about 0.45 to about 0.55 molar equivalents of molecular bromine to a mixture resulting from step (iv-b) over a period of time sufficient to maintain the mixture5861828748.1at a temperature of from about -25 °C to about 25 °C (e.g., from about -10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about -5 °C to about 5 °C); and(ivb-d) agitating a mixture resulting from step (ivb-c) for at least one hour at a temperature of from about -25 °C to about 25 °C (e.g., from about -10 °C to about 20 °C, from about -10 °C to about 0 °C, from about -0 °C to about 20 °C, from about -5 °C to about 5 °C).

[0228] In one embodiment, the solvent of step (ivb) comprises methanol, ethanol, isopropanol, tert-butanol, or any combination thereof.

[0229] In another embodiment, the solvent of step (ivb) comprises methanol.

[0230] In one embodiment, the solvent of step (iiic) comprises an organic solvent.

[0231] In one embodiment, the organic solvent of step (iiic) comprises a ketone (e.g., MEK, MIBK), an ester (e.g., EtOAc, IPAC, or the like), a hydrocarbon (e.g., hexane, heptane, toluene, or the like), or a halogenated solvent (e.g., DCM, CHCh, dichloroethane, PhCFs, or the like), an ether (e.g., THF, MeTHF, CPME. MTBE, DME, dioxane), or any combination thereof. In some embodiments, the organic solvent comprises an ether, an ester, a hydrocarbon, or any combination thereof. In some embodiments, the organic solvent comprises an ether. In one embodiment, the solvent comprises an ester. In another embodiment, the solvent comprises ethyl acetate.

[0232] In another embodiment, the organic solvent of step (iiic) comprises acetone, ethyl acetate, isopropyl acetate, hexane, heptane, dichloromethane, chloroform, methanol, ethanol, isopropyl alcohol, a butyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethylformamide, toluene, or dimethylsulfoxide, or any combination thereof.

[0233] In a further embodiment, the organic solvent of step (iiic) comprises ethyl acetate or acetone.

[0234] In one embodiment, the contacting step (iiic) is performed at a temperature of from about 0 °C to about 80 °C. In another embodiment, the contacting step is performed at a temperature of from about 10 °C to about 60 °C. In another embodiment, the contacting step is performed at a temperature of from about 20 °C to about 50 °C. In one embodiment, the contacting step is performed at a temperature of from about 25 °C to about 45 °C. In one embodiment, the contacting step is performed at a temperature of from about 28 °C to about 45 °C (e.g.. from about 30 °C to about 40 °C).

[0235] The reaction time for step (iiic) is as described above for step (iii). In one embodiment, step (iiic) is performed under mixing for up to about 1 hour or at least about 25961828748.1hours.

[0236] In one aspect the invention includes a process of preparing Compound 1HO H Compound 1 , , or a pharmaceutically acceptable salt thereof, comprising the steps of:(v) oxidizing Compound 4Compound 4 in a reaction mixture comprising a ruthenium reagent, an oxidizing reagent, and a solvent to obtain Compound 3Compound 3(iv) contacting Compound 3 with a brominating reagent to obtainCompound 2Compound 2; and(iii) contacting Compound 2 with 4-cyanopyrazole or a salt thereof in the presence of a base and a solvent to obtain Compound 1 or a pharmaceutically acceptable salt thereof.6061828748.1

[0237] The details of step (v), (iv) and (iii) are each independently as described above for each respective step.

[0238] In one embodiment, the oxidizing agent of step (v) comprises O2, oxone, a metal bromate, a metal periodate, a metal chlorate, a metal iodate, metal dichromate, pyridinium chlorochromate, pyridinium dichromate, Dess-Martin periodinane, oxalyl chloride and DMSO, chromium(VI) oxide with pyridine in dichloromethane, or chromium trioxide in aqueous sulfuric acid. In another embodiment, the oxidizing agent comprises O2, oxone. NaIO4, NaCICh, NaIO3, or NaBrCh, KIO4, KCIO3, KIO3, or KBrO3.

[0239] In yet another embodiment, the oxidizing agent of step (v) comprises a metal bromate.

[0240] In a further embodiment, the metal bromate is an alkali metal bromate.

[0241] In still a further embodiment, the alkali metal bromate is NaBrO? or KBrCh.

[0242] In one embodiment, the reaction mixture of step (v) further comprises a ruthenium reagent.

[0243] In a further embodiment, the ruthenium reagent of step (v) comprises RuCk or any hydrate thereof, ruthenium tetroxide (RuOi), or tetrapropylammonium perruthenate (TPAP).

[0244] In yet a further embodiment, the ruthenium reagent comprises RuCh or any hydrate thereof.

[0245] In yet a further embodiment, the step (v) is as described above for step (va).

[0246] In some embodiments, the brominating reagent of step (iv) comprises molecular bromine, N-bromosuccinimide, dibromo-dimethyl-hydantoin. tribromotriazinone, dibromohydantoin, N-bromosaccharin, or tribromocyanuric acid.

[0247] In one embodiment, the contacting step (iv) comprises adding the brominating agent to a reaction mixture comprising Compound 3 over a period of time sufficient to maintain the reaction mixture at a temperature of from about -25 °C to about 25 °C.

[0248] In some embodiments, the brominating reagent of step (iv) comprises molecular bromine. In some embodiments, the details of step (iv) employing molecular bromine as the brominating reagent are as described above for step (ivb).

[0249] In another embodiments, the contacting of step (iv) employing molecular bromine are the brominating agent comprises: (iv-a) the molecular bromine is added to a reaction mixture comprising Compound 3 over a period time sufficient to maintain the reaction mixture at a temperature of from about -25 °C to about 25 °C. In other embodiments, the contacting of step (iv) employing molecular bromine are the brominating agent further comprises: (iv-b) mixing (e.g., agitating) a mixture resulting from step (iv-a) at a temperature of from about -25 °C to about 25 °C.6161828748.1

[0250] In one embodiment, step (iv) comprises adding the brominating agent (e.g., molecular bromine) at one time to a reaction mixture comprising Compound 3. In another embodiment, step (iv) comprises steps (iv-a) and (iv-b) in two aliquots of at least 0.5 molar equivalents per aliquot.

[0251] In some embodiments, in step (iv), the Compound 3 is contacted with the brominating agent in the presence of a solvent and a catalytic amount of a protic acid. In one embodiment, the protic acid comprises HBr.

[0252] In one embodiment, the Compound 3 is contacted with molecular bromine in the presence of a solvent and a catalytic amount of HBr.

[0253] In one embodiment, the solvent of step (iv) comprises an alcohol. In one embodiment, the solvent comprises methanol, ethanol, isopropanol, or / -butanol. In another embodiment, the solvent comprises methanol. In some embodiments, the molecular bromine is added to a mixture of Compound 3, HBr, and methanol.

[0254] In one embodiment, the base in step (iii) comprises a metal carbonate.

[0255] In one embodiment, the metal carbonate base comprises lithium carbonate, sodium carbonate, cesium carbonate or potassium carbonate.

[0256] In a further embodiment, the metal carbonate base is cesium carbonate or potassium carbonate.

[0257] In one embodiment, the solvent of step (iii) comprises an organic solvent.

[0258] In a further embodiment, the organic solvent comprises acetone, ethyl acetate, isopropyl acetate, hexane, heptane, dichloromethane, chloroform, methanol, ethanol, isopropyl alcohol, butanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethylformamide, toluene, or dimethylsulfoxide, or any combination thereof.

[0259] In another embodiment, the organic solvent comprises ethyl acetate or acetone.

[0260] In one embodiment, the step (iii) is performed at a temperature of from about 0 °C to about 80 °C. In a further embodiment, step (iii) is performed at a temperature of from about 30 °C to about 40 °C.

[0261] In one embodiment, step (iii) is performed under mixing for at least 1 hour.

[0262] In one aspect, the invention includes a process of preparing 4-cyanopyrazole4-cyanopyrazole or a salt thereof, comprising:(ia) contacting the 3-amino-4-cyanopyrazole with a nitrite reagent in the presence6261828748.1of a solvent to provide a first reaction mixture; and(iia) contacting the first reaction mixture of step (ia) with hypophosphorous acid (H3PO2) to provide 4-cyanopyrazole or a salt thereof.

[0263] In another aspect, the invention includes a process of preparing 4-cyanopyrazole4-cyanopyrazole or a salt thereof, comprising:(ia-1) contacting hydrazine or a hydrate thereof (e.g., hydrazine monohydrate) withCompound A:CIS 4 a||xy| optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-4 alkyl, and C1-4 haloalkyl, to provide 3-amino-4-cyanopyrazole3-amino-4-cyanopyrazole .(ia-2) contacting the 3-amino-4-cyanopyrazole with a nitrite reagent in the presence of a solvent to provide a first reaction mixture; and(iia) contacting the first reaction mixture of step (ia-2) with hypophosphorous acid (H3PO2) to provide 4-cyanopyrazole or a salt thereof

[0264] Details of steps (ia), (ia-1 ), and (iia) are each and independently as described above for each respective step.

[0265] In one embodiment, R1is C1-4 alkyl. In another embodiment, R1is methyl or ethyl. In yet another embodiment. Compound A is 2-(ethoxymethylene)malonodinitrile (EMM).

[0266] In one embodiment, the nitrite reagent comprises sodium nitrite, tert-butyl nitrite, or amyl nitrite. In a further embodiment, the nitrite reagent comprises sodium nitrite.

[0267] In one embodiment, step (ia-1) comprises contacting the hydrazine or a hydrate thereof (e.g., hydrazine monohydrate) with Compound A in the presence of a solvent.

[0268] In one embodiment, the solvent of step (ia-1) is water or an alcoholic solvent (examples provided herein).

[0269] In a further embodiment, the solvent of step (ia-2) is water.6361828748.1

[0270] In one embodiment, step (iia) comprises adding the hypophosphorous acid (H3PO2) to the first reaction mixture as an aqueous solution. In a further embodiment, the aqueous solution of hypophosphorous acid is about 50% aqueous solution.

[0271] In one embodiment, the process further comprises recrystallizing 4-cyanopyrazole. In some embodiments, 4-cyanopyrazole is recrystallized from a solvent system comprising an acetate and a heptane. In one embodiment, the acetate comprises ethyl acetate. In another embodiment, the heptane comprises n-heptane. In yet another embodiment. 4-cyanopyrazole is recrystallized from a solvent system comprising ethyl acetate and heptane.

[0272] In another aspect, the invention includes a process of preparing 4-cyanopyrazole4-cyanopyrazole or a salt thereof, comprising the steps of:O / A ' KN-J(ib) contacting Compound B, Compound B , wherein R2of Compound B is C1-4 O alkyl or phenyl, with NEh’FbO to provide lH-pyrazole-4-carboxamide,and(iib) contacting l / f-pyrazole-4-carboxamide with a dehydrating reagent in the presence of a base and a solvent to form 4-cyanopyrazole.

[0273] Details of steps (ib) and (iib) are each and independently as described above for each respective step.

[0274] In some embodiments, R2of Compound B is C1-4 alkyl. In some embodiments, R2of Compound B is methyl or ethyl. In some embodiments, Compound B is I / / -pyrazole-4- carboxylate,, where R2is ethyl.

[0275] In some embodiments, the NH^FEO of step (ib) comprises a concentration of from about 20 to about 40 % of NH3 (w / v) in water. In one embodiment, the NI E’l EO comprises a concentration of from about 20 to about 35 % of NH3 (w / v) in water. And, in one embodiment, the NHs’FhO comprises a concentration of from about 20 to about 30 % of NH3 (w / v) in water.6461828748.1

[0276] In some embodiments, about 3 volume equivalents to about 10 volume equivalents of NH3*H2O to Compound B are employed. In some embodiments, about 10 volume equivalents of NH3»H2O to Compound B is employed.

[0277] In some embodiments, the contacting step (ib) is performed at a temperature of from about 0 °C to about 200 °C. In one embodiment, the temperature is from about 0 °C to about 80 °C. In another embodiment, the temperature of is from about 10 °C to about 60 °C. In one embodiment, the temperature is from about 10 °C to about 40 °C. In one embodiment, the temperature is from about 15 °C to about 35 °C. In another embodiment, the temperature is from about 20 °C to about 30 °C. And, in one embodiment, the temperature is from about 80 °C to about 150 °C.

[0278] In some embodiments, the dehydrating reagent of step (iib) comprises POCh, SOCh. trifluoroacetic anhydride (TFAA), methyl-trimethyl-silyl-trifluoroacetamide (MSTFA), 2,2- dimethylpropanoyl chloride, oxalyl chloride, methyl N- (triethylammoniumsulfonyl)carbamate (Burgess Reagent), pyridine, or triethylamine (TEA), or any combination thereof. In some embodiments, the dehydrating reagent of step (iib) comprises POCh, SOCh, trifluoroacetic anhydride (TFAA), methyl-trimethyl-silyl- trifluoroacetamide (MSTFA), pyridine, triethylamine (TEA), or any combination thereof. In other embodiments, the dehydrating reagent of step (iib) comprises POCh, SOCh, trifluoroacetic anhydride (TFAA), pyridine, or triethylamine (TEA), or any combination thereof. In one embodiment, the dehydrating reagent comprises POCI3. In another embodiment, the dehydrating reagent comprises SOCh. In one embodiment, the dehydrating reagent comprises TFAA. In one embodiment, the dehydrating reagent comprises MSTFA. In one embodiment, the dehydrating reagent comprises 2,2-dimethylpropanoyl chloride. In one embodiment, the dehydrating reagent comprises oxalyl chloride. In one embodiment, the dehydrating reagent comprises Burgess Reagent. In one embodiment, the dehydrating reagent comprises pyridine. In one embodiment, the dehydrating reagent comprises tri ethyl amine.

[0279] In some embodiments, about 1 molar equivalent to about 5 molar equivalents of the dehydrating reagent to 17 / -pyrazole-4-carboxamide are employed.

[0280] In some embodiments, the base of step (iib) comprises an amine base. In some embodiments, the base of step (iib) comprises Et3N, pyridine, N,N-diisopropylethylamine, N- methylmorpholine, lutidine, or picoline, or any combination thereof. In one embodiment, the base comprises E N. In another embodiment, the base comprises pyridine. In another embodiment, the base comprises N,N-diisopropylethylamine. In another embodiment, the6561828748.1base is N-methylmorpholine. In another embodiment, the base comprises lutidine. In another embodiment, the base comprises picoline.

[0281] In some embodiments, step (iib) comprises contacting 17 / -pyrazole-4-carboxamide with TFAA in the presence of EhN. In other embodiments, step (iib) comprises contacting I / / -pyrazole-4-carboxamide with 2,2-dimethylpropanoyl chloride in the presence of pyridine. In yet other embodiments, step (iib) comprises contacting I H-pyrazole-4-carbo.\amide with POCh in the presence of EtsN. In yet other embodiments, step (iib) comprises contacting 177-pyrazole-4-carboxamide with POCI3 in the presence of pyridine. And, in yet other embodiments, step (iib) comprises contacting 177-pyrazole-4-carboxamide with POCh in the presence ofN,N-diisopropylethylamine.

[0282] In some embodiments of this aspect, the solvent of step (iib) comprises an organic solvent. In one embodiment, the organic solvent comprises a ketone (e.g., acetone, MEK, MIBK), an ester (e.g., EtOAc, IPAC), a hydrocarbon (e.g., hexane, heptane, toluene), a halogenated solvent (e.g., DCM, CHCh, dichloroethane, PI1CF3), , an ether (e.g., THF, MeTHF, CPME, MTBE, DME, dioxane), or a polar aprotic solvent (e.g., DMF, DMAc, NMP, NEP. MeCN. DMSO, sulfolane, DMPU. HMPA).

[0283] In one embodiment, the organic solvent of step (iib) is selected from acetone, ethyl acetate, hexane, heptane, dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, dimethylformamide, toluene, or dimethylsulfoxide, or any combination thereof. In another embodiment, the organic solvent comprises dimethylformamide, tetrahydrofuran, toluene, acetonitrile, dichloromethane, or any combination thereof. In another embodiment, the organic solvent comprises toluene.

[0284] In some embodiments, step (iib) comprises contacting 17 / -pyrazole-4-carboxamide with POCh in the presence of in the presence of a base and a solvent to form 4- cyanopyrazole, wherein the base comprises EtsN and wherein the solvent comprises toluene.

[0285] In some embodiments, the contacting step (iib) is performed at a temperature of from about 0 °C to about 150 °C. In one embodiment, the temperature is from about 15 °C to about 35 °C. In another embodiment, the temperature is from about 20 °C to about 30 °C. In one embodiment, the temperature is from about 50 °C to about 150 °C. In another embodiment, the temperature is from about 80 °C to about 120 °C. In one embodiment, the temperature is from about 60 °C to about 100 °C. And, in one embodiment, the temperature is from about 70 °C to about 90 °C.

[0286] In one embodiment, the contacting step (iib) is performed under mixing for about 1 hour to about 20 hours. In another embodiment, the contacting step (iib) is performed under6661828748.1mixing for about 4 hours to about 20 hours. In one embodiment, the contacting step (iib) is performed under mixing for about 2 hours to about 10 hours. In one embodiment, the contacting step (iib) is performed under mixing for about 4 hours to about 8 hours. In another embodiment, the contacting step (iib) is performed under mixing for about 10 hours to about 20 hours. In one embodiment, the contacting step (iib) is performed under mixing for about 10 hours to about 14 hours. And, in one embodiment, the contacting step (iib) is performed under mixing for about 14 hours to about 18 hours.

[0287] In some embodiments, step (iib) further comprises purifying 4-cyanopyrazole. In one embodiment, 4-cyanopyrazole is crystallized from a solvent dichloromethane, ethyl acetate, and / or a heptane. In another embodiment, the crystallization comprises:(iib- 1) dissolving crude 4-cyanopyrazole in amixture of dichloromethane, ethyl acetate, and heptane at a temperature of about 20 °C to about 40 °C to form a solution of 4- cyanopyrazole;(iib-2) cooling the solution of 4-cyanopyrazole to a temperature of from about -10 °C to about 10 °C; and(iib-3) collecting crystallized 4-cyanopyrazole.

[0288] One aspect of the invention provides a substantially pure 4-cyanopyrazole or a salt thereof:4-cyanopyrazole wherein the substantially pure 4-cyanopy azole comprises no more than about 1.0 %w / w of any impurities. In some embodiments, the substantially pure 4-cyanopyazole comprises no more than about 0.7 %w / w, no more than about 0.5 %w / w, no more than about 0.3 %w / w, no more than about 0.2 %w / w, no more than about 0.1 %w / w, of any impurities.

[0289] In some embodiments, the impurities comprise potentially genotoxic impurities. In such an embodiment, the process for preparing 4-cyanopyrazole advantageously provides 4- cyanopyrazole substantially free (i.e., no more than about 2,000 ppm. no more than about 1,000 ppm, no more than about 500 ppm, no more than about 200 ppm, no more than about 100 ppm, no more than about 50 ppm, no more than about 10 ppm, or no more than about 6 ppm) of potentially genotoxic impurities (e.g.. 3-amino-4-cyanopyrazole). In one embodiment, the impurities comprise 3-amino-4-cyanopyrazole6761828748.13-amino-4-cyanopyrazole

[0290] In one embodiment, the impurities comprise hydrazine. The process for preparing 4- cyanopyrazole advantageously provides 4-cyanopyrazole substantially free (i.e., no more than about 20 ppm, no more than about 10 ppm, no more than about 5 ppm, no more than about 2 ppm, or no more than about 0.4 ppm) of hydrazine.

[0291] Another aspect of the present invention provides a composition comprising such substantially pure 4-cyanopyrazole or a salt described above.

[0292] Another aspect of the present invention provides a composition comprising 99.0% w / w or greater of 4-cyanopyrazole4-cyanopyrazole

[0293] In some embodiments, the composition comprises 99.3 %w / w or greater, 99.5 %w / w or greater, 99.7 %w / w or greater, or 99.9 %w / w or greater, of 4-cyanopyazole. In some embodiments, the composition may be 99.9 % w / w, or greater of 4-cyanopyrazole. In some embodiments, the compositions comprise at least 1 kg (e.g.. at least 5 kg or at least 10 keg) of 4-cyanopyazole.

