3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethenyl)benzonitrile (0.068 g, 0.215 mmol), 4-chloro-1H-imidazole-5-carboxylic acid (0.040 g, 0.273 mmol), and DIPEA (0.075 mL, 0.429 mmol) were combined in THF (6 mL) and treated with EDC (0.082 g, 0.429 mmol) at 50° C. for three days. The reaction mixture was concentrated to dryness and partitioned between EtOAc and brine. The organic phase was isolated, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 40 to 100% EtOAc/hexanes to give impure product. This material was repurified by mass-directed HPLC on a SunFire prep C-18 column eluted with 30 to 85% CH3CN/H2O (0.1% formic acid buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(1-methylethenyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (0.013 g, 0.029 mmol, 13.60% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 (br. s., 1H), 8.30 (br. s., 1H), 7.73-7.78 (m, 2H), 7.50 (d, J=8.52 Hz, 1H), 7.43 (s, 1H), 7.36 (t, J=7.76 Hz, 1H), 7.26 (s, 1H), 5.57 (s, 1H), 5.25 (s, 1H), 4.52 (d, J=5.36 Hz, 2H), 2.10 (s, 3H). LC-MS (ES−) m/z 443.08, 445.16 [M−1]. LC-MS (ES+) m/z 445.07, 447.07 [M+H].
