To a stirred mixture of 5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine (97 mg, 0.42 mmol) (prepared as shown in Scheme 5 using isoquinoline-6-carboxylic acid, commercially available from AstaTech Product List (Order Number 62874), instead of 4-chlorothieno[2,3-c]pyridine-2-carboxylic acid) and (±)-cis-1-(tert-butoxycarbonyl)-3-phenylpyrrolidine-2-carboxylic acid ((Damour et al. Synlett 1999, 2, 189-192), 149 mg, 0.51 mmol) in DMF (5.0 mL) was added EDC (122 mg, 0.64 mmol), HOBt (86 mg, 0.64 mmol) and DIEA (0.22 mL, 1.3 mmol). The mixture was stirred at room temperature for 24 hours. Aqueous NH4Cl (5 mL), water (5 mL) and DCM (10 mL) were added. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude residue was purified by flash column chromatography (eluting with a gradient from DCM to 5% MeOH in DCM) to provide (±)-cis-tert-butyl 2-((5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)carbamoyl)-3-phenylpyrrolidine-1-carboxylate as a white foam (64 mg, 30%). LCMS (M+H) 502.2 calc. for C27H28N5O3S 502.2.
