Br[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:11][C:7]1[CH:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[CH:10]=[CH:9][CH:8]=1A mixture of 3-chloroaniline (50 g, 0.39 mol) and 1,2-dibromoethane (73 g, 0.39 mol) in MeCN (500 mL) was heated at 80° C. for 2 days. The reaction mixture was concentrated on rotavap and subjected to silica flash column chromatography using 0 to 30% EtOAc in PE to isolate N-(2-bromoethyl)-3-chloroaniline (397) (9.0 g, 10%) as a yellow solid. To a solution of N-(2-bromoethyl)-3-chloroaniline (397) (9.0 g, 38.46 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (7.74 g, 38.46 mmol) in THF (100 mL) was added DIEA (14.88 g, 115.38 mmol). The resulting mixture was stirred at 70° C. for 2 days. It was partitioned in EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous was extracted with EtOAC (50 mL×3). The combined organic layer was washed with brine, dried, concentrated and subjected to silica flash column chromatography using 0 to 5% MeOH in DCM to isolated (R)-tert-butyl 3-(2-(3-chlorophenylamino)ethylamino)piperidine-1-carboxylate (398) (10.1 g, 74.4%) as a white solid.
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