[0294] In some embodiments, such substantially pure form of 4-cyanopyrazole is prepared by a process comprising steps (ia) and (iia) described above. In some embodiments, such substantially pure form of 4-cyanopyrazole is prepared by a process comprising steps (ia- 1), (ia-2) and (iia) described above. In other embodiments, such substantially pure form of 4- cyanopyrazole is prepared by a process comprising steps (ib) and (iib) described above.

[0295] In one aspect, the invention includes a process of preparing Compound S-3bCompound S-3b or a pharmaceutically acceptable salt thereof, comprising:(S-3a) contacting Compound 26861828748.1Compound 2 with an alkali metal acetate in the presence of an organic solvent to obtain Compound S-3aCompound S-3a .anc|(S-3b) contacting Compound S-3a with a hydroxide base to obtain Compound S3- b

[0296] In some embodiments, the alkali metal acetate of step (S-3a) comprises sodium acetate or potassium acetate.

[0297] In some embodiments, the organic solvent of step (S-3a) comprises N,N- dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, or methyl tert-butyl ether, or any combination thereof.

[0298] In some embodiments, the hydroxide base of step (S-3b) comprises sodium hydroxide, calcium hydroxide, or potassium hydroxide.

[0299] In one aspect, the invention includes Compound S-3bCompound S-3b

[0300] In one aspect, the invention includes a compound of Formula (X)6961828748.1(X), or a pharmaceutically acceptable salt thereof, whereinZ1is Ci-6 alkyl optionally substituted with one or more halo, or a 6- 10 membered mono- or bi-cyclic aryl optionally substituted with alkyd (e.g., methyl) or halo.

[0301] In some embodiments, Z1is selected from unsubstituted Ci-6 alkyl, phenyl optionally substituted with one of methyl or -Br, or naphthyl optionally substituted with one of -Cl, - Br, or methyl.

[0302] In some embodiments, the compound of Formula (X) is selected from the groupthereof.

[0303] In another aspect, the invention includes a process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising:(S-3c) contacting Compound S-3bCompound S-3b with a compound of Formula (X)7061828748.1(X), or a pharmaceutically acceptable salt thereof, wherein Z1is Ci-6 alkyl optionally substituted with one or more halo, or a 6-10 membered mono- or bi-cyclic aryl optionally substituted with alkyl (e.g., methyl) or halo, in the presence of a base and an organic solvent to obtainCompound 1 or a pharmaceutically acceptable salt thereof.

[0304] In one embodiment, Z1is selected from the group consisting of unsubstituted Ci-6 alkyl, phenyl optionally substituted with one of methyl or -Br, and naphthyl optionally substituted with one of -Cl, -Br, or methyl.

[0305] In one embodiment, the compound of Formula (X) is selected from the group consisting ofthereof.

[0306] In one embodiment, the base of step (S-3c) comprises a carbonate base or an amine base (e.g., trimethylamine or DIPEA). In another embodiment, the base of step (S-3c) comprises a carbonate base.

[0307] In a further embodiment, the base of step (S-3c) comprises potassium carbonate or cesium carbonate.

[0308] In one embodiment, the organic solvent of step (S-3c) comprises acetonitrile, dichloromethane, or tetrahydrofuran, or any combination thereof.

[0309] In one embodiment, the process further comprises:(S-3a) contacting Compound 2with an alkali metal acetate in the presence of an organic solvent to obtain Compound S-3a7161828748.1(S-3b) contacting Compound S-3a with a hydroxide base to obtain Compound S3- b

[0310] In one embodiment, the alkali metal acetate of step (S-3a) comprises sodium acetate or potassium acetate.

[0311] In one embodiment, the organic solvent of step (S-3a) comprises N,N- dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, or methyl tert-butyl ether, or any combination thereof.

[0312] In one embodiment, the hydroxide base of step (S-3b) comprises sodium hydroxide, calcium hydroxide, or potassium hydroxide.

[0313] In one aspect, the invention includes a compound of Formula (X-l)or a salt thereof, whereinZ2is Ci-6 alkyl optionally substituted with 1-3 groups independently selected from halo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from halo, C1-3 alkyl, or oxo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from the group consisting of halo, C1-3 alkyl, and oxo.

[0314] In one embodiment, Z2is selected from the group consisting of unsubstituted C1-67261828748.1alky l, phenyl optionally substituted with one of methyl or -Br, naphthyl optionally substituted with one of -Cl, -Br. or methyl, cyclohexyl optionally substituted with oxo or two methyl groups, and bicycle[2.2.1]heptyl optionally substituted with oxo or two methyl groups.

[0315] In one embodiment, the compound of Formula (X-l) is selected from the group consisting of

[0316] In one aspect, the invention includes a process of preparing a compound of Formula(X-l)or a salt thereof, whereinZ2is Ci-6 alkyl optionally substituted with one or more groups (e.g., 1-3 groups)7361828748.1independently selected from halo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from halo, C1-3 alkyd, or oxo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups (e.g.. 1-3 groups) independently selected from the group consisting of halo, C1.3 alkyd, and oxo, comprising(S-4a) contacting Compound S-3bCompound S-3b with a compound of Formula (X-la)OZOZ3'S'Z2(X-la) wherein Z3is a leaving group in the presence of a nitrogen base and an organic solvent to form the compound of Formula (X-l). In one embodiment, the Z3leaving group is a halogenOZO (ZO 2 or forms an anhydride of the Formulaz 0 z. In another embodiment, Z3is selected from Cl, Br, -O-mesyl, -O-tosyl, and -O-trifluoromethyl. In a further embodiment. Z3is Cl.

[0317] The details of a compound of Formula (X-l) in the process, including but not limited to, specific examples, are as described above for the compounds of Formula (X-l).

[0318] In one embodiment, the nitrogen base of step (S-4a) comprises pyridine, lutidine, tri ethyl amine, or N,N-diisopropylethylarnine (DIPEA), or any combination thereof. In a further embodiment, the nitrogen base comprises tri ethyl amine.

[0319] In one embodiment, the organic solvent comprises a ketone (e.g., acetone, MEK,MIBK), an ester (e.g., EtOAc, IPAC), a hydrocarbon (e.g., hexane, heptane, toluene), a halogenated solvent (e.g., DCM, CHCh, dichloroethane, PI1CF3), an ether (e.g., THF,7461828748.1MeTHF, CPME, MTBE, DME, dioxane), or a polar aprotic solvent (e.g., DMF, DMAc, NMP, NEP, MeCN. DMSO, sulfolane, DMPU. HMPA).

[0320] In one embodiment, the organic solvent of step (S-4a) comprises acetonitrile, dichloromethane, tetrahydrofuran, or 2-MeTHF, or any combination thereof.

[0321] In another aspect, the invention includes a process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising(S-4b) contacting a compound of Formula (X-l)or a pharmaceutically acceptable salt thereof, whereinZ2is Ci-6 alkyl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from halo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups (e.g., 1-3 groups) independently selected from halo, C1-3 alkyl, or oxo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups (e.g., 1-3 groups)independently selected methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups (e.g. 1-3 groups) independently selected from the group consisting of halo, C1.3 alkyl, and oxo, with 4-cyanopyrazole in the presence of a base and an organic solvent to obtain Compound 1 or a pharmaceutically acceptable salt thereof.

[0322] The details of Formula (X-l) of the process, including but not limited to, specific examples, are as described above for those of the compounds of Formula (X-l).

[0323] In one embodiment, Z2is selected from the group consisting of unsubstituted C1-67561828748.1alky l, phenyl optionally substituted with one of methyl or -Br, naphthyl optionally substituted with one of -Cl, -Br. or methyl, cyclohexyl optionally substituted with oxo or two methyl groups, and bicycle[2.2.1]heptyl optionally substituted with oxo or two methyl groups.

[0324] In some embodiments, the compound of Formula (X-l) is selected from the group consisting of

[0325] In one embodiment, wherein the base of step (S-4b) comprises a carbonate base. In one embodiment, the carbonate base is an alkali metal carbonate. In one embodiment, the base of step (S-4b) comprises potassium carbonate and cesium carbonate.

[0326] In one embodiment, the process further comprises:(S-4a) contacting Compound S-3b7661828748.1Compound S-3b with a compound of Formula (X-la)Os ZOZ Z(X-la), wherein Z3is a leaving group, in the presence of a nitrogen base and an organic solvent to form the compound of Formula (X-l).

[0327] In one embodiment, the Z3leaving group is a halogen or forms an anhydride of theFormula. In another embodiment, Z3is selected from -Cl, -Br, -O-mesyl, -O-tosyl, and -O-trifluoromethyl. In a further embodiment, Z3is -Cl.

[0328] In one embodiment, the nitrogen base of step (S-4a) comprises pyridine, lutidine, tri ethyl amine, or DIPEA, or any combination thereof. In a further embodiment, the nitrogen base comprises tri ethylamine.

[0329] In one embodiment, the organic solvent comprises a ketone (e.g., acetone, MEK, MIBK), an ester (e g., EtOAc, IPAC), a hy drocarbon (e.g., hexane, heptane, toluene), a halogenated solvent (e.g., DCM. CHCL, dichloroethane, PhCF?), an ether (e.g., THF, MeTHF, CPME, MTBE, DME, dioxane), or a polar aprotic solvent (e.g., DMF, DMAc, NMP, NEP, MeCN, DMSO, sulfolane, DMPU, HMPA).

[0330] In one embodiment, the organic solvent of step (S-4a) comprises acetonitrile, dichloromethane, tetrahydrofuran, or 2-MeTHF. or any combination thereof. In one embodiment, the organic solvent of step (S-4a) comprises acetonitrile, dichloromethane, or tetrahydrofuran, or any combination thereof.

[0331] IV. GENERAL SYNTHETIC SCHEMES

[0332] One embodiment of the present invention provides a method for generating Compound 1 and pharmaceutically acceptable salts thereof according to Scheme 1 below.7761828748.1

[0334] In certain embodiments, the invention provides a method for generating Compound 1 and pharmaceutically acceptable salts thereof according to Scheme 1 above, wherein step (iii) is as described for step (iiia), (iiib), or (iiic). In certain embodiments, the invention provides a method for generating Compound 1 and pharmaceutically acceptable salts thereof according to Scheme 1 above, wherein step (iv) is as described for step (ivb). In certain embodiments, the invention provides a method for generating Compound 1 and pharmaceutically acceptable salts thereof according to Scheme 1 above, wherein step (v) is as described for step (va).

[0335] In certain embodiments, the invention provides a method for generating Compound 1 and pharmaceutically acceptable salts thereof according to Scheme 1 above, wherein step7861828748.1(vii) is as described for step (viia) or (viib). In certain further embodiments, the invention provides a method for generating Compound 1 and pharmaceutically acceptable salts thereof according to Scheme 1 above, wherein the steps of Scheme 1 are each independently as described in such certain embodiments; or wherein step (iii) is as described above for step (iiia), and the other steps are as described above in such certain embodiments; or wherein step (iii) is as described above for (iiib), and the other steps are as described above in such certain embodiments; or wherein step (iii) is as described above for step (iiic), and the other steps are as described above in such certain embodiments. In some embodiments, the invention provides a method for generating Compound 1 and pharmaceutically acceptable salts thereof according to Scheme 1 above, wherein step (ix) is as described for step (ixb). The details of such steps are each and independently as described above.

[0336] Another embodiment of the present invention provides a method of generating 4- cyanopyrazole according to Scheme 2A below.

[0337] Scheme 2A:

[0338] Another embodiment of the present invention provides a method of generating 4- cyanopyrazole according to Scheme 2B below.

[0339] Scheme 2B:O 0NH3«H2Q dehydration / ^ ,CN step(ib) N jj ^NH2step (iib) J]HN"HN

[0340] One embodiment of the present invention provides a method for generatingCompound 1 and thereof according to Scheme 3 A below.

[0341] Scheme 3A:Compound 3 Compound 27961828748.1

[0342] One embodiment of the present invention provides a method for generatingCompound 1 and pharmaceutically acceptable salts thereof according to Scheme 3B below.

[0343] Scheme 3B:

[0344] One embodiment of the present invention provides a method for generatingCompound 1 and pharmaceutically acceptable salts thereof according to Scheme 3C below.8061828748.1

[0345] Scheme 3C:

[0346] One embodiment of the present invention provides a method for generating Compound 1 and pharmaceutically acceptable salts thereof according to Scheme 3D below.

[0347] Scheme 3D:

[0348] One embodiment of the present invention provides a method for generatingCompound 1 and pharmaceutically acceptable salts thereof according to Scheme 3E below.8161828748.1

[0349] Scheme 3E:Step 2

[0350] One embodiment of the present invention provides a method for generatingCompound 1 and pharmaceutically acceptable salts thereof according to Scheme 3F below.

[0351] Scheme 3F:2 3, ,Step 2 Compound 1

[0352] One embodiment of the present invention provides a method for generatingCompound 1 and pharmaceutically acceptable salts thereof according to Scheme 3G below.8261828748.1

[0353] Scheme 3G:

[0354] One embodiment of the present invention provides a method for generatingCompound 1 and pharmaceutically acceptable salts thereof according to Scheme 3H below.

[0355] Scheme 3H:

[0356] One embodiment of the present invention provides a method for generatingCompound 1 and pharmaceutically acceptable salts thereof according to Scheme 31 below.8361828748.1

