Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:9](O)=O)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][N:19]=2)[CH2:14][CH2:13]1>>[C:1]1([CH2:9][N:12]2[CH2:13][CH2:14][CH:15]([C:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][N:19]=3)[CH2:16][CH2:17]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C(O)C1=Cc2ccccc21
Product: C1=C(CN2CCC(c3noc4ccccc34)CC2)c2ccccc21

Procedure:
3-[1-(Benzocyclobuten-1-ylmethyl)-4-piperidyl]-1,2-benzisoxazole was prepared from benzocyclobutene-1-carboxylic acid and 3-piperid-4-yl-1,2-benzisoxazole according to the process described in Example 19, stages A and B.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:10]2)=[CH:6][CH:5]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([C:11]1([C:16]([O:18][CH3:19])=[O:17])[C:12](=[O:15])[CH2:13][CH2:14][N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:21][CH:20]=2)[CH2:10]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1CN(Cc2ccc(Cl)cc2)CCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccccc2)CN(Cc2ccc(Cl)cc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
In a three-necked flask, under a azote atmosphere, sodium hydride (0.115 g, 60% in mineral oil, 2.871 mmol) was added at 0° C. by small portions to a solution of methyl 1-(4-chlorobenzyl)-4-oxopiperidine-3-carboxylate obtained above (0.809 g, 2.871 mmol) in 1.80 mL of anhydrous DMF. The resulting mixture was stirred 30 min at room temperature and then a solution of benzyl bromide (0.341 mL, 2.871 mmol) in 2.20 mL of anhydrous DMF was added. The reaction was followed by HPLC and UPLC-MS. After 24 h at room temperature, it was diluted with ethyl acetate. The organic phase was washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo to give a yellow oil that was purified by flash chromatography (SiO2, petroleum ether:ethyl acetate 95:5 as eluent). Evaporation and drying in vacuo of the pure fractions gave pure methyl 3-benzyl-1-(4-chlorobenzyl)-4-oxopiperidine-3-carboxylate as a colorless oil. (0.623 g, 1.675 mmol, 58% yield). 372.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:19]([CH:20]=O)=[CH:18][C:17]2[C:12](=[C:13]([CH3:22])[CH:14]=[CH:15][CH:16]=2)[N:11]=1.[CH2:23]([NH2:32])[C:24]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[CH:26][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:29][O:28][C:27]1[CH:30]=[CH:31][C:24]([CH2:23][NH:32][CH2:20][C:19]2[C:10]([C:3]3[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1cccc(F)c1-c1nc2c(C)cccc2cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CNCc2cc3cccc(C)c3nc2-c2c(F)cccc2OC)cc1

Procedure:
Prepared according to Procedure F using 2-(2-fluoro-6-methoxyphenyl)-8-methylquinoline-3-carbaldehyde (1.086 g, 3.68 mmol), DCE (18 mL), PMBNH2 (0.95 mL, 7.36 mmol, 2.0 eq), and NaBH(OAc)3 (2.3387 g, 11.03 mmol, 3 eq) After purification, N-(4-methoxybenzyl)(2-(2-fluoro-6-methoxyphenyl)-8-methylquinolin-3-yl)methanamine was obtained as yellow syrup. 1H NMR (DMSO-d6) δ ppm 8.42 (1H, s), 7.84 (1H, d, J=7.4 Hz), 7.55-7.62 (1H, m), 7.43-7.54 (2H, m), 7.13 (2H, d, J=8.6 Hz), 6.90-7.01 (2H, m), 6.77-6.85 (2H, m), 3.71 (3H, s), 3.65 (3H, s), 3.47-3.62 (4H, m), 2.64 (3H, s), 2.43 (1H, s). Mass Spectrum (ESI) m/e=417.3 (M+1).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH3:32][O:31][C:28]1[N:27]=[CH:26][C:25]([NH:24][C:17]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:23][C:20]([CH2:21][N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[CH:19][N:18]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: C1CCNC1
Product: COc1ccc(Nc2ncc(CN3CCCC3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde and pyrrolidine (Aldrich, St. Louis, Mo.). 1H NMR (400 MHz, CDCl3) δ 11.64 (s, 1H); 8.71 (d, J=2.35 Hz, 1H); 8.36 (d, J=2.54 Hz, 1H); 8.20 (d, J=2.35 Hz, 1H); 8.13 (dd, J=8.80, 2.74 Hz, 1H); 6.76 (d, J=8.80 Hz, 1H); 6.33 (br. s., 2H); 3.94 (s, 3H); 3.58 (s, 2H); 2.57 (br. s., 4H); 2.54 (s, 3H); 1.80-1.90 (m, 4H). m/z (ESI, +ve ion) 392.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH3:18]>C(O)C>[NH:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:3]1[N:4]=[C:5]([NH2:18])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccc(Cl)c(-c2nc3ccccc3[nH]2)n1
Reactant: N
Solvent: CCO
Product: Nc1ccc(Cl)c(-c2nc3ccccc3[nH]2)n1
Reaction time: 16.67 h
Yield: 21 %

