[CH:1]1[C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=[C:3]([C:9]([OH:11])=[O:10])[CH:2]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[ClH:19]>[Pd].C(O)C>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:9]([OH:11])=[O:10])=[CH:2][CH:1]=2)[CH2:15][CH2:14]1.[ClH:8].[ClH:19]Referencing scheme 1 below, the synthesis begins with treatment of 2-methyl-5-nitroaniline (1) with 65% nitric acid in ethanol followed by the addition of cyanoamide to give the corresponding 2-methyl-5-nitroaniline-guanidine nitrate (2). Once completed, 3-acetylpyridine (3) is first reacted with phenyl chloroformate at nitrogen position and then regioselectively alkylated using Grignard reagents and catalytic amounts of copper (I) iodide to obtain intermediate dihydropyridine. The dihydropyridine was further deprotected to obtain 3-acetyl-4-methyl-pyridine(4) (Tanis et al., 1996). Product (4) was treated with methyl dimethoxyforamide to give 3-dimethylamino-1-(3-(4-methyl-pyridyl)-2-propene-1-one (5). Nitrate salt (2) is treated with (5) and sodium hydroxide in refluxing isopropanol to give N-(2-Methyl-5-nitrophenyl)-4-(3-(4-methyl-pyridyl))-2-pyrimidine-amine (6) which is subsequently hydrogenated with 10% palladium on carbon to give N-(2-Methyl-5-aminophenyl)-4-(3-4-methyl-pyridyl)-2-pyrimidine-amine (7). The first WBZ1 synthesis consists of the reaction of α-chloro-p-toluylic acid (8) with 4-methyl-piperazine in ethanol followed by treatment with concentrated HCl to give the corresponding dihydrochloride 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (9) which is subsequently treated with thionyl chloride to give the corresponding acid chloride dihydrochloride (10). Subsequent condensation with N-(2-Methyl-5-aminophenyl)-4-(3-(4-methyl)-pyridyl)-2-pyrimidine-amine (7) in pyridine affords the Gleevec analog WBZ1 (PCT publication WO2004108699).
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