[0357] Scheme 31:Step 2

[0358] In another aspect, disclosed herein are certain exemplary Embodiments 1-202, wherein the structures of specified compounds (e.g.. Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound S-3a, Compound S-3b, Compound A, and Compound B) are as depicted above or in the Claims:1. A process of preparing Compound 1 or a pharmaceutically acceptable salt thereof, comprising:(iiic) contacting Compound 2 with 4-cyanopyrazole or a salt thereof in the presence of cesium carbonate and a solvent to form Compound 1.2. The process according to Embodiment 1, wherein the solvent comprises an organic solvent.3. The process according to Embodiment 2, wherein the organic solvent comprises acetone, ethyl acetate, isopropyl acetate, hexane, heptane, dichloromethane, chloroform, methanol, ethanol, isopropyl alcohol, a butyl alcohol, tetrahydrofuran, 2- methyltetrahydrofuran, acetonitrile, dimethylformamide, toluene, dimethylsulfoxide, or any combination thereof.4. A process of preparing Compound 1 or a pharmaceutically acceptable salt thereof, comprising:(ia) contacting 3-amino- 1 / 7-pyrazole-4-carbonilnle or a salt thereof with a nitrite8461828748.1reagent in an aqueous solvent system to form a first reaction mixture;(iia) contacting the first reaction mixture with hypophosphorous acid to form 4- cyanopyrazole or a salt thereof; and(iiia) contacting Compound 2 with 4-cyanopyrazole or a salt thereof in the presence of a base and a solvent to form Compound 1.5. The process according to Embodiment 4, wherein the nitrite reagent comprises sodium nitrite, tert-butyl nitrite, or amyl nitrite.6. The process according to Embodiment 5, wherein the nitrite reagent comprises sodium nitrite.7. The process according to any one of Embodiments 4-6, wherein the base of step (iiia) comprises a carbonate base or an alkylamine base.8. The process according to any one of Embodiments 4-7, wherein the base of step (iiia) comprises a metal carbonate base.9. The process according to Embodiment 8, wherein the metal carbonate base of step (iiia) comprises lithium carbonate, sodium carbonate, potassium carbonate, or cesium carbonate.10. The process according to any one of Embodiments 4-9, wherein the solvent of step (iiia) comprises an organic solvent.11. The process according to Embodiment 10, wherein the organic solvent comprises acetone, ethyl acetate, isopropyl acetate, hexane, heptane, dichloromethane, chloroform, methanol, ethanol, isopropyl alcohol, a butyl alcohol, tetrahydrofuran, 2- methyltetrahydrofuran, acetonitrile, dimethylformamide, toluene, dimethylsulfoxide, or any combination thereof.12. A process of preparing Compound 1 or a pharmaceutically acceptable salt thereof, comprising:(ib) contacting Compound B, wherein R2of Compound B is Ci-4 alkyl or phenyl, with NH3*H2O to form 177-pyrazole-4-carboxamide;(iib) contacting 177-py razole-4-carboxamide with a dehydrating reagent in the presence of a base and a solvent to form 4-cyanopyrazole; and(iiib) contacting Compound 2 with 4-cyanopyrazole in the presence of a base and a solvent to form Compound 1.13. The process according to Embodiment 12, wherein R2of Compound B is Ci-4 alkyl.14. The process according to Embodiment 12, wherein Compound B is I H-py razole-4-8561828748.1carboxylate,15. The process according to any one of Embodiments 12-14, wherein Compound B is contacted with NEE’EEO in a reaction mixture comprising a concentration of about 20 % to about 40 % of NH3(w / v) in water.16. The process according to any one of Embodiments 12-15. wherein about 3 volume equivalents to about 10 volume equivalents of NEE’EBO to Compound B are employed.17. The process according to any one of Embodiments 12-16, wherein the dehydrating reagent of step (iib) comprises POCh, SOCh, trifluoroacetic anhydride (TFAA), methyl- trimethyl-silyl-trifluoroacetamide (MSTFA), 2,2-dimethylpropanoyl chloride, oxalyl chloride, methyl N-(triethylammoniumsulfonyl)carbamate (Burgess Reagent), pyridine, or tri ethylamine (TEA), or any combination thereof.18. The process according to Embodiment 17, wherein the dehydrating reagent of step (iib) comprises POCI3.19. The process according to any one of Embodiments 12-18. wherein about 1 molar equivalent to about 5 molar equivalents of the dehydrating reagent to l / f-pyrazole-4- carboxamide are employed.20. The process according to any one of Embodiments 12-19, wherein the base of step (iib) comprises EtsN, pyridine. N,N-diisopropylethylamine, N-methylmorpholine, lutidine. or picoline, or any combination thereof.21. The process according to any one of Embodiments 1-20, further comprising(iv) contacting Compound 3 with a brominating reagent to obtain Compound 2.22. The process according to Embodiment 21, wherein the brominating reagent of step (iv) comprises molecular bromine. N-bromosuccinimide, dibromo-dimethyl-hydantoin, tribromotriazinone, dibromohydantoin, N-bromosaccharin, or tri bromocyanuric acid.23. The process according to Embodiment 22, wherein Compound 3 is contacted with the brominating reagent in the presence of a solvent and a catalytic amount of a protic acid.24. The process according to Embodiment 23, wherein the protic acid comprises HBr.25. The process according to any one of Embodiments 23-24, wherein the solvent comprises an alcohol.26. The process according to Embodiment 25, wherein the solvent comprises an alcohol.27. The process according to Embodiment 25, wherein the solvent comprises methanol, ethanol, isopropanol, or tert-butanol, or any combination thereof.8661828748.128. The process according to any one of Embodiments 21-27, wherein the process further comprises (v) oxidizing Compound 4 in a reaction mixture comprising a ruthenium reagent, an oxidizing reagent, and a solvent, to obtain Compound 3.29. The process according to Embodiment 28, wherein the solvent of step (v) comprises a mixture of an organic solvent and water.30. The process according to Embodiment 29, wherein the organic solvent comprises methyl tert-butyl ether, ethyl acetate, isopropyl acetate, diethyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-buty l ether, dimethyl ether, toluene, hexane, heptane, or any combination thereof.31. The process according to any one of Embodiments 28-30, wherein the ruthenium reagent comprises RuCh or any hydrate thereof, ruthenium tetroxide, or tetrapropylammonium perruthenate (TPAP).32. The process according to Embodiment 31, wherein the ruthenium reagent comprises RuCh or any hydrate thereof.33. The process according to any one of Embodiments 28-32, wherein the ruthenium reagent is present in a catalytic amount in the reaction mixture of step (v).34. The process according to any one of Embodiments 28-33, wherein the reaction mixture of step (v) further comprises a phase transfer catalyst and a buffer.35. The process according to Embodiment 34, wherein the phase transfer catalyst comprises a quaternary ammonium ion.36. The process according to Embodiment 35, wherein the phase transfer catalyst comprises tetrabutylammonium bromide.37. The process according to any one of Embodiments 34-36, wherein the buffer is a phosphate buffer.38. The process according to any one of Embodiments 28-37, wherein the oxidizing reagent comprises O2, oxone, a metal bromate, a metal periodate, a metal chlorate, a metal iodate, metal dichromate, pyridinium chlorochromate, pyridinium dichromate, Dess-Martin periodinane, oxalyl chloride and DMSO, chromium(VI) oxide with pyridine in dichloromethane, or chromium trioxide in aqueous sulfuric acid.39. The process according to Embodiment 38, wherein the oxidizing reagent comprises O2, oxone, a metal bromate, a metal periodate, a metal chlorate, a metal iodate, or a metal dichromate.40. The process according to Embodiment 39, wherein the oxidizing reagent comprises a metal bromate.8761828748.141. The process according to Embodiment 39, wherein the oxidizing reagent comprises NaIO4, NaClOs, NaIO3, NaBrCh, KIO4, KCIO3, KIO3, or KBrOs.42. The process according to Embodiment 41, wherein the oxidizing reagent comprises NaBrCh or KBrO3.43. The process according to any one of Embodiments 28-42, further comprising:(vi) crystallizing Compound 3 from a reaction mixture resulting from step (v).44. The process according to any one of Embodiments 28-43. wherein the process further comprises:(vii) contacting Compound 5 with a reaction mixture comprising a boron reducing agent and a solvent, to obtain Compound 4.45. The process according to Embodiment 44. wherein the boron reducing agent of step (vii) comprises 9-borabicyclo[3.3.1]nonane (9-BBN), THF-BH3, pinacolborane, thexyl-BEE, disiamylborane, catecholborane, borane-DMS (dimethylsulfide), BH3»Me2S, BF3»Et2O, NaBH, or any combination thereof.46. The process according to Embodiment 44 or 45, wherein the solvent of step (vii) comprises an organic solvent.47. The process according to Embodiment 46, wherein the organic solvent comprises hexane, heptane, toluene, dichloromethane, CHCI3, dichloroethane, PhCFs. tetrahydrofuran, 2-MeTHF, cyclopentyl methyl ether, methyl tert-butyl ether, dimethyl ether, dioxane, or any combination thereof.48. The process according to any one of Embodiments 44-47, further comprising: (vii-a) adding aqueous sodium hydroxide to the reaction mixture of step (vii), followed by aqueous hydrogen peroxide.49. The process according to any one of Embodiments 44-48, further comprising:(viii) contacting Compound 6 with a reaction mixture comprising ethyl triphenyl phosphonium bromide, a base, and a solvent, to obtain Compound 5.50. The process according to Embodiment 49, wherein the base of step (viii) comprises an alky l lithium, a metal alkoxide, a metal amylate, a metal hydride, or a metal dialkylamide.51. The process according to Embodiment 50. wherein the base of step (viii) comprises n- butyl lithium, / -but l lithium, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride, sodium amylate, potassium amylate, lithium amylate, or lithium diisopropylamide.52. The process according to any one of Embodiments 49-51, wherein the solvent of step8861828748.1(viii) comprises an organic solvent.53. The process according to Embodiment 52, wherein the organic solvent comprises acetonitrile, dichloromethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, 2-MeTHF, hexane, heptane, cyclohexane, pyridine, 1,4-di oxane, or any combination thereof.54. The process according to any one of Embodiments 49-53, wherein the process further comprises:(ixa) contacting Compound 7 with a reaction mixture comprising methyl aluminum bis(2.6-di- / c / 7-butyl-4-methylphenoxide) (MAD reagent), methyl magnesium bromide, and a solvent, to obtain Compound 6.55. The process according to Embodiment 54. wherein the MAD reagent is formed in situ by contacting trimethylaluminum with 2,6-di-ter / -butyl-4-methylphenol (BHT).56. The process according to Embodiment 55, wherein Compound 7 is added to the in situ formed MAD reagent to form a mixture of MAD reagent and Compound 7, and the methyl magnesium bromide is reacted with the mixture of MAD reagent and Compound 7.57. The process according to any one of Embodiments 54-56. wherein the solvent of step(ixa) comprises dichloromethane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, hexane, heptane, 1,4-di oxane, or cyclohexane, or any combination thereof.58. The process according to any one of Embodiments 54-57, further comprising:(xia) crystallizing Compound 6 from a reaction mixture resulting from step (ixa).59. The process according to any one of Embodiments 54-58, further comprising:(ixb) contacting Compound 7 with a methylating reagent in the presence of a solvent to obtain Compound 6, wherein the methylating reagent is trimethylaluminum (AlMe?).60. The process according to Embodiment 59, wherein about 3 molar equivalents to about 4 molar equivalents of trimethyl aluminum (AIMe?) to Compound 6 is employed in step(ixb).61. The process according to Embodiment 59 or 60, wherein the solvent of step (ixb) comprises an organic solvent.62. The process of Embodiment 61, wherein the solvent of step (I-ix) comprises ethyl acetate, isopropyl acetate, a hexane, a heptane, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethy lformamide, or toluene, or any combination thereof.63. The process of any one of Embodiments 59-62, wherein the solvent of step (I-ix)8961828748.1comprises dichloromethane, a hexane, or a heptane, or any combination thereof.64. The process according to any one of Embodiments 59-63, further comprising:(xii) reducing Compound 8 in presence of a solvent to obtain Compound 7.65. The process according to Embodiment 64, wherein the reduction of step (xii) is performed in the presence of a metal catalyst and a source of hydrogen.66. The process according to Embodiment 65, wherein the metal catalyst comprises a palladium on carbon catalyst, an iridium catalyst, a nickel catalyst, a platinum catalyst, or a rhodium catalyst, or any combination thereof.67. The process according to Embodiment 65 or 66, wherein the source of hydrogen is molecular hydrogen.68. The process according to any one of Embodiments 64-67, wherein the solvent of step (xii) comprises ethyl acetate, isopropyl acetate, methanol, ethanol, isopropyl alcohol, a butyl alcohol, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, hexane, heptane, 1,4-di oxane, pyridine, cyclohexane, or a combination thereof.69. The process according to any one of Embodiments 64-68, further comprising adding an acid to the reaction mixture resulting from step (xii).70. The process according to Embodiment 69, wherein the acid comprises HC1, HBr. / ?- toluenesulfonic acid, acetic acid, citric acid, nitric acid, or sulfuric acid.71. The process according to Embodiment 69 or 70, wherein the acid is provided in a catalytic amount.72. A process of preparing Compound 1 or a pharmaceutically acceptable salt thereof, comprising the steps of:(ivb) contacting Compound 3 with molecular bromine to obtain Compound 2; and (iiic) contacting Compound 2 with 4-cyanopyrazole or a salt thereof in the presence of a cesium carbonate base and a solvent to obtain Compound 1 or a pharmaceutically acceptable salt thereof.73. The process according to Embodiment 72, wherein the Compound 3 is contacted with molecular bromine in the presence of a solvent and a catalytic amount of a protic acid.74. The process according to Embodiment 73. wherein the protic acid is HBr.75. The process according to any one of Embodiments 72-74, wherein the solvent of step (iv) comprises an alcohol.76. The process according to Embodiment 75, wherein the solvent of step (iv) comprises methanol, ethanol, isopropanol, or tert-butanol.77. The process according to any one of Embodiments 72-76, wherein the solvent of step9061828748.1(iiic) comprises an organic solvent.78. The process according to Embodiment 77, wherein the organic solvent comprises acetone, ethyl acetate, isopropyl acetate, hexane, heptane, dichloromethane, chloroform, methanol, ethanol, isopropyl alcohol, a butyl alcohol, tetrahydrofuran, 2- methyltetrahydrofuran, acetonitrile, dimethylformamide, toluene, dimethylsulfoxide, or any combination thereof.79. The process according to any one of Embodiments 72-78. wherein the contacting of step (iv) comprises adding molecular bromine to a reaction mixture comprising Compound 3 over a period of time sufficient to maintain the reaction mixture at a temperature of from about -25 °C to about 25 °C.80. A process of preparing Compound 1 or a pharmaceutically acceptable salt thereof, comprising:(v) oxidizing Compound 4 in a reaction mixture comprising a ruthenium reagent, an oxidizing reagent, and a solvent to obtain Compound 3;(iv) contacting Compound 3 with a brominating reagent to obtainCompound 2; and(iii) contacting Compound 2 with 4-cyanopyrazole or a salt thereof in the presence of a base and a solvent to obtain Compound 1.81. The process according to Embodiment 80, wherein the oxidizing reagent of step (v) comprises O2, oxone, a metal bromate, a metal periodate, a metal chlorate, a metal iodate, metal dichromate, pyridinium chlorochromate, pyridinium dichromate, Dess-Martin periodinane, oxalyl chloride and DMSO, chromium (VI) oxide with pyridine in dichloromethane, or chromium trioxide in aqueous sulfuric acid.82. The process according to Embodiment 81, wherein the oxidizing reagent of step (v) comprises O2, oxone, a metal bromate, a metal periodate, a metal chlorate, or a metal iodate.83. The process according to Embodiment 82, wherein the oxidizing reagent comprises a metal bromate.84. The process according to Embodiment 82, wherein the oxidizing reagent of step (v) comprises NaIO4, NaClCty NaIO3. or NaBrCh, KIO4, KCIO3, KIO3. or KBrO3.85. The process according to Embodiment 84, wherein the oxidizing reagent of step (v) comprises NaBrOs or KBrOs.86. The process according to any one of Embodiments 80-85, wherein the ruthenium reagent comprises RuCh or any hydrate thereof, ruthenium tetroxide, or tetrapropylammonium perruthenate (TPAP).9161828748.187. The process according to Embodiment 86, wherein the ruthenium reagent comprises RuCh or any hydrate thereof.88. The process according to any one of Embodiments 80-87, wherein the brominating reagent of step (iv) comprises molecular bromine, N-bromosuccinimide, dibromo-dimethyl- hydantoin, tribromotri azinone, dibromohydantoin, N-bromosaccharin, or tribromocyanuric acid.89. The process according to any one of Embodiments 80-88. wherein in step (iv) the Compound 3 is contacted with the brominating agent in the presence of a solvent and a catalytic amount of a protic acid.90. The process according to Embodiment 89, wherein the protic acid is HBr.91. The process according to any one of Embodiments 80-90, wherein the brominating agent is molecular bromine.92. The process according to any one of Embodiments 89-91, wherein the solvent of step (iv) comprises an alcohol.93. The process according to Embodiment 92, wherein the solvent of step (iv) comprises methanol, ethanol, isopropanol, or tert-butanol.94. The process according to any one of Embodiments 80-93, wherein the contacting of step (iv) comprises adding the brominating agent to a reaction mixture comprising Compound 3 over a period of time sufficient to maintain the reaction mixture at a temperature of from about -25 °C to about 25 °C.95. The process according to any one of Embodiments 80-94, wherein the base in step (iii) comprises a metal carbonate.96. The process according to Embodiment 95, wherein the metal carbonate base is lithium carbonate, sodium carbonate, cesium carbonate or potassium carbonate.97. The process according to any one of Embodiments 80-96, wherein the solvent of step (iii) comprises acetone, ethyl acetate, isopropyl acetate, hexane, heptane, dichloromethane, chloroform, methanol, ethanol, isopropyl alcohol, butanol, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, dimethylformamide, toluene, dimethylsulfoxide, or any combination thereof.98. A process of preparing Compound 1 or a pharmaceutically acceptable salt thereof, comprising:(xiia) reducing Compound 8 in presence of hydrogen gas, a Pd / C catalyst, and a solvent to obtain Compound 7; and(ix) contacting Compound 7 with a reaction mixture comprising methyl aluminum9261828748.1bis(2.6-di- / c / 7-butyl-4-methylphenoxide). methyl magnesium bromide, and a solvent (ixa), or contacting Compound 7 with a methylating agent in the presence of a solvent, to produce Compound 6 (ixb), wherein the methylating agent is trimethylaluminum (AIMe-)i(viii) contacting Compound 6 with a reaction mixture comprising ethyl triphenyl phosphonium bromide, potassium / -butoxide. and a solvent, to produce Compound 5;(viia) reacting Compound 5 in a reaction mixture comprising 9- borabicyclo[3.3. l]nonane (9-BBN) and a solvent (viia). or reacting Compound 5 in a reaction mixture comprising BH3-THF and a solvent (viib), to obtain Compound 4;(va) oxidizing Compound 4 in a reaction mixture comprising tetrabutylammonium bromide, a phosphate buffer, NaBrOs. a catalytic amount of a ruthenium reagent, an oxidizing reagent, and a solvent to obtain Compound 3:(iva) contacting Compound 3 with a reaction mixture comprising molecular bromine and a catalytic amount of HBr to obtain Compound 2;(iiic) contacting Compound 2 with 4-cyanopyrazole in a reaction mixture comprising cesium carbonate and a solvent to provide Compound 1.99. The process of Embodiment 98, wherein Compound 7 is contacted with the reaction mixture comprising methyl aluminum bis(2,6-di-te / 7-butyl-4-methylphenoxide), methyl magnesium bromide to produce Compound 6.100. The process of Embodiment 99, wherein Compound 5 is contacted with the reaction mixture comprising 9-borabicyclo[3.3.1]nonane (9-BBN) to obtain Compound 4.101. The process of Embodiment 99, wherein Compound 5 is contacted with BEE THF to obtain Compound 4.102. The process of Embodiment 98, wherein Compound 7 is contacted with trimethylaluminum (AlMes) in the presence of a solvent, to produce Compound 6.103. The process of Embodiment 102, wherein Compound 5 is contacted with the reaction mixture comprising 9-borabicyclo[3.3.1]nonane (9-BBN) to obtain Compound 4.104. The process of Embodiment 102, wherein Compound 5 is contacted with BH3-THF to obtain Compound 4.105. The process of any one of Embodiments 98-104. further comprising crystallizing Compound 1 in ethyl acetate.106. A process of preparing 4-cyanopyrazole or a salt thereof, comprising the steps of: (ia-1) contacting hydrazine or a hydrate thereof with Compound A, wherein R1isC1-4 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-4 alkyl, and C1-4 haloalkyl, to provide 3-amino-4-9361828748.1cyanopyrazole;(ia-2) contacting the 3-amino-4-cyanopyrazole with a nitrite reagent in the presence of a solvent to provide a first reaction mixture; and(iia) contacting the first reaction mixture of step (ia-2) with hypophosphorous acid (H3PO2) to provide 4-cyanopyrazole or a salt thereof.107. The process according to Embodiment 106, wherein R1is methyl or ethyl.108. The process according to Embodiment 106, wherein Compound A is 2- (ethoxymethylene)malonodinitrile (EMM).109. The process according to any one of Embodiments 106-108, wherein step (ia-1) comprises contacting the hydrazine with Compound A in the presence of a solvent.110. The process according to Embodiment 109, wherein the solvent of step (ia-1) comprises water and / or an alcoholic solvent.111. The process according to any one of Embodiments 106-110, wherein the solvent of step (ia-2) comprises w ater.112. The process according to any one of Embodiments 106-111, wherein step (iia-1) comprises adding the hypophosphorous acid (H3PO2) to the first reaction mixture as an aqueous solution.113. A process of preparing 4-cyanopyrazole or a salt thereof, comprising:(ib) contacting Compound B, wherein R2is C1-4 alkyl or phenyl, with NHs’FhO to provide lH-pyrazole-4-carboxamide; and(iib) contacting l / ¥-pyrazole-4-carboxamide with a dehydrating reagent in the presence of a base and a solvent to form 4-cyanopyrazole.114. The process according to Embodiment 113, wherein the NEh’EEO of step (ib) comprises a concentration of from about 20 to about 40 % of NH3 (w / v) in water.115. The process according to Embodiment 113 or 114, wherein the dehydrating reagent of step (iib) comprises POCI3, SOCh, trifluoroacetic anhydride (TFAA), methyl-trimethyl- silyl-trifluoroacetamide (MSTFA), 2,2-dimethylpropanoyl chloride, oxalyl chloride, methyl N-(triethylammoniumsulfonyl)carbamate (Burgess Reagent), pyridine, or triethylamine (TEA), or any combination thereof.116. The process according to Embodiment 115, wherein the dehydrating reagent of step (iib) comprises POCI3 or pyridine, or any combination thereof.117. The process according to Embodiment 115, wherein the dehydrating reagent of step (iib) comprises POCI3.118. The process according to any one of Embodiments 113-117, wherein the base of step9461828748.1(iib) comprises EtsN, pyridine, N,N-diisopropylethylamine, N-methylpiperidine, N- methylmorpholine. lutidine, or picoline, or any combination thereof.119. The process according to any one of Embodiments 113-118, wherein R2is methyl or ethyl.120. The process according to any one of Embodiments 113-119, wherein Compound B0 is 17 / -pyrazole-4-carboxylate,121. A process of preparing Compound S-3b or a pharmaceutically acceptable salt thereof, comprising:(S-3a) contacting Compound 2 with an alkali metal acetate in the presence of an organic solvent to obtain Compound S-3a; and(S-3b) contacting Compound S-3a with a hydroxide base to obtain Compound S3- b122. The process according to Embodiment 121, wherein the alkali metal acetate of step (S-3a) comprises sodium acetate or potassium acetate.123. The process according to Embodiment 121 or 122, wherein the organic solvent of step (S-3a) comprises N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, or methyl tert-buty l ether, or any combination thereof.124. The process according to any one of Embodiments 121-123, wherein the hydroxide base of step (S -3b) comprises sodium hydroxide, calcium hydroxide, or potassium hydroxide.125. A process of preparing Compound 1 or a pharmaceutically acceptable salt thereof, comprising:(S-3c) contacting Compound S-3b with a compound of Formula (X)(X), or a pharmaceutically acceptable salt thereof, wherein Z1is Ci-6 alkyl optionally substituted with one or more halo, or a 6-10 membered mono- or bi-cyclic aryl optionally substituted with methyl or halo, in the presence of a base and an organic solvent to obtain Compound 1 or a pharmaceutically acceptable salt thereof.126. The process according to Embodiment 125, wherein Z1is selected from the group9561828748.1consisting of unsubstituted C 1-6 alkyl, phenyl optionally substituted with one of methyl or - Br, and naphthyl optionally substituted with one of -Cl. -Br, or methyl.127. The process according to Embodiment 125 or 126, wherein the base of step (S-3c) comprises a carbonate base.128. The process according to any one of Embodiments 125-127, wherein the organic solvent of step (S-3c) comprises acetonitrile, dichloromethane, or tetrahydrofuran, or any combination thereof.129. The process according to any one of Embodiments 125-128, further comprising: (S-3a) contacting Compound 2 with an alkali metal acetate in the presence of an organic solvent to obtain Compound S-3a; and(S-3b) contacting Compound S-3a with a hydroxide base to obtain Compound S3- b130. The process according to Embodiment 129, wherein the alkali metal acetate of step (S-3a) comprises sodium acetate or potassium acetate.131. The process according to Embodiment 129 or 130, wherein the organic solvent of step (S-3a) comprises N.N-dimethylformamide. dimethyl sulfoxide, tetrahydrofuran. or methyl tert-butyl ether, or any combination thereof.132. The process according to any one of Embodiments 129-131, wherein the hydroxide base of step (S-3b) comprises sodium hydroxide, calcium hydroxide, or potassium hydroxide.133. A compound of Formula (X-l)or a salt thereof, whereinZ2is Ci-6 alkyl optionally substituted with one or more groups independently selected from halo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups independently selected from methyl, halo, or oxo, or a 3-8 membered mono- or bicyclic cycloalkyl optionally substituted with one or more groups independently selected from halo, Ci-? alkyl, or oxo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups independently selected methyl, halo, or oxo, or a 3-8 membered mono- or9661828748.1bi-cyclic cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of halo, C1-3 alkyl, and oxo.134. The compound or salt of Embodiment 133, wherein Z2is selected from the group consisting of unsubstituted C1-6 alkyl, phenyl optionally substituted with one of methyl or - Br, naphthyl optionally substituted with one of -Cl, -Br, or methyl, cyclohexyl optionally substituted with oxo or two methyl groups, and bicycle[2.2.1]heptyl optionally substituted with oxo or two methyl groups.135. The compound or salt of Embodiment 133, wherein the compound of Formula (X-l)136. A process of preparing a compound of Formula (X-l)9761828748.1(X-1), or a salt thereof, whereinZ2is Ci-6 alkyl optionally substituted with one or more groups independently selected from halo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups independently selected from methyl, halo, or oxo, or a 3-8 membered mono- or bicyclic cycloalkyl optionally substituted with one or more groups independently selected from halo. Ci-? alkyl, or oxo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups independently selected methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of halo, C1-3 alkyl, and oxo. comprising:(S-4a) contacting Compound S-3b with a compound of Formula (X-la)OZO z3z2(X-la) wherein Z3is a leaving group in the presence of a nitrogen base and an organic solvent to form the compound of Formula (X-1).137. The process according to Embodiment 136, wherein the nitrogen base of step (S-4a) comprises pyridine, lutidine, triethylamine, or bfN-diisopropylethylamine (DIPEA), or any combination thereof.138. The process according to Embodiment 136 or 137, wherein the organic solvent of step (S-4a) comprises acetonitrile, dichloromethane, tetrahydrofuran, or 2-MeTHF, or any combination thereof.139. A process of preparing Compound 1 or a pharmaceutically acceptable salt thereof, comprising:(S-4b) contacting a compound of Formula (X-1)or a pharmaceutically acceptable salt thereof, whereinZ2is C1-6 alkyl optionally substituted with one or more groups independently selected9861828748.1from halo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups independently selected from methyl, halo, or oxo, or a 3-8 membered mono- or bicyclic cycloalkyl optionally substituted with one or more groups independently selected from halo, Ci-3 alkyl, or oxo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with 1-3 groups independently selected methyl, halo, or oxo, or a 3-8 membered mono- or bicyclic cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of halo. C1-3 alkyl, and oxo, with 4-cyanopyrazole in the presence of a base and an organic solvent to obtainCompound 1.140. The process according to Embodiment 139, wherein Z2is selected from the group consisting of unsubstituted C1-6 alkyl; phenyl optionally substituted with one of methyl or - Br; naphthyl optionally substituted with one of -Cl, -Br, or methyl; cyclohexyl optionally substituted with oxo or two methyl groups; and bicycle[2.2.1]heptyl optionally substituted with oxo or two methyl groups.141. The process according to Embodiment 139 or 140, wherein the compound ofFormula (X-l) is9961828748.1142. The process according to any one of Embodiments 139-141, wherein the base of step (S-4b) comprises a metal carbonate base.143. The process according to Embodiment 142, wherein the base of step (S-4b) comprises potassium carbonate or cesium carbonate.144. The process according to any one of Embodiments 141-143, further comprising:(S-4a) contacting Compound S-3b with a compound of Formula (X-la)Os ZO z3z2(X-la) wherein Z3is a leaving group in the presence of a nitrogen base and an organic solvent to form the compound of Formula (X-l).145. The process of Embodiment 144, wherein the nitrogen base of step (S-4a) comprises pyridine, lutidine, DIPEA, or triethylamine.146. The process of Embodiment 144 or 145, wherein the organic solvent of step (S-4a) comprises acetonitrile, dichloromethane, tetrahydrofuran. or any combination thereof.147. A process of preparing Compound 3, comprising:(v) oxidizing Compound 4 in a reaction mixture comprising a catalytic amount of a ruthenium reagent, an oxidizing reagent, and a solvent to obtain Compound 3.148. The process according to Embodiment 147, wherein the solvent of step (v) comprises a mixture of an organic solvent and water.149. The process according to Embodiment 148, wherein the organic solvent comprises methyl tert-buty l ether, ethyl acetate, isopropyl acetate, diethyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-buty l ether, dimethyl ether, toluene, hexane, heptane, or any combination thereof.150. The process according to any one of Embodiments 147-149, wherein the ruthenium reagent comprises RuCh or any hydrate thereof, ruthenium tetroxide, or tetrapropylammonium perruthenate (TPAP).151. The process according to Embodiment 150, wherein the ruthenium reagent comprises RuCE or any hydrate thereof.152. The process according to any one of Embodiments 147-151, wherein the ruthenium reagent is present in a catalytic amount in the reaction mixture of step (v).153. The process of any one of Embodiments 147-151, wherein the reaction mixture of step (v) further comprises a phase transfer agent and a buffer.154. The process of Embodiment 153, wherein the phase transfer agent comprises a10061828748.1quaternary ammonium ion and the buffer comprises a phosphate buffer.155. The process of Embodiment 154, wherein the phase transfer agent comprises tetrabutylammonium bromide.156. The process according to any one of Embodiments 147-155, wherein the oxidizing reagent of step (v) comprises O2, oxone, a metal bromate, a metal periodate, a metal chlorate, a metal iodate, metal dichromate, pyridinium chlorochromate, pyridinium dichromate, Dess- Martin periodinane, oxalyl chloride and DMSO. chromium(VI) oxide with pyridine in di chloromethane, or chromium trioxide in aqueous sulfuric acid.157. The process according to Embodiment 156, wherein the oxidizing reagent comprises O2, oxone, a metal bromate, a metal periodate, a metal chlorate, a metal iodate, or metal dichromate.158. The process according to Embodiment 157, wherein the oxidizing reagent comprises a metal bromate.159. The process according to Embodiment 157, wherein the oxidizing reagent comprises NaIO4, NaClOs, NaIO3, NaBrO3, KIO4, KC1O3, KIO3, or KBrO3.160. The process according to Embodiment 159, wherein the oxidizing agent comprises NaBrO3or KBrO3.161. A process of preparing Compound 6, comprising contacting Compound 7 with a methylating agent in the presence of a solvent to obtain Compound 6, wherein the methylating agent is trimethylaluminum (AlMe3).162. The process according to Embodiment 161, wherein about 3 molar equivalents to about 4 molar equivalents of trimethylaluminum (AlMe3) to Compound 7 is employed.163. The process according to Embodiment 161 or 162, wherein the solvent comprises an organic solvent.164. The process according to Embodiment 163, wherein the solvent comprises ethyl acetate, isopropyl acetate, hexane, heptane, dichloromethane, chloroform, tetrahydrofuran, 2- methyltetrahydrofuran, acetonitrile, dimethylformamide, or toluene, or any combination thereof.165. The process of Embodiment 164. wherein the solvent comprises di chloromethane, hexane, or heptane, or any combination thereof.166. A process of preparing Compound 4, comprising:(viib) reacting Compound 5 with borane-THF (BEI3-THF) in a solvent to obtain Compound 4.167. The process according to Embodiment 166, further comprising:10161828748.1(viib-a)adding aqueous sodium hydroxide to the reaction mixture of step (viib), followed by aqueous hydrogen peroxide.168. The process according to Embodiment 166 or 167, wherein about 1 molar equivalent to about 3 molar equivalents of BFE-THF to Compound 5 are employed.169. The process according to any one of Embodiments 166-168, wherein Compound 4 is obtained with a selectivity of at least about 98% diastereomeric excess.170. The process according to any one of Embodiments 166-169. wherein the solvent of step (vii) comprises hexane, heptane, toluene, CHCh, dichloroethane, PhCFs, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dimethyl ether, dioxane, or any combination thereof.171. The process according to any one of Embodiments 166-170, further comprising:(viii) contacting Compound 6 with a reaction mixture comprising ethyl triphenyl phosphonium bromide, a base, and a solvent, to obtain Compound 5.172. The process according to Embodiment 171, wherein the base of step (viii) comprises an alkyl lithium, a metal alkoxide, a metal amylate, a metal hydride, or a metal dialkylamide.173. The process of Embodiment 171 or 172, wherein the base of step (viii) comprises n- butyl lithium, / e / V-butyl lithium, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium te / 7-butoxide, potassium to7-butoxide, sodium hydride, potassium hydride, sodium amylate, potassium amylate, lithium amylate. or lithium diisopropylamide.174. The process according to any one of Embodiments 171-173, wherein the solvent of step (viii) comprises an organic solvent.175. The process according to Embodiment 174, wherein the organic solvent of step (viii) comprises acetonitrile, dichloromethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, hexane, heptane, cyclohexane, pyridine, 1,4-di oxane, or any combination thereof.176. The process according to any one of Embodiments 171-175, wherein the process further comprises:(ixa) contacting Compound 7 with a reaction mixture comprising methyl aluminum bis(2.6-di- / -butyl-4-methylphenoxide) (MAD reagent), methyl magnesium bromide, and a solvent, to obtain Compound 6.177. The process according to Embodiment 176, wherein the MAD reagent is formed in situ by contacting trimethylaluminum with 2.6-di- / c77-butyl-4-methylphenol (BHT).10261828748.1178. The process according to Embodiment 177, wherein Compound 7 is added to the in situ formed MAD reagent to form a mixture of MAD reagent and Compound 7, and the methyl magnesium bromide is reacted with the mixture of MAD reagent and Compound 7.179. The process according to any one of Embodiments 176-178, wherein the solvent of step (ixa) comprises dichloromethane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, hexane, heptane, 1.4-dioxane, or cyclohexane, or any combination thereof.180. The process according to any one of Embodiments 171-175. further comprising:(I-ix) contacting Compound 7 with a methylating agent in the presence of a solvent to obtain Compound 6, wherein the methylating agent is trimethylaluminum (AlMes).181. The process according to Embodiment 180, wherein about 3 molar equivalents to about 4 molar equivalents of trimethylaluminum (AlMes) to Compound 7 are employed.182. The process of Embodiment 181, wherein the solvent of step (I-ix) comprises an organic solvent.183. The process of Embodiment 182, wherein the solvent of step (I-ix) comprises ethyl acetate, isopropyl acetate, hexane, heptane, dichloromethane, chloroform, tetrahydrofuran, 2- methyltetrahydrofuran. acetonitrile, dimethylformamide, or toluene, or any combination thereof.184. A composition comprising 98.0% w / w or greater of Compound 3.185. The composition of Embodiment 184, wherein Compound 3 is prepared by a process according to any one of Embodiments 153-166.186. A composition comprising 98.0% w / w or greater of Compound 4.187. The composition of Embodiment 186, wherein Compound 4 is prepared by a process according to any one of Embodiments 166-183.188. A composition comprising 95.0% w / w or greater of Compound 6.189. The composition according to Embodiment 188, wherein Compound 6 is prepared by a process according to any one of Embodiments 161-165.190. A composition comprising 99.0% w / w or greater of 4-cyanopyrazole.191. The composition of Embodiment 190, wherein the 4-cyanopyrazole is prepared by a process according to any one of Embodiments 106-120.192. A crystalline form of Compound 4, wherein the crystalline form is a methanol solvate of Compound 4.193. The crystalline form of Embodiment 192, further characterized by one or more peaks corresponding to 2-theta values measured in degrees of 6.2 ± 0.2, 12.3 ± 0.2, 12.4 ± 0.2, 15.4 ± 0.2, and 16.3 ± 0.2 in an X-ray powder diffraction pattern.10361828748.1194. The crystalline form of Embodiment 193, wherein the cry stalline form is further characterized by one or more peaks corresponding to 2-theta values measured in degrees of 18. 1 ± 0.2, 18.2 ± 0.2, and 18.4 ± 0.2, in an X-ray powder diffraction pattern.195. The crystalline form of Embodiment 192, wherein the crystalline form is in an orthorhombic cry stal system.196. The crystalline form of Embodiment 195, wherein the crystalline form is in P2(l)2( 1)2(1) space group.197. The crystalline form of Embodiment 196, wherein the crystalline form is in P2(l)2(l)2(l) space group with a = 7.4((±0.5) A, b = 9.8((±0.5) A, c = 28.5(±0.5) A.198. A compound comprising 99.0% w / w or greater of Compound 1.199. The composition according to Embodiment 198, wherein the composition comprises 99.3% w / w or greater, 99.5% w / w or greater, 99.7% w / w or greater, 99.8% w / w or greater, or 99.9% w / w or greater, of Compound 1.200. The composition according to Embodiment 198, wherein the composition comprises no more than 0.7% w / w, 0.5% w / w, 0.3% w / w, 0.2% w / w, or 0.1% w / w, of any impurities.201. The composition according to any one of Embodiments 198-200, wherein the impurities comprise a brominated side product, an isomer, and a starting material.202. The composition according to any one of Embodiments 198-201, wherein the composition comprises less than 0.2 %w / w of any of the following impurities:203. The composition according to any one of Embodiments 198-202, wherein Compound 1 is prepared by any one of the methods according to Embodiments 1-105.

