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In mixture of (R)-6-amino-7-(4-phenoxyphenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-one (62) (95 mg, 0.24 mmol), (E)-4-(cyclobutyl(methyl)amino)but-2-enoic acid hydrochloride (76 mg, 0.37 mmol) and DIPEA (213 μL, 1.2 mmol) in 5 mL dry DMF was cooled to 0° C., HBTU (190 mg, 0.49 mmol) was added in one portion. The reaction mixture was allowed to warm up to rt, and stirred for 2 hrs under N2, and purified directly by preparative-HPLC (RP C18, 10 to 95% acetonitrile in water (0.2% NH3.H2O)) to give (R,E)-6-amino-9-(1-(4-(cyclobutyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (64) (36 mg, 25.9%) as a light yellow solid. LC-MS (ESI): m/z (M/M+2) 518/520. 1H NMR (400 MHz, DMSO) δ 8.11 (d, J=6.0 Hz, 1H), 7.48-7.36 (m, 4H), 7.23-7.07 (m, 5H), 6.69-6.55 (m, 1H), 6.34 (dd, J=35.9, 15.1 Hz, 1H), 5.89-5.67 (m, 2H), 5.18-4.95 (m, 1H), 4.15-3.42 (m, 4H), 2.97 (dd, J=18.6, 6.2 Hz, 2H), 2.85-2.73 (m, 1H), 2.73-2.58 (m, 1H), 2.33-2.10 (m, 1H), 1.98 (d, J=12.6 Hz, 3H), 1.95-1.87 (m, 2H), 1.80-1.67 (m, 2H), 1.63-1.48 (m, 2H).

1. temperatureto warm up to rt
2. custompurified directly by preparative-HPLC (RP C18, 10 to 95% acetonitrile in water (0.2% NH3.H2O))