General procedure for the synthesis of 5-bromo-2-methoxyisonicotinaldehyde from 5-bromo-2-methoxypyridine and N,N-dimethylformamide: First, a solution of tetrahydrofuran (THF, 0.5 L) with diisopropylamine (22.7 g, 0.22 mol) was cooled down to -30 °C, followed by the slow addition of n-butyllithium (n-BuLi, 140 mL, 0.22 mol). After the addition was completed, the reaction solution was stirred for 30 minutes. Next, the mixture was further cooled to -60 °C and 5-bromo-2-methoxypyridine (35.1 g, 0.19 mol) dissolved in THF (200 mL) was slowly added dropwise, ensuring that the reaction temperature was maintained below -60 °C. After completion of the dropwise addition, stirring of the reaction solution was continued for 1 hour. Subsequently, N,N-dimethylformamide (DMF, 20.4 g, 0.28 mol) was slowly added dropwise at -60 °C, and after completion of the dropwise addition, stirring of the reaction solution was continued for 1 hour. Upon completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride (NH4Cl, 200 mL) and the reaction mixture was allowed to warm slowly to room temperature. Extraction was performed with ethyl acetate (EtOAc, 200 mL x 2). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. Finally, the crude product was purified by silica gel column chromatography to obtain the pure 5-bromo-2-methoxyisonicotinaldehyde (26.4 g, yield 64.3%) as a white solid. Nuclear magnetic resonance hydrogen spectrum (1H NMR, 400 MHz, CDCl3) δ 10.28 (s, 1H), 8.40 (s, 1H), 7.16 (s, 1H), 3.95 (s, 3H).