Procedure:
2-(3,6-Dichloro-pyridin-2-yl)-1H-benzoimidazole (20 mg; 0.076 mmol) was dissolved in ethanol (1.5 ml) and concentrated ammonia (2 ml) in a pressure tube. After 1000 minutes in a microwave at 140° C. and 200 psi, the solvents were removed and the residue dissolved in isopropyl alcohol (1 ml) and concentrated ammonia (1 ml) before microwaving as before. The solvents wore evaporated and the residue chromatographed on silica gel with 80% ethyl acetate in heptane to give 6-(1H-benzoimidazol-2-yl)-5-chloro-pyridin-2-ylamine (4 mg, 21%).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C1C=CC=CC=1>O>[N:8]1([C:4]2[CH2:5][CH2:6][S:1][CH2:2][CH:3]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCSCC1
Reactant: C1CCNC1
Solvent: O
Solvent: c1ccccc1
Product: C1=C(N2CCCC2)CCSC1

Procedure:
A solution of 103 g (0.89 mole) of tetrahydrothiopyran-4-one, 95 g (1.33 moles) of pyrrolidine, and one l. of anhydrous benzene is heated under reflux in a nitrogen atmosphere for 2 hours until the theoretical amount of water has collected in a Dean-Stark trap. The solvent is distilled, and the residue is fractionated under reduced pressure to provide 5,6-dihydro-4-(1-pyrrolidinyl)-2H-thiopyran as a colorless liquid, b.p. 124° (0.01 mm).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[CH3:12])[C:3]=1[C:4]#[N:5].[S:13](Cl)(=[O:16])(=[O:15])[NH2:14]>CN(C)C(=O)C>[S:13]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[CH3:12])[C:3]=1[C:4]#[N:5])(=[O:16])(=[O:15])[NH2:14]
Reactant: NS(=O)(=O)Cl
Reactant: C/C=C/c1cccc(N)c1C#N
Solvent: CC(=O)N(C)C
Product: C/C=C/c1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A solution of (E)-2-amino-6-(prop-1-enyl)benzonitrile (Example 130b) (0.60 g, 3.82 mmol) in N,N-dimethylacetamide (DMA) (15.5 mL), under a nitrogen atmosphere, was treated with sulfamoyl chloride (0.88 g, 7.63 mmol) at room temperature. The obtained mixture was stirred at room temperature for 2 h and the reaction was quenched with water (20 mL). The mixture was extracted with EtOAc (4×80 mL), the combined extract was washed with water (2×20 mL) and brine, and dried with MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using gradient hexanes to hexanes/EtOAc (1:1) to give 0.83 g (92%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.39 (broad s, 1H), 7.48-7.60 (m, 2H), 7.38-7.43 (m, 1H), 7.21 (broad s, 2H), 6.51-6.65 (m, 2H), 1.88-1.94 (m, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[N:6]=[CH:5]2.[NH2:17][CH:18]([CH3:29])[CH:19]([C:21]1[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.C1(C)C=CC=CC=1.[Cu]I>[CH3:28][O:27][C:24]1[N:23]=[CH:22][C:21]([CH:19]([O:20][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=[CH:5]3)[CH:18]([NH2:17])[CH3:29])=[CH:26][CH:25]=1
Reactant: Ic1ccc2c(cnn2-c2cccnc2)c1
Reactant: COc1ccc(C(O)C(C)N)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Solvent: Cc1ccccc1
Product: COc1ccc(C(Oc2ccc3c(cnn3-c3cccnc3)c2)C(C)N)cn1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
5-Iodo-1-(3-pyridinyl)indazole (750 mg, 2.3 mmole), 2-Amino-1-[6-methoxypyridin-3-yl]propan-1-ol (410 mg, 2.2 mmol), copper(I)iodide (42 mg, 0.22 mmol) and caesium carbonate (1.45 g, 4.5 mmole) were suspended in butyronitrile (2.4 mL) and toluene (4.8 mL). The reaction vessel was capped and the mixture was stirred at 130° C. for 20 hours. Then the solvent was removed i.vac., and the product purified by chromatography on silica gel. Yield 254 mg (3 0%) as a racemic mixture of two diastereomeres.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10](=[O:27])[C@@H:11]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12][CH:13]([S:16][S:17][CH3:18])[CH2:14]Br)([CH3:8])([CH3:7])[CH3:6]>CN(C)C=O>[C:5]([O:9][C:10](=[O:27])[C@@H:11]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12][CH:13]([S:16][S:17][CH3:18])[CH2:14][N:1]=[N+:2]=[N-:3])([CH3:8])([CH3:6])[CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CSSC(CBr)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSSC(CN=[N+]=[N-])C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
Sodium azide (2.44 g, 37.6 mmol) was added to a solution of the crude (S)-5-bromo-2-tert-butoxycarbonylamino-4-methyldisulfanyl-pentanoic acid tert-butyl ester (Compound 32) obtained in the foregoing in N,N-dimethylformamide (100 ml), and the reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-5-azido-2-tert-butoxycarbonylamino-4-methyldisulfanyl-pentanoic acid tert-butyl ester (Compound 33) (1.87 g, 64%).
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][NH:5]1)#[N:2].[H-].[Na+].Cl[CH2:12][C:13]#[C:14][CH2:15][NH:16][C:17](=[O:32])[C:18]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O>[C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[CH2:12][C:13]#[C:14][CH2:15][NH:16][C:17](=[O:32])[C:18]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)([OH:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)#[N:2]
Reactant: O=C(NCC#CCCl)C(O)(c1ccccc1)C1CCCCC1
Reactant: N#CN=C1NCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CN=C1NCCN1CC#CCNC(=O)C(O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 75.2 %

