Patent Description:
The triazole is a heterocyclic organic five-membered ring with three nitrogen and two carbon atoms that is prevalent in biologically active compounds (<NPL>; <NPL>)). The triazole acts as an effective amide surrogate due to its strong dipole moment and possesses additional important features such as hydrogen bonding, dipole-dipole and pi-stacking interactions, and improved solubility (Dheer, D. The N-<NUM>/N-<NUM>-substituted <NUM>,<NUM>,<NUM>-triazole has been well-exploited, primarily due to advances in the azide-dipolarophile cycloaddition methodologies (i.e., Sharpless' Click variation of the Huisgen reaction (<NPL>)). The N-<NUM> substituted <NUM>,<NUM>,<NUM>-triazole has been less well studied, since there are no effective general synthetic methods beyond several unselective or specialized syntheses. Thus the need exists for the regioselective preparation of N-<NUM> substituted <NUM>,<NUM>,<NUM>-triazoles (Wang, X-j.

<CIT> discloses sulfonyl ureas and related compounds which have advantageous properties and show useful activity in the inhibition of activation of the NLRP3 inflammasome. Such compounds are disclosed as being useful in the treatment of a wide range of disorders in which the inflammation process, or more specifically the NLRP3 inflammasome, have been implicated as being a key factor.

<NPL>) describes how the optimization of the previously described fused azadecalin series of selective glucocorticoid receptor (GR) antagonists led to the identification of CORT125134, a candidate being evaluated in a phase <NUM> clinical study in patients with Cushing's syndrome.

<CIT> describes heteroaryl ether fused azadecalin compounds and methods of using the compounds as glucocorticoid receptor modulators.

In a first aspect, the present invention provides a method of making a compound of Formula I:
<CHM>
wherein the content of the compounds of Formula Ia and Formula Ib:
<CHM>
is less than <NUM>% by weight,
comprising:.

In a second aspect, the present invention provides a method of making a compound of Formula I:
<CHM>
wherein the content of the compounds of Formula Ia and Formula Ib:
<CHM>
is less than <NUM>% by weight, comprsising:.

The present invention provides a method of preparing N-<NUM> alkylated triazoles such as <NUM>-(benzylthio)-<NUM>-methyl-<NUM>-<NUM>,<NUM>,<NUM>-triazole, substantially free from N-<NUM> and N-<NUM> alkylated triazoles. The key to the invention is the subsequent alkylation of any N-<NUM> and N-<NUM> alkylated triazoles that are formed, resulting in doubly-alkylated salts which are subsequently removed by an aqueous washing step.

"Forming a reaction mixture" refers to the process of bringing into contact at least two distinct species such that they mix together and can react. It should be appreciated, however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

"Substantially free" refers to a composition of regioisomers, wherein the undesired regioisomer content is less than <NUM>%, preferably less than <NUM>%, more preferably less than <NUM>% or even less than <NUM>% by weight.

"Non-nucleophilic base" refers to a base that is a moderate to strong base but at the same time is a poor nucleophile. Representative non-nucleophilic bases include bases such as potassium carbonate, sodium carbonate, potassium tert-butoxide, and sodium tert-butoxide, as well as nitrogen bases, such as triethylamine, diisopropylethyl amine, N,N-diethylaniline, pyridine, <NUM>,<NUM>-lutidine, <NUM>,<NUM>,<NUM>-collidine, <NUM>-dimethylaminopyridine, and quinuclidine.

"Solvent" refers to a substance, such as a liquid, capable of dissolving a solute. Solvents can be polar or non-polar, protic or aprotic. Polar solvents typically have a dielectric constant greater than about <NUM> or a dipole moment above about <NUM>, and non-polar solvents have a dielectric constant below about <NUM> or a dipole moment below about <NUM>. Protic solvents are characterized by having a proton available for removal, such as by having a hydroxy or carboxy group. Aprotic solvents lack such a group. Representative polar protic solvents include alcohols (methanol, ethanol, propanol, isopropanol, etc.), acids (formic acid, acetic acid, etc.) and water. Representative polar aprotic solvents include dichloromethane, chloroform, tetrahydrofuran, diethyl ether, acetone, ethyl acetate, dimethylformamide, dimethylacetamide, acetonitrile and dimethyl sulfoxide. Representative non-polar solvents include alkanes (pentanes, hexanes, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene, toluene, and <NUM>,<NUM>-dioxane. Other solvents are useful in the present invention.

"Partition mixture" refers to an immiscible mixture of an organic solvent layer and an aqueous water layer used in solvent-solvent extractions in order to isolate a desired substance. Suitable organic solvents include, but are not limited to, hexane, diethyl ether, ethyl acetate, and dichloromethane. Suitable aqueous water layers include, but are not limited to, water, and various water soluble salt solutions, for example, <NUM>% sodium chloride solution.

"Leaving group" refers to groups that maintain the bonding electron pair during heterolytic bond cleavage. For example, a leaving group is readily displaced during a nucleophilic displacement reaction. Suitable leaving groups include, but are not limited to, chloride, bromide, iodide, mesylate, tosylate, triflate, <NUM>-nitrobenzenesulfonate, <NUM>-chlorobenzenesulfonate, sulfate, etc. One of skill in the art will recognize other leaving groups useful in the present invention.

