Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[C@@H:29]([OH:41])[C@@H:30]([NH2:40])[CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>ClCCl.C(OCC)(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[C@@H:29]([OH:41])[C@@H:30]([NH:40][C:1](=[O:3])[CH3:2])[CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(=O)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
Add 1-acetylimidazole (0.035 g, 0.315 mmol) and triethylamine (0.04 mL, 0.286 mmol) to solution of 2-(R)-[2-(S)-amino-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-piperidine-1-carboxylic acid tert-butyl ester (0.106 mg, 0.286 mmol) in dichloromethane (10 mL) and stir 18 h at room temperature. Dilute with ethyl acetate and wash with 1 N hydrochloric acid (3×), saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with dichloromethane and ethyl acetate) to give the title compound as a white solid (0.089 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](O)(=O)[CH2:10][C:11](O)=O>O>[CH2:10]([C:11]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[C:9]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)CC(=O)O
Solvent: O
Product: c1ccc2sc(Cc3nc4ccccc4s3)nc2c1
Reaction time: 1 h

Procedure:
To a flask were added 50 g polyphosphoric acid. After heating to 70 C under nitrogen, a mixture of 3.13 g 2-aminothiophenol and 1.3 g malonic acid was added. The reaction mixture was heated to 135 C for 1 hour, then 145 C for 1 hour. After cooling to 70 C, the mixture was poured into 100 ml water. The slurry was cooled to 22 C, filtered and the solid was washed with water. The solid was added to 50 ml ethanol and basified with aqueous ammonium hydroxide. After cooling to 5 C, the solid was filtered and washed with water. The solid was dissolved in 14 ml hot ethanol and 7 ml water was added and the solution was cooled to 5 C. Following filtration, the white solid was washed with 50% ethanol and dried, leaving 1.1 g.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3](O)[CH2:2]1.ClC(F)C(N(CC)CC)(F)F.C(O)C>CN(C=O)C>[CH3:16][C:15]1[C:13](=[O:14])[N:12]=[C:10]2[N:9]([C@@H:1]3[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([O:11]2)[CH2:2]3)[CH:17]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CCN(CC)C(F)(F)C(F)Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cn2c(nc1=O)O[C@H]1C[C@H]2O[C@@H]1CO
Temperature: 70 °C

Procedure:
Thymidine (85.4 g: 0.353 mol) was dissolved in 500 ml dry DMF and added to N-(2-chloro-1,1,2-trifluoroethyl) diethylamine (100.3 g: 0.529 mol) (prepared according to the method of D. E. Ayer, J. Med. Chem. 6, 608 (1963). This solution was heated at 70° C. for 30 minutes them poured into 950 ml ethanol (EtOH) with vigorous stirring. The product precipitated from this solution was filtered. The EtOH supernatent was refrigerated then filtered to yield a total of 47.75 g (0.213 mol. 60.3%) mp=228°-230° c.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16]>C(#N)C>[CH2:7]([O:4][C:1]1[CH:12]=[CH:13][C:8]([CH2:16][C:15]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:10]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl-4-hydroxy phenyl acetate (10 g, 55.49 mmol) in 50 mL of dry acetonitrile was added in a drop wise manner to a suspension of cesium carbonate (36 g, 110.98 mmol) in 50 mL of dry acetonitrile. Reaction mixture was allowed to stir at rt for 10 min then benzyl bromide (7.25 mL, 61.03 mmol) was added drop wise and continued to stir overnight at rt. Reaction was quenched with water and solid was filtered through Buchner funnel, filtrate obtained was diluted with ethyl acetate, and organic layer was washed with water, brine and dried over anhydrous sodium sulphate. Solvent was removed under reduced pressure to obtain crude product which was purified using column chromatography using 5-10% ethyl acetate in hexane to afford 8.0 g of liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)[CH3:5].[CH2:17]([OH:20])[CH2:18][OH:19]>O>[CH3:1][O:2][C:3](=[O:16])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:19][CH2:18][CH2:17][OH:20])=[O:15])=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc(N=C=O)cc1
Reactant: OCCO
Solvent: O
Product: COC(=O)C(C)Oc1ccc(NC(=O)OCCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.76 %