Procedure:
To a solution of 2-(cyanoimino)imidazolidine (0.28 g) in dimethyl sulfoxide (10 ml}was added 60% sodium hydride dispersed in mineral oil (0.1 g) and the mixture was stirred at room temperature for 25 minutes. After an addition of N-(4-chloro-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide (0.40 g), the mixture was stirred at the same temperature for further 45 minutes and then quenched with cold water (50 ml). The mixture was extracted with ethyl acetate (50 ml×3). The combined extracts were washed with sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol (20:1) as an eluent to give N-[4-{2-(cyanoimino)-1-imidazolidinyl}-2-butynyl]-2-cyclohexyl-2-hydroxy-2-phenylacetamide (0.37 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16]O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:14][C:15]([CH3:19])([CH3:18])[CH3:16])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)CO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a suspension of 4-trifluoromethylbenzoic acid (75.0 g, 394 mmol) and 2,2-dimethyl-propyl alcohol (70.5 g, 800 mmol) in toluene (500 mL) was added concentrated sulfuric acid (3.0 mL). The mixture was stirred at reflux for 4 hours, cooled to room temperature, poured into saturated aqueous sodium carbonate (250 mL) and the layers were separated. The organic layer was washed with saturated aqueous sodium carbonate (250 mL), and brine (100 mL), and was concentrated to give 4-trifluoromethyl-benzoic acid, 2,2-dimethyl-propyl ester (102 g, 99% yield) as a yellow liquid: Rf : 0.66 (ethyl acetate/hexanes 25,75); IR 2932, 1727, 1327, 1280, 1133, 1066, 862. 775, 704 cm-1 ; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=7.9 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 4.04 (s, 2H), 1.04 (s, 9); 13C NMR (100 MHz, CDCl3) δ 26.51, 31.61, 74.72, 123.63 (q, J=272.7 HZ), 125.4, 129.9, 133.7, 134.35 (q, J=31.7 Hz), 165.35.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].CCN(CC)CC.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[OH:8][CH2:7][C@H:5]([NH:6][C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:4]([O:3][CH3:2])=[O:9]
Reactant: COC(=O)[C@@H](N)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 93.2 %