"Alkyl" refers to a straight or branched acyclic hydrocarbon containing normal, secondary, or tertiary carbon atoms. For example, an alkyl group can have <NUM> to <NUM> carbon atoms (i.e., C<NUM>-C<NUM> alkyl), <NUM> to <NUM> carbon atoms (i.e., C<NUM>-C<NUM> alkyl), or <NUM> to <NUM> carbon atoms (i.e., C<NUM>-C<NUM> alkyl). Alkyl can include any number of carbons, such as C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM> and C<NUM>-<NUM>. Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH<NUM>), ethyl (Et, -CH<NUM>CH<NUM>), <NUM>-propyl (n-Pr, n-propyl, -CH<NUM>CH<NUM>CH<NUM>), <NUM>-propyl (i-Pr, i-propyl, -CH(CH<NUM>)<NUM>), <NUM>-butyl (n-Bu, n-butyl, - CH<NUM>CH<NUM>CH<NUM>CH<NUM>), <NUM>-methyl-<NUM>-propyl (i-Bu, i-butyl, -CH<NUM>CH(CH<NUM>)<NUM>), <NUM>-butyl (s-Bu, s-butyl, -CH(CH<NUM>)CH<NUM>CH<NUM>), <NUM>-methyl-<NUM>-propyl (t-Bu, t-butyl, -C(CH<NUM>)<NUM>), <NUM>-pentyl (n-pentyl, -CH<NUM>CH<NUM>CH<NUM>CH<NUM>CH<NUM>), <NUM>-pentyl (s-Pn, s-Pentyl, -CH(CH<NUM>)CH<NUM>CH<NUM>CH<NUM>), <NUM>-pentyl (-CH(CH<NUM>CH<NUM>)<NUM>), <NUM>-methyl-<NUM>-butyl (t-Pn, <NUM>-Pentyl, -C(CH<NUM>)<NUM>CH<NUM>CH<NUM>), <NUM>-methyl-<NUM>-butyl (neo-Pn, neo-Pentyl, -CH(CH<NUM>)CH(CH<NUM>)<NUM>), <NUM>-methyl-<NUM>-butyl (-CH<NUM>CH<NUM>CH(CH<NUM>)<NUM>), <NUM>-methyl-<NUM>-butyl (-CH<NUM>CH(CH<NUM>)CH<NUM>CH<NUM>), <NUM>-hexyl (-CH<NUM>CH<NUM>CH<NUM>CH<NUM>CH<NUM>CH<NUM>), <NUM>-hexyl (-CH(CH<NUM>)CH<NUM>CH<NUM>CH<NUM>CH<NUM>), <NUM>-hexyl (-CH(CH<NUM>CH<NUM>)(CH<NUM>CH<NUM>CH<NUM>)), <NUM>-methyl-<NUM>-pentyl (-C(CH<NUM>)<NUM>CH<NUM>CH<NUM>CH<NUM>), <NUM>-methyl-<NUM>-pentyl (-CH(CH<NUM>)CH(CH<NUM>)CH<NUM>CH<NUM>), <NUM>-methyl-<NUM>-pentyl (-CH(CH<NUM>)CH<NUM>CH(CH<NUM>)<NUM>), <NUM>-methyl-<NUM>-pentyl (-C(CH<NUM>)(CH<NUM>CH<NUM>)<NUM>), <NUM>-methyl-<NUM>-pentyl (-CH(CH<NUM>CH<NUM>)CH(CH<NUM>)<NUM>), <NUM>,<NUM>-dimethyl-<NUM>-butyl (-C(CH<NUM>)<NUM>CH(CH<NUM>)<NUM>), <NUM>,<NUM>-dimethyl-<NUM>-butyl (-CH(CH<NUM>)C(CH<NUM>)<NUM>, and octyl (-(CH<NUM>)<NUM>CH<NUM>).

"Haloalkyl" refers to an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom. The alkyl portion of a haloalkyl group can have <NUM> to <NUM> carbon atoms (i.e., C<NUM>-C<NUM> haloalkyl), <NUM> to <NUM> carbon atoms (i.e., C<NUM>-C<NUM> haloalkyl), or <NUM> to <NUM> carbon atoms (i.e., C<NUM>-C<NUM> haloalkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF<NUM>, -CHF<NUM>, -CFH<NUM>, -CH<NUM>CF<NUM>, and the like.

"Alkoxy" refers to a group having the formula -O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can have <NUM> to <NUM> carbon atoms (i.e., C<NUM>-C<NUM> alkoxy), <NUM> to <NUM> carbon atoms (i.e., C<NUM>-C<NUM> alkoxy), or <NUM> to <NUM> carbon atoms(i.e., C<NUM>-C<NUM> alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH<NUM> or -OMe), ethoxy (-OCH<NUM>CH<NUM> or -OEt), t-butoxy (-O-C(CH<NUM>)<NUM> or -O-t-Bu), and the like.

"Haloalkoxy" refers to a group having the formula -O-haloalkyl, in which a haloalkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of a haloalkyl group can have <NUM> to <NUM> carbon atoms (i.e., C<NUM>-C<NUM> haloalkoxy), <NUM> to <NUM> carbon atoms (i.e., C<NUM>-C<NUM> haloalkoxy), or <NUM> to <NUM> carbon atoms (i.e., C<NUM>-C<NUM> haloalkoxy). Examples of suitable haloalkoxy groups include, but are not limited to, -OCH<NUM>F, -OCHF<NUM>, and -OCF<NUM>.

"Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can include any suitable number of ring atoms, such as, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> ring atoms, as well as from <NUM> to <NUM>, <NUM> to <NUM>, or <NUM> to <NUM> ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene linking group. Some aryl groups have from <NUM> to <NUM> ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from <NUM> to <NUM> ring members, such as phenyl or naphthyl. Some other aryl groups have <NUM> ring members, such as phenyl.

"Room temperature" is the range of air temperatures generally considered to be suitable for human occupancy, or between about <NUM> degrees Celsius (<NUM> degrees Fahrenheit) and <NUM> degrees Celsius (<NUM> degrees Fahrenheit).

"Benzyl" refers to -CH<NUM>-Ph, where "Ph" refers to phenyl.

"Tosyl" (Ts) refers to the toluene-<NUM>-sulfonyl radical, -SO<NUM>C<NUM>H<NUM>CH<NUM>.

"Tosylate" (OTs) refers to the anion of p-toluenesulfonic acid, -OSO<NUM>C<NUM>H<NUM>CH<NUM>.

"Tautomer" refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. For example, the tautomerism of <NUM>,<NUM>,<NUM>-triazole in aqueous solution has been described (<NPL>).

