A solution of (5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(4-(methylsulfonyl)piperazin-1-yl)methanone (0.163 g, 0.220 mmol) and titanium (IV) isopropoxide (0.194 mL, 0.661 mmol) in THF (2 mL) at 0° C. under nitrogen was treated dropwise with ethylmagnesium bromide (1.0 M solution in tert-butyl methyl ether; 1.322 mL, 1.322 mmol). The reaction was warmed to ambient temperature and an additional 3 equiv. EtMgBr was added. After 1 h, the reaction was quenched with ice and DCM, and was filtered through Celite® (diatomaceous earth) rinsing with copious amounts of DCM. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3×) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give an orange solid. The solid was taken up in TFA (1.5 mL) and 20 drops TfOH was added from a Pasteur pipette. The resulting mixture was sealed and heated at 80° C. for 1 h. The reaction was cooled in an ice bath and treated with ice and 10 N NaOH until basic. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3×) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This material was dissolved in DMSO and purified by prep HPLC (5-50% MeCN/H2O with 0.1% TFA). Product-containing fractions were concentrated to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)cyclopropyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine 2,2,2-trifluoroacetate (0.0063 g, 10.07 μmol, 4.57% yield) as an orange solid. m/z (ESI, +ve ion) 512 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.80 (s, 1H); 8.68 (d, J=2.3 Hz, 1H); 8.52 (d, J=2.5 Hz, 1H); 8.27 (d, J=2.2 Hz, 1H); 8.16 (dd, J=8.8, 2.7 Hz, 1H); 7.90 (br. s., 1H); 7.74 (br. s., 1H); 6.83 (d, J=8.8 Hz, 1H); 3.85 (s, 3H); 3.01-3.23 (m, 4H); 2.84 (s, 3H); 2.60-2.79 (m, 4H); 2.44 (s, 3H); 1.00-1.13 (m, 2H); 0.84-0.97 (m, 2H).