Procedure:
(U. Larsson and R. Carlson, Acta Chem. Scand. 1994, 48, 511-516; M. Meyer et al., J. Am. Chem. Soc. 1997, 119, 10093-10103). Using the preceding procedure and using L-serine methyl ester hydrochloride (20.00 g, 0.13 mol), Et3N (35.82 mL, 0.26 mol) and TrCl (36.53 g, 0.13 mol) gave 43.80 g (94%) of crude desired product as a pale yellow crystalline solid: Rf=0.50 (1/1 EtOAc/hexanes); 1H NMR (CDCl3) δ 2.31 (br s, 1H), 2.84-3.02 (br m, 1H), 3.29 (s, OCH3), 3.50-3.59 (m, CHH′OH, CH), 3.63-3.74 (m, CHH′OH), 7.18-7.29 (m, 9 PhH), 7.48-7.50 (m, 6 PhH).
Reaction SMILES: [CH3:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].I[CH2:14][C@@H:15]1[CH2:19][N:18]([C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:17](=[O:28])[CH2:16]1.O>CS(C)=O>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH3:1])([CH2:14][C@H:15]1[CH2:16][C:17](=[O:28])[N:18]([C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[CH2:19]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](CI)CC1=O
Reactant: COC(=O)C(C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C)(C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1)C(=O)OC
Yield: 67.1 %

Procedure:
To dimethyl methylmalonate (1.06 g, 7.29 mmol) in DMSO (7 mL) at room temperature was added NaH (291 mg of a 60% dispersion in oil). After the effervescence had ceased the lactam 85 (2 g, 7.29 mol) in DMSO (5 mL) was added. After 1 hour water was added and the aqueous solution extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (1:1 hexane/acetone) of the residue gave the product as an oil (1.7 g, 81%). MS n/z 348 (M+H, 100%).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[Br:24])[C:2]([CH3:4])=[O:3].C1(N)CCCCC1>C(O)C>[C:2]([NH:1][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([OH:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[Br:24])(=[O:3])[CH3:4]
Reactant: CC(=O)Nc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1Br
Solvent: NC1CCCCC1
Solvent: CCO
Product: CC(=O)Nc1ccc(-c2ccc(C(O)CCC(=O)O)cc2)cc1Br
Yield: 53 %

Procedure:
Prepared analogous to Example 25 from 4-(4'-acetamino-3'-bromo-4-biphenylyl)-4-oxo-butyric acid. Yield: 53% of theory, m.p. 125°-126° C. Melting point of the cyclohexylamine salt: 165°-167° C. (from ethanol).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])[C:15]#[N:16]
Reactant: CC(C)(C)OC(=O)NCc1cc(C#N)cc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)c(F)c(CN)c1
Reaction time: 8 h

Procedure:
To a solution of (3-chloro-5-cyano-2-fluoro-benzyl)-carbamic acid tert-butyl ester (645 mg, 2.27 mmol) in CH2Cl2 (15 mL) was added TFA (1.75 mL, 22.7 mmol), and stirring was continued at RT overnight. Volatiles were removed under reduce pressure, water was added and the mixture was washed with EtOAc. The aqueous layer was basified to pH=12 by addition of 4M NaOH solution and extracted twice with EtOAc. The combined organics were dried (phase separator) and evaporated to afford the title compound as a beige solid. MS (LC/MS): 185.0 [M+H]+; tR (HPLC conditions c): 2.62 min.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O:5]=[C:6]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]2[CH2:17][CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH:8]2[CH2:7]1.O>C(O)(=O)C>[N+:1]([C:14]1[CH:15]=[CH:16][C:10]2[N:9]3[CH2:17][CH2:18][N:19]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:20][CH:8]3[CH2:7][C:6](=[O:5])[NH:12][C:11]=2[CH:13]=1)([O-:4])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2c3ccc([N+](=O)[O-])cc3NC(=O)CC2C1
Reaction time: 3 h

