Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH2:12][CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[C:4](=[O:20])[C:3]=1[C:21](OC)=[O:22].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>CCO>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:21]([C:3]2[C:4](=[O:20])[N:5]([CH2:12][CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:16])=[O:17])[C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[CH:8][CH:7]=3)=[O:22])=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(O)c2ncccc2n(CCN(C)S(C)(=O)=O)c1=O
Reactant: NCc1ccc(F)cc1
Solvent: CCO
Product: CN(CCn1c(=O)c(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc21)S(C)(=O)=O

Procedure:
In a manner similar to that described in Example 2, methyl 4-hydroxy-1-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate was dissolved in EtOH and treated with 4-fluorobenzylamine at reflux. After cooling the product fell out of solution and was collected. The crude was dissolved in CHCl3, washed with 10% KHSO4 solution, the organic was dried over MgSO4, filtered and evaporated to give the product as a white foam.
Reaction SMILES: [CH2:1]([N:6]1[C:10](=[O:11])[CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8][CH:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[CH2:1]([N:6]1[C:10](=[O:11])[CH:9]([CH:12]([CH3:25])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8][CH:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)CC1SC(c2ccccc2)N(CCC(C)C)C1=O
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C1SC(c2ccccc2)N(CCC(C)C)C1=O
Reaction time: 16 h
Yield: 13.7 %

Procedure:
To a stirred solution of ethyl 2-(3-isopentyl-4-oxo-2-phenylthiazolidin-5-yl)acetate (84 mg, 0.25 mmol) in THF at 0° C. was added LiHMDS (0.28 ml of 1 N, 0.28 mmol) dropwise and the reaction mixture was stirred from 0° C. to RT over 16 hours. The reaction mixture was poured in to 1 N HCl and extracted with EtOAc (4×). The organics were combined, dried (MgSO4) and evaporated to dryness. Purification by preparative TLC (7:1; Hx:EtOAc) gave the desired product as an oil (12 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[C-:29]#[N:30].[Na+]>CN1C(=O)CCC1.[Ni](Br)Br>[C:29]([C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:24])([CH3:25])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1)#[N:30]
Reactant: [C-]#N
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(Cl)cc(N2CCOCC2)c1
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(C#N)cc(N2CCOCC2)c1
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 39.9 %

Procedure:
A mixture of 2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.25 mmol), sodium cyanide (24.5 mg, 0.5 mmol), nickel(II) bromide (54.6 mg, 0.25 mmol) in NMP (0.5 mL) was stirred for 10 minutes at 200° C. with microwave. After removal of the solid, the rediue was purificated by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(3-cyano-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (39 mg, 40%) as a white solid: LC/MS m/e calcd for C23H25N3O3 (M+H)+: 392.5, observed: 392.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:1][CH2:2][CH2:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][O:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=3)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: OCCN1c2ccccc2COc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.99 g (4.1 mmol) of 5,11-dihydro-5-(2-hydroxyethyl) dibenzo[b,e][1,4]oxazepine was dissolved in 6 ml of anhydrous pyridine. 0.94 g (4.9 mmol) of p-toluenesulfonyl chloride was added to the obtained solution, and they were stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane. The obtained solution was washed with 5% aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution successively. After drying, the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with ethyl acetate and hexane (1:3). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain 5,11-dihydro-5-[2-(4-methylphenylsulfonyl)oxyethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (1.25 g, 76.6%).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)=[CH:6][CH:5]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])[N:20]=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)F)cc2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 1-(4-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-9) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=399.1 (M+H)+
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.ClC1C=CC([C@@H](CNC(C)C)[C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][N:31]=[C:30]4[NH:40][N:41]=[C:42]([O:43][CH3:44])[C:29]=34)[CH2:24][CH2:23]2)=[O:21])=CC=1.[C:50]([O:54][C:55]([NH:57][C@H:58]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65][CH:64]=1)C(O)=O)=[O:56])([CH3:53])([CH3:52])[CH3:51].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:69][C:66]1[CH:65]=[CH:64][C:63]([CH2:62][C@@H:58]([NH:57][C:55](=[O:56])[O:54][C:50]([CH3:52])([CH3:51])[CH3:53])[C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][N:31]=[C:30]4[NH:40][N:41]=[C:42]([O:43][CH3:44])[C:29]=34)[CH2:24][CH2:23]2)=[O:21])=[CH:68][CH:67]=1
Reactant: COc1n[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@H](CNC(C)C)c4ccc(Cl)cc4)CC3)c12
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1n[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.0558 mL, 0.320 mmol) was added to 3-methoxy-5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.034 g, 0.080 mmol, see Example 9), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.024 g, 0.080 mmol) and TBTU (0.0308 g, 0.0961 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was then concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2M) was added. It was stirred for 20 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by chromatography (hexane:ethyl acetate, 1:1) to give (R)-tert-butyl 3-(4-chlorophenyl)-1-(4-(3-methoxy-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (R)-2-amino-3-(4-chlorophenyl)-1-(4-(3-methoxy-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.036 g, 79%). MS APCI (+) m/z 491.3 detected.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[NH:22][N:21]=3)[C:7]=2[CH:27]=1)#[N:2].Br[CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][O:13][CH3:14])([CH2:15][O:16][CH3:17])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:29][CH2:30][CH3:31])[N:21]=3)[C:7]=2[CH:27]=1)#[N:2]
Reactant: CCCBr
Reactant: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)[nH]n2)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1nc(N[C@@H]2c3cc(C#N)ccc3OC(COC)(COC)[C@H]2O)ccc1=O
Yield: 49.8 %