Procedure:
2-(4-Isocyanato-phenoxy)-propionic acid methyl ester 32 (20 g, 90.49 mmol) was added to ethylene glycol (40 ml) at room temperature. The reaction was exothermic and the temperature rose to 58° C. The mixture was allowed to cool and later stirred at room temperature for 16 hours. Water (150 ml) was added and crude 33 was extracted into chloroform, washed with water (2×50 ml), dried over sodium sulphate and distilled. Crude 33 was purified by column chromatography on silica gel using chloroform as eluant to get pure 33 (13 gr, 50.76%) as a syrup which crystallized in 48 hours as a white powder. M.p: 90.5-92.8° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([CH3:30])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH3:20])[CH:13]=3)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])(O)=O.[Na+].Cl[C:37]([O:39][C:40]([CH3:42])=[CH2:41])=[O:38]>CCOC(C)=O>[CH2:41]=[C:40]([O:39][C:37](=[O:38])[NH:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([CH3:30])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([N:19]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH3:20])[CH:13]=3)[CH:5]=[CH:6][C:7]=1[F:8])[CH3:42]
Reactant: C=C(C)OC(=O)Cl
Reactant: COc1ccc(CN(C)c2cc3nc(C)c(-c4ccc(F)c(N)c4)cc3cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(N(C)Cc4ccc(OC)cc4)cc3nc2C)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Treat a solution of 3-(3-amino-4-fluorophenyl)-N-(4-methoxybenzyl)-N,2-dimethyl-1,6-naphthyridin-7-amine (0.334 g, 0.830 mmol) in EtOAc (10 mL) with satd. NaHCO3 (10 mL), add isopropenyl chloroformate (0.100 mL, 0.913 mmol) and stir at RT for 2 h. Separate the layers, extract the aqueous layer with EtOAc (2×), dry the combined organics over MgSO4 and concentrate to dryness to afford the title compound (398 mg, 99%). MS (ESI) m/z: 487.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[Cl:19][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[C:24](Cl)[N:23]=[CH:22][N:21]=1.O>C1COCC1>[Cl:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([O:11][C:3]3[N:2]([CH3:1])[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[N:4]=3)=[CH:13][CH:14]=2)[C:25]=1[N+:26]([O-:28])=[O:27]
Reactant: Cn1c(Oc2ccc(N)cc2)nc2ccccc21
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(Oc2ccc(Nc3ncnc(Cl)c3[N+](=O)[O-])cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
To a solution of 4-[(1-methyl-1H-benzimidazol-2-yl)oxy]aniline (0.30 g) and TEA (0.26 mL) in THF (15 mL) was added 4,6-dichloro-5-nitropyrimidine (0.24 g) at room temperature, and the mixture was stirred at room temperature for 2 h. The mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, silica gel, eluted with 5%-50% AcOEt in hexane) to give 6-chloro-N-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-5-nitropyrimidin-4-amine (0.24 g) as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:21])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[N:5]1.[C:22]([C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1)(=[O:24])[CH3:23]>>[C:22]([C:25]1[CH:29]=[C:28]([C:30]([NH:1][C@@H:2]([CH3:21])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=3)=[N:5]2)=[O:31])[NH:27][N:26]=1)(=[O:24])[CH3:23]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(C(F)(F)F)c3)n2)[nH]n1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)-benzonitrile (110 mg, 0.374 mmol) and 3-acetyl-1H-pyrazole-5-carboxylic acid (58 mg, 0.374 mmol). The product was purified twice with flash-chromatography. Yield 8 mg (4%). 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (d, 3H), 2.48 (m, 3H), 4.29-4.38 (m, 2H), 4.41-4.50 (m, 1H), 7.01 (d, 1H), 7.29 (s, 1H), 7.84 (d, 1H), 8.15-7.19 (m, 1H), 8.24 (s, 1H), 8.44-8.50 (m, 2H), 14.13 (m, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23](SC)=[N:24][CH:25]=2)=[CH:15][CH:14]=1>N1C=CC=CC=1>[OH2:28].[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:23]2[NH:22][C:21](=[O:28])[C:20]([CH2:19][C:16]3[CH:17]=[N:18][C:13]([CH3:12])=[CH:14][CH:15]=3)=[CH:25][N:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCc1ccccc1
Reactant: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCCc3ccccc3)[nH]c2=O)cn1
Product: O

