cis-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acid (1.000 g, 3.34 mmol) was suspended in thionyl chloride (12.18 mL, 167 mmol), and the mixture was stirred at RT for 30 minutes. The reaction mixture was concentrated in vacuo, dissolved in THF (33.4 mL), and then cooled to 0° C. under a nitrogen atmosphere. To the cooled reaction was added tert-butyl-piperazine-1-carboxylate (0.684 g, 3.67 mmol) as a solution in THF (1 mL). The reaction mixture was stirred at 0° C. for 15 minutes and allowed to warm to RT and stirred overnight. To the reaction mixture was added additional tert-butyl-piperazine-1-carboxylate (0.684 g, 3.67 mmol) in THF (1 mL) (×2, stirring for about 1 h after each addition). Upon completion, the reaction mixture was diluted with aqueous NH4Cl and extracted with DCM (×2). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residual material was purified via silica gel chromatography, eluting with isocratic 90:10:1 DCM:MeOH:NH4OH, to provide tert-butyl 4-(cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylate (1.51 g, 70% yield) as a yellow solid. MS m/z=468.0 [M+H], calc 467.95 for C21H30ClN5O5.
