[F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@H:17]([C:19](=[O:26])[CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@H:17]([C:19]3[O:26][NH:33][C:21](=[O:22])[CH:20]=3)[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:10])([F:9])[F:11]Trans-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate (110 mg, 0.25 mmol) (from example 70, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. Sodium hydroxide (0.066 mL, 0.25 mmol) dissolved in water (0.500 mL) was added. After 20 min at −40° C., hydroxylamine (50% by weight in water, 7.71 μL, 0.25 mmol) was added and stirring continued for 4 h. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M hydrogen chloride (1.299 mL, 7.80 mmol) and stirred for 1 h. The solvent was evaporated in vacuo. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 20-65% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 30 minutes with a flow of 19 mL/min. Trans-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (7.00 mg, 6.85%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.61-1.73 (m, 1H), 1.90-2.01 (m, 1H), 2.06 (dt, 1H), 2.56 (d, 1H), 2.76 (t, 1H), 2.89 (t, 1H), 3.78 (s, 3H), 4.13-4.47 (m, 1H), 5.46-5.74 (m, 1H), 5.68 (s, 1H), 6.89 (d, 2H). MS m/z 407 (M+H)+
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