[0359] IV. EXAMPLES

[0360] The following examples are provided so that the processes described herein can be more fully understood, and are not intended to limit the scope of the invention in any7way.10461828748.1

[0361] Example 1-1: Synthesis of 4-cyanopyrazole.Step 1(2-ethoxymethylene)- 5-amino-4- malononitrile cyanopyrazole EMM.Step 2 4-cyanopyrazole

[0362] Step 1 : 5-amino-4-cyanopyrazole

[0363] Water (950 L) was charged to a reaction vessel and cooled to 0-5 °C. 2- (ethoxymethylene) malonodinitrile (EMM; 100 kg) was then added to the reaction vessel and the resultant mixture was maintained at about 0-5 °C. Hydrazine monohydrate (61.5 kg) was then added to the reaction vessel at a rate sufficient to keep the mixture at about 20 °C or under, and after completed addition, the mixture was warmed to about 20-25 °C and stirred for at least 20 hours. When the reaction was complete, the mixture was cooled again to about 0-5 °C, agitated for about 2 hours, and then filtered. The reaction vessel was washed once with cold water (200 L) and once with cold n-heptane (400 L), each wash was poured over the product filter cake. Then the cake was dried to provide 5-amino-4-cyanopyrazole as a solid (typical yield: 63-70 kg).

[0364] Step 2: 4-cyanopyrazole

[0365] 50% Aqueous hypophosphorous acid (H3PO2; 762.5 kg) w as charged to a first reaction vessel and cooled to a temperature of about 0-5 °C with stirring. To a second reaction vessel, was added water (1060 kg) and 5-amino-4-cyanopyrazole (125 kg), and the mixture was stirred. To the second reaction vessel was added an aqueous solution of sodium nitrite (NaNCh; 96 kg) in w ater (250 kg), the mixture was stirred for about 30-60 minutes. The mixture in the second reaction vessel was then added to the hypophosphorous acid mixture in the first reaction vessel at a rate as to keep the combined solution at a temperature of about 0-25 °C (the second vessel was rinsed with whaler into the first one). The reaction mixture was then stirred at rt for 1-2 hours. When the reaction was complete, the mixture was cooled to a temperature of about 0-5 °C, and a sufficient amount of 48% aqueous NaOH solution (e.g., 466 kg or 4.8 eq.) was added over a minimum of 1 hour to quench the acid and achieve a neutral pH value. The reaction mixture was filtered and the reaction vessel was10561828748.1washed with water. Sodium chloride was added to the filtrate, and the solution was extracted several times with ethyl acetate. The combined organic layers were then extracted with dilute aqueous acid (pH of approximately 2) and then washed several times with water. Activated carbon and ethyl acetate were added to the organic layer, and the mixture was filtered (the cake is washed with ethyl acetate). The filtrate was concentrated under reduced pressure to 200-300 L, and then re-diluted with ethyl acetate (2x), and concentrated to 200-300 L again. The solution was heated to about 50-55 °C, and heptane (250 L) was added slowly to achieve crystallization while maintaining the temperature at about 50-55 °C. Additional heptane (750 L) was charged to the solution while maintaining the temperature at about 50-55 °C to achieve further crystallization. The mixture was then cooled slowly to about 0-5 °C and filtered to provide the crude product (typical yield = 70-80%).

[0366] Recrystallization. 80 kg of the crude 4-cyanopyrazole (exemplary amount) was then dissolved in MBTE (1200 L), extracted with dilute aqueous sodium hydroxide, and then washed twice with water The solution was then concentrated to 200 to 280 L by distillation under vacuum, and ethyl acetate (800 L) was added. The resulting mixture was cooled to about 10-15 °C and concentrated under vacuum to 200 to 280 L. Ethyl acetate (800 L) was again added, the resulting mixture was cooled to about 10-15 °C, and concentrated under vacuum to 200 to 280 L. The solution w as then heated to about 50-55 °C, and heptane (160 L) was added slowly to achieve crystallization while maintaining the temperature at about 50- 55 °C. Additional heptane (640 L) was charged to the solution while maintaining the temperature at about 50-55 °C to achieve further crystallization. The mixture was then cooled slowly to about 0-5 °C, filtered, and dried to provide the final product (typical yield = 45-53%).

[0367] The reaction product, i.e., 4-cyanopyrazole, generated from the reaction step of this Example 1-1 was analyzed against a purified reference standard of 4-cyanopyrazole using negative atmospheric pressure chemical ion scanning, which confirmed the structure and composition of the product of this example as 4-cyanopyrazole. The spectrum of this scan for the reference standard of 4-cyanopyrazole is provided in Fig. 1, wherein 4-cyanopyrazole, in 10% aqueous formic acid solution, was analyzed to provide a molecular weight [M-H]+of 93.089. The spectrum of the positive electrospray ionization scan for the reaction product of this Example 1-1 was found to conform to the spectrum in Fig. 1.10661828748.1

[0368] Example 1-2; Synthesis of 4-cyanopyrazole.

[0369] Syntheses of 17 / -pyrazole-4-carboxamide

[0370] Ethyl l f / -pyrazole-4-carbo\ylate (l-2a-l) (purity 99.1 %) was mixed with a solution of ammonium hydroxide (NH3*H2O. cone. 25-28%) according to the reaction conditions set forth in Tables 1A and IB below, to generate lT7-pyrazole-4-carboxamide (l-2a-2).

[0371] Table 1A: Reaction conditions (temperature and time) for syntheses of 1H- pyrazole-4-carboxamide.

[0372] Table IB: Reaction conditions (volume and time) for syntheses of 17 / -pyrazole-4- carboxamide.10761828748.1

[0373] Syntheses of 4-cvanopyrazol via dehydration of 17 / -pyrazole-4-carboxamide.

[0374] I H-pyrazole-4-carboxamide was reacted with dehydration agents under the reaction conditions set forth in Tables 2A and 2B to generate 4-cyanopyrazole.

[0375] Table 2A: Syntheses of 4-cyanopyrazole via dehydration of l / / -pyrazole-4- carboxamide.10861828748.1

[0376] Table 2B: Syntheses of 4-cyanopyrazole via POCh-mediated dehydration of IH- pyrazole-4-carboxamide.10961828748.1

[0377] HPLC Analyses were made using Agilent Poroshell 120 Bonus-RP column at room temperature with a mobile phase (A: 0.05% aq. TFA, B: acetonitrile); a needle wash (acetonitrile: water (1 : 1 v / v)); a diluent (acetonitrile); and UV detection at 220 nm for the HPLC data provided in Examples 1-2 and 1-3. The retention times for starting materials and products are provided in Table 3.

[0378] Table 3: Retention times for starting materials and products.

[0379] Example 1-3; Synthesis of 4-cyanopyrazole.r ,

[0380] 5.00 L (10.0 V) of NHs’FLO (cone. 25-28%) was charged to a 10 L reactor followed by 500 g of ethyl I / / -pyrazole-4-carbo\ylate. The reaction mixture was held at 25-30 °C for ca. 72 hrs until a heterogeneous solution was observed. The mixture was cooled to -10 °C to -20 °C and held for 2 hrs until solids precipitated, then transferred to fdter at 0 °C, and the filter cake was washed with 50 mL of ice water (5 °C). The cake was dried under vacuum with nitrogen bleed at 40 °C for 3 hrs to give 320 g of l / / -pyrazole-4-carboxamide as solid11061828748.1(HPLC: 98.6%, yield 80%).

[0381] 1.4 L of toluene was charged into a 5 L reactor followed by 200 g of lH-pyrazole-4- carboxamide and Et N (376 ml, 1.5 eq.). Dropwise, POCE (201 mL, 1.2 eq.) was added and the temperature was held under 40 °C. Following the addition, the temperature of the reaction mixture was held at 80-85 °C under stirring for 6 hrs following by cooling to 20-30 °C. 1.4 L of water was slowly added (~10 mL / min) to the reaction mixture and the temperature was maintained at 20-25 °C. The toluene layer was discarded, the aqueous layer was extracted with EtOAc (1.6 L, 8 Vol by volume) four times, and the organic phase was washed with 10% NaCl aqueous solution (80g in 720 mL H2O, 600 mL). The washed product was dried over Na2SC>4 (50g, 0.25 X by weight), filtered, and washed with EtIOAc (200 mL). The mother liquor was concentrated at 40-50 °C under vacuum (-0.8 to -1 MPa) to dryness to obtain a solid. The crude product was transferred to a second reactor, charged with 800 mL of DCM (4 vol), and heated to 40 °C. Dropwise, 300 mL of EtOAc (1.5 vol) at 40 °C was added to the reactor and the temperature was held at 40 °C for 1 hr until the mixture was homogenous. Then, dropwise, 400 mL of heptane was added at 40 °C into the reactor and the temperature was held at 40 °C for 1 hr until solids precipitated from the mixture. The mixture was cooled to 0 °C, filtered, and washed with 50 mL of heptane. The filter cake was dried under vacuum with nitrogen bleed at 40 °C for 2 hrs to give 125 g of solid 4- cyanopyrazole (HPLC: 99.6%, yield 75%).