Procedure:
(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-[(1,6-dihydro-6-oxo-3-pyridazinyl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol (60 mg, 0.16 mmol) obtained in Example 8 and 1-bromopropane (0.017 ml, 0.19 mmol) were dissolved in dimethylformamide (1.0 ml). Potassium carbonate (45 mg) was added and the mixture was reacted at 70° C. for 3 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (methanol:chloroform=4:96) to give 33 mg of the title compound (50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:20]([C:14]2[C:15](=[O:19])[NH:16][C:17]3[C:12]([C:13]=2[OH:25])=[N:11][CH:10]=[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:18]=3)=[O:22])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: NC1CC1
Product: O=C(NC1CC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclopropylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.80 (1H, br), 10.35 (1H, br), 8.35 (1H, br), 7.38 (1H, s), 7.30 (2H, m), 7.15 (2H, t, J=8.7 Hz), 4.06 (2H, br s), 2.85 (1H, m), 0.74 (2H, m), 0.51 (2H, m); HRMS calcd for C19H16FN3O3+H+: 354.1254. Found: 354.1255.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:25][CH2:26][CH3:27])[N:18]([CH2:19][CH2:20][CH2:21][C:22](=O)[CH3:23])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:9][C:8]=2[N:7]=1>C(O)C.O>[CH3:3][O:2][N:4]=[C:22]([CH2:21][CH2:20][CH2:19][N:18]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:9][C:8]=3[N:7]=[C:6]([NH2:5])[C:15]=2[N:16]=[C:17]1[CH2:25][CH2:26][CH3:27])[CH3:23]
Reactant: CON
Reactant: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)=NOC
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
Methoxylamine hydrochloride (0.98 g, 11.79 mmol) was added to a solution of 5-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one (3.8 g, 9.83 mmol) in ethanol (50 mL) and water (10 mL) and stirred at ambient temperature for 3 hours. The mixture was then concentrated under reduced pressure, diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 5% methanol in dichloromethane) and recrystallized from methanol and water to afford 3.6 g of 5-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-methyloxime as a tan solid, mp 191-192° C. MS (APCI) m/z 416.2 (M+H+); C25H29N5O
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:18]=[C:17]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28][CH3:29])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=1[NH:30][C:31](=[O:39])[C@:32]([OH:38])([CH3:37])[C:33]([F:36])([F:35])[F:34]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[C:17]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:29])=[O:6])(=[O:20])=[O:21])[CH:16]=[CH:15][C:14]=1[NH:30][C:31](=[O:39])[C@:32]([OH:38])([CH3:37])[C:33]([F:35])([F:36])[F:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccccc1S(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccccc1S(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.4 %

