The cyclization of 3-(4-chlorobutylsulfanylmethyl)pyridine (I) by means of n-BuLi in THF/HMPT gives 3-(tetrahydrothiopyran-2-yl)pyridine (II), which is treated with CS2, CH3I and KOtBu in the same solvent to yield the methyl carbodithioate (IV). The controlled oxidation of (IV) with MCPBA in dichloromethane affords the sulfoxide (IV), which is treated with methylamine in ethanol to provide a mixture of two racemic diastereomers that are separated by chromatography; however, the authors do not indicate the configuration of both racemates.

The reaction of 3-(chloromethyl)pyridine (I) with thiourea (II) in ethanol gives S-(3-pyridylmethyl)isothiourea (III), which is condensed with 4-chlorobutyl bromide (IV) by means of NaOH in dichloromethane to yield 3-(4-chlorobutylsulfanylmethyl)pyridine (V). The careful oxidation of (V) with MCPBA in dichloromethane affords the corresponding sulfoxide (VI), which is cyclized by means of potassium tert-butoxide in THF, providing a mixture of cis- and trans-2-(3-pyridyl)tetrahydrothiopyran S-oxide (VII + VIII). This mixture can be separated by conventional methods; however, when this mixture (VII + VIII), or either (VII) or (VIII) separately, are treated with NaNH2 and methyl isothiocyanate, only the target (1RS,2RS)-compound is obtained. Alternatively, the mixture (VII + VIII) or either (VII) or (VIII) can also be treated with potassium tert-butoxide, CS2 and methyl iodide to yield the (1RS,2RS)-dithioester (IX), which is finally converted into the target compound by reaction with methylamine.

The condensation of 2-(3-pyridinyl)tetrahydrothiopyran-2-carboxylic acid (I) with L-proline tert-butyl ester (II) by means of SOCl2 gives the corresponding amide as a diastereomeric mixture (S,S)-(III) + (R,S)-(III) that is separated by chromatography. The desired isomer (R,S)-(III) is hydrolyzed with conc. HCl to yield 2-(3-pyridinyl)tetrahydrothiopyran-2-carboxylic acid (R)-(IV), which is treated first with SOCl2 and methylamine, and then with Lawesson reagent or P2S5 to afford the thioamide (R)-(V). The reaction of (R)-(V) with methyl iodide, n-BuLi and H2S in pyridine provides the dithioester (R)-(VI), which is carefully oxidized with MCPBA in dichloromethane to provide the corresponding sulfoxide as a diastereomeric mixture (1R,2R)-(VII) + (1S,2R)-(VII) that is separated by chromatography. Finally, the desired isomer (1R,2R)-(VII) is treated with methylamine in ethanol to furnish the target thioamide.