Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH:17]3[CH2:18][CH2:19][N:20]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:21][CH2:22]3)=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1(3′-Chloro-biphenyl-4-yl)-piperidine-4-yl-methanone hydrochloride (2, 23.4 kg, 69.6 mol), 2-chloropyrimidine (8.9 kg, 1.3 equiv), and 325-mesh potassium carbonate (25 kg, 3 equiv) were mixed in acetonitrile (211 L) in a 100-gallon reactor. The batch was heated with agitation at 55-65° C. for 16 h. The batch was then cooled to 20-30° C., followed by the addition of water (70 L) and further stirred for 15 min. The batch was transferred to a 300-gallon reactor and rinsed with water (360 L) to afford a thick white suspension. After stirring for 2 h, the batch was filtered and washed with water (2×70 L) and dried to constant weight at 45-55° C. to afford crude compound 3 (23.5 kg, 89.5% yield, >99% purity) as a white crystalline solid.
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