Isopropyl 4-[(6-chloro-5-methoxypyrimidin-4-yl)oxy]piperidine-1-carboxylate → Isopropyl 4-((5-methoxy-6-((2-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)pyrimidin-4-yl)oxy)piperidine-1-carboxylate

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Bis[(2-diphenylphosphino)phenyl] ether (0.274 g, 0.51 mmol) was added in one portion to Palladium(II) acetate (0.057 g, 0.25 mmol) in toluene (5 mL) (degassed by bubbling N2 through it for 30 minutes) at 20°C under nitrogen (this mixture was also degassed by vacuum / N2 six times). After a few minutes a yellow suspension had formed. This was added by pipette to a mixture of isopropyl 4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (4.19 g, 12.71 mmol), 2-methyl-6-(methylsulfonyl)pyridin-3-amine (2.366 g, 12.71 mmol) and Sodium tert-butoxide (2.333 mL, 19.06 mmol) in toluene (40 mL) at 60°C under nitrogen. The resulting mixture was degassed using N2 / vacuum six times. The resulting suspension was stirred at 60 °C for 18 hours. Sodium tert-butoxide (2.333 mL, 19.06 mmol) was added to the reaction mixture followed by another amount of pre-formed catalyst using Bis[(2-diphenylphosphino)phenyl] ether (0.274 g, 0.51 mmol) was added in one portion to Palladium(II) acetate (0.057 g, 0.25 mmol) in toluene (5 mL) as above. The mixture was heated at 60°C for 7 hours then further catalyst added using Bis[(2-diphenylphosphino)phenyl] ether (0.274 g, 0.51 mmol) was added in one portion to Palladium(II) acetate (0.057 g, 0.25 mmol) in toluene (5 mL) as above. The mixture was stirred at 60°C for 18 hours. Work up was by diluting with water (30 ml) and DCM (100 ml) then filtering through a pad of celite and washing through well with DCM (6 x 50 ml). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography (330g column), elution gradient 0 to 100% EtOAc in heptane (material applied in DCM). Pure fractions were evaporated to dryness to leave a yellow solid, EN05005-04-01. The solid was triturated with Et2O (20 ml) and the solid filtered off and washed with Et2O (2 x 10ml) then heptane ( 2 x 10ml) to afford isopropyl 4-(5-methoxy-6-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)pyrimidin-4-yloxy)piperidine-1-carboxylate (4.78 g, 78 %), EN05005-04-02, as a white solid.

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