[0382] Recrystallization of crude 4-cyanopyrazole (2.00 g) in DCM / EtOAc / Heptane (4: 1.5: 2 v / v / v) afforded 4-cyanopyrazole with 99.6% purity as measured by HPLC and a purification yield of 90%.

[0383] The reaction product, i.e., 4-cyanopyrazole, generated from the reaction step of this Example 1-3 was analyzed against a purified reference standard of 4-cyanopyrazole using negative atmospheric pressure chemical ion scanning, which confirmed the structure and composition of the product of this example as 4-cyanopyrazole. The spectrum of this scan for the reference standard of 4-cyanopyrazole is provided in Fig. 1, wherein 4-cyanopyrazole, in 10% aqueous formic acid solution, was analyzed to provide a molecular weight [M-H]+of 93.089. The spectrum of the positive electrospray ionization scan for the reaction product of this Example 1-3 was found to conform to the spectrum in Fig. 1.11161828748.1

[0384] Example 2; Synthesis of 19-norandrostane-3, 17-dione (Compound 7).

[0385] 19-norandrostane-3,17-dion-4-ene (Compound 8; 238 kg, 873.7 mol, 1.0 eq; CAS Registry No. 734-32-7), Pd / C (10% Pd, wet, 14.3 kg; 13.5 mol Pd, 0.015 eq Pd), and aqueous hydrobromic acid (12.6 M; 4.1 kg; 2.42 L; 30.5 mol HBr, 0.035 eq HBr) were dissolved / suspended in THF (1,975 L) and about 2 to 4 L water, and pressurized with hydrogen gas. When the reaction was complete and no more hydrogen gas was consumed. THF (1829 L), potassium carbonate (4.76 kg; 13.5 mol, 0.039 eq.), and water (4 L) were charged to the reaction mixture. The resulting mixture was filtered, and the filter was washed with THF. The reaction mixture was then distilled to a volume of about 600 to 700 L. The concentrated mixture was then heated to about 50 °C, and treated with / r-heptane (714 L) while keeping the temperature constant and stirred for about 30 minutes. The mixture was then cooled to a temperature of about 3 °C over 3 hours, and stirred for another 4 hours, during which time the product crystallized. The resulting slurry was filtered, and the filter cake was washed twice with w-heptane and dried under vacuum to provide Compound 7 (yield = 92-94%).

[0386] The reaction product, i.e.. Compound 7, generated from the reaction step of this Example 2 was analyzed against a purified reference standard of Compound 7 using positive electrospray ionization scanning, which confirmed the structure and composition of the product of this example as Compound 7. The spectrum of the positive electrospray ionization scan for the reference standard of Compound 7 is provided in Fig. 2, wherein Compound 7, in 10% aqueous formic acid solution, was analyzed to provide a molecular weight [M-H2O+H ; [M+H]+of 274.40. The spectrum of the positive electrospray ionization scan for the reaction product of this Example 2 was found to conform to the spectrum in Fig. 2.11261828748.1

[0387] Example 3-1; Synthesis of 3a-hydroxy-3b-methyl-19-norandrostane-17-one(Compound 6).3) MTBE, / / -heptaneCompound 7 Compound 6

[0388] BHT (535 kg, 2427 mol, 6.4 eq.) and AIMes, (491.5 kg of a 2 M solution in toluene;3.2 eq.) were combined in toluene (-2,200 L) in a first reaction vessel, to create the MAD reagent, followed by the addition of Compound 7 (111 kg, 1.0 eq.). A solution of MeMgBr (468.5 kg of a 3.2 M solution in MeTHF; 3.6 eq.) was diluted to about 1000 L of MeTHF in a second reaction vessel and cooled to from about -55 to about -70 °C. The mixture in the first reaction vessel and the MeMgBr solution in the second reaction vessel were combined while maintaining cryogenic temperature. After the reaction was complete, the reaction mixture was added to aqueous citric acid. Toluene was then added to the resultant mixture. The aqueous layer was discarded, and the organic phase was swapped to methanol by performing a series of concentrations and dilutions with methanol. Water (888 L) was then added to the resultant methanol solution (777-999 L) containing the crude product to precipitate BHT, which is filtered away from the organic phase. The organic phase was concentrated to about (1110-1221 L) to remove methanol and the resultant aqueous suspension was extracted with MTBE (1665 L). The biphasic mixture was separated, and the aqueous layer was discarded. The organic phase was concentrated to about 222 L and treated with w-heptane (2442 L) to crystallize Compound 6. The resultant slurry was filtered, and the filter cake was washed with n-heptane and dried under vacuum to provide Compound 6.

[0389] The reaction product, i.e., Compound 6, generated from this reaction step (immediately above) was analyzed against a purified reference standard of Compound 6 using positive electrospray ionization scanning, which confirmed the structure and composition of the product of this example as Compound 6. The spectrum of the positive electrospray ionization scan for the reference standard of Compound 6 is provided in Fig. 3, wherein Compound 6 was analyzed to provide a molecular weight [M-2H2O+H]+of 290.45. The spectrum of the positive electrospray ionization scan for the reaction product of this Example 3-1 was found to conform to the spectrum in Fig. 3.11361828748.1

[0390] Example 3-2; Alternative Syntheses of 3a-hydroxy-3b-methyl-19-norandrostane-17-one (Compound 6).

[0391] Compound 7 (1 wt, 1 eq.) in DCM (6.0 V) was charged to the reactor and cooled to -25 °C. Al Me? (2.0M solution in toluene, 6.3 vol, 3.5 eq.) was charged keeping the temperature below -25 °C. The reaction mixture was stirred for 1 hr at -25 °C. The reaction was quenched by addition to aqueous solution of citric acid (3 wt) in water (15 vol) and stirred for 1 hr. The organic layer was separated and extracted with DCM:Heptane = 1 : 1 (10 V). The combined organic layer was fdtrated with Celite. After distillation to 3V under atmospheric pressure, heptane (10 V) was charged and the solvent swap was repeated once. The batch was cooled from 90 °C to 10 °C in 4 hr and stirred for 1 hr. Incrustation was observed during cooling. The resultant suspension was filtered, washed with heptane (2.0 V), and dried at 40 °C under vacuum with N2 bleeding for 24 hr to give 8.68 g Compound 6 (y ield: 80.6%, purity7: 98.1, assay: 98.0%) as solid.

[0392] In another example, Compound 7 (1 wt, 1 eq.) in DCM (6.0 V) was charged to a reactor and cooled to -20 °C. Al Me? (1.0M solution in heptane. 15.0 vol. 3.5 eq.) was charged keeping the temperature below -20 °C. The reaction mixture was stirred for Ih at - 20 °C. The reaction was quenched by addition of an aqueous solution of citric acid (3 wt) in water (15 vol) and stirred for Ih. The aqueous layer was separated and extracted with DCM:heptane = 1 :1 (10 V) The combined organic layer was filtrated through Celite. After distillation to 8V under atmospheric pressure, heptane (3.0 V) was charged and the mixture was cooled to 85 °C. 1.0 wt% Compound 6 was charged at 85 °C (suspension) and then the batch was cooled to 15 °C in 4h and stirred for 1 h. No incrustation was observed. The resultant suspension was filtered, washed with heptane (2.0 V), and dried at 40 °C under vacuum with N2 bleeding for 24h to give 19.4g Compound 6 (yield: 87.7%, purity: 97.8%, assay: 95.5%) as a solid.

[0393] In a further example, Compound 7 (1 wt, 1 eq.) in DCM (6.0 V) and heptane (6.0 V) was charged to the reactor and cooled to -20 °C. AlMe? (2.0M solution in hexane, 6.3 vol, 3.5 eq.) was charged keeping the temperature below -20 °C. The reaction mixture was stirred11461828748.1for Ih at -20 °C. The reaction was quenched by addition to an aqueous solution of citric acid (3 wt) in water (15 vol) and stirred for Ih. The aqueous layer is separated and extracted with DCM:heptane = 1 : 1 (10 V). The combined organic layer was filtrated through Celite. After distillation to 8V under atmospheric pressure, heptane (3.0 V) was charged and the mixture was cooled to 85 °C. 1.0 wt% Compound 6 was charged at 85 °C (suspension) and then the batch was cooled to 15 °C in 4h and stirred for 1 h. No incrustation was observed. The suspension was filtered, washed with Heptane (2.0 V), and dried at 40 °C under vacuum with N2 bleeding for 24h to give 18.0g Compound 6 (yield: 83.1 %, purity: 99.7, assay: 97.7%) as a solid.

[0394] Example 4; Synthesis of Z-3a-hydroxy-3b-methyl-19-norpregnane-17-ene(Compound 5).Compound 6 Compound 5

[0395] Ethyltriphenylphosphonium bromide (256 kg, 689 mol, 2.0 eq.) and potassium tert- butoxide (77.5 kg, 690 mol, 2.0 eq.) was added to a reaction vessel with 1550 L THF, and agitated for at least 90 minutes to provide a solution of Wittig reagent derived from EtP(Ph)3Br. A solution of Compound 6 (100 kg, 344 mol, 1.0 eq.) in 500 L THF was added to the reaction vessel at a rate slow' enough to maintain a reaction temperature of about 15- 25 °C. When the reaction was complete, the reaction mixture was quenched with 50% aqueous acetic acid. The resulting suspension of triphenylphosphine oxide was filtered away, and the THF was removed via distillation. ^-Heptane was charged to the mixture, the aqueous layer was removed and back extracted with heptane. The combined organic layers were washed with aqueous acetic acid, aqueous potassium carbonate and then water. The n- heptane w as exchanged with THF via a series of distillations and dilutions with THF to provide a solution of Compound 5 in THF that was used directly in the next step.

[0396] The reaction product, i.e., Compound 5, generated from this Example 4 was analyzed against a purified reference standard of Compound 5 using positive electrospray ionization scanning, w hich confirmed the structure and composition of the product of this example as Compound 5. The spectrum of the positive electrospray ionization scan for the reference standard of Compound 5 is provided in Fig. 4, wherein Compound 5, in 75% aqueous11561828748.1acetonitrile was analyzed to provide a molecular weight | M-I EO-e'l of 302.50. The spectrum of the positive electrospray ionization scan for the reaction product of this Example 4 was found to conform to the spectrum in Fig. 4.

[0397] Example 5-1; Synthesis of 20(S)-3a-hydroxy-3b-methyl-20-hydroxy-19- norpregnane (Compound 4).Compound 5 Compound 4

[0398] The solution of Compound 5 in THF from the previous example was treated with 9- BBN (1480 kg of 0.5 M solution, 105 kg active 9-BBN. 861 mol. 2.5 eq.), and the resulting mixture was heated to about 42-48 °C and stirred for about 2 hours. The reaction mixture was assessed for the consumption of Compound 5 (HPLC), and treated with aqueous sodium hydroxide (333 L of a 30% (w / v)), followed by aqueous hydrogen peroxide (328 kg, 98.5 kg at 100%; 2817 mol, 8.4 eq ). The reaction mixture was assessed for conversion to Compound 4, and ^-Heptane (1500 L) was then added to the mixture, the aqueous layer was removed, and the organic solution was washed with aqueous sodium bisulfite and then water. The resulting organic phase was exchanged to methanol via a series of distillations and dilutions with methanol, and finally diluted with methanol to a total volume of about 2000 L. The mixture was then heated to reflux and stirred until complete dissolution of the solids, followed by distillation at atmospheric temperature to about 700 to 800 L. The solution was then cooled to a temperature of about 0-5 °C over two hours, and then held at temperature for another 1 hour. The resulting slurry is filtered and dried to give crude Compound 4.

[0399] Recrystallization. 95 kg of the Compound 4 (exemplar)’ amount) was then added to 3205 L methanol and heated to reflux until complete dissolution of the sohds. The mixture was then concentrated by distillation at atmospheric temperature to a total volume of 665-760 L, and then cooled to about 0-5 °C over at least 2 hours, and then held at temperature for at least 1 hour. The resulting slurry was filtered to afford Compound 4 (y ield = 73-100% overall from Compound 6).

[0400] The reaction product, i.e.. Compound 4, generated from this Example 5-1 (after recrystallization) w as analyzed against a purified reference standard of Compound 4 using11661828748.1positive electrospray ionization scanning, which confirmed the structure and composition of the product of this example as Compound 4 • MeOH. The spectrum of the positive electrospray ionization scan for the reference standard of Compound 4 • MeOH is provided in Fig. 5, wherein Compound 4 • MeOH, in 40% aqueous acetonitrile solution was analyzed to provide a molecular weight [M-2H2O+H]+of 320.52. The spectrum of the positive electrospray ionization scan for the reaction product of this Example 5-1 was found to conform to the spectrum in Fig. 5. HPLC analysis of the reaction product of this Example 5- 1 in acetonitrile gave a total impurity profile of ~ 0.1%.

[0401] Example 5-2: Alternative Syntheses of 20(S)-3a-hvdroxy-3b-methyl-20-hvdroxy- 19-norpregnane (Compound 4).

[0402] Preparation of Compound 4:

[0403] To a solution of PPhjEtBr (204.52 g. 550.89 mmol) in THF (500 mL) was added a solution of t-BuOK (61.82 g. 550.89 mmol) in THF (300 mL) at 0°C. After the addition was completed, the reaction mixture was stirred for 1 h 60 °C, then Compound 5 (40.0 g. 137.72 mmol) dissolved in THF (300 mL) was added dropwise at 60°C. The reaction mixture was heated to 60 °C for 18 h. The reaction mixture was cooled to room temperature and quenched with sat. NH4CL extracted with EtOAc (3><500 mL). The combined organic layers were washed with brine, dried and concentrated to give the crude product, which was purified by a11761828748.1flash column chromatography (Petroleum ether / ethyl acetate 50: 1 to 10: 1) to afford Compound 4 (38.4 g, yield: 92%) as a white powder.NMR: (400 MHz, CDC13) 6 5. 17- 5.06 (m, 1H), 2.42-2.30 (m, 1H), 2.27-2.13 (m, 2H). 1.89-1.80 (m, 3H), 1.76-1.61 (m, 6H). 1.55-1.43 (m. 4H), 1.42-1.34 (m, 3H), 1.33-1.26 (m, 6H), 1.22-1.05 (m, 5H), 0.87 (s, 3H).

[0404] Syntheses of Compound 4 using BHa-THF as the boron reducing agent.

[0405] Compound 5 (15 g, purity 98.2%) dissolved in THF (5 vol) was reacted using BH?- THF (1.07 eq.) at 0-5 °C (as the borane agent) in THF as described in Table 4, below. After reacting for approximately 2 hours, the reaction mixture was extracted by heptane (15 V) and 2-methyltetrahydrofuran, follow ed by filtration. The final crude product w as obtained after washing with NazSOs and water, followed by solvent swap with MeOH and subsequent concentration (yield 81.6%). The crude product was crystallized in MeOH. The crystallized product was filtered and dried (yield 76.2%).

[0406] Synthesis of Compound 4 using (thexyl)BH2.

[0407] Preparation of (thexyl)BH2 reagent:

[0408] The (thexyl)BH2 boron reducing agent was prepared by reacting 1 equiv. of BH3-THF with 1 equiv. of 2,3-dimethylbut-2-ene at 0 °C for 2 hrs. The resulting (thexyl)BH2 reagent (97% purity) was used directly in the following experiments (~0.9 M in THF) without further purification.

[0409] Compound 5 (15 g, purity 98.1%) dissolved in THF (5 vol) was reacted using (thexyl)BH2 (1.3 equiv.) at approximately 40 - 45 °C (as the borane agent) in THF, followed by H2O2 (8.6 equiv.). added at hour 20. The resulting reaction mixture was extracted with heptane (15 V) and 2-MeTHF, followed by filtration. The final crude product was obtained after washing with ISfeSOs and water, followed by solvent swap with MeOH and subsequent concentration (yield 83.8%). The crude product was cry stallized in MeOH. The crystallized product was filtered and dried, (yield 69.9%).

[0410] Synthesis of Compound 4 using BH3.

[0411] Compound 4 was also synthesized using various boron reagents, as described in Table 4.11861828748.1

[0412] Table 4: Synthesis of Compound 4 with various boron reagents.1Reaction conditions from Org. Process Res. Dev., 2018, 22, 846.2Reaction conditions from Org. Process Res. Dev. 2003, 7. 115.

[0413] Analytical Methods of Example 5-2: HPLC Analyses were made using a Thermo U 3000 HPLC with: a CAD detector or equivalent at room temperature; a ACE Excel C18-PFP column (150 x 3.0 mm, 3.0 pm); a mobile phase (A: 0.1% aq. TFA), B: acetonitrile:MeOH = 1: 1 v / v); a needle wash (EtOH); a diluent (EtOH); and UV detection at 215 nm. Sample preparation was made with 0.5 mL reaction mixture + 1 mL diluent (EtOH).

[0414] Retention Time (RT) of Starting Material (Compound 5) and Product (Compound 4):

[0415] Compound 5: 32.681 mini Compound 4: 20.995 min

[0416] Example 6: Synthesis of 3a-hvdroxy-3b-methyl-19-norpregnane-20-one (Compound 3).Compound 4 Compound 3

[0417] Compound 4 (67.0 kg; 209 mol; 1 eq.) was dissolved in MTBE and the mixture was11961828748.1concentrated by distillation at atmospheric pressure and re-diluted with additional MTBE several times to remove residual methanol. When substantially all residual methanol was removed, the solution was diluted with MTBE to a final volume of 536 L. Then a homogenous solution of disodium hydrogen phosphate (ISfeHPOrVEEO; 105 kg), tetrabuty lammonium bromide (Ov-BufiNBr); 6.30 kg), and sodium bromate (NaBrCh; 22.1 kg; 1.5 eq.) in water (335 kg) was added and the solution stirred at room temperature. An aqueous solution of ruthenium trichloride monohydrate (RuCh AEhO; 0.224 kg; cat) was then added, and the reaction mixture was warmed to about 40-50 °C and stirred for at least 16 hours. Once complete, isopropanol (60.3 kg) was added and the resulting solution was stirred for at least 2 hours at about 40 to 50 °C to consume any excess oxidant. «-f leptane (114 kg) was then added to the mixture and the layers were allowed to separate at about 35-45 °C. The aqueous layer was discarded and the organic layer was filtered and washed with water twice. The organic layer was then distilled at reduced pressure to a total volume of about 402 L, then heated to a temperature of about 45-50 °C. w-Heptane (184 kg) was then added while keeping the mixture at temperature, and the mixture was again distilled under reduced pressure and a temperature of about 45-50 °C to a total volume of 268 L. w-Heptane (184 kg) was again added while keeping the mixture at temperature, and the mixture was again distilled under reduced pressure and a temperature of about 45-50 °C to a total volume of 402 L. The resulting concentrated mixture was then cooled to room temperature and held for at least one hour, and then the solid product (Compound 3) was isolated by filtration (yield = 80-91%).

[0418] The reaction product, i.e., Compound 3, generated from this Example 6 was analyzed against a purified reference standard of Compound 3 using positive electrospray ionization scanning, which confirmed the structure and composition of the product of this example as Compound 3. The spectrum of the positive electrospray ionization scan for the reference standard of Compound 3 is provided in Fig. 6, wherein Compound 3 (in aqueous solution) was analyzed to provide a molecular weight [M-2H2O+H]+; [M-FEO+Ffp of 318.501. The spectrum of the positive electrospray ionization scan for the reaction product of this Example 6 was found to conform to the spectrum in Fig. 6. HPLC analysis of the reaction product of this Example 5-1 in acetonitrile gave a total impurity profile of ~ 0. 1%.12061828748.1

[0419] Example 7; Synthesis of 21-bromo-3a-hvdroxy-3b-methyl-19-norpregnane-20- one (Compound 2).