It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention. For example, compounds of the Formula II:
<CHM>
may exist in such tautomeric forms as compounds of the Formula IIa and Formula IIb:
<CHM>
All such tautomeric forms of the compounds being within the scope of the disclosure.

The compounds of Formula I can be prepared by a variety of means. For example, the compounds of Formula I can be prepared as described below, via N-alkylation of a compound of Formula II with a compound of Formula III, namely methyl p-toluenesulfonate, or methyl iodide.

In one embodiment, the present invention provides a method of making a compound of Formula I:
<CHM>
substantially free of the compounds of Formula Ia and Formula Ib:
<CHM>
The method of making the compound of Formula I includes forming a first reaction mixture comprising a compound of Formula II:
<CHM>
a non-nucleophilic base, a first solvent, and a compound of Formula IIIa:.

wherein the molar ratio of the compound of Formula IIIa to the compound of Formula II is greater than <NUM>, and wherein the reaction mixture is mixed for at least two hours at or above room temperature under conditions suitable to form an intermediate mixture comprising the compound of Formula I and at least one compound of Formula Ia and Ib. The method also includes forming a second reaction mixture comprising the intermediate mixture, and a compound of Formula IIIb:.

wherein the molar ratio of the compound of Formula IIIb to the compounds of the intermediate mixture is greater than <NUM>, and wherein the second reaction mixture is mixed for at least two hours at or above room temperature under conditions suitable to form at least one compound of Formula IVa or Formula IVb:
<CHM>
The method also includes forming a partition mixture comprising the second reaction mixture, water and an organic solvent to form an aqueous layer and an organic layer, and separating the organic layer and aqueous layer to isolate the compound of Formula I substantially free of the compounds of Formula Ia, Formula Ib, Formula IVa and Formula IVb. For the compounds of Formula I, Ia, Ib, II, IIIa, IIIb, IVa and IVb, R1a and R1b are independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or cyclopropylmethyl; R<NUM> is halogen, SCH<NUM>Ar or SCHAr<NUM>, wherein each Ar is phenyl optionally substituted with <NUM>-<NUM> R2a groups each independently halogen, C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, C<NUM>-C<NUM> alkoxy, or C<NUM>-C<NUM> haloalkoxy; LG1a is Br, I or OSO<NUM>R<NUM> and LG1b is OSO<NUM>R<NUM>; and R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>.

Any suitable non-nucleophilic base can be used in the method of the present invention. Representative non-nucleophilic bases include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, and sodium tert-butoxide. In some embodiments, the non-nucleophilic base can be potassium carbonate, sodium carbonate, potassium tert-butoxide, or sodium tert-butoxide. In some embodiments, the non-nucleophilic base can be potassium carbonate, or sodium carbonate. In some embodiments, the non-nucleophilic base can be potassium carbonate. In some embodiments, the non-nucleophilic base can be sodium tert-butoxide.

The first solvent can be any suitable solvent. Representative solvents include, but are not limited to, acetone, acetonitrile, dimethylacetamide, tetrahydrofuran, dimethylsulfoxide, toluene, methyl tert-butyl ether, ethanol, dimethylformamide, or combinations thereof. In some embodiments, the first solvent can be dimethylacetamide, methyl tert-butyl ether, ethanol, or combinations thereof. In some embodiments, the first solvent can be dimethylacetamide. In some embodiments, the first solvent can be dimethylformamide.

Any suitable combination of non-nucleophilic base and solvent can be used in the methods disclosed herein. In some embodiments, the non-nucleophilic base can be potassium carbonate, sodium carbonate, potassium tert-butoxide, or sodium tert-butoxide, and the solvent can be acetone, acetonitrile, dimethylacetamide, tetrahydrofuran, dimethylsulfoxide, toluene, methyl tert-butyl ether, ethanol, dimethylformamide, or combinations thereof. In some embodiments, the non-nucleophilic base can be potassium carbonate or sodium carbonate, and the solvent can be dimethylacetamide, methyl tert-butyl ether, ethanol, or combinations thereof. In some embodiments, the non-nucleophilic base can be potassium tert-butoxide or sodium tert-butoxide, and the solvent can be selected from dimethylacetamide, methyl tert-butyl ether, ethanol, or combinations thereof. In some embodiments, the non-nucleophilic base can be sodium tert-butoxide, and the solvent can be dimethylacetamide, methyl tert-butyl ether, ethanol, or combinations thereof. In some embodiments, the non-nucleophilic base can be potassium carbonate, and the solvent can be selected from dimethylacetamide, methyl tert-butyl ether, ethanol, or combinations thereof. In some embodiments, the non-nucleophilic base can be potassium carbonate, and the solvent can be dimethylacetamide.

The N-alkylation of the compound of Formula II can be performed in one step or two steps. When the N-alkylation is performed using two steps, the first N-alkylation step can include any suitable molar ratio of the compound of Formula IIIa to the compound of Formula II, wherein the ratio is greater than <NUM>. Representative molar ratios include, but are not limited to, at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or greater than <NUM>. The molar ratio of the compound of Formula IIIa to the compound of Formula II can be from <NUM> to <NUM>. The molar ratio of the compound of Formula IIIa to the compound of Formula II is greater than <NUM>.

The second N-alkylation step can include any suitable molar ratio of the compound of Formula IIIb to the compounds of the intermediate mixture, wherein the ratio is greater than <NUM>. Representative molar ratios include, but are not limited to, at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or greater than <NUM>. The molar ratio of the compound of Formula IIIb to the compounds of the intermediate mixture can be from <NUM> to <NUM>. In some embodiments, the molar ratio of the compound of Formula IIIb to the compounds of the intermediate mixture can be at least <NUM>. In some embodiments, the molar ratio of the compound of Formula IIIb to the compounds of the intermediate mixture can be greater than <NUM>.

