Methanol → Methyl 6-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylate

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A 250 mL flask was charged with 2-methylsulfanyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid (11.6 g, 62.5 mmol), toluene (60 mL), thionyl chloride (60 mL, 0.8 mol, 13 eq.), DMF (0.3 mL), and pyridine (1 mL), and the resultant stirred suspension was heated to reflux. The suspension clarified after 30 min. After 3 hours at reflux, the mixture was concentrated in vacuo, and co-evaporated with additional toluene (30 mL). The biphasic brown residue was dissolved in chloroform (100 mL), cooled to 0° C., and DIEA (56 mL, 0.31 mol, 5 eq.) added dropwise over 20 min followed by methanol (12.7 mL, 0.31 mol, 5 eq.) over 5 min. The mixture was warmed to room temperature, and poured into saturated aqueous sodium bicarbonate (350 mL). The organic layer was washed with saturated aqueous ammonium chloride (350 mL), dried (Na2SO4), filtered, and concentrated in vacuo to a brown semi-solid. Overnight drying under high vacuum afforded 6-chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid methyl ester that was taken to the next step without further purification. 1H NMR (500 MHz, CDCl3) □ 7.60 (s, 1H), 3.98 (s, 3H), 2.60 (s, 3H); ESI-MS m/z 218.9 (M+H)+.

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