Lithium Hexamethyldisilazide → 1-(4-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide

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Reaction Steps

A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (117 mg, 0.466 mmol) and THF (1944 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (466 μl, 0.466 mmol) was added drop wise. The flask was removed from the cooling bath for 3 min, then recooled in the bath. A solution of perfluorophenyl 1-(4-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE NNN, 200.53 mg, 0.389 mmol) in THF (1 mL with a 0.5 mL-flask wash) was added drop wise. After another minute, the flask was transferred to an ice-water bath. After 10 min, the mixture was diluted with saturated aq ammonium chloride and water, then extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim 25-micron column, 25-75% EtOAc/Heptane) to give 1-(4-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (217 mg, 0.372 mmol, 96% yield) as a white foam. m/z (ESI) 583.0 (M+H)+.

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