When the N-alkylation is performed using a single step, the N-alkylation step can include any suitable molar ratio of the compounds of Formula IIIa and Formula IIIb to the compound of Formula II, wherein the ratio is at least <NUM>. Representative molar ratios include, but are not limited to, at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or greater than <NUM>. The molar ratio of the compound of Formula IIIa and Formula IIIb to the compounds of Formula II can be about <NUM>.

The N-alkylation steps of forming the compound of Formula I can be performed for any suitable reaction time, wherein the reaction time is is at least two hours. For example, the reaction time can be for minutes, hours, or days. In some embodiments, the reaction time can be for several hours, such as at least eight hours. In some embodiments, the reaction time can be for several hours, such as at least overnight. In some embodiments, the reaction time can be for several days. The reaction time is for at least two hours. In some embodiments, the reaction time can be for at least eight hours. In some embodiments, the reaction time can be for at least several days. In some embodiments, the reaction time can be for about two hours, or for about <NUM> hours, or for about <NUM> hours, or for about <NUM> hours, or for about <NUM> hours, or for about <NUM> hours, or for about <NUM> hours, or for about <NUM> hours, or for about <NUM> hours, or for about <NUM> hours, or for about <NUM> hours, or for about <NUM> hours. In some embodiments, the reaction time can be for about <NUM> day, or for about two days, or for about three days, or for about four days, or for about five days, or for about six days, or for about a week, or for about more than a week.

The reaction mixture of the N-alkylation steps of forming the compound of Formula I can be performed at any suitable reaction temperature, wherein the reaction temperature is at or above room temperature. Representative temperatures include at room temperature, or above room temperature. Other temperatures useful in the methods disclosed herein include from about room temperature to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>. The first reaction mixture can be at a temperature of about room temperature, or at a temperature of about <NUM>, or at about <NUM>, or at about <NUM> or at about <NUM>, or at about <NUM>, or at about <NUM>, or at about <NUM>, or at about <NUM>, or at about <NUM>, or at about <NUM>, or at about <NUM>. The first reaction mixture is at a temperature of room temperature or above room temperature. In some embodiments, the first reaction mixture can be a temperature of from about room temperature to about <NUM>. In some embodiments, the first reaction mixture can be a temperature of from about <NUM> to about <NUM>.

The method of preparing the compound of Formula I also includes forming a partition mixture of the first or second reaction mixture, water and an organic solvent to form an aqueous layer and an organic layer. In some embodiments, the organic solvent can be formed from diethyl ether, ethyl acetate, or dichloromethane. In some embodiments, the organic solvent can be dichloromethane. In some embodiments, the organic solvent can be ethyl acetate. In some embodiments, the partition mixture can be formed by combining the first reaction mixture, water, and dichloromethane. In some embodiments, the partition mixture can be formed by combining the first reaction mixture, water, and ethyl acetate.

R1a and R1b of Formula I, Ia, Ib, IIIa, IIIb, IVa, IVb are as defined above. In some embodiments, R1a and R1b can independently be methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, or cyclopropylmethyl. In some embodiments, R1a and R1b can independently be methyl, ethyl, or cyclopropylmethyl. In some embodiments, R1a can be ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or cyclopropylmethyl, and R1b can be methyl. In some embodiments, R1a can be iso-propyl, and R1b can be methyl. In some embodiments, R1a and R1b can be methyl.

R<NUM> of Formula I, Ia, Ib, II, IVa, IVb is as defined above. In some embodiments, R<NUM> can be halogen, SCH<NUM>Ar or SCHAr<NUM>, wherein each Ar is phenyl optionally substituted with <NUM>-<NUM> R2a groups each independently halogen, C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, C<NUM>-C<NUM> alkoxy, or C<NUM>-C<NUM> haloalkoxy. In some embodiments, R<NUM> can be SCH<NUM>Ar, wherein Ar is phenyl optionally substituted with <NUM>-<NUM> R2a groups each independently halogen, C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, C<NUM>-C<NUM> alkoxy, or C<NUM>-C<NUM> haloalkoxy. In some embodiments, R<NUM> can be SCH<NUM>Ar, wherein Ar is phenyl optionally substituted with <NUM>-<NUM> R2a groups each independently halogen, C<NUM>-C<NUM> alkyl, or C<NUM>-C<NUM> haloalkyl. In some embodiments, R<NUM> can be SCH<NUM>Ar, wherein Ar is phenyl or p-tolyl. In some embodiments, R<NUM> can be SCH<NUM>Ar, where Ar is phenyl. In some embodiments, R<NUM> can be halogen.

In some embodiments, LG1a can independently be Br, I or OSO<NUM>R<NUM>, wherein R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>. In some embodiments, LG1a can independently be I or OSO<NUM>R<NUM>, wherein R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>. In some embodiments, LG1a can be Br or I. In some embodiments, LG1a can be Br.

LG1b is OSO<NUM>R<NUM>, wherein R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>. In some embodiments, LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>. In some embodiments, LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently C<NUM>-C<NUM> alkyl. In some embodiments, LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is Me, CF<NUM> or phenyl, wherein the phenyl is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>. In some embodiments, LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is Me, CF<NUM> or phenyl, wherein the phenyl is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, Me, F, Cl, Br, or NO<NUM>. In some embodiments, LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is phenyl, substituted with <NUM>-<NUM> R3a groups each independently hydrogen, Me, F, Cl, Br, or NO<NUM>. In some embodiments, LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is p-tolyl.

In some embodiments, LG1a and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>. In some embodiments, LG1a and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>. In some embodiments, LG1a and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently C<NUM>-C<NUM> alkyl. In some embodiments, LG1a and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is Me, CF<NUM> or phenyl, wherein the phenyl is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>. In some embodiments, LG1a and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is Me, CF<NUM> or phenyl, wherein the phenyl is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, Me, F, Cl, Br, or NO<NUM>. In some embodiments, LG1a and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is phenyl, substituted with <NUM>-<NUM> R3a groups each independently hydrogen, Me, F, Cl, Br, or NO<NUM>. In some embodiments, LG1a and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is p-tolyl.

