II.Br[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([F:11])[CH:5]=1.CON(C)[C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]>C1COCC1>[F:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([CH3:10])[CH:7]=1)[C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]A 100 mL three-neck flask was charged with Mg (638 mg, 26.6 mmol), a small crystal of iodine. The flask was degassed and refilled into N2. A solution of 1-bromo-3-fluoro-5-methyl-benzene (5 g, 26.6 mmol) in anhydrous THF was added. The reaction mixture was stirred and heated to reflux for 2 h. Once most of the Mg disappeared the reaction was cooled to −78° C. Then (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (1.45 g, 5.32 mmol) in anhydrous THF was added dropwise slowly, and the mixture was stirred overnight. The mixture was quenched with saturated NH4Cl solution (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product (R)-tert-butyl 3-(3-fluoro-5-methylbenzoyl)piperidine-1-carboxylate (1.7 g, 99%), which was used immediately without further purification.
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