[0420] Compound 3 (72.1 kg; 1.0 eq.) was dissolved in methanol (517 kg) and the resultant solution was cooled to approximately 0 °C. Hydrobromic acid was added as a 48% aqueous solution (2.29 kg; 0.06 molar eq. HBr) and then bromine (18.5 kg; 0.51 eq.) was added gradually at a rate to maintain the temperature in the range of -5 to 5 °C. The resultant mixture was stirred at that temperature for at least 1.5 hours, and then another charge of bromine (18.5 kg; 0.51 eq.) was added. The mixture was stirred for at least one hour at from about -5 to about 5 °C, during which time a slurry formed. The reaction was checked for completion by HPLC and more bromine was added if the reaction was incomplete. Once is the reaction was deemed to be complete, water (361 kg) was added over 30-90 minutes while maintaining the temperature in the range of from about 0 to about 10 °C. Then the slurry was stirred for at least an additional 60 minutes at this temperature and filtered. The resultant cake was washed with a mixture of methanol and water (1 x), followed by water (3x). The cake was dried under vacuum at about 40-50 °C to a constant weight to provide Compound 2 as a white to off-white solid (yield = 90-97%).

[0421] The reaction product, i.e., Compound 2, generated from this Example 7 was analyzed against a purified reference standard of Compound 2 using positive electrospray ionization scanning, which confirmed the structure and composition of the product of this example as Compound 2. The spectrum of the positive electrospray ionization scan for the reference standard of Compound 2 is provided in Fig. 7, wherein Compound 2, in acetonitrile and 25% water solution was analyzed to provide a molecular weight [M-H20+H]+of 397.40. The spectrum of the positive electrospray ionization scan for the reaction product of this Example 7 was found to conform to the spectrum in Fig. 7. HPLC analysis of the reaction product of this Example 7 in acetonitrile gave a total impurity profile of < 5%.12161828748.1

[0422] Example 8; synthesis of 21-(4-cyanopyrazol-lyl)-3a-hydroxy-3b-methyl-19- norpregnane-20-one (Compound 1).Compound 2 Compound 1

[0423] A reaction vessel was charged with Compound 2 (63 kg; 1.0 eq.), 4-cyanopyrazole (16.2 kg, 1.1 eq.), cesium carbonate (CS2CO3; 72.5 kg; 1.3 eq.), and ethyl acetate (995kg) and the resultant mixture was heated to about 30-40 °C with stirring. The reaction was stirred for at least two hours at about 30-40 °C (additional 4-cyanopyrazole was added if the reaction stalled). When the reaction was complete, the reaction mixture was washed four times with water by: adding water to the mixture, increasing the temperature to 45-55°C, stirring for 10 minutes, and then discarding the aqueous layer (4x). The solution was heated to reflux and distilled at atmospheric pressure to a volume of 315 L. Additional ethyl acetate (567 kg) w as charged, and the solution was again atmospherically distilled to a final volume of 630 L. n- Heptane (428 kg) was added slowly while keeping the temperature between about 70-77 °C, then the mixture w as cooled to about 65-75 °C and held at this temperature for at least 2 hours. The reaction mixture was then slowly cooled over a period of at least 6 hours to about 30-35 °C, held in this range for 1-24 hours, and then filtered. The product was washed with ethyl acetate and heptane and dried under vacuum at less than or equal to about 50 °C to provide crude Compound 1.

[0424] Recrystallization'. Crude Compound 1 (50.587 kg) was combined with ethyl acetate (1098 kg) in a reactor and the mixture was heated to reflux, causing the solids to dissolve. The solution was polish-filtered and the filtrate was concentrated by atmospheric distillation to a total volume of 759 L. Once the desired volume was reached, the temperature w as lowered to about 65-75 °C and the resulting slurry was stirred at this temperature for at least 2 hours. rt-He tane (519 kg) w as then added while keeping the temperature at about 65- 75 °C, and the mixture was held at this temperature for about 6 hours. The temperature was then slowly lowered to about 30-35 °C over a period of at least 6 hours. The slurry was held at this temperature for 1-24 hours and filtered. The resulting cake was washed with ethyl acetate and heptane. The product could be further recrystallized using the same procedure as12261828748.1above to enhance the purity of the product. The final filter cake was dried under vacuum at less than or equal to about 50 °C to afford Compound 1 as a white to off-white solid (yield = 68-75%).

[0425] The reaction product i.e., Compound 1, generated from this Example 8 was analyzed against a purified reference standard of Compound 1 using negative electrospray ionization scanning, which confirmed the structure and composition of the product of this example as Compound 1. The spectrum of the negative electrospray ionization scan for the reference standard of Compound 1 is provided in Fig. 8, wherein Compound 1, in acetonitrile and 25% water solution was analyzed to provide a molecular weight [M-FhO+Ffp of 409.57. The spectrum of the positive electrospray ionization scan for the reaction product of this Example 7 was found to conform to the spectrum in Fig. 7. HPLC analysis of the reaction product of this Example 7 in acetonitrile gave a total impurity profile of < 5%.

[0426] Micronizatior . After recrystallization, purified Compound 1 was micronized using ajet mill to provide Compound 1 in a micronized form.

[0427] Example 9A: Synthetic Scheme 3A.

[0428] Step 1 : l-tosyl-lH-pyrazole-4-carbonitrile

[0429] To a solution of 4-cyanopyrazole (100 mg, 1.07 mmol) in THF (4 mb) was added NaH (60% dispersion in mineral oil, 51.3 mg, 2.14 mmol) at about 0 °C under N2 atmosphere. After stirring at about 0 °C for about 5 min, TsCl (264 mg, 1.39 mmol) was added. After stirring at about 20 °C for about 30 mins, to the mixture was added water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated. The crude product was purified by column (0- 50% of EtOAc in PE) to give 1 -tosyl- lH-pyrazole-4-carbonitrile (177 mg) as a white solid. 'H NMR (400 MHz, CDCh) 5H 8.51 (s, 1H), 7.95-7.91 (m, 3H), 7.40-7.38 (m, 2H), 2.46 (s, 3H).12361828748.1

[0430] Step 2: 2-bromo-l-((3R.5R.8R.9R.10S.13S.14S.17S)-3-hvdroxv-3.13- dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)ethanone

[0431] To a solution of Compound 3 (20 g, 62.7 mmol) in MeOH (200 mL) was added HBr (2.52 g, 12.5 mmol, 40% aq.in water) and Br2 (11 g. 68.9 mmol) at about 0 °C. After stirring at about 25 °C for about 1 hr, the mixture was poured into NaHCOs (100 mL). The aqueous phase was extracted with EtOAc (3 x 200 mL). The combined organic phase was washed with brine (500 mL), dried over anhydrous ISfeSCL, filtered and concentrated. The residue was purified by column (0-100% of EtOAc in PE) to give Compound 2 (20 g, 80.3%) as an off-white solid. H NMR (400 MHz, CDCh) 5H 3.94-3.87 (m, 2H), 2.82 (t, J= 9.2Hz, 1H), 2.22-2.14 (m, 1H), 1.93-1.37 (m, 15H), 1.37-1.01 (m, 11), 0.63 (s, 3H).

[0432] Step 3: 2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13- dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl acetate (Compound S3-A)

[0433] To Compound 2 (17 g, 42.7 mmol) in DMF (50 mL) was added NaOAc (7 g, 85.4 mmol). After stirring at about 25 °C for about 18 hrs, to the suspension water (100 mL) was added. The solid formed was filtered and the filter cake was dried under vacuum to give Compound S-3a (21 g, crude) as a brown solid. ’H NMR (400 MHz, CDCL) 5H 4.72-4.68 (m, 1H), 4.55-4.50 (m, 1H), 2.51 (t, 8.8Hz, 1H), 2.23-2.16 (m, 4H), 2.02-1.98 (m, 1H),1.87-1.58 (m, 10H), 1.58-1.26 (m. 10H), 1.26-0.99 (m, 5H), 0.65 (s, 3H).12461828748.1

[0434] Step 4: 2-hvdroxv-l-((3R.5R.8R.9R.10S.13S.14S.17S)-3-hvdroxv-3.13- dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-l 7-yl)ethanone (Compound S-3b)Compound S-3a Compound S-3b

[0435] To Compound S-3a (21 g, 55.7 mmol) in THF (20 mL), MeOH (20 mL) and water (5 mL) was added K2CO3 (15.3 g, 111 mmol). After stirring at about 25 °C for about 18 hrs, the suspension was extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column (5-80% of EtOAc in PE) to give Compound S-3b (13 g) as yellow oil.1H NMR (400 MHz, CDCI3) 5H 4.23-4. 14 (m, 2H), 3.30-3.22 (m, 1H), 2.45 (t, . / =8,8Hz. 1H), 2.25-2.15 (m, 1H), 1.89-1.52 (m, 10H), 1.52-1.27 (m, 10H), 1.27-0.99 (m, 6H), 0.63 (m, 3H).

[0436] Step 5: Compound 1Compound S-3b Compound 1

[0437] To Compound S-3b (500 mg, 1.49 mmol) and l-(4-methylbenzenesulfonyl)-lH- pyrazole-4-carbo-nitrile (440 mg, 1.78 mmol) in acetonitrile (20 mL) was added CS2CO3 (677 mg, 2.08 mmol) under N2. After stirring at about 90 °C for about 16 hrs, the reaction was treated with water (20 mL), extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column (5-70% of EtOAc in PE) to give Compound 1 (1.0317 g) as a white solid.(400 MHz, CDCh) 5H 7.85 (s, 1H). 7.80 (s. 1H), 5.03- 4.87 (m, 2H), 2.60 (t, J= 9.2Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H), 1.53-1.27 (m, 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS12561828748.1ESI calcd. for C25H36N3O2 [M+H]+410 found 410.

[0438] Example 9B: Synthetic Scheme 3B.

[0439] Step 1 : 1 -(methylsulfonyl)- lH-pyrazole-4-carbonitrile

[0440] To a solution of 4-cyanopyrazole (5 g, 53.7 mmol) in DCM (100 mL) at about 0 °C under N2 was added TEA (13.5 g, 18.5 mL, 0.728 g / mL) and MsCI (12.2 g, 107 mmol, 8.24 mL, 1.48 g / mL). After stirring at about 25 °C for about 1 hr, the solution was added to NaHCCh (100 mL. aq). The solution was extracted with DCM (2 x 100 mL). The combined organic phase was washed with brine (500 mL) and dried over anhydrous Na2SC>4. filtered and concentrated in vacuum to give 1 -(methylsulfonyl)- lH-pyrazole-4-carbonitrile (9.7 g, crude) as a yellow solid. ' H NMR (400 MHz, CDCI3) 5H8.48 (s, 1H), 8.05 (s, 1H), 3.44 (s, 3H).

[0441] Step 2: Compound 1Compound S-3b Compound 1

[0442] To Compound S-3b (500 mg, 1.49 mmol) and l-methanesulfonyl-lH-pyrazole-4- carbonitrile (510 mg, 2.98 mmol) in acetonitrile (20 mL) was added CS2CO3 (970 mg, 2.98 mmol) under N2. After stirring at about 90 °C for about 16 hrs, the reaction was treated with water (20 mL), extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum.The residue was purified by column (5-70% of EtOAc in PE) to give Compound 1 (134.2 mg) as a white solid. 'H NMR (400 MHz, CDCh) 5H 7.85 (S, 1H), 7.80 (s, 1H), 5.03-4.87 (m. 2H), 2.60 (t, J= 9.2 Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H), 1.53-1.27 (m, 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410 found 410.12661828748.1

[0443] Example 9C: Synthetic Scheme 3C.

[0444] Step 1 : l-((4-bromophenyl)sulfonyl)-lH-pyrazole-4-carbonitrile

[0445] To a solution of 4-cyanopyrazole (500 mg, 5.37 mmol) in DCM (20 mL) at 0 °C under N2 was added TEA (1.35 g, 1.85 mL, 0.728 g / mL) and 4-bromobenzene-l -sulfonyl chloride (2.73 g, 10.7 mmol). After stirring at about 25 °C for about 16 hrs, the solution was added to NaHCCL (100 mL, aq). The solution was extracted with EtOAc (2 x 100 mL). The combined organic phase was washed with brine (500 mL) and dried over anhydrous Na2SC>4, filtered and concentrated in vacuum to give l-((4-bromophenyl)sulfonyl)-lH-pyrazole-4- carbonitrile (1.9 g, crude) as ayellow solid. 'H NMR (400 MHz, CDCI3) 6H 8.51 (s, 1H), 7.93-7.89 (m, 3H). 7.76-7.74 (m, 2H).

[0446] Step 2: Compound 1

[0447] To a solution of Compound S-3b (500 mg, 1.49 mmol) and l-(4- bromobenzenesulfonyl)-lH-pyrazole-4-carbonitrile (930 mg, 2.98 mmol) in acetonitrile (20 mL) was added cesium Carbonate (970 mg, 2.98 mmol) under N2. After stirring at about 90 °C for about 16 hrs, the reaction was treated with water (20 mL), extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column (5-70% of EtOAc in PE) to give Compound 1 (266.3 mg) as a white solid. 'H NMR (400 MHz, CDCh) 5H 7.85 (S, 1H), 7.80 (s, 1H), 5.03-4.87 (m, 2H), 2.60 (t, J= 92 Hz, 1H), 2.23- 2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H), 1.53-1.27 (m, 11H), 1.27-1.04 (m. 7H), 0.67 (s. 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410 found 410.12761828748.1

[0448] Example 9D: Synthetic Scheme 3D.

[0449] Step 1 : 1 -(naphthal en-2-ylsulfonyl)- lH-pyrazole-4-carbonitrile

[0450] To a solution of lH-pyrazole-4-carbonitrile (500 mg, 5.37 mmol) in DCM (20 mL) at 0 °C under N2 was added TEA (1.35 g, 1.85 mL, 0.728 g / mL) and naphthalene-2-sulfonyl chloride (2.42 g. 10.7 mmol). After stirring at about 25 °C for 16 hrs. the solution was added to NaHCCh (100 mL, aq). The solution was extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine (500 mL) and dried over anhydrous Na2SC>4, filtered and concentrated in vacuum to give l-(naphthalen-2-ylsulfonyl)-lH-pyrazole-4- carbonitrile (1.9 g, crude) as a yellow solid. 'H NMR (400 MHz. CDCI3) bn 8.70 (s, 1H), 8.61-8.58 (m, 1H), 8.05-7.91 (m, 6H), 7.77-7.66 (m, 2H).

[0451] Step 2: l-(2-((3R.5R.8R.9R.10S.13S.14S.17S)-3-hvdroxv-3.13- dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-lH-pyrazole-4- carbonitrile

[0452] To a solution of Compound S-3b (500 mg, 1.49 mmol) and 1 -(naphthal ene-2- sulfonyl)-lH-pyrazole-4-carbonitrile (844 mg, 2.98 mmol) in acetonitrile (20 mL) was added cesium carbonate (970 mg, 2.98 mmol) under N2. After stirring at 90 °C for 16 h, the reaction was treated with water (20 mL), extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column (5-70% of EtOAc in PE) to give Compound 1 (79.5 mg) as a white solid. 'H NMR (400 MHz, CDCh) 5H 7.85 (s, 1H), 7.80 (s, 1H), 5.03-4.87 (m, 2H), 2.60 (t, J= 9.2 Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H), 1.53-1.27 (m, 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410 found 410.12861828748.1

[0453] Example 9E: Synthetic Scheme 3E.Compound 1 Step 2

[0454] Step 1 : 2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13- dimethylhexadecahydro- IH-cy clopenta[a]phenanthren- 17-yl)-2-oxoethyl methanesulfonate (Compound S-3e)

[0455] To a solution of Compound S-3b (1 g, 2.98 mmol) in DCM (20 mL) at about 0 °C was added TEA (753 mg, 1.03 mL, 0.728 g / mL) under a nitrogen atmosphere. MsCl (682 mg, 5.96 mmol, 1.48 g / mL) was added at about 0 °C under a nitrogen atmosphere. After stirring at about 25 °C for about 30 mins, the solution was added to NaHCCh (20 mL, aq). The solution was extracted with DCM (2 x 30 mL). The combined organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give Compound S-3e (1.4 g. crude) as yellow oil.1H NMR (400 MHz. CDCL) 5H 4.86-4.69 (m, 2H), 3.23 (s, 3H), 2.54-2.46 (m, 1H), 2.39-2.11 (m, 2H), 2.00-1.45 (m, 10H), 1.45-0.82 (m, 15H), 0.65 (s, 3H).

[0456] Step 2 (Condition 1): Compound 1

[0457] To Compound S-3e (1.4 g, 3.39 mmol) and lH-pyrazole-4-carbonitrile (631 mg, 6.78 mmol) in ACN (20 mL) was added NazCCh (718 mg, 6.78 mmol) under N2. After stirring at about 90 °C for 16 hrs, the reaction was treated with water (20 mL), extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column (5-70% of EtOAc in PE) to give Compound 1 (184.1 mg, 68.4%) as a white solid.12961828748.1JH NMR (400 MHz, CDCh) 5H 7.85 (s, 1H), 7.80 (s, 1H), 5.03-4.87 (m, 2H), 2.60 (t, J= 9.2Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H), 1.53-1.27 (m, 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N O2 [M+H]+410 found 410.

[0458] Step 2 (Condition 2): Compound 1

[0459] To a solution of Compound S-3e (1.45 g, 3.51 mmol) and lH-pyrazole-4- carbonitrile (653 mg, 7.02 mmol) in acetone (40 mL) was added K2CO3 (970 mg, 7.02 mmol) under N2. After stirring at about 50 °C for about 16 hrs, the reaction was treated with water (20 mL), extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column (0-50% of EtOAc in PE) to give Compound 1 (325.0 mg, 35.4%) as a white solid. 'H NMR (400 MHz, CDCh) 5H 7.85 (s, 1H), 7.80 (s, 1H), 5.03-4.87 (m, 2H), 2.60 (t, J= 9.2Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H), 1.53-1.27 (m, 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H3sN3O2Na [M+Na]+432 found 432.

[0460] Step 2 (Condition 3): Compound 1

[0461] To a solution of Compound S-3e (1.45 g, 3.51 mmol) and lH-pyrazole-4- carbonitrile (653 mg, 7.02 mmol) in acetone (40 mL) was added was added CS2CO3 (2.28 g, 7.02 mmol) under N2. After stirring at about 25 °C for about 16 hrs, the reaction was treated with water (50 mL), extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column (0-60% of EtOAc in PE) to give Compound 1 (343.8 mg, 85.9%) as a white solid.JH NMR (400 MHz, CDCh) 5H 7.85 (s, 1H), 7.80 (s, 1H), 5.03-4.87 (m, 2H), 2.60 (t, J= 9.2Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85- 1.60 (m, 7H), 1.53-1.27 (m, 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410 found 410.

[0462] Example 9F : Synthetic Scheme 3F.13061828748.12 3, ,Step 2 Compound 1

[0463] Step 1 : 2-((3R.5R.8R.9R.10S.13S.14S.17S)-3-hvdroxv-3.13- dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl 4- methylbenzenesulfonate

[0464] To a solution of Compound S-3b (1 g, 2.98 mmol) in DCM (20 mL) at about 0 °C was added TEA (904 mg, 1.24 mL, 0.728 g / mL) and TsCl (1.13 g, 5.96 mmol) under a nitrogen atmosphere. After stirring at about 25 °C for about 5 hours to give yellow suspension, water (20 mL) was added. The solution was extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with brine (100 mL) and dried over anhydrous N zSCL, filtered and concentrated in vacuum. The residue was purified by column (5-30% of EtOAc in PE) to give Compound S-3f (1.3 g) as a white solid.1H NMR (400 MHz, CDCL) 5H7.83-7.81 (m, 2H), 7.36-7.34 (m, 2H), 4.55-4.49 (m, 2H), 2.59 (t, J= 8.8Hz, 1H), 2.45 (s, 3H), 2.16-2.07 (m, 1H), 1.86-1.54 (m, 8H), 1.54-1.16 (m, 15H), 1.16-0.97 (m, 3H), 0.57 (s, 3H).

[0465] Step 2 (Condition 1): Compound 1

[0466] To Compound S-3f (1.3 g, 2.66 mmol) and lH-pyrazole-4-carbonitrile (495 mg, 5.32 mmol) in ACN (20 mL) was added Na2CO3(563 mg, 5.32 mmol) under N2. After stirring at about 90 °C for about 16 hrs, the reaction was treated with water (20 mL), extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column (5%~70% of EtOAc in PE) to give Compound 1 (648 mg) as a white solid. 'H NMR (400 MHz, CDCL) On 7.85 (s. 1H), 7.80 (s, 1H), 5.03-4.87 (m, 2H), 2.60 (t, J = 9.2Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H), 1.53-1.27 (m, 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410 found 410.

