Methyl 4-(5-cyano-7-methyl-1,3-benzoxazol-2-yl)benzoate (134 mg, INTERMEDIATE 22) and lithium hydroxide (22 mg) were combined in 10 ml of a 1:1:1 mixture of tetrahydrofuran, methanol, and water. The solution was stirred overnight. The solvents were removed in vacuo to provide the desired intermediate, lithium 4-(5-cyano-7-methyl-1,3-benzoxazol-2-yl)benzoate, as an off-white solid (140 mg). Mass spectrum (ESI) 279.0 (M+1). To a solution of lithium 4-(5-cyano-7-methyl-1,3-benzoxazol-2-yl)benzoate (28 mg) in 2 ml of dichloromethane was added 2.5 ml of a 2M solution of oxalyl chloride in dichloromethane followed by 10 μl of dimethylformamide. The mixture was warmed and stirred until the solids dissolved (about 0.5 h). The mixture was concentrated in vacuo with minimal or no heating (<30° C.) and then dried under high vacuum to remove traces of water. To the residue was added 2 ml of dichloromethane, 28 mg of ({1-[4-(trifluoromethyl)phenyl]piperidin-4-yl}methyl)amine, and 87 μl of diisopropylethylamine. The mixture was stirred at room temperature for 15 min and then was added directly to a 40M samplet. The product was purified via flash chromatography on a Biotage Horizon, 40M column, eluting with 1 column volume of 10% ethyl acetate in hexanes, followed by a linear gradient of ethyl acetate in hexanes from 10 to 100% over 10 column volumes to provide the title compound (38 mg, 73%). Mass spectrum (ESI) 519.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.35 (d, J=8.5 Hz, 2H), 7.95 (m, 4H), 7.49 (m, 4H), 6.37 (bs, 2H), 3.83 (d, J=12.6 Hz, 2H), 3.49 (m, 2H), 3.47 (t, J=6.4 Hz, 2H), 2.87 (m, 2H), 2.65 (s, 3H), 1.92 (m, 3H).
