To a solution of 3-chloromethyl-7-trifluoromethyl-quinoline (140 mg, 0.57 mmol, 1.1 eq.) in DMF (10 ml) was added potassium carbonate (345 mg, 2.5 mmol, 5 eq.) then 2-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-piperazin-1-yl-ethanone hydrochloride (233 mg, 0.5 mmol, 1 eq.) was added. The solution was stirred overnight at 70° C. and diluted with EtOAc (25 ml) and washed with water (25 ml), saturated aqueous lithium chloride (25 ml) and brine (25 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with methanol in dichloromethane. The semi-purified material was further purified by HPLC to afford 2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(7-trifluoromethyl-quinolin-3-ylmethyl)-piperazin-1-yl]-ethanone as a yellow solid (111.2 mg, 30%). (CI, m/z): [M+H]+ 640; 1H NMR (400 MHz, CDCl3): δ 1.20-1.36 (m, 2H), 1.40-1.54 (m, 2H), 2.08-2.21 (m, 4H), 2.46-2.61 (m, 4H), 3.32-3.49 (m, 2H), 3.53-3.62 (m, 2H), 3.63-3.71 (m, 2H), 3.76 (s, 2H), 4.20 (s, 2H), 4.46 (d, J=7.6 Hz, 1H), 6.63 (dd, J=9.1, 2.6 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 7.75 (dd, J=8.5, 1.6 Hz, 1H) 7.94 (d, J=8.5 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H), 8.43 (s, 1H), 9.03 (d, J=2.1 Hz, 1H).
