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A 250-mL round-bottom flask was charged with (Rac)-tert-butyl 3-methy 1-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol) and purged with nitrogen. THF (47.0 ml) was introduced and the reaction mixture was cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /er/-butoxide (1.6 M in THF, 19.0 mL, 29.9 mmol) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the reaction mixture was cooled to -78 °C. Methyl 3 -methoxy aery late (5.29 ml, 49.2 mmol) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the resultant red reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonamide (13.2 g, 37.0 mmol) was added to the vigorously stirred, cooled reaction mixture in one portion and the reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in two portions (100-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane) to afford a mixture of (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-2-methy 1-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (11.75 g, 27.4 mmol, 117 percent yield) as a yellow solid.A 20-mL vial was charged with a mixture of (Rac)-(E)-tert-buty 1 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((lrifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-buty\ 3-(3-methoxy-3-oxoprop-1 -en-1 -yl)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (716 mg, 1.668 mmol), 2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny 1]-4-amine (Preparation 4h, 352 mg, 1.39 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (101 mg, 0.174 mmol), cesium carbonate (1.36 g, 4.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.9 mg, 0.07 mmol), and 1,4-dioxane (6.95 mL) then sparged with nitrogen for 10 min. The needle was then removed and the reaction was heated to 100 °C. After 3 h, the reaction mixture was allowed to cool to ambient temperature and was diluted with EtOAc (15 mL) and filtered through a Celite? pad. The pad was rinsed with EtOAc (3 x 15 mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (50-g silica gel Biotage column, eluent: gradient, 0 to 35percent 3:1 EtOAc/EtOH in heptane with DCM as a 10percent additive) to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,r-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-bu\y\ 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (587 mg, 1.17 mmol, 84.0percent) as a brown solid,A 20-mL vial was charged with a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxy late (587 mg, 1.173 mmol) and trifluoroacetic acid (5.86 mL) at ambient temperature. After 30 min, the reaction mixture was concentrated under reduced pressure, dissolved in DCM (15 mL) and carefully poured into saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated and the aqueous layer extracted with additional DCM (3 x 15 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,l'-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (400 mg, 1.00 mmol, 85.0percent) as a tan amorphous solid, which was used without further purification.20-mL vial was charged with a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (400 mg, 1.00 mmol), N-(isoxazol-3-yl)-2-oxooxazol... |
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