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.