Procedure:
m-Chloroperoxybenzoic acid (50%, 0.293 g) was added to a solution of (R)-N-[2-chloro-4-(2-methylsulphanylphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 1) (0.384 g) in DCM (40 ml). The mixture was stirred at ambient temperature for 6 hours then washed with saturated aqueous sodium hydrogen carbonate solution (3×100 ml), water (100 ml) and brine and then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 50-70% ethyl acetate/hexane to give the title compound (0.26 g) as a solid. Mp 118-120° C.; NMR (CDCl3): 1.70 (s, 3H), 3.0 (m, 3H), 4.85 (brs, 1H), 7.75 (t, 1H), 7.85 (m, 2H), 8.0 (m, 1H), 8.15 (d, 1H), 8.3 (d, 1H), 8.65 (dd, 1H), 9.40 (brs, 1H); MS (ESP−): 468; EA: found: C, 44.3; H, 3.7; N, 2.6%; C17H15ClF3NO5S2.0.125 C4H8O2.0.3 C4H10O requires: C, 44.64; H, 3.81; N, 2.78%.
Reaction SMILES: [C:1]([CH:3](OC(=O)C1C=CC=CC=1)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)#[N:2]>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][CH2:3][C:1]#[N:2])=[CH:7][CH:8]=1
Reactant: COc1ccc(C=CC(C#N)OC(=O)c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C=CCC#N)cc1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
Benzoic acid 1-cyano-3-(4-methoxy-phenyl)-allyl ester (15 g; ca 0.050 mol) is dissolved in 100 ml of anhydrous tetrahydrofuran. Tetrakis(triphenylphosphine)palladium (0.88 g; 0.8 mmol) and 4.8 ml of poly(methylhydrosiloxane) (ca 80 meq; Aldrich) are added, and the mixture is stirred at ca 20° C., cooling with a cold water bath. After 3 h 30 min, the mixture is concentrated by rotary evaporation, stirred with 150 ml of water to hydrolyze the siloxane. The polymer and organic materials are redissolved in CH2Cl2 and washed with saturated sodium bicarbonate to remove benzoic acid. Evaporation of the solvent and flash chromatography (150 g SiO2; hexane:ethyl acetate 80:20 v:v) affords 4.9 g (57%) of pure 4-(4-methoxy-phenyl)-but-3-enenitrile, mp 75-76° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li].Cl[Si](C)(C)C.[CH3:14][C:15]1([CH3:22])[C:20](=[O:21])[CH2:19][CH2:18][O:17][CH2:16]1.C(N(CC)CC)C.[Br:30]N1C(=O)CCC1=O>C1COCC1>[Br:30][CH:19]1[CH2:18][O:17][CH2:16][C:15]([CH3:22])([CH3:14])[C:20]1=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)COCCC1=O
Agent: C[Si](C)(C)Cl
Agent: [Li]
Solvent: CCN(CC)CC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1(C)COCC(Br)C1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 18.6 %