Procedure:
Nitric acid (65% solution, 0.20 mL, 3.2 mmol) was added to a solution of Example 1C (1.0 g, 3.2 mmol) in acetic acid (5 mL) at room temperature. The solution was stirred for 3 hours, and then the reaction mixture was poured into water (200 mL). The precipitate was collected by filtration from the aqueous solution to afford the title compound. 1H NMR (300 MHz, DMSO-d6) d ppm 8.00 (dd, J=8.92, 2.58 Hz, 1H), 7.79 (d, J=2.78 Hz, 1H), 7.24 (d, J=9.12 Hz, 1H), 3.86-4.10 (m, 2H), 3.36-3.50 (m, 1H), 3.20-3.29 (m, 1H), 2.81-2.99 (m, 1H), 2.62-2.77 (m, 1H), 2.18 (d, J=13.48 Hz, 1H); MS (APCI+) m/z 307 (M+H-tBu)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[C:5]([CH3:12])[C:4]=1[CH3:13].[H][H]>N.[Ni]>[NH3:11].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[C:5]([CH3:12])[C:4]=1[CH3:13]
Reactant: [H][H]
Reactant: COc1ccc(CC#N)c(C)c1C
Agent: [Ni]
Agent: N
Product: COc1ccc(CCN)c(C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (4-methoxy-2,3-dimethyl-phenyl)-acetonitrile (200 mg, 1.14 mmol) and Raney® nickel (50 mg) in 2M methanolic ammonia (10 mL) was stirred under 60 psi of hydrogen gas at room temperature for 18 hours. Tlc analysis showed that not all of the starting material had been consumed and so further Raney® nickel (50 mg) in 2M methanolic ammonia (10 mL) was added. The reaction mixture was stirred under 60 psi of hydrogen gas for an additional 18 hours at room temperature and was then filtered through Arbocel®. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1 to afford the title product as a pale brown solid, 233 mg.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[N:6][CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[O:9]1[CH2:10][CH:11]=[C:12]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][N:6]=2)[CH2:13][CH2:14]1
Reactant: Fc1nccnc1I
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1nccnc1C1=CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a glass microwave vial was added 2-fluoro-3-iodopyrazine (1.6485 g, 7.36 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.319 g, 11.04 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.413 g, 0.589 mmol), and sodium carbonate (3.90 g, 36.8 mmol) in DME (19.63 mL) and water (4.91 mL) to stir at 80° C. overnight. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with water, sat NaCl, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide 2-(3,6-dihydro-2H-pyran-4-yl)-3-fluoropyrazine. MS (ESI, pos. ion) m/z: 181.1.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C:14]2[C:15]([CH3:27])([CH3:26])[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[CH3:3].[CH3:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C:14]2[C:15]([CH3:27])([CH3:26])[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][N:22]([S:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=4)(=[O:37])=[O:36])[CH2:21][CH2:20]3)[N:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[CH3:3]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCOc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OCC
Agent: Cl
Product: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C)c4)CC3)C(=O)C2(C)C)cc1OCC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-diethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B2*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: C[CH2:2][O-:3].[Na+].[H-].[Na+].C(=O)(OCC)OCC.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][C@H:24]([CH2:28][OH:29])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CCO>[O:3]=[C:2]1[N:25]2[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:23][C@H:24]2[CH2:28][O:29]1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)OCC
Product: CC(C)(C)OC(=O)N1CCN2C(=O)OC[C@@H]2C1
Temperature: 80 °C

Procedure:
A NaOEt solution, prepared from sodium hydride (60% dispersion in mineral oil) (0.990 g, 26 mmol) and 100 mL EtOH, diethyl carbonate (9.00 mL, 74 mmol) and (S)-4-N-BOC-2-hydroxymethyl-piperazine (2.17 g, 10 mmol) was heated at 80° C. The reaction was cooled to RT and filtered. The filtrate was concentrated to dryness to give an off-white amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=1)=[O:5])[CH3:2].[C:23]([O:27][C:28]([CH2:30][NH:31][C@H:32]1[C@H:36]([O:37][CH3:38])[CH2:35][NH:34][CH2:33]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:34]3[CH2:35][C@@H:36]([O:37][CH3:38])[C@H:32]([NH:31][CH2:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:33]3)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2nccs2)c2nc(Cl)ccc2c1=O
Reactant: CO[C@@H]1CNC[C@H]1NCC(=O)OC(C)(C)C
Product: CCOC(=O)c1cn(-c2nccs2)c2nc(N3C[C@@H](NCC(=O)OC(C)(C)C)[C@H](OC)C3)ccc2c1=O

Procedure:
With use of 7-chloro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester obtained in Example A-1 (4) and (+)-trans-3-(N-t-butoxycarbonylmethylamino)-4-methoxypyrrolidine obtained in Example B-2, there was produced (-)-7-[trans-3-(N-t-butoxycarbonylmethylamino)-4-methoxy-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester (amorphous) in the same manner as in Example C-1 (1).