Procedure:
A mixture of 4-phenylbutylamine (2.7 g), 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone (3.0 g) and dry pyridine (20 ml) was heated under reflux for 40 hours, and evaporated to dryness. Water was added to the residue and the pH of the mixture was adjusted to 7. The solid was filtered off and was recrystallized from aqueous ethanol to give 2-(4-phenylbutylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone hydrate m.p. 151°-152°.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[OH:18])=[O:3].Cl[CH:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[O:18][CH:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:3])[CH3:1]
Reactant: CCOC(=O)CCC(Cl)c1ccccc1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C(C)=O)c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A mixture of 4-benzyloxy-2-hydroxyaceto-phenone (1.2 g), ethyl (RS)-4-chloro-4-phenyl-butanoate (1.21 g), potassium carbonate (760 mg), potassium iodide (35 mg) and dimethylformamide (30 mL) is stirred at 100° C. for 8 hours. It is evaporated to dryness and the resulting residue is partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer is dried over magnesium sulphate, filtered and concentrated in vacuo. Flash chromatography of the resulting oil, eluting with 15-30% ethyl acetate/hexane, affords ethyl (RS)-4-(2-acetyl-5-benzyloxy-phenoxy)-4-phenylbutanoate (0.73 g), in the form of a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[C:41]3[C:37]([CH2:38][C:39](=[O:43])[NH:40]3)=[CH:36][CH:35]=2)O1>>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:34]3[CH:42]=[C:41]4[C:37]([CH2:38][C:39](=[O:43])[NH:40]4)=[CH:36][CH:35]=3)=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)C3)OC1(C)C
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2ccc3c(c2)NC(=O)C3)c(-c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one in a manner analogous to Example 269. MS (M+H)+ 497.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:34][C:35]1[N:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>O1CCCC1.O>[C:11]([O:10][C:9](=[O:15])[N:8]([CH2:7][C:4]1[CH:3]=[C:2]([Br:1])[N:6]([S:41]([C:38]2[CH:39]=[N:40][C:35]([CH3:34])=[CH:36][CH:37]=2)(=[O:43])=[O:42])[CH:5]=1)[CH3:16])([CH3:12])([CH3:13])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cn1
Reactant: CN(Cc1c[nH]c(Br)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2Br)cn1
Reaction time: 0.17 h
Yield: 78.5 %

Procedure:
To a solution of tert-butyl [(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate (207 mg) in tetrahydrofuran (30 mL) was added sodium hydride (60% in oil, 31 mg) at 0° C., and the mixture was stirred at the same temperature for 10 min. A solution (3 mL) of 15-crown-5 (0.16 mL) and 6-methylpyridin-3-ylsulfonyl chloride (117 mg) in tetrahydrofuran was added at the same temperature. After stirring at room temperature for 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give the title compound as a brown oil (yield 213 mg, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]([O:21][CH3:22])(=[O:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17].N1CCCCC1.C(O)(=O)C>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]([C:14]([O:21][CH3:22])=[O:20])[C:16]([O:18][CH3:19])=[O:17])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1
Reactant: COC(=O)CC(=O)OC
Solvent: C1CCNCC1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1ccc(OC)cc1[N+](=O)[O-])C(=O)OC
Yield: 72 %

Procedure:
A mixture of 4-methoxy-2-nitrobenzaldehyde (21.3 g, Org. Synth., Vol. V, p-139, 1973), dimethyl malonate (16.5 g), piperidine (2.5 ml), and acetic acid (0.25 ml) in methanol (125 ml) was heated under reflux for 24 hr. The reaction mixture was concentrated, diluted with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate:hexane=1:2) to obtain the titled compound (25 g).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.CN1CCOCC1.[CH2:17]([N:24]1[C:29]2[CH:30]=[C:31]([Cl:37])[CH:32]=[C:33]([C:34]([Cl:36])=[O:35])[C:28]=2[O:27][C:26](CC)([CH3:38])[C:25]1=[O:41])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[ClH:36].[CH2:17]([N:24]1[C:29]2[CH:30]=[C:31]([Cl:37])[CH:32]=[C:33]([C:34]([NH:1][CH:2]3[CH:7]4[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]4)[CH2:3]3)=[O:35])[C:28]=2[O:27][CH:26]([CH3:38])[C:25]1=[O:41])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC1CN2CCC1CC2
Reactant: CCC1(C)Oc2c(C(=O)Cl)cc(Cl)cc2N(Cc2ccccc2)C1=O
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: CC1Oc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc2N(Cc2ccccc2)C1=O
Product: Cl