Procedure:
A solution of lithium diisopropylamine (2.0 M in heptanes/THF/ethylbenzene) (2.5 ml, 5.1 mmol) diluted with THF (10 mL) under argon was cooled to −78° C. Chlorotrimethylsilane (2.5 mL, 19.5 mmol) was added followed by 3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1, 500 mg, 3.9 mmol) in THF (5 mL) and triethylamine (8.0 mL, 57 mmol). The resulting mixture was stirred at −78° C. for 5 minutes and then quenched with saturated NaHCO3 (20 mL). The mixture was extracted with ether (30 mL) and the organics was washed with 1M citric acid (50 mL), dried (K2CO3), filtered and concentrated in vacuo. The residue was dissolved in THF (5 mL) and cooled to 0° C. N-Bromosuccinimide (694 mg, 3.9 mmol) was added and the resulting mixture was stirred at room temperature for 2 hrs and then quenched with saturated NaHCO3 (10 mL). The mixture was extracted with ether (2×20 mL) and the organics was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (8% ethyl acetate in hexane) to yield the title compound as an oil (150 mg, 18%).
Reaction SMILES: CC([N:5]([C@@H:9]([CH3:13])[CH2:10][C:11]#[N:12])[C:6](=[O:8])[O-:7])(C)C.CS(OC[C@@H](NC(O[C:26]([CH3:29])([CH3:28])[CH3:27])=O)C)(=O)=O.[C-]#N.[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O.O>[C:11]([CH2:10][C@@H:9]([NH:5][C:6](=[O:8])[O:7][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:13])#[N:12]
Reactant: C[C@@H](CC#N)N(C(=O)[O-])C(C)(C)C
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H](CC#N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 88 %

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).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([S:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[N:7][CH:8]=1)#[N:2].[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>ClCCl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:12][CH2:11][CH2:10][S:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1
Reactant: CC(C)(C)OC(=O)NCCSc1ccc(C#N)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(SCCN)nc1

Procedure:
6-[(2-Aminoethyl)thio]nicotinonitrile trifluoroacetate (Example 45A) is prepared in analogy to Example 40A from tert-butyl {2-[(5-cyanopyridin-2-yl)thio]ethyl}carbamate (Example 42A) (580 mg, 2.1 mmol) and trifluoroacetic acid (3.2 ml, 42 mmol) in dichloromethane (20 ml). 500 mg of the product are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[N:9]3[C:10](=[N:15][C:16]([CH3:17])=[C:8]3[C:7]1=[O:18])[CH:11]=[CH:12][CH:13]=2.C(N(CC)CC)C.[C:26](Cl)(=[O:29])[O:27][CH3:28]>C(Cl)Cl>[CH3:17][C:16]1[N:15]=[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[N:9]2[C:8]=1[C:7](=[O:18])[N:6]3[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26]([O:27][CH3:28])=[O:29]
Reactant: COC(=O)Cl
Reactant: Cc1nc2cccc3n(CCCCN)c(=O)c1n23
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCCCn1c(=O)c2c(C)nc3cccc1n32
Yield: 78.9 %

Procedure:
To a solution of 1.22 g (5.0 mmol) of 1-[4-(amino) butan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 1.1 ml (7.9 mmol) of triethylamine in 40 ml of methylene chloride was added, while stirring under ice-cooling, 0.50 ml (6.5 mmol) of methyl chlorocarbonate. The mixture was stirred for 0.5 hour at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from methylene chloride-methanol-ether to give 1.192 g of the desired compound (78.9%, colorless crystals), m.p.175-176° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([O:12][CH3:13])[N:5]=2)[CH2:3][CH2:2]1.[N+:14]([CH3:17])([O-:16])=[O:15].Cl.CN.C([O-])(=O)C.[Na+]>>[CH:1]1([C:4]2[N:5]=[C:6]([O:12][CH3:13])[C:7](/[CH:8]=[CH:17]/[N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: C[N+](=O)[O-]
Reactant: COc1nc(C2CC2)ccc1C=O
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Product: COc1nc(C2CC2)ccc1/C=C/[N+](=O)[O-]
Reaction time: 4 h
Yield: 89.8 %

Procedure:
6-Cyclopropyl-2-methoxynicotinaldehyde (121 mg, 0.683 mmol) was diluted with nitromethane (259 μL, 4.78 mmol) followed by the addition of methylamine hydrochloride (27.7 mg, 0.410 mmol) and sodium acetate (33.6 mg, 0.410 mmol). After stirring for 4 hours, the reaction was loaded directly onto a silica gel column and eluted with 5% ethyl acetate/hexanes to 50% ethyl acetate hexanes to yield (E)-6-cyclopropyl-2-methoxy-3-(2-nitrovinyl)pyridine (135 mg, 0.613 mmol, 89.8% yield).