[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:9][C:8]=2[C:20]([O:22]CC)=[O:21])=[CH:4][C:3]=1[F:27].O1CCCC1.CO.[OH-].[Na+].O>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:9][C:8]=2[C:20]([OH:22])=[O:21])=[CH:4][C:3]=1[F:27]To a solution of ethyl 3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate in tetrahydrofuran (5.64 mL, 69.6 mmol) was added methanol (2.5 mL, 62 mmol) and 1 M sodium hydroxide in water (4.23 mL, 4.23 mmol) and the resulting suspension was stirred at room temp. The reaction was stirred for 16 hours at room temperature. Volatiles were then removed in vacuo, and the residue diluted with EtOAc (30 mL). Mixture was then transferred to a separatory funnel containing 1N HCl (5.0 mL) and water (10 mL), at which time the pH of aqueous layer was measured at ˜2.0. Layers were separated, and the aqueous layer was extracted 3×20 mL with EtOAc. Combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo. Resulting residue was adsorbed to celite, and the resulting solid was placed into a dryload cartridge and purified via column chromatography (gradient elution, 0-5% MeOH:CH2Cl2) to afford 3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylic acid (94) as a white solid (0.128 g, yield 66.3%). LCMS: (FA) ES+ 381, 383; 1H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 7.52 (dd, J=8.1, 8.1, 1H), 7.22 (dd, J=1.9, 10.5, 1H), 7.05 (dd, J=1.5, 8.3, 1H), 4.31 (s, 2H), 3.80-3.65 (dd, J=4.5, 5.2, 4H), 3.59-3.47 (dd, J=4.5, 5.2, 4H).
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