Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:34])[C:15]([OH:33])=[C:16]2[C:30](=[O:31])[N:20]3[C@@H:21]([CH3:29])[CH2:22][CH2:23][N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[C@@H:19]3[CH2:18][N:17]2[CH:32]=1)=[O:12].N[C@@H:36]([CH3:44])[CH2:37][CH2:38]NCC(C)C.[C:45]([OH:48])(=O)[CH3:46].[Cl:49][CH2:50]Cl>>[ClH:49].[ClH:49].[NH2:20][C@@H:21]([CH3:29])[CH2:22][CH2:23][NH:24][CH2:25][CH:26]([CH3:28])[CH3:27].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:34])[C:15]([OH:33])=[C:16]2[C:30](=[O:31])[N:20]3[C@@H:21]([CH3:29])[CH2:22][CH2:23][N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[C@@H:19]3[CH2:18][N:17]2[CH:32]=1)=[O:12].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:34])[C:15]([O:48][CH2:45][C:46]2[CH:44]=[CH:36][CH:37]=[CH:38][CH:50]=2)=[C:16]2[C:30](=[O:31])[N:20]3[C@@H:21]([CH3:29])[CH2:22][CH2:23][N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[C@@H:19]3[CH2:18][N:17]2[CH:32]=1)=[O:12]
Reactant: CC(=O)O
Reactant: ClCCl
Agent: CC(C)CN1CC[C@H](C)N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3C[C@@H]12
Agent: CC(C)CNCC[C@H](C)N
Product: CC(C)CN1CC[C@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3C[C@@H]12
Product: Cl
Yield: 76 %

Procedure:
1,1-Dimethylethyl[(1S)-2-cyano-1-methylethyl]carbamate. The nitrile was prepared in two steps using a modified procedure as described in example Z-29. To a stirred solution of (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl methanesulfonate (8.40 g, 33.2 mmol) in DMSO (50 mL) and KCN (6.51 g, 100.0 mmol) cooled to 0° C. was added 18-crown-6 (9.05 g, 34.3 mmol). The solution was allowed to warm to room temperature and then heated to 70° C. for 1 hour. After cooling at room temperature, water was added and the mixture was extracted with Et2O. The ethereal layers were washed with a brine solution, dried over Na2SO4, filtered and concentrated to give 1,1-dimethylethyl [(1S)-2-cyano-1-methylethyl]carbamate (5.37 g, 88%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.32 (d, J=6.8 Hz, 3H), 1.44 (s, 9H), 2.52 (dd, J=4.0, 16.4 Hz, 1H), 2.74 (m, 1H), 3.95 (m, 1H), 4.65 (br s, 1H). b) [(3S)-3-Aminobutyl](2-methylpropyl)amine dihydrochloride was prepared in a similar manner as described in example Z-29. 1H NMR (400 MHz, CDCl3/CD3OD) δ 0.99 (m, 6H), 1.34 (m, 3H), 2.13-2.27 (m, 3H), 2.76 (m, 2H), 3.07 (m, 2H), 3.47 (m, 1H), 8.22 (m, 1H), 8:83 (m, <1H). c) (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two steps using a similar process to that described in example Z-2. 16a (80 mg, 0.17 mmol) and free based [(3S)-3-aminobutyl](2-methylpropyl)amine (107 mg, 0.74 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(2-methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (76 mg, 76%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (39 mg, 80%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 0.76 (d, J=6.4 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 1.32 (d, J=7.2 Hz, 3H), 1.45-1.50 (m, 1H), 1.60-1.69 (m, 1H), 2.03-2.12 (m, 2H), 2.21-2.27 (m, 1H), 2.73-2.79 (m, 1H), 2.87-2.93 (m, 1H), 4.16-4.25 (m, 2H), 4.45 (s, 1H), 4.57-4.68 (m, 2H), 4.96-5.01 (m, 1H), 6.75-6.82 (m, 2H), 7.32-7.38 (m, 1H), 8.26 (s, 1H), 10.45 (s, 1H), 12.56 (s, 1H); ES+ MS: 475 (M+1).