[0467] Step 2 (Condition 2): Compound 1

[0468] To a solution of Compound S-3f (415 mg, 0.849 mmol) and lH-pyrazole-4- carbonitrile (158 mg, 1.69 mmol) in acetone (20 mL) was added K2CO3 (233 mg, 1.69 mmol)13161828748.1under N2. After stirring at about 50 °C for about 16 hrs, the reaction was treated with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column (5-70% of EtOAc in PE) to give Compound 1 (138 mg) as a white solid. 'H NMR (400 MHz, CDCI3) 5H7.80-7.85 (m, 2H), 4.87-5.03 (t, 2H), 2.60 (t, J= 9.2Hz. 1H), 1.60-2.24 (m, 9H), 1.37-1.50 (m. 8H), 1.06-1.36 (m, 10H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N O2 [M+H]+410.3. found 410.3.

[0469] Step 2 (Condition 3): Compound 1

[0470] To Compound S-3f (415 mg, 0.8492 mmol) and lH-pyrazole-4-carbonitrile (79.0 mg, 849 pmol) in acetone (20 mL) was added CS2CO3 (550 mg, 1.69 mmol) under N2. After stirring at about 25 °C for about 16 hrs, the reaction was treated with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column (5%-70% of EtOAc in PE) to give Compound 1 (176. 1 mg) as a white solid. 'H NMR (400 MHz, CDCI3) 5H 7.80-7.85 (m, 2H). 4.87-5.03 (t, 2H), 2.58-2.62 (t.1H), 2.02-2.24 (m. 2H), 1.60-1.87 (m. 6H), 1.32-1.51 (m. 9H), 1.0-1.29 (m, 10H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410.3, found 410.3.

[0471] The experimental procedures described in this Example 3F were modified according to the description set forth in Table 6 to react Compound S-3f with 4-cyanopyrazole (i.e., lH-pyrazole-4-carbonitrile) to obtain Compound 1.

[0472] Table 5: Summary of reaction conditions and results from Examples 3F.

[0473] As shown in Table 6, CS2CO3 in acetone advantageously provided a higher yield ofCompound 1 at 25 °C (i.e., Example 3F-6) as compared to Na2CC>3 and K2CO3 in similar13261828748.1conditions. Specifically, Na2COs in CH3CN results in no Compound 1 at 25 °C (i.e., Example 3F-1) and only a 60% yield at an elevated temperature (i.e., 70 °C Example 3F-2). And, K2CO3 in acetone only provides a comparable yield to CS2CO3 (i.e., -100%) at an elevated temperature (i.e., 50 °C as compared to 25 °C; Example 3F-4). Additionally, Examples 3F-4 through 3F-6 also demonstrate that CS2CO3 in acetone advantageously provided a higher reaction rate as compared to K2CO3. The reaction reported in Example 3F- 6 yielding -100% of Compound 1 was performed at a temperature that was 50% of (i.e., 50% lower that) the temperature needed to achieve comparable results using K2CO3 in acetone the reaction of Example 3F-4 as the reaction of Compound S-3f with 4- cyanopyrazole using CS2CO3 in acetone was performed at a temperature that was 50% of temperature used in Example 3F-4 to yield similar results. Without wishing to be bound by theory, because the reaction of Example 3F proceeds under milder conditions with CS2CO3 as compared to K2CO3, it is believed that CS2CO3 exhibits a faster reaction time than K2CO3.

[0474] Example 9G: Synthetic Scheme 3G.

[0475] Step 1 : l-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13- dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-lH-pyrazole-4- carbonitrile

[0476] To a solution of Compound S-3b (1 g, 2.98 mmol) in DCM (20 mL) at about 0 °C was added TEA (753 mg, 1.03 mL, 0.728 g / mL) under N2. 4-bromobenzene-l -sulfonyl chloride (1.52 g, 5.96 mmol) was added at about 0 °C to give yellow solution. After stirring13361828748.1at about 25 °C for about 5 hrs, water (20 mL) was added to the solution. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with brine (300 mL) and dried over anhydrous NaNO-i. filtered and concentrated in vacuum. The residue was purified by column (5-30% of EtOAc in PE) to give Compound S-3g (1.3 g, impure) as yellow oil. *HNMR (400 MHz, CDCh) 6H7.83-7.80 (m, 2H), 7.72-7.69 (m, 2H), 4.67-4.52 (m, 2H), 2.55 (t. J= 8.8Hz, 1H), 2.20-2.08 (m, 1H), 1.88-1.41 (m, 10H), 1.41-1.23 (m, 10H), 1.23-0.96 (m, 6H). 0.58 (s. 3H).

[0477] Step 2 (Condition 1 ):

[0478] To Compound S-3g (1.3 g, 2.34 mmol) and lH-pyrazole-4-carbonitrile (435 mg, 4.68 mmol) in ACN (20 mL) was added NazCOs (496 mg, 4.68 mmol) under N2. After stirring at about 90 °C for about 16 hrs, to the mixture was added water (20 mL). and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column (5-70% of EtOAc in PE) to give Compound 1 (587.3 mg) as a white solid. 'H NMR (400 MHz, CDCh) 5H 7.85 (s, 1H), 7.80 (s, 1H), 5.03-4.87 (m. 2H), 2.60 (t, J = 9.2Hz, 1H). 2.23-2. 16 (m, 1H). 2.06-2.02 (m, 1H). 1.85-1.60 (m, 7H). 1.53-1.27 (m, 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410 found 410.

[0479] Step 2 (Condition 2):

[0480] To a solution of Compound S-3g (1.75 g, 3.16 mmol) and lH-pyrazole-4- carbonitrile (588 mg, 6.32 mmol) in ACN (80 mL) was added K2CO3 (872 mg, 6.32 mmol) under N2. After stirring at about 50 °C for about 16 hrs, the reaction was treated with water (80 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (100 mL). dried over anhydrous NazSO-i. filtered and concentrated in vacuum. The residue was purified by column (5-70% of EtOAc in PE) to give Compound 1 (548.9 mg) as a white solid. 'H NMR (400 MHz, CDCh) 5H 7.85 (s, 1H), 7.80 (s, 1H), 5.03-4.87 (m, 2H), 2.60 (t, J= 9.2Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H), 1.53-1.27 (m, 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410 found 410.

[0481] Step 2 (Condition 3):

[0482] To a solution of Compound S-3g (1.75 g, 3.16 mmol) and lH-pyrazole-4- carbonitrile (588 mg. 6.32 mmol) in ACN (80 mL) was added CS2CO3 (2.06 g, 6.32 mmol) under N2. After stirring at about 25 °C for about 16 hrs. the reaction was treated with water (80 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed13461828748.1with brine (100 mL), dried over anhydrous NazSC , filtered and concentrated in vacuum.The residue was purified by column (5-70% of EtOAc in PE) to give Compound 1 (751.8 mg) as a white solid. 'H NMR (400 MHz, CDCL) 5H 7.85 (s, 1H), 7.80 (s, 1H), 5.03-4.87 (m, 2H), 2.60 (t, J= 9.2Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H),1.53-1.27 (m, 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410 found 410.

[0483] Example 9H: Synthetic Scheme 3H.

[0484] Step 1 : 2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13- dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl naphthalene-2- sulfonate (Compound S-3h)

[0485] To a solution of Compound S-3b (1 g, 2.98 mmol) in DCM (20 mL) at about 0 °C was added TEA (753 mg, 1.03 mL, 0.728 g / mL) under N2. Naphthalene-2-sulfonyl chloride (1.35 g, 5.96 mmol) was added at about 0 °C. After stirring at about 25 °C for about 5 hrs, the mixture was added to NaHCCL (20 mL, aq). The solution was extracted with EtOAc (2 x 30 mL). The combined organic phase was washed with bnne (200 mL) and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column (0-50% of EtOAc in PE) to give Compound S-3h (1.1 g, impure) as yellow7oil. 'H NMR (400 MHz, CDCh) 5H 8.51 (s, 1H), 8.01-7.93 (m, 4H), 7.71-7.63 (m, 2H), 4.66-4.50 (m, 2H), 2.59 (t, J = 8.8 Hz. 1H), 2.17-2.04 (m. 1H), 1.86-1.50 (m. 10H), 1.50-1.13 (m 12H), 1.13-0.89 (m. 4H), 0.53 (s, 3H).

[0486] Step 2 (Condition 1): Compound 113561828748.1

[0487] To Compound S-3h (1.1 g, 2.09 mmol) and lH-pyrazole-4-carbonitrile (495 mg, 5.32 mmol) in ACN (20 mL) was added Na2COs (563 mg, 5.32 mmol) under N2. After stirring at about 90 °C for about 16 hrs, to the mixture was added water (20 mL), and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column (5-70% of EtOAc in PE) to give Compound 1 (580.6 mg) as a white solid. 'H NMR (400 MHz, CDCL) 6n 7.85 (s. 1H), 7.80 (s, 1H), 5.03-4.87 (m, 2H), 2.60 (t, .7= 9.2Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H), 1.53-1.27 (m, 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410 found 410.

[0488] Step 2 (Condition 2): Compound 1

[0489] To a solution of Compound S-3h (1.58 g, 3.01 mmol) and lH-pyrazole-4- carbonitrile (560 mg, 6.02 mmol) in acetone (40 mL) was added K2CO3 (832 mg, 6.02 mmol) under N2. After stirring at about 50 °C for about 16 hrs, the reaction was treated with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (100 mL). dried over anhydrous Na2SO4. filtered and concentrated. The residue was purified by column (0-50% of EtOAc in PE) to give Compound 1 (578 mg, 83%) as a white solid. 'H NMR (400 MHz, CDCI3) 5H 7.85 (s, 1H), 7.80 (s, 1H), 5.03-4.87 (m, 2H), 2.60 (t, J= 9.2Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H), 1.53-1.27 (m. 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410 found 410.

[0490] Step 2 (Condition 3): Compound 1

[0491] To a solution of Compound S-3h (1.58 g, 3.01 mmol) and lH-pyrazole-4-carbonitrile (560 mg, 6.02 mmol) in acetone (40 mL) was added CS2CO3 (1.96 g, 6.02 mmol) under N2. After stirring at about 25 °C for about 16 hrs, the reaction was treated with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column (0-50% of EtOAc in PE) to give Compound 1 (544.1 mg) as a white solid. 'H NMR (400 MHz. CDCh) 5H7.85 (S, 1H), 7.80 (s, 1H), 5.03-4.87 (m, 2H). 2.60 (t, J= 9.2Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H), 1.53-1.27 (m, 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410 found 410.13661828748.1

[0492] Example 91: Synthetic Scheme 31.Step 2

[0493] Step 1 : 2-((3R.5R.8R.9R.10S.13S.14S.17S)-3-hvdroxv-3.13- dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl ((l R,4S)-7,7- dimethyl-2-oxobicyclo[2.2. l]heptan-l-yl)methanesulfonate (Compound S-3i)

[0494] To a solution of Compound S-3b (1 g, 2.98 mmol) in DCM (20 mL) at 0 °C was added TEA (753 mg. 1.03 mL, 0.728 g / mL) and [(lR.4S)-7,7-dimethyl-2- oxobicyclo[2.2.1]heptan-l-yl]methanesulfonyl chloride (1.49 g, 5.96 mmol) under N2. After stirring at about 25 °C for about 5 hrs, water (20 mL) was added. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with brine (300 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column (5-30% of EtOAc in PE) to give Compound S-3i (430 mg, 26.3%) as colorless oil. 'H NMR (400 MHz, CDCI3) 5H 4.87-4.70 (m, 2H), 3.74-3.70 (m, 1H), 3.28-3.24 (m, 2H), 2.54 (t, J= 8.8Hz, 1H), 2.48-2.35 (m, 2H), 2.25-2.07 (m, 3H), 1.97-1.48 (m, 15H), 1.48- 1.17 (m, 9H), 1.17-1.10 (m, 7H), 0.89 (s, 3H), 0.66 (m, 3H).

[0495] Step 2 (Condition 1): Compound 1

[0496] To Compound S-3i (430 mg, 0.783 mmol) and lH-pyrazole-4-carbonitrile (145 mg, 1.56 mmol) in ACN (20 mL) was added Na2COs (165 mg, 1.56 mmol) under N2. After stirring at about 90 °C for about 16 hrs, the reaction mixture was treated with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue13761828748.1was purified by column (5-70% of EtOAc in PE) to give Compound 1 (159.5 mg) as a white solid. 'H NMR (400 MHz, CDCh) 6H 7.85 (s. 1H), 7.80 (s, 1H), 5.03-4.87 (m, 2H), 2.60 (t, J = 9.2 Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H), 1.53-1.27 (m, 1 1H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410 found 410.

[0497] Step 2 (Condition 2): Compound 1

[0498] To a solution of Compound S-3i (500 mg. 0.9111 mmol) and lH-pyrazole-4- carbonitrile (169 mg, 1.82 mmol) in acetone (20 mL) was added K2CO3 (251 mg, 1.82 mmol) under N2. After stirring at about 50 °C for about 16 hrs, the reaction was treated with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (100 mL). dried over anhydrous Na2SO4. filtered and concentrated in vacuum. The residue was purified by column (5-70% of EtOAc in PE) to give Compound 1 (262.9 mg) as a white solid. 'H NMR (400 MHz, CDCls) 5H7.85 (s, 1H), 7.80 (s, 1H), 5.03-4.87 (m, 2H), 2.60 (t, J= 9.2 Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H), 1.53-1.27 (m, 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410 found 410.

[0499] Step 2 (Condition 3): Compound 1

[0500] To a solution of Compound S-3i (500 mg, 0.911 mmol) and lH-pyrazole-4- carbonitrile (169 mg, 1.82 mmol) in acetone (20 mL) was added CS2CO3 (593 mg, 1.82 mmol) under N2. After stirring at about 25 °C for about 16 hrs, the reaction was treated with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column (5-70% of EtOAc in PE) to give Compound 1 (293.1 mg) as a white solid.XH NMR (400 MHz, CDCh) 5H 7.85 (s, 1H), 7.80 (s, 1H). 5.03- 4.87 (m, 2H), 2.60 (t, J = 9.2 Hz, 1H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.85-1.60 (m, 7H), 1.53-1.27 (m, 11H), 1.27-1.04 (m, 7H), 0.67 (s, 3H). LC-ELSD / MS purity' 99%, MS ESI calcd. for C25H36N3O2 [M+H]+410 found 410.

[0501] Example 10A: Synthesis of 4-cyanopyrazole.

[0502] Step 1

[0503] EMM (29.6 kg, 245.7 mol, 1.0 eq,) and water (600 L) were added to an 800 L glass- lined reactor and the suspension was cooled to 18.5 °C. Hydrazine monohydrate (18.5 kg, 368.6 mol, about 1.5 eq.) was added to the suspension between 18.5-20.4 °C over 30 min. The reaction was stirred until sufficient conversion was reached, then the solution was evaporated at < 50 °C until a total volume of 150 L remained. The suspension was cooled to13861828748.15 °C, stirred 0.5 h, and filtered. The filter cake was washed with water (30 L) and dried in a tray dryer at 49 °C to yield 18.0 kg (68.7%) of 3-amino-4-cyanopyrazole as a brown solid with a purity of 98.2 area%.

[0504] Step 2

[0505] Sodium nitrite (12.5 kg, 181.2 mol, 1.09 eq.) was dissolved in water (270 L). 3- amino-4-cyanopyrazole (17.9 kg, 165.6 mol) was added and the suspension was heated to 30 °C and stirred for 0.5 h. The suspension was added to a cold solution of 50% hypophosphorous acid (90 L, 5 vol) in water at 1 -18 °C over 2 h. The solution was stirred for 1 h at 18-20 °C after which the target conversion was achieved. The reaction was quenched with 50% sodium hydroxide (60.0 kg) to pH = 7 over 0.5 h while keeping the temperature between 16-19 °C. The reaction stirred for 12 h and then filtered over celite (4.4 kg) and washed with water. Sodium chloride (81.2 kg) was added to the aqueous layer and the layer was stirred for 5 min to dissolve the salt. The aqueous layer was extracted with ethyl acetate (163. 1 kg) and the organic layer was washed with 2 N HC1 and water (36. 1 kg). Decolorizing carbon (9.0 kg) was added, and the mixture was stirred at 45 °C for 2 h, then cooled to 20 °C and filtered over celite. The cake was washed with ethyl acetate (62.5 kg). The filtrate was evaporated below 40 °C then ethyl acetate (160. 1 kg) was added, and the solution was evaporated to a volume of 50 L. Ethyl acetate (157.7 kg) was added again and the solution was evaporated to a volume of 50 L. Ethyl acetate (160.4 kg) was added one more time and the solution was evaporated to a volume of 50 L. The solution was heated to 55 °C and n- heptane (136 kg) was added over 25 min maintaining the temperature between 45-55 °C. The suspension was cooled to 5 °C, stirred 15 h and then filtered. The solid was washed with n- heptane (37.1 kg) and dried to yield 9.13 kg (59.3%) of 4-cyanopyrazole.

[0506] Example 10B: Synthesis of 4-cyanopyrazole.

[0507] Step 1

[0508] Precooled (0-5 °C) w ater (9.5 kg) was added to a pre-cooled 15 L reactor containing EMM (1.0 kg 1.0 eq.). The transfer was carried out within 2 minutes reaching a final temperature of 7.0 °C. The suspension was then adjusted down to 0-5 °C and then hydrazine monohydrate (0.618 kg, 1.5 eq.) was added over 31 minutes. The temperature was maintained at 0-25 °C. The transfer equipment was rinsed with water (0.50 kg). Then the batch temperature was adjusted to 20-30 °C. After stirring for approximately 18 hours the reaction was sampled for in process testing to verify completion. The reaction was then transferred to the 25 L reactor containing sodium chloride followed by rinsing of the transfer equipment with ethyl acetate (9.02 kg). The batch was allowed to agitate for a minimum of13961828748.130 minutes at 20-25 °C. The mixture was allowed to settle for a minimum of 30 minutes to allow layer separation. The lower aqueous layer was separated and extracted with ethyl acetate twice (9.02 kg x 2). All three organic layers were combined and washed twice with a saturated brine solution (2.40 kg) at 20-25 °C. The organic layer was then distilled under vacuum to approximately 2 volumes, then ethyl acetate was charged (4.5 kg) and the distillation was repeated to remove residual water, and then ethyl acetate was charged (4.5 kg). The batch was concentrated down to 2.0 L residual volume under vacuum. The batch was heated to 50-55 °C and was agitated for 1 .0 to 1.5 hours at this temperature. To the batch at 50-55 °C was charged n-heptane (6.858 kg) over a minimum of 1.0 hour. The resulting suspension was stirred for 1.0 to 1.5 hour at 50-55 °C and then was gradually adjusted to 0- 5 °C over a minimum of 4 hours. The slurry’ was agitated at 0-5 °C for minimum of 2.0 hours and filtered. The solid was washed with chilled (0-5 °C) n-heptane (1.36 kg) and dried to afford 3-amino-4-cyanopyrazole (0.711 kg, 80% yield).

[0509] Step 2

[0510] 3-Amino-4-cyanopyrazole (0.7 kg) was suspended in water (4.0 vol) and the solution of sodium nitrite (0.54 kg) was added. This suspension was then transferred to precooled hypophosphorous acid (4.27 kg) below 15 °C. The addition was completed within approximately 3.3 hours. After completion of the addition, the flask was rinsed with 1.4 kg of water and the temperature of the reaction was adjusted to 20-25 °C. The reaction was maintained at 20-25 °C for 1 hour and monitored for residual starting material. The pH was adjusted to 7.2 by addition of 50% w / aqueous NaOH (2.559 kg) while maintaining the temperature below 20-25 °C. The yellow suspension was filtered through a Buchner funnel after adding hyflo supercel (0.353 kg) into the reaction. The filtrate was added to sodium chloride (1.40 kg) and the mixture extracted with MTBE (10.36 kg total, 4 x 5.0 parts). The combined organic layers were washed with 2.0 M HC1 and then the organic layer was further washed twice with water (0.7 kg) to remove excess HC1. The organic later was then subjected to a NaOH wash. After separation of the layers, the organic layer w as further w ashed twice with 1.4 kg w ater to remove any traces of base. The batch was then subjected to the Darco KBG treatment (0.35 kg) at 50-55 °C. The batch was maintained for 1-2 hours at 50-55 °C, but during the filtration the batch temperature was reduced to 40-50 °C to avoid filtration near the boiling point of MTBE. The batch was filtered through hyflo supercel and the cake was rinsed with 1.0 kg of hot (40-50 °C) MTBE. The clear filtrate was distilled under vacuum to a target volume of two parts with respect to the starting material. The concentrated solution was diluted with 5.18 kg MTBE and again subjected to vacuum14061828748.1distillation to remove residual water (KF). The batch was further subjected to multiple MTBE distillations under vacuum, then heated to 45-50 °C and n-heptane (0.96 kg) was added to the batch over 30 minutes. The batch was maintained at 45-50 °C for 20 minutes and additional n-heptane (2.87 kg) was added over 30 minutes. The batch temperature was adjusted to 20-25 °C over 1.0 hour and was maintained for 1.0 hour 20-25 °C. The batch was then further cooled down to 0-5 °C over 30 minutes and then was maintained at 0-5 °C for 1.0 hour. The product was isolated by filtration and washed with cold heptane and dried to afford 4-cyanopyrazole (0.252 kg, 42%).

