[F:1][C:2]1[CH:3]=[C:4]([C:10](=[N:18][OH:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Li])CCC.[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:25]([OH:27])([CH3:26])[O:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]A dry, 250 mL 3-neck round-bottom flask, equipped with a thermometer, magnetic stirring bar, reflux condenser and rubber septum was charged with 1-(3-fluoro-4-methoxyphenyl)-2-phenyl-ethan-1-one oxime (from Example 2, Step 2) (2.50 g, 9.64 mmol) and anhydrous THF (100 mL) under a nitrogen blanket. The solution was cooled to -20° C., and n-butyllithium (1.6 N, 15.0 mL) was added, via syringe, over 20 minutes, keeping the reaction temperature <-10° C. The deep red suspension was stirred at -20° C. for 1 hour, warmed to room temperature, and stirred at room temperature for 1 hour. Acetic anhydride (1.1 mL, 11.6 mmol) was added in one portion, and the yellow reaction was stirred for 2 hours without temperature control. The reaction was poured into aqueous hydrochloric acid (1 N, 100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic solution was washed once each with aqueous hydrochloric acid (1 N, 100 mL) and brine (100 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to yield a crude oil. The oil was applied to a column of silica gel (250 ml) and eluted with ethyl acetate/hexane (10-40% ethyl acetate) to yield, upon concentration of the appropriate fractions, 986 mg of 3-(3-fluoro-4-methoxyphenyl)-4-hydrido-5-hydroxy-4-phenyl-5-methylisoxazole. This intermediate was dissolved in tetrahydrofuran (40 mL). Sulfuric acid (conc., 0.9 mL) was added, and the reaction was warmed to reflux. After one hour, the solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (2×50 mL). The combined organic solution was washed with aqueous hydrochloric acid (1 N, 50 mL), saturated aqueous sodium bicarbonate (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to yield a crude, dark oil. Washing the oil with 50% dichloromethane in hexane dissolved the compound but did not dissolve the dark impurities. The resulting solution was evaporated under reduced pressure to yield 797 mg (29%) of 3-(3-fluoro-4-methoxyphenyl)-5-methyl-4-phenylisoxazole as a foam. Mass Spectrum: MH+=284. Anal. Calc'd. for C17H14NO2F: C, 72.07; H, 4.98; N, 4.94. Found: C, 72.13; H, 4.98; N, 4.92.
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