Example 89 - Preparation of Intermediate 25: The synthesis of Intermediate 25 followed the following general procedure. To a solution of 5-bromopyridine-2-carboxylic acid (50.0 g, 0.247 mol, 1.0 eq.) in anhydrous methanol (400 mL) cooled to 0 °C was added thionyl chloride (107.0 mL, 2.47 mol, 10.0 eq.) dropwise. The reaction mixture was slowly warmed to room temperature and subsequently heated at 50 °C for 12 hours. The reaction process was monitored by thin layer chromatography (TLC) and liquid chromatography-mass spectrometry (LC-MS). After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a white solid residue. The residue was slowly quenched with saturated sodium bicarbonate solution and the white solid was collected by filtration to afford the target product methyl 5-bromopyridine-2-carboxylate (43.0 g, 80% yield). The product was characterized by mass spectrometry (m/z 216.14) and nuclear magnetic resonance hydrogen spectroscopy (1H NMR, 400 MHz, DMSO): δ 8.86 (d, J=1.9 Hz, 1H), 8.28 (dd, J=8.4,2.4 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 3.89 (s, 3H) ppm.