[0511] Example 11: Single Crystal Growth of Methanol Solvate of Compound 4 and Single Crystal Structure Determination.

[0512] Single crystals suitable for SCXRD (single crystal X-ray diffraction) were obtained via layer diffusion of MeOH (1 ml) into a solution of Compound 4 (31.8 mg) in 2Me-THF (1 ml) at room temperature.

[0513] The cry stal structure of Compound 4 was determined by SCXRD. The crystallographic data and the information of structure refinements are listed in Table 6.

[0514] Error! Reference source not found.The SCXRD revealed that the crystal adopted the orthorhombic crystal system and P2(l)2(l)2(l) space group with a = 7.3685(5) A, b = 9.7868(6) A, c = 28.5425(18) A, a = 90°, = 90°, y= 90°. The asymmetric unit contains one Compound 4 plus one discrete methanol (CH3OH) solvent molecule, i.e., a mono-MeOH solvate of Compound 4.OTHER EMBODIMENTS

[0515] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.14161828748.1

Claims

WHAT IS CLAIMED IS:

1. A process of preparing Compound 1Compound 1 or a pharmaceutically acceptable salt thereof, comprising:(iiic) contacting Compound 2Compound 2 with 4-cyanopyrazole or a salt thereof in the presence of cesium carbonate and a solvent to formCompound 1.

2. A process of preparing Compound 1Compound 1 or a pharmaceutically acceptable salt thereof, comprising:(ia) contacting 3-amino-177-pyrazole-4-carbonitrile or a salt thereof with a nitrite reagent in an aqueous solvent system to form a first reaction mixture;(iia) contacting the first reaction mixture with hypophosphorous acid to form 4- cyanopyrazole or a salt thereof; and14261828748 1(iiia) contacting Compound 2Compound 2 with 4-cyanopyrazole or a salt thereof in the presence of a base and a solvent to form Compound 1.

3. The process according to claim 2, wherein the nitrite reagent comprises sodium nitrite, tert-butyl nitrite, or amyl nitrite.

4. The process according to claim 2 or claim 3, wherein the base of step (iiia) comprises a carbonate base or an alkylamine base.

5. A process of preparing Compound 1Compound 1 or a pharmaceutically acceptable salt thereof, comprising:Compound B(ib) contacting Compound B, , wherein R2of Compound B is Ci-4 alkyl or phenyl, with NHs’TfcO to form l / f-pyrazole-4-carboxamide,(iib) contacting l / / -pyrazole-4-carboxamide with a dehydrating reagent in the presence14361828748 1of a base and a solvent to form 4-cyanopyrazole; and(iiib) contacting Compound 2Compound 2 with 4-cyanopyrazole in the presence of a base and a solvent to form Compound 1.

6. The process according to claim 5, wherein Compound B is l / 7-pyrazole-4-carboxylate,7. The process according to claim 5 or claim 6, wherein the dehydrating reagent of step (iib) comprises POCI3, SOCh, trifluoroacetic anhydride (TFAA), methyl-trimethyl-silyl- tri fluoroacetamide (MSTFA), 2,2-dimethylpropanoyl chloride, oxalyl chloride, methyl N- (triethylammoniumsulfonyl)carbamate fBurgess Reagent), pyridine, or triethylamine (TEA), or any combination thereof.

8. The process according to any one of claims 1-7, further comprising (iv) contacting Compound 3with a brominating reagent to obtain Compound 2.

9. The process according to claim 8, wherein the brominating reagent of step (iv) comprises14461828748 1molecular bromine, N-bromosuccinimide, dibromo-dimethyl-hydantoin, tribromotriazinone, dibromohydantoin, N-bromosaccharin, or tribromocyanuric acid.

10. The process according to claim 8 or claim 9, wherein the process further comprises:(v) oxidizing Compound 4in a reaction mixture comprising a ruthenium reagent, an oxidizing reagent, and a solvent, to obtain Compound 3.

11. The process according to claim 10, wherein the ruthenium reagent comprises RuCh or any hydrate thereof, ruthenium tetroxide, or tetrapropylammonium perruthenate (TPAP).

12. The process according to claim 10 or claim 11, wherein the oxidizing reagent comprises O2, oxone, a metal bromate, a metal periodate, a metal chlorate, a metal iodate, metal dichromate, pyridinium chlorochromate, pyridinium dichromate, Dess-Martin periodinane, oxalyl chloride and DMSO, chromium(VI) oxide with pyridine in dichloromethane, or chromium trioxide in aqueous sulfuric acid.

13. The process according to any one of claims 10-12, wherein the process further comprises:(vii) contacting Compound 5Compound 514561828748 1with a reaction mixture comprising a boron reducing agent and a solvent, to obtain Compound 414. The process according to claim 13, wherein the boron reducing agent of step (vii) comprises 9-borabicyclo[3.3.1]nonane (9-BBN), THF-BH3, pinacolborane, thexyl-BH2, disiamylborane, catechol borane, borane-DMS (dimethylsulfide), BHs»Me2S, BF3*Et2O, NaBH, or any combination thereof.

15. The process according to claim 13 or claim 14, further comprising:(viii) contacting Compound 6Compound 6 with a reaction mixture comprising ethyl triphenyl phosphonium bromide, a base, and a solvent, to obtain Compound 5.

16. The process according to claim 15, wherein the base of step (viii) comprises an alkyl lithium, a metal alkoxide, a metal amylate, a metal hydride, or a metal dialkylamide.

17. The process according to claim 15 or claim 16, wherein the process further comprises: (ixa) contacting Compound 7Compound 7 with a reaction mixture comprising methyl aluminum bis(2,6-di-ter / -butyl-4-methylphenoxide) (MAD reagent), methyl magnesium bromide, and a solvent, to obtain Compound 6.14661828748 118. The process according to claim 17, further comprising:(ixb) contacting Compound 7with a methylating reagent in the presence of a solvent to obtain Compound 6, wherein the methylating reagent is trimethylaluminum (AlMea).

19. The process according to claim 17 or claim 18, further comprising:(xii) reducing Compound 8in presence of a solvent to obtain Compound 7.

20. The process according to claim 19, wherein the reduction of step (xii) is performed in the presence of a metal catalyst and a source of hydrogen.

21. A process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising the steps of:(ivb) contacting Compound 314761828748 1with molecular bromine to obtain Compound 2Compound 2; and(iiic) contacting Compound 2 with 4-cyanopyrazole or a salt thereof in the presence of a cesium carbonate base and a solvent to obtain Compound 1 or a pharmaceutically acceptable salt thereof.

22. The process according to claim 21, wherein the Compound 3 is contacted with molecular bromine in the presence of a solvent and a catalytic amount of a protic acid.

23. A process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising:(v) oxidizing Compound 414861828748 1in a reaction mixture comprising a ruthenium reagent, an oxidizing reagent, and a solvent to obtain Compound 3(iv) contacting Compound 3 with a brominating reagent to obtainCompound 2Compound 2; and(iii) contacting Compound 2 with 4-cyanopyrazole or a salt thereof in the presence of a base and a solvent to obtain Compound 1.

24. The process according to claim 23, wherein the oxidizing reagent of step (v) comprises O2, oxone, a metal bromate, a metal periodate, a metal chlorate, a metal iodate, metal dichromate, pyridinium chlorochromate, pyridinium dichromate, Dess-Martin periodinane, oxalyl chloride and DMSO, chromium(VI) oxide with pyridine in dichloromethane, or chromium trioxide in aqueous sulfuric acid.14961828748 125. The process according to claim 24, wherein the oxidizing reagent of step (v) comprises O2, oxone, a metal bromate, a metal periodate, a metal chlorate, or a metal iodate.

26. The process according to claim 25, wherein the oxidizing reagent comprises a metal bromate.

27. The process according to claim 25, wherein the oxidizing reagent of step (v) comprises NaBrCh or KB1O3.

28. The process according to any one of claims 23-27, wherein the ruthenium reagent comprises RuCh or any hydrate thereof, ruthenium tetroxide, or tetrapropylammonium perruthenate (TPAP).

29. The process according to any one of claims 23-28, wherein the base in step (iii) comprises a metal carbonate.

30. The process according to claim 29, wherein the metal carbonate base is lithium carbonate, sodium carbonate, cesium carbonate or potassium carbonate.

31. A process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising:(xiia) reducing Compound 815061828748 1Compound 8 in presence of hydrogen gas, a Pd / C catalyst, and a solvent to obtain Compound 7(ix) contacting Compound 7 with a reaction mixture comprising methyl aluminum bis(2,6-di-to7-butyl-4-methylphenoxide), methyl magnesium bromide, and a solvent (ixa), or contacting Compound 7 with a methylating agent in the presence of a solvent, to produce Compound 6 (ixb), wherein the methylating agent is trimethylaluminum (AIMea):Compound 6 .(viii) contacting Compound 6 with a reaction mixture comprising ethyl triphenyl phosphonium bromide, potassium / c / 7-butoxide, and a solvent, to produce Compound 5Compound 5(viia) reacting Compound 5 in a reaction mixture comprising 9- borabicyclo[3.3.1]nonane (9-BBN) and a solvent (viia), or reacting Compound 5 in a reaction mixture comprising BH3-THF and a solvent (viib), to obtain Compound 4;15161828748 1Compound 4(va) oxidizing Compound 4 in a reaction mixture comprising tetrabutylammonium bromide, a phosphate buffer, NaBrCh, a catalytic amount of a ruthenium reagent, an oxidizing reagent, and a solvent to obtain Compound 3Compound 3(iva) contacting Compound 3 with a reaction mixture comprising molecular bromine and a catalytic amount of HBr to obtain Compound 2Compound 2(iiic) contacting Compound 2 with 4-cyanopyrazole in a reaction mixture comprising cesium carbonate and a solvent to provide Compound 1.

32. A process of preparing 4-cyanopyrazole4-cyanopyrazole or a salt thereof, comprising the steps of:(ia-1) contacting hydrazine or a hydrate thereof with Compound A:15261828748 1Compound A , ^gj-g^ pj jsQ_4^pyi optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1.4 alkyl, and C1-4 haloalkyl, to provide 3-amino-4-cyanopyrazole3-amino-4-cyanopyrazole .(ia-2) contacting the 3-amino-4-cyanopyrazole with a nitrite reagent in the presence of a solvent to provide a first reaction mixture; and(iia) contacting the first reaction mixture of step (ia-2) with hypophosphorous acid (H3PO2) to provide 4-cyanopyrazole or a salt thereof.

33. The process according to claim 32, wherein R1is methyl or ethyl.

34. The process according to claim 32, wherein Compound A is 2- (ethoxymethylene)malonodinitrile (EMM).

35. A process of preparing 4-cyanopyrazole4-cyanopyrazole or a salt thereof, comprising:(ib) contacting Compound B, Compound B , ^gj-g^ p2 Q_4orpheny]; withON^^^NH2NH3*H2O to provide lH-pyrazole-4-carboxamide, HN ;and(iib) contacting 177-pyrazole-4-carboxamide with a dehydrating reagent in the presence15361828748 1of a base and a solvent to form 4-cyanopyrazole.

36. The process according to claim 35, wherein the dehydrating reagent of step (iib) comprises POCh, SOCh, trifluoroacetic anhydride (TFAA), methyl-trimethyl-silyl- trifluoroacetamide (MSTFA), 2,2-dimethylpropanoyl chloride, oxalyl chloride, methyl N- (triethylammoniumsulfonyl)carbamate (Burgess Reagent), pyridine, or triethylamine (TEA), or any combination thereof.

37. The process according to claim 35 or claim 36, wherein the base of step (iib) comprises EtaN, pyridine, N,N-diisopropylethylamine, N-methylpiperidine, N-methylmorpholine, lutidine, or picoline, or any combination thereof.

38. The process according to any one of claims 35-37, wherein Compound B is IH-O pyrazole-4-carboxylate, HNJ0Et39. A process of preparing Compound S-3bCompound S-3b or a pharmaceutically acceptable salt thereof, comprising:(S-3a) contacting Compound 215461828748 1with an alkali metal acetate in the presence of an organic solvent to obtain Compound S-3a(S-3b) contacting Compound S-3a with a hydroxide base to obtain Compound S3-b.

40. A process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising:(S-3c) contacting Compound S-3bCompound S-3b with a compound of Formula (X)15561828748 1(X), or a pharmaceutically acceptable salt thereof, wherein Z1is Ci-6 alkyl optionally substituted with one or more halo, or a 6-10 membered mono- or bi-cyclic aryl optionally substituted with methyl or halo, in the presence of a base and an organic solvent to obtain Compound 1 or a pharmaceutically acceptable salt thereof.

41. The process according to claim 40, wherein Z1is selected from the group consisting of unsubstituted Ci-6 alkyl, phenyl optionally substituted with one of methyl or -Br, and naphthyl optionally substituted with one of -Cl, -Br, or methyl.

42. The process according to claim 40 or claim 41, further comprising:(S-3a) contacting Compound 2with an alkali metal acetate in the presence of an organic solvent to obtain Compound S-3a(S-3b) contacting Compound S-3a with a hydroxide base to obtain Compound S3-b.15661828748 143. A compound of Formula (X-l)or a salt thereof, whereinZ2is Ci-6 alkyl optionally substituted with one or more groups independently selected from halo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups independently selected from methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups independently selected from halo, C1-3 alkyl, or oxo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups independently selected methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of halo, C1-3 alkyl, and oxo.

44. The compound or salt of claim 43, wherein Z2is selected from the group consisting of unsubstituted Ci-6 alkyl, phenyl optionally substituted with one of methyl or -Br, naphthyl optionally substituted with one of -Cl, -Br, or methyl, cyclohexyl optionally substituted with oxo or two methyl groups, and bicycle[2.2.1 ]heptyl optionally substituted with oxo or two methyl groups.wherein the compound of Formula (X-l) is15761828748 146. A process of preparing a compound of Formula (X-l)or a salt thereof, whereinZ2is Ci-6 alkyl optionally substituted with one or more groups independently selected from halo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups independently selected from methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups independently selected from halo, C1-3 alkyl, or oxo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups independently selected methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of halo, C1-3 alkyl, and oxo, comprising:(S-4a) contacting Compound S-3b15861828748 1Compound S-3b with a compound of Formula (X-la)Ox ZO o'SC 9 z3z2(X-la) wherein Z3is a leaving group in the presence of a nitrogen base and an organic solvent to form the compound of Formula (X-l).

47. A process of preparing Compound 1or a pharmaceutically acceptable salt thereof, comprising:(S-4b) contacting a compound of Formula (X-l)or a pharmaceutically acceptable salt thereof, whereinZ2is Ci-6 alkyl optionally substituted with one or more groups independently selected from halo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with one or more groups independently selected from methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic15961828748 1cycloalkyl optionally substituted with one or more groups independently selected from halo, C1-3 alkyl, or oxo, a 3-10 membered mono- or bi-cyclic aryl optionally substituted with 1-3 groups independently selected methyl, halo, or oxo, or a 3-8 membered mono- or bi-cyclic cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of halo, C1-3 alkyl, and oxo, with 4-cyanopyrazole in the presence of a base and an organic solvent to obtain Compound 1.

48. The process according to claim 47, wherein the compound of Formula (X-l) ispharmaceutically acceptable salt thereof.

49. The process according to claim 47 or claim 48, further comprising:(S-4a) contacting Compound S-3b16061828748 1Compound S-3b with a compound of Formula (X-la)Ck / O z3z2(X-la) wherein Z3is a leaving group in the presence of a nitrogen base and an organic solvent to form the compound of Formula (X-l).

50. A process of preparing Compound 3 having the structure:comprising:(v) oxidizing Compound 4in a reaction mixture comprising a catalytic amount of a ruthenium reagent, an oxidizing reagent, and a solvent to obtain Compound 3.

51. The process according to claim 50, wherein the ruthenium reagent comprises RuClr or16161828748 1any hydrate thereof, ruthenium tetroxide, or tetrapropylammonium perruthenate (TPAP).

52. The process according to claim 51, wherein the ruthenium reagent comprises RuCh or any hydrate thereof53. The process of any one of claims 50-52, wherein the reaction mixture of step (v) further comprises a phase transfer agent and a buffer.

54. The process of claim 53, wherein the phase transfer agent comprises a quaternary ammonium ion and the buffer comprises a phosphate buffer.

55. The process of claim 54, wherein the phase transfer agent comprises tetrabutylammonium bromide.

56. The process according to any one of claims 50-55, wherein the oxidizing reagent of step (v) comprises O2, oxone, a metal bromate, a metal periodate, a metal chlorate, a metal iodate, metal dichromate, pyridinium chlorochromate, pyridinium dichromate, Dess-Martin periodinane, oxalyl chloride and DMSO, chromium(VI) oxide with pyridine in dichloromethane, or chromium trioxide in aqueous sulfuric acid.

57. The process according to claim 56, wherein the oxidizing reagent comprises a metal bromate.

58. A process of preparing Compound 6 having the structure:Compound 6 comprising: contacting Compound 716261828748 1Compound 7 with a methylating agent in the presence of a solvent to obtain Compound 6, wherein the methylating agent is trimethylaluminum (AlMea).

59. The process according to claim 58, wherein about 3 molar equivalents to about 4 molar equivalents of trimethylaluminum (AlMes) to Compound 7 is employed.

60. A process of preparing Compound 4 having the structure:comprising:Compound 5 with borane-THF (BH3-THF) in a solvent to obtain Compound 4.

61. The process according to claim 60, wherein about 1 molar equivalent to about 3 molar equivalents of BH3-THF to Compound 5 are employed.16361828748 162. The process according to any one of claim 60 or claim 61, wherein Compound 4 is obtained with a selectivity of at least about 98% diastereomeric excess.

63. The process according to any one of claims 60-62, further comprising:(viii) contacting Compound 6Compound 6 with a reaction mixture comprising ethyl triphenyl phosphonium bromide, a base, and a solvent, to obtain Compound 5.

64. The process according to claim 63, wherein the base of step (viii) comprises an alkyl lithium, a metal alkoxide, a metal amylate, a metal hydride, or a metal dialkylamide.

65. The process according to claim 63 or claim 64, wherein the process further comprises: (ixa) contacting Compound 7Compound 7 with a reaction mixture comprising methyl aluminum bis(2,6-di-to7-butyl-4-methylphenoxide) (MAD reagent), methyl magnesium bromide, and a solvent, to obtain Compound 6.

66. The process according to claim 63 or claim 64, further comprising:(I-ix) contacting Compound 716461828748 1with a methylating agent in the presence of a solvent to obtain Compound 6, wherein the methylating agent is trimethylaluminum (AlMes).

67. A compositi on compri sing :(i) 98.0% w / w or greater of Compound 3:; orCompound 6 .Qr99.0% w / w or greater of 4-cyanopyrazole:16561828748 14-cyanopyrazole68. A crystalline form of Compound 4:Compound 4 wherein the crystalline form is a methanol solvate of Compound 4.

69. The crystalline form of claim 68, further characterized by one or more peaks corresponding to 2-theta values measured in degrees of 6.2 ± 0.2, 12.3 ± 0.2, 12.4 ± 0.2, 15.4 ± 0.2, and 16.3 ± 0.2 in an X-ray powder diffraction pattern.

70. The crystalline form of claim 68, wherein the methanol solvate of Compound 4 is in an orthorhombic crystal system.

71. A compound comprising 99.0% w / w or greater of Compound 1:Compound 1.

72. The composition according to claim 71, wherein the composition comprises less than0.2 %w / w of any of the following impurities:16661828748 1Impurity 1 Impurity 2 or167618287481

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