Journal of Medicinal Chemistry removed. The residue was subjected to a mass-triggered HPLC puriﬁcation to give 1a as well as 1b. 1H NMR for 1a (400 MHz, CD3OD) δ 7.59−7.63 (m, 2H), 7.09 (t, J = 6.4 Hz, 2H), 6.95−7.02 (m, 1H), 6.46−6.52 (m, 1H), 6.34−6.38 (m, 1H), 5.92 (s, 1H), 4.33 (dd, J = 4.4, 14 Hz, 1H), 3.96 (dd, J = 4.8, 13.2 Hz, 1H), 3.70−3.78 (m, 1H), 3.46−3.54 (m, 1H), 1.73 (s, 3H), 1.36 (s, 3H). m/z = 428.1 (M + 1). 1H NMR for 1b (400 MHz, CD3OD) δ 7.75−7.78 (m, 2H), 6.95−7.01 (m, 3H), 6.44−6.50 (m, 1H), 6.32−6.36 (m, 1H), 4.19 (dd, J = 1.6, 6.8 Hz, 2H), 4.00 (dd, J = 1.6, 6.8 Hz, 2H), 1.47 (s, 6H). m/z = 426.1 (M + 1). Synthesis of 10 (R1R2Me). To a solution of 2-bromo-1-(4- ﬂuorophenyl)ethanone (46.5 g, 214.29 mmol) in DMF (400 mL) was added 2-(benzyloxycarbonyl)-2-methylpropanoic acid (55.8 g, 236.4 mmol) and potassium carbonate (35.4 g, 256.5 mmol). The resulting solution was stirred for 4 h at rt. The resulting solution was diluted with 1000 mL of water. The resulting solution was extracted with ethyl acetate (2 × 800 mL), and the combined organic layer was washed with water (2 × 800 mL) and then brine (1 × 800 mL). The resulting organic phase was concentrated under vacuum. This resulted in 67 g (84%) of compound 4 as a white solid. m/z = 374 (M + 1). To a solution of compound 4 (70 g, 187.7 mmol) in toluene (700 mL) was added NH4OAc (144.5 g, 1.88 mol). The resulting solution was heated to reﬂux for 3 h in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 800 mL of water. The resulting solution was extracted with ethyl acetate (2 × 500 mL), and the combined organic layer was washed with water (2 × 800 mL) and brine (1 × 800 mL). The resulting mixture was concentrated under vacuum. This resulted in 58 g (88%) of compound 5 as a white solid. 1H NMR (300 Hz, DMSO-d6) δ 11.91 (s, NH), 7.80−7.75 (m, 2H), 7.54−7.12 (m, 8H), 4.97 (m, 2H), 1.6 (s, 6H). To a solution of compound 5 (58 g, 164.3 mmol) in DMF (400 mL) was added cesium carbonate (134 g, 411.0 mmol). This was followed by the addition of ethyl 2-bromoacetate (33 g, 197.6 mmol) dropwise with stirring at rt in 30 min. The resulting solution was stirred for 2 h at rt. The resulting solution was diluted with 1000 mL of water/ice. The resulting solution was extracted with ethyl acetate (2 × 700 mL), and the combined organic layer was washed with water (2 × 800 mL) and brine (1 × 800 mL). The resulting mixture was dried concentrated under vacuum. This resulted in 60 g (83%) of compound 6 as a yellow solid. 1H NMR (300 Hz, DMSO-d6) δ 7.76−7.72 (m, 2H), 7.32−7.28 (m, 5H), 7.08−7.03 (m, 3H), 5.08 (m, 2H), 4.87 (m, 2H), 4.23 (q, J = 5.4 Hz, 2H), 2.0 (s, 6H), 1.28 (t, J = 5.4 Hz, 3H). Article To a solution of compound 6 (70 g, 159.45 mmol, 1.00 equiv) in methanol (800 mL) was added palladium on carbon (10 g). The resulting solution was degassed and backﬁlled with hydrogen. The solution was stirred for 3 days at 25 °C. The solids were ﬁltered out and washed with MeOH. The ﬁltrate was concentrated under reduced pressure. This resulted in 7 (38 g, 145.56 mmol, 91%) as a white solid. LC-MS: (ES, m/z) [M + H]+ calcd for C14H14FN3O, 260; found, 260. 1H NMR (300 Hz, DMSO-d6) δ 7.79−7.74 (m, 2H), 7.13−7.07 (m, 3H), 6.35 (s, 1H), 4.73 (s, 2H), 1.79 (s, 6H). To a stirred solution of compound 7 (5 g, 19.2 mmol, 1 equiv) was dissolved in 50 mL of THF, 1 M borane/THF complex (57 mL, 57 mmol, 3 equiv) was added slowly and reaction was reﬂuxed overnight. LCMS indicated that the reaction was complete. THF was removed under reduced pressure. The reaction was quenched with MeOH. The crude product of 8 (4.5 g, 18.3 mmol, 95%) was used in the next step. LC-MS: (ES, m/z) [M + H]+ calcd for C14H17FN3 246, found 246. 1H NMR (DMSO, 300 Hz) δ 7.75−7.70 (m, 2H), 7.4 (s, 1H), 7.14 (t, J = 9.0 Hz, 2H), 3.9 (t, J = 5.4 Hz, 2H), 2.51 (t, J = 5.4 Hz, 2H), 1.41(s, 6H); NH proton not observed. To a stirred solution of compound 8 (2.9 g, 11.82 mmol, 1.1 equiv) and 2-(tert-butoxycarbonylamino)acetic acid (2.27 g, 13 mmol, 1.1 equiv) in 15 mL of dichloromethane were added DIEA (2.47 mL, 14.18 mmol, 1.2 equiv) and HATU (5.39 g, 14.18 mmol, 1.2 equiv). The reaction mixture was stirred at rt for 8 h. HPLC/MS analysis showed that desired product compound 9 was the major product. The reaction was further diluted with dichloromethane (70 mL). The organic layer was washed with washed with water (1 × 30 mL), followed by saturated NaHCO3 (1 × 30 mL) and ﬁnally with brine (1 × 30 mL). The organic layer was then dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting oil was puriﬁed using column chromatography with hexanes/ethyl acetate (0−100% linear gradient) used as eluant. The desired product compound 9 was obtained as oil (3.3 g, 8.27 mmol, 70%). 1H NMR (300 Hz, DMSO-d6,) δ 7.77−7.72 (m, 2H), 7.54 (s, 1H), 7.20−7.14 (m, 2H), 6.84−6.80 (m, 1H), 4.07 (s, 2H), 3.90 (d, J = 3.0 Hz, 2H), 3.70 (s, 2H), 1.80 (s, 6H), 1.40 (s, 9H). LC-MS: (ES, m/z) [M + H]+ calcd for C21H28FN4O3, 403; found, 403. To a stirred solution of compound 9 (3.02 g, 7.51 mmol) in dichloromethane (30 mL) was added Br2 (0.43 mL, 8.26 mmol) in acetic acid (3 mL). The reaction mixture was stirred at rt for 30 min. 4252 dx.doi.org/10.1021/jm300041e | J. Med. Chem. 2012, 55, 4244−4273