Reaction Steps
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed at reduced pressure, and the residue was suspended in ACN (2 mL) and re-concentrated to remove residual thionyl chloride. The residue was resuspended in ACN (2 mL), cooled to 0° C., and 2-(pyrrolidin-3-yl)propan-2-ol hydrochloride (110 mg, 0.663 mmol) and TEA (0.154 mL, 1.105 mmol) were added. The reaction was stirred for 16 hours at RT, followed by 4 hours at 50° C. and 6 hours at 80° C. The reaction was cooled to RT, DBU (0.17 mL, 1.105 mmol) was added, and the reaction was stirred overnight at 40° C. The reaction was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH4OH)/DCM, to provide (E)-4-fluoro-N-(6-((3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a light-yellow powder (65 mg, 52.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 6H), 1.11 (d, J=6.7 Hz, 6H), 1.54-1.79 (m, 7H), 2.09-2.19 (m, 3H), 2.36 (br. s., 2H), 2.52 (br. s., 1H), 2.59 (br. s., 1H), 2.69-2.84 (m, 2H), 3.55 (br. s., 1H), 3.68 (br. s., 1H), 3.99-4.10 (m, 2H), 4.83 (br. s., 1H), 7.14-7.19 (m, 1H), 7.24 (dd, J=8.9 Hz, 8.9 Hz, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.55-7.66 (m, 2H), 8.32 (dd, J=8.7, 6.0 Hz, 2H), 12.74 (br. s., 1H). MS, m/z (C32H42FN5O3): calcd, 563.3. found, 564.0 [M+H].