Any suitable combination of R1a, R1b, LG1a and LG1b can be used in the methods disclosed herein. In some embodiments, R1a and R1b can independently be methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, or cyclopropylmethyl, while LG1a can independently be Br, I or OSO<NUM>R<NUM>, wherein R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>. In some embodiments, R1a and R1b can independently be methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, or cyclopropylmethyl, while LG1a can independently be I or OSO<NUM>R<NUM>, wherein R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>.

In some embodiments, R1a and R1b can be different such that R1a and R1b can independently be methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, or cyclopropylmethyl, while LG1a can independently be Br, I or OSO<NUM>R<NUM>, wherein R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>. In some embodiments, R1a can be n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, or cyclopropylmethyl, R1b can be methyl or ethyl, while LG1a can be Br or I, and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>. In some embodiments, R1a can be iso-propyl, R1b can be methyl, while LG1a can be Br, and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>.

In some embodiments, R1a can be n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, or cyclopropylmethyl, and LG1a can be Br or I. In some embodiments, R1a can be iso-propyl, and LG1a can be Br. In some embodiments, R1a-LG1a can be isopropyl bromide.

In some embodiments, R1b can be methyl or ethyl, and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>. In some embodiments, R1b can be methyl or ethyl, and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is methyl, trifluoromethyl, <NUM>,<NUM>,<NUM>-trifluoroethyl, or phenyl, wherein the phenyl is substituted with methyl, bromo or NO<NUM>. In some embodiments, R1b can be methyl, and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is phenyl substituted with methyl. In some embodiments, LG1b can be toluenesulfonyl, p-bromobenzenesulfonyl, nitrobenzenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, or <NUM>,<NUM>,<NUM>-trifluoroethyl-<NUM>-sulfonyl. In some embodiments, R1b-LG1b can be methyl tosylate.

In some embodiments, R1a and R1b are the same and can be methyl, ethyl, or cyclopropylmethyl, while LG1a and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is Me, CF<NUM> or phenyl, wherein the phenyl is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, Me, F, Cl, Br, or NO<NUM>. In some embodiments, R1a and R1b can be methyl, ethyl, or cyclopropylmethyl, while LG1a and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is p-tolyl. In some embodiments, R1a and R1b can be methyl, ethyl, or cyclopropylmethyl, while LG1a can be I. In some embodiments, R1a and R1b can be methyl, while LG1a and LG1b can be OSO<NUM>R<NUM>, wherein R<NUM> is p-tolyl. In some embodiments, R1a and R1b can be methyl, while LG1a can be I. In some embodiments, R1a-LG1a and R1b-LG1b can be methyl p-toluenesulfonate. In some embodiments, R1a-LG1a can be methyl iodide.

Any suitable combination of non-nucleophilic base and R1a-LG1a of Formula IIIa can be used in the methods disclosed herein. In some embodiments, the non-nucleophilic base can be selected from potassium carbonate, sodium carbonate, potassium tert-butoxide, and sodium tert-butoxide, while R1a-LG1a can be selected from isopropyl bromide, methyl p-toluenesulfonate and methyl iodide. In some embodiments, the non-nucleophilic base can be selected from potassium carbonate, and sodium carbonate, while R1a-LG1a can be selected from isopropyl bromide, methyl p-toluenesulfonate and methyl iodide. In some embodiments, the non-nucleophilic base can be potassium carbonate, while R1a-LG1a can be selected from isopropyl bromide, methyl p-toluenesulfonate and methyl iodide. In some embodiments, the non-nucleophilic base can be potassium carbonate, while R1a-LG1a can be methyl p-toluenesulfonate. In some embodiments, the non-nucleophilic base can be potassium carbonate, while R1a-LG1a can be methyl iodide. In some embodiments, the non-nucleophilic base can be potassium carbonate, while R1a-LG1a can be isopropyl bromide. In some embodiments, the non-nucleophilic base can be selected from potassium tert-butoxide, and sodium tert-butoxide, while R1a-LG1a can be selected from methyl p-toluenesulfonate and methyl iodide. In some embodiments, the non-nucleophilic base can be sodium tert-butoxide, while R1a-LG1a can be methyl p-toluenesulfonate.

When R1a-LG1a and R1b-LG1b are the same, any suitable combination of non-nucleophilic base and R1a-LG1a and R1b-LG1b can be used in the method of the present invention. In some embodiments, the non-nucleophilic base can be selected from potassium carbonate, sodium carbonate, potassium tert-butoxide, and sodium tert-butoxide, while R1a-LG1a can be selected from isopropyl bromide, methyl p-toluenesulfonate and methyl iodide. In some embodiments, the non-nucleophilic base can be selected from potassium carbonate, and sodium carbonate, while R1a-LG1a can be selected from isopropyl bromide, methyl p-toluenesulfonate and methyl iodide. In some embodiments, the non-nucleophilic base can be potassium carbonate, while R1a-LG1a can be selected from isopropyl bromide, methyl p-toluenesulfonate and methyl iodide. In some embodiments, the non-nucleophilic base can be potassium carbonate, while R1a-LG1a and R1b-LG1b can be methyl p-toluenesulfonate. In some embodiments, the non-nucleophilic base can be potassium carbonate, while R1a-LG1a can be methyl iodide. In some embodiments, the non-nucleophilic base can be potassium carbonate, while R1a-LG1a can be isopropyl bromide. In some embodiments, the non-nucleophilic base can be selected from potassium tert-butoxide, and sodium tert-butoxide, while R1a-LG1a can be selected from methyl p-toluenesulfonate and methyl iodide. In some embodiments, the non-nucleophilic base can be sodium tert-butoxide, while R1a-LG1a and R1b-LG1b can be methyl p-toluenesulfonate.

