F[C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=C2\NC3C=CC(CO)=CC=3N\2[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.N1CC(C(O)(C)C)C1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:32]=[CH:33][CH:2]=[CH:3][CH:4]=1To 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 on a rotovap, and the residue suspended in ACN (2 mL) and re-concentrated to remove residual thionyl chloride. The residue was resuspended in DMF (2 mL), cooled to 0° C., and 2-(azetidin-3-yl)propan-2-ol hydrochloride (101 mg, 0.663 mmol) and DBU (0.10 mL, 0.663 mmol) were added. After stirring for 16 hours at RT, the reaction mixture was concentrated and purified by reverse-phase preparative HPLC, using 0.1% TFA in ACN/water, (gradient 15% to 90%). The product fractions were combined, neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (E)-4-fluoro-N-(6-((3-(2-hydroxypropan-2-34)azetidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene) as a white powder benzamide (26 mg, 21.4% yield). MS, m/z (C31H40FN5O3): calcd, 549.3. found, 549.9 [M+H].
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