2-amino-6-methoxy-N-methylbenzamide → 2-[[2-[(1,3-dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]amino]-6-methoxy-N-methyl-benzamide

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A suspension of 2-amino-6-methoxy-N-methylbenzamide (9.55 g, 52.99 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (13.5 g, 35.33 mmol), diacetoxypalladium (0.397 g, 1.77 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.044 g, 3.53 mmol) and cesium carbonate (20.72 g, 63.59 mmol) in dioxane (150 mL) was degassed with argon, which was also let to bubble for 10 minutes then stirred at 100 °C overnight (yellow-ish dense suspension turning grey lighter). The reaction mixture was allowed to cool to rt, the insolubles were removed by filtration, washed with EtOAc and the filtrate was concentrated. (Insolubles~25g, which seemed to contain very little P1 by TLC and LCMS). The crude product (24.5g) was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetate (pure AcOEt to remove by- product coming from overreaction). The solvent was evaporated to dryness to afford a foam (12.5g) which was dissolved in dichloromethane (100ml). The resulting crystalline precipitate was collected by filtration, washed with dichloromethane. The filtrate was concentrated down, taken up into DCM and a second crop was collected by filtration, which was combined with the first batch and dried to a constant weight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy- N-methylbenzamide (11.51 g, 75.0 %) as a white crystalline solid. The filtrate was concentrated to dryness, taken up into DCM and collected by filtration to give a second sample EN02972-35-02 (0.41 g, 0.944 mmol, 2.67 %).

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