2,2,6,6-Tetramethylpiperidine → N4-Cyclopentyl-5-(3,6-dimethoxy-4-pyridazinyl)-2,4-pyrimidinediamine

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A solution of butyllithium (2.5 m solution in hexanes) (7.5 mL, 19 mmol) was added to cold (acetonitrile-dry ice bath, −34° C. internal), stirred 2,2,6,6-tetramethylpiperidine (3.4 mL, 20 mmol). The resulting mixture was allowed to stand at 0° C. (ice-H2O bath) for 30 min. The ice-H2O was then replaced with dry ice-2-propanol bath and the mixture was cooled to −0° C. THF (24 mL) was added. A pre-cooled (ice-H2O bath) solution of 3,6-dimethoxypyridazine (2.40 g, 17 mmol) in THF (40 mL) was added through a cannula over a period of 30 min. The internal temperature was observed fluctuating between −72° C. and −55° C. The resulting mixture was stirred at −70° C. for 1.5 h. A solution of zinc(II) chloride (0.5 M in THF) (34 mL, 17 mmol) was added through a syringe over a period of 15 min. The internal temperature fluctuated between −73° C. and −64° C. The cold bath was removed and the resulting mixture was allowed to warm up to rt (20.5° C.). A solution of compound 243 (1.7 g, 5.7 mmol) and tetrakis(triphenylphosphine)palladium (0.33 g, 0.29 mmol) in THF (20 mL) was added and the resulting mixture was heated at reflux for 18 h. Upon workup, the crude mixture was cooled in an ice-H2O before poured into ice and saturated NH4Cl aqueous solution and extracted with ethyl acetate (2×). The combined organics were combined, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (methanol/DCM with Et3N) to give pure compound 316 (1.2 g, 66% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.53 (1 H, s), 7.01 (1 H, s), 6.18-6.38 (3 H, m), 4.35-4.51 (1 H, m, J=7.3, 7.3, 7.3, 7.3, 7.0 Hz), 3.95 (3 H, s), 3.91 (3 H, s), 1.77-1.90 (2 H, m), 1.55-1.69 (2 H, m), 1.35-1.55 (4 H, m). LCMS-ESI (POS), M/Z, M+1: Found 317.2.

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