In some embodiments, the methods disclosed herein involve two alkylation steps where the compounds of Formula IIIa and Formula IIIb are different. In some embodiments, the present invention provides a method of making a compound of Formula I:
<CHM>
substantially free of the compounds of Formula Ia and Formula Ib:
<CHM>
The method of the present invention includes forming a first reaction mixture comprising a compound of Formula II:
<CHM>
a non-nucleophilic base, a first solvent, and a compound of Formula IIIa:.

wherein the molar ratio of the compound of Formula III to the compounds of the intermediate mixture is greater than <NUM>, and wherein the second reaction mixture is mixed for at least two hours at or above room temperature under conditions suitable to form at least one compound of Formula IVa or Formula IVb:
<CHM>
The method also includes forming a partition mixture comprising the second reaction mixture, water and an organic solvent to form an aqueous layer and an organic layer, and separating the organic layer and aqueous layer to isolate the compound of Formula I substantially free of the compounds of Formula Ia, Formula Ib, Formula IVa and Formula IVb. For the compounds of Formula I, Ia, Ib, II, IIIa, IIIb, IVa and IVb, R1a is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or cyclopropylmethyl; R1b is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or cyclopropylmethyl, such that R1b is different than R1a; LG1a is independently Br, I or OSO<NUM>R<NUM>; LG1b is OSO<NUM>R<NUM>; and R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>.

In some embodiments, R1a is ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or cyclopropylmethyl; and R1b is methyl.

In some embodiments, the compound of Formula I has the structure:
<CHM>
the compounds of Formula Ia and Formula Ib have the structures:
<CHM>
and the method includes forming the first reaction mixture of the compound of Formula II having the structure:
<CHM>
potassium carbonate, dimethylacetamide, and the compound of Formula IIIa having the structure:.

wherein the molar ratio of the compound of Formula IIIa to the compound of Formula II is greater than <NUM>, and wherein the reaction mixture is mixed for at least two hours at or above room temperature under conditions suitable to form the intermediate mixture comprising the compound of Formula I and at least one compound of Formula Ia or Formula Ib. The method also includes forming the second reaction mixture of the intermediate mixture, dimethylacetamide, and the compound of Formula IIIb:.

wherein the molar ratio of the compound of Formula IIIb to the compounds of the intermediate mixture is greater than <NUM>, and wherein the second reaction mixture is mixed for at least two hours at or above room temperature under conditions suitable to form at least one compound of Formula IVa or Formula IVb:
<CHM>
The method also includes forming the partition mixture of the second reaction mixture, water and dichloromethane to form the aqueous layer and the organic layer, and separating the organic layer and the aqueous layer to isolate the compound of Formula I substantially free of the compounds of Formula Ia, Formula Ib, Formula IVa and Formula IVb.

In some embodiments, the methods disclosed herein involve a single alkylation step where the compounds of Formula IIIa and Formula IIIb are the same. In some embodiments, the present invention provides a method of making a compound of Formula I:
<CHM>
substantially free of the compounds of Formula Ia and Formula Ib:
<CHM>
The method of the present invention includes forming a first reaction mixture comprising a compound of Formula II:
<CHM>
the non-nucleophilic base, the first solvent, a compound of Formula IIIa:.

wherein the molar ratio of the compounds of Formula IIIa and IIIb to the compound of Formula II is at least <NUM>, and wherein the reaction mixture is mixed for at least two hours at or above room temperature under conditions suitable to form the compound of Formula I and at least one compound of Formula IVa or Formula IVb:
<CHM>
The method also includes forming a partition mixture comprising the first reaction mixture, water and an organic solvent to form an aqueous layer and an organic layer, and separating the organic layer and aqueous layer to isolate the compound of Formula I substantially free of the compounds of Formula Ia, Formula Ib, Formula IVa and Formula IVb. For the compounds of Formula I, Ia, Ib, II, IIIa, IIIb, IVa and IVb, R1a and R1b are the same and are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or cyclopropylmethyl; R<NUM> is halogen, SCH<NUM>Ar or SCHAr<NUM>, wherein each Ar is phenyl optionally substituted with <NUM>-<NUM> R2a groups each independently halogen, C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, C<NUM>-C<NUM> alkoxy, or C<NUM>-C<NUM> haloalkoxy; LG1b is OSO<NUM>R<NUM>; and R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>.

In some embodiments, the compound of Formula I has the structure:
<CHM>
the compounds of Formula Ia and Formula Ib have the structures:
<CHM>
and the method includes forming the first reaction mixture of the compound of Formula II having the structure:
<CHM>
potassium carbonate, dimethylacetamide, and the compounds of Formula IIIa and IIIb each having the structure:.

wherein the molar ratio of the compounds of Formula IIIa and IIIb to the compound of Formula II is greater than <NUM>, and wherein the reaction mixture is mixed for at least two hours at or above room temperature under conditions suitable to form the compound of Formula I and at least one compound of Formula IVa or Formula IVb having the structures:
<CHM>
The method also includes forming the partition mixture of the first reaction mixture, water and dichloromethane to form the aqueous layer and the organic layer, and separating the organic layer and the aqueous layer to isolate the compound of Formula I substantially free of the compounds of Formula Ia, Formula Ib, Formula IVa and Formula IVb.

In some embodiments where the compounds of Formula IIIa and IIIb are the same, the present invention provides a method of making a compound of Formula I:
<CHM>
substantially free of the compounds of Formula Ia and Formula Ib:
<CHM>
including the step of forming a first reaction mixture of a compound of Formula II:
<CHM>
a non-nucleophilic base, a first solvent, and a compound of Formula III:.

wherein the molar ratio of the compound of Formula III to the compound of Formula II is at least <NUM>, and wherein the reaction mixture is mixed for at least two hours at or above room temperature under conditions suitable to form the compound of Formula I and at least one compound of Formula IVa or Formula IVb:
<CHM>
The methods disclosed herein also include the step of forming a partition mixture including the first reaction mixture, water and an organic solvent to form an aqueous layer and an organic layer, and separating the organic layer and aqueous layer to isolate the compound of Formula I substantially free of the compounds of Formula Ia, Formula Ib, Formula IVa and Formula IVb. For the compounds of Formula I, Ia, Ib, II, III, IVa and IVb, R<NUM> is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or cyclopropylmethyl, R<NUM> is halogen, SCH<NUM>Ar or SCHAr<NUM>, wherein each Ar is phenyl optionally substituted with <NUM>-<NUM> R2a groups each independently halogen, C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, C<NUM>-C<NUM> alkoxy, or C<NUM>-C<NUM> haloalkoxy, LG is OSO<NUM>R<NUM>, and R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>.