Procedure:
To a solution of 1.09 g of 3-aminoquinuclidine and 0.9 g of N-methylmorpholine in 20 ml of chloroform is added a solution of 3.25 g of 4-benzyl-6-chloro-2-ethyl-3,4-dihydro -2-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid chloride in 20 ml of chloroform under cooling and stirring followed by stirring at room temperature for 4 hours. The resultant solution is washed with water, aqueous sodium hydrogen carbonate and then water, and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is recrystallized from ethanolisopropyl ether and treated with ethanolic hydrochloric acid to give 4-benzyl-6-chloro-3,4-dihydro-2-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting at 267°-270° C. with decomposition.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](/[CH:29]=[CH:30]/[CH:31]=[O:32])[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=1)[CH2:29][CH:30]1[C:31](=[O:32])[O:13][C:12]2[NH:11][C:10]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])=[N:9][C:8]=2[CH:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Reactant: O=C/C=C/c1cccc(Cl)c1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1Cc1cccc(Cl)c1
Yield: 46 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(3-chlorophenyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 13 as a white solid (62 mg, 46%). Analytical data for 13: 1H NMR (500 MHz, CDCl3) δ 9.41 (s, 1H), 7.88 (ddd, J=9.1, 6.0, 3.2 Hz, 1H), 7.40-7.29 (m, 3H), 7.31-7.22 (m, 2H), 7.10-7.02 (m, 2H), 7.02-6.93 (m, 4H), 4.09 (d, J=6.8 Hz, 1H), 3.58 (ddd, J=9.8, 6.9, 4.9 Hz, 1H), 3.31 (dd, J=14.9, 4.9 Hz, 1H), 2.42 (dd, J=14.9, 9.8 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.6, 159.1 (d, JCF=243.4 Hz), 155.4 (d, JCF=241.8 Hz), 148.9, 140.0, 136.8, 136.5, 134.4, 129.9, 129.3, 129.1, 128.5, 127.9, 127.3, 127.0, 118.3 (dd, JCF=12.6, 8.9 Hz), 117.1 (dd, JCF=25.6, 8.9 Hz), 116.6 (dd, JCF=24.8, 9.3 Hz), 114.5 (dd, JCF=26.8, 3.6 Hz), 110.7 (d, JCF=3.8 Hz), 47.0, 38.6, 32.6; IR (film) cm−1 1773, 1636, 1597, 1528, 1481, 1464, 1171, 1117, 1079, 813, 741; LRMS (ESI): Mass calcd for [M+H]+ C25H18ClF2N2O2: 451.1. found 451.3; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 5% IPA/3% MeOH/hexanes 0.5 mL/min, 280 nm), Rt1 (minor)=49.1, Rt2 (major)=70.2 min; er=>99:1.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2].[CH3:54][N:55](C)C=O.O>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.[C-]#N.[Zn+2].[C-]#N.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([C:54]#[N:55])=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:33]=[C:34]([C:42]([F:45])([F:43])[F:44])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OS(=O)(=O)C(F)(F)F)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1c2ccc(C#N)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of (2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (732 mg), tetrakis(triphenylphosphine)palladium (catalytic amount), zinc cyanide (142 mg) and N,N-dimethylformamide (10 ml) is stirred at 95° C. under nitrogen flow for 8 hours. After cooling to room temperature, water and ethyl acetate are added to the reaction solution. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→2:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-cyano-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (572 mg). MS (m/z): 664 [M+H]+
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13].Br[CH2:18]/[CH:19]=[CH:20]/[Sn:21]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:30]([Sn:21]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])/[CH:20]=[CH:19]/[CH2:18][N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13])[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn](/C=C/CBr)(CCCC)CCCC
Reactant: OCCNCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC[Sn](/C=C/CN(CCO)CCO)(CCCC)CCCC
Temperature: 20 °C
Reaction time: 15 h

Procedure:
N-Ethyl-N,N-diisopropylamine (315 mg) was added to a solution of diethanolamine (256 mg) in dry DMF (5 mL) at 0° C. [(1E)-3-bromoprop-1-enyl](tributyl)stannane (600 mg) was added to the reaction after 10 min. The reaction mixture was stirred for 15 h at 20° C. and then quenched with saturated NH4Cl (aq.). Extraction with Et2O and drying (MgSO4) of the organic phase gave, after concentration in vacuo, the crude product. Purification was done by chromatography eluting with Et2O/MeOH 100:4 to afford the title compound as a liquid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]([O:8][C:9](=[O:30])[N:10]([C:19]1[CH:24]=[C:23](Br)[N:22]=[C:21]([NH2:26])[C:20]=1[N+:27]([O-:29])=[O:28])[CH2:11][C:12]1[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:7]>>[CH2:6]([O:8][C:9](=[O:30])[N:10]([C:19]1[CH:24]=[C:23]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[N:22]=[C:21]([NH2:26])[C:20]=1[N+:27]([O-:29])=[O:28])[CH2:11][C:12]1[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:7]
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: c1cscn1
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2nccs2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using thiazole (42 mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg), giving the product (79 mg) as a yellow gum.