The general procedure for the synthesis of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzonitrile from 4-fluoro-3-methoxybenzonitrile and 4-methylimidazole was as follows: under nitrogen protection, 4-methylimidazole (249 mg, 3.03 mmol), 4-fluoro-3-methoxybenzonitrile (417 mg, 2.76 mmol), and caesium carbonate (1.89 g 5.80 mmol) were added to the reaction vessel followed by N,N-dimethylformamide (5.0 mL). The reaction mixture was stirred at room temperature for 96 hours. After completion of the reaction, water (2 mL) and ethyl acetate (6 mL) were sequentially added to the mixture for extraction, and after separation of the aqueous layer, the organic layer was washed with water (5 mL). The organic layer was again extracted by adding ethyl acetate (5 mL) and water (5 mL) to the organic layer, and after separating the aqueous layer, the organic layer was washed with water (5 mL) and concentrated under reduced pressure to give 499 mg of crude product. The crude product was dissolved in tert-butyl methyl ether (2.5 mL) to form a suspension, filtered, and the solid was washed three times with tert-butyl methyl ether/heptane (2.5 mL; 1:3) to give 431 mg of crude product. The crude product was dissolved in tert-butyl methyl ether (4.3 mL) under nitrogen protection, and the mixture was stirred at 50 °C for 30 min, then cooled naturally to room temperature. The solid was collected by filtration, washed twice with tert-butyl methyl ether/heptane (2.1 mL; 1:3) and dried under reduced pressure to give 310 mg of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzonitrile in 53% yield.