The N-alkylation step of forming the compound of Formula I can be performed using any suitable molar ratio of the compound of Formula III to the compound of Formula II, wherein the ratio is at least <NUM>. Representative molar ratios include, but are not limited to, greater than <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or greater than <NUM>. In some embodiments, the molar ratio of the compound of Formula III to the compound of Formula II can be about four.

Any suitable combination of non-nucleophilic base and R<NUM>-LG of Formula III can be used in the methods disclosed herein. In some embodiments, the non-nucleophilic base can be selected from potassium carbonate, sodium carbonate, potassium tert-butoxide, and sodium tert-butoxide, while R<NUM>-LG can be methyl p-toluenesulfonate. In some embodiments, the non-nucleophilic base can be selected from potassium carbonate, and sodium carbonate, while R<NUM>-LG can be methyl p-toluenesulfonate. In some embodiments, the non-nucleophilic base can be potassium carbonate, while R<NUM>-LG can be methyl p-toluenesulfonate. In some embodiments, the non-nucleophilic base can be potassium carbonate, while R<NUM>-LG can be methyl p-toluenesulfonate. In some embodiments, the non-nucleophilic base can be selected from potassium tert-butoxide, and sodium tert-butoxide, while R<NUM>-LG can be methyl p-toluenesulfonate. In some embodiments, the non-nucleophilic base can be sodium tert-butoxide, while R<NUM>-LG can be methyl p-toluenesulfonate.

In some embodiments where the compounds of Formula IIIa and IIIb are the same, the methods disclosed herein provide a method of preparing the compound of Formula I having the structure:
<CHM>
substantially free of the compounds of Formula Ia and Formula Ib having the structures:
<CHM>
including the step of forming the first reaction mixture of the compound of Formula II having the structure:
<CHM>
potassium carbonate, dimethylacetamide, and the compounds of Formula IIIa and Formula IIIb having the structure:.

wherein the molar ratio of the compounds of Formula IIIa and IIIb to the compound of Formula II is greater than <NUM>, and wherein the reaction mixture is mixed for at least two hours at or above room temperature under conditions suitable to form the compound of Formula I and at least one compound of Formula IVa or Formula IVb having the structures:
<CHM>
forming the partition mixture including the first reaction mixture, water and dichloromethane to form the aqueous layer and the organic layer; and separating the organic layer and the aqueous layer to isolate the compound of Formula I substantially free of the compounds of the compounds of Formula Ia, Formula Ib, Formula IVa and Formula IVb.

In some embodiments, the methods disclosed herein provide a method of preparing a compound of Formula I having the structure:
<CHM>
substantially free of the compounds of Formula Ia and Formula Ib having the structures:
<CHM>
including the step of forming the first reaction mixture of the compound of Formula II having the structure:
<CHM>
potassium carbonate, dimethylacetamide, and the compound of Formula III having the structure:.

wherein the molar ratio of the compound of Formula III to the compound of Formula II is about <NUM>, and wherein the reaction mixture is mixed for at least two hours at or above room temperature under conditions suitable to form the compound having the structure:
<CHM>
and at least one compound of Formula IVa or Formula IVb having the structures:
<CHM>
forming the partition mixture including the first reaction mixture, water and dichloromethane to form the aqueous layer and the organic layer; and separating the organic layer and the aqueous layer to isolate the compound having the structure:
<CHM>
substantially free of the compounds having the structures:
<CHM>.

Also described, but not claimed, is a method of preparing a compound of Formula II:
<CHM>
wherein R<NUM> is halogen, SCH<NUM>Ar or SCHAr<NUM>, wherein each Ar is phenyl optionally substituted with <NUM>-<NUM> R2a groups each independently halogen, C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, C<NUM>-C<NUM> alkoxy, or C<NUM>-C<NUM> haloalkoxy.

Also described, but not claimed is a method of preparing a compound having the structure:
<CHM>
including the step of forming a first reaction mixture of sodium <NUM>-<NUM>,<NUM>,<NUM>-triazole-<NUM>-thiolate, ethanol, and benzyl bromide, under conditions suitable to form the benzyl thio compound.

Preparation of <NUM>-(benzylthio)-<NUM>-methyl-<NUM>-<NUM>,<NUM>,<NUM>-triazole is described.

Benzyl bromide (<NUM>, <NUM> mmol) was added dropwise to a solution of sodium <NUM>-<NUM>,<NUM>,<NUM>-triazole-<NUM>-thiolate (<NUM>, <NUM> mmol) in ethanol (<NUM>) at <NUM>. The reaction mixture was allowed to warm to room temperature and stirred for <NUM> minutes. The reaction mixture was diluted with ethyl acetate (<NUM>) and washed with water (<NUM>), brine (<NUM>) and then dried (sodium sulfate). The solvent was removed to give <NUM>-(benzylthio)-<NUM>-<NUM>,<NUM>,<NUM>-triazole (<NUM>) as a white solid, LCMS: RT <NUM>, m+H = <NUM>; <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (<NUM>, v br s), <NUM> (<NUM>, s), <NUM>-<NUM> (<NUM>, m), <NUM> (<NUM>, s).

Sodium <NUM>-<NUM>,<NUM>,<NUM>-triazole-<NUM>-thiolate. (<NUM>, <NUM> mmol, <NUM> equivalent) was suspended in <NUM> of ethanol. Benzyl bromide (<NUM>, <NUM>, <NUM> mmol, <NUM> equivalents) was added drop wise over a period of <NUM> hour at <NUM>. The dosing bulb was rinsed with <NUM> of ethanol. The resulting suspension was stirred for <NUM> hour. Analyses indicated full consumption of the benzyl bromide. The reaction mixture was concentrated to <NUM> by distilling under reduced pressure. Next, <NUM> MTBE, <NUM> <NUM>% sodium chloride solution and <NUM> of water were added and the mixture was stirred until a clear solution was obtained. The layers were separated and the aqueous layer was extracted one time with <NUM> of MTBE. The organic layers were combined and the mixture was partially concentrated to approximately <NUM> by distilling at reflux under atmospheric pressure. Weight of solution <NUM>, <NUM> wt% of <NUM>-(benzylthio)-<NUM>-<NUM>,<NUM>,<NUM>-triazole, (<NUM>, <NUM> mmol, <NUM>%). The crude solution was used directly in the next step without the need for purification.

Potassium carbonate (<NUM>, <NUM> mmol, <NUM> equivalents) and <NUM>-(benzylthio)-<NUM>-<NUM>,<NUM>,<NUM>-triazole (<NUM>, <NUM> mmol, <NUM> equivalent) in approximately <NUM> of MTBE/ethanol mixture were suspended in <NUM> of dimethylacetamide. Methyl p-toluenesulfonate (<NUM>, <NUM> mmol, <NUM> equivalents) was added dropwise over a period of <NUM>. Afterwards the dosing bulb was rinsed with <NUM> of dimethylacetamide. The resulting reaction mixture was heated to <NUM> and stirred for <NUM> hours. Analyses indicated that the ratio between the desired regioisomer and the alternative regioisomers was ><NUM>:<NUM> area%. The resulting mixture was heated to <NUM> and stirred for <NUM> hours. The ratio was further increased to <NUM>:<NUM> area% and the amount of methyl p-toluenesulfonate had decreased to < <NUM> area%. The mixture was cooled to <NUM> and <NUM> of water was added dropwise. The mixture was stirred until a clear solution was obtained. Next, <NUM> of dichloromethane (<NUM> rel. volumes) was added and the layers were separated. The aqueous layer was extracted two more times with <NUM> of dichloromethane. The organic layers were combined and washed two times with <NUM> of water. The mixture was concentrated to <NUM> by distilling at reflux under atmospheric pressure. Weight of solution <NUM>, <NUM> wt% of <NUM>-(benzylthio)-<NUM>-methyl-<NUM>-<NUM>,<NUM>,<NUM>-triazole (<NUM>, <NUM> mmol, <NUM>%). The crude solution can be used directly in a subsequent step without the need for purification.

A crude solution of <NUM>-(benzylthio)-<NUM>-<NUM>,<NUM>,<NUM>-triazole (as prepared in Example <NUM>) and potassium carbonate (<NUM> equivalents) in dimethylacetamide was heated to <NUM> and then <NUM>-bromopropane (<NUM> equivalents) was added over <NUM> minutes. The resultant mixture was stirred for <NUM> hours (ratio desired regioisomer to undesired isomers <NUM>:<NUM>:<NUM>) and then methyl p-toluenesulfonate (<NUM> equivalents) in dimethylacetamide was added over <NUM> minutes. The resultant mixture was stirred at <NUM> for <NUM> days (ratio desired regioisomer to undesired isomers <NUM>:<NUM>:<NUM>) and then heated to <NUM> to destroy any excess methyl p-toluenesulfonate. After stirring at <NUM> for <NUM> hours the reaction mixture was quenched by the addition of water and the mixture was extracted <NUM> times with dichloromethane. The organic phases were combined and washed several times with water and then concentrated at atmospheric pressure. The resultant solution was used directly in the next step of the synthesis without the need for purification.

Claim 1:
A method of making a compound of Formula I:
<CHM>
wherein the content of the compounds of Formula Ia and Formula Ib:
<CHM>
is less than <NUM>% by weight,
comprising:
a) forming a first reaction mixture comprising a compound of Formula II:
<CHM>
a non-nucleophilic base, a first solvent, and a compound of Formula IIIa:

        R1a-LG1a     (IIIa) ,

wherein the molar ratio of the compound of Formula IIIa to the compound of Formula II is greater than <NUM>, and wherein the reaction mixture is mixed for at least two hours at or above room temperature under conditions suitable to form an intermediate mixture comprising the compound of Formula I and at least one compound of Formula Ia and Ib;
a1) forming a second reaction mixture comprising the intermediate mixture, and a compound of Formula IIIb:

        R1b-LG1b     (IIIb) ,

wherein the molar ratio of the compound of Formula IIIb to the compounds of the intermediate mixture is greater than <NUM>, and wherein the second reaction mixture is mixed for at least two hours at or above room temperature under conditions suitable to form at least one compound of Formula IVa or Formula IVb:
<CHM>
b) forming a partition mixture comprising the second reaction mixture, water and an organic solvent to form an aqueous layer and an organic layer; and
c) separating the organic layer and aqueous layer to isolate the compound of Formula I, wherein the content of the compounds of Formula Ia, Formula Ib, Formula IVa and Formula IVb is less than <NUM>% by weight,
wherein
R1a and R1b are independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or cyclopropylmethyl, such that R1b is different than R1a;
R<NUM> is halogen, SCH<NUM>Ar or SCHAr<NUM>, wherein each Ar is phenyl optionally substituted with <NUM>-<NUM> R2a groups each independently halogen, C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, C<NUM>-C<NUM> alkoxy, or C<NUM>-C<NUM> haloalkoxy;
LG1a is Br, I or OSO<NUM>R<NUM>;
LG1b is OSO<NUM>R<NUM>; and
R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> haloalkyl, or C<NUM>-C<NUM> aryl, wherein the aryl group is substituted with <NUM>-<NUM> R3a groups each independently hydrogen, C<NUM>-C<NUM> alkyl, halogen, or NO<NUM>.