Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3](C(O)=O)=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C([N:22](CC)CC)C.P(N=[N+]=[N-])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(O)(C)(C)C>[CH3:1][C:2]1[C:3]([NH2:22])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: CCN(CC)CC
Reactant: Cc1cn2nc(-c3ccccc3)nc2cc1C(=O)O
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1cn2nc(-c3ccccc3)nc2cc1N
Reaction time: 18 h
Yield: 28.2 %

Procedure:
To a suspension of 6-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (172 mg, 679 μmol) and triethylamine (206 mg, 284 μl, 2.04 mmol) in tert-butanol (10 ml) is added at 25° C. diphenyl phosphorazidate (220 μl, 1.02 mmol). The resulting mixture is heated to reflux and stirred for 18 hours. The crude material is loaded on silica and purified by flash chromatography on a 20 g silica column using heptane/ethyl acetate 10-100% as eluent affording 6-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (43 mg, 28%) as an off-white solid. mp.: >250° C. MS: m/z=225.3 (M+H+). The hydrochloride can be prepared by stirring in tetrahydrofurane/6N hydrochloric acid in diethylether (1:6) for 2 hours and final evaporation to dryness. Light brown solid (quant.). MS: m/z=225.3 (M+H+).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C@H:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1.[O-]CC.[Na+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH:31]=O)[CH:28]=[N:29][CH:30]=2)=[CH:21][CH:20]=1.[BH4-].[Na+].Cl>C(O)C.O>[ClH:1].[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[C:27]([CH2:31][NH:2][CH2:3][C@H:4]3[CH2:13][CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[O:5]3)[CH:28]=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: O=Cc1cncc(-c2ccc(F)cc2)c1
Reactant: NC[C@H]1CCc2ccccc2O1
Agent: CC[O-]
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2cncc(CNC[C@H]3CCc4ccccc4O3)c2)cc1
Yield: 69.5 %

Procedure:
20.3 g of (R)-2-aminomethylchroman hydrochloride are introduced into 150 ml of ethanol, and 36.8 g of a 20% solution of sodium ethoxide in ethanol are added dropwise with stirring. 20.5 g of 5-(4-fluorophenyl)pyridine-3-carbaldehyde are added to the suspension at 35° C., and the mixture is stirred for a further 3 hours. After addition of 4.2 g of sodium borohydride, the mixture is stirred for a further 4 hours, and 62 ml of water are then added dropwise at room temperature. The pH of the reaction mixture is then adjusted to pH 4 using 37% hydrochloric acid over the course of one hour. The crystals are filtered off, rinsed with ethanol and dried under reduced pressure, giving 27.2 g of (R)-(−)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman hydrochloride (69% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[CH:33][CH:32]=3)=[N:28]2)=[CH:23][CH:22]=1.[CH:44]([C:46]1[O:47][C:48](B(O)O)=[CH:49][CH:50]=1)=[O:45].C(=O)([O-])[O-].[Na+].[Na+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O.O1CCOCC1>[CH3:43][N:40]1[CH2:41][CH2:42][N:37]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:27]3[N:26]=[CH:25][C:24]4=[CH:23][CH:22]=[C:21]([C:48]5[O:47][C:46]([CH:44]=[O:45])=[CH:50][CH:49]=5)[N:29]4[N:28]=3)=[CH:36][CH:35]=2)[CH2:38][CH2:39]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccc(C=O)o5)n4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.1 %

Procedure:
Into a 8-dram vial, Palladium Acetate (0.00988 g, 0.0440 mmol), Triphenylphosphine (0.0338 g, 0.129 mmol) and 1,4-Dioxane (2 mL) were added and stirred at room temperature for 10 minutes. (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.320 g, 0.826 mmol), 2-Formylfuran-5-boronic acid (0.2312 g, 1.652 mmol), N,N-Dimethylformamide (2 mL) and 1.50 M of Sodium carbonate in Water (6 mL, 10 mmol) were added. The reaction mixture was heated at 90° C. overnight. The reaction was cooled to room temperature. Solvent was removed under vacuum to give a yellow solid. The resulting solid was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (5 to 25% methanol). The collected fractions afforded 5-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-furan-2-carbaldehyde as a yellow solid (110 mg, 33%). LCMS (E/I+) 403.19 (M+H). NMR 1H (DMSO-d6)-963 (s, 1H), 9.40 (s, 1H), 9.04 (s, 1H), 7.78 (d, 1H, J=3.07 Hz), 7.62 (d, 2H, J=9.05 Hz), 7.45 (d, 1H, J=3.77 Hz), 7.21 (d, 1H, J=4.90 Hz), 7.01 (d, 2H, J=9.05 Hz), 6.97 (d, 1H, J=4.90 Hz), 3.11 (t, 4H, J=4.91 Hz), 2.47 (t, 4H, J=4.91 Hz), 2.23 (s, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([NH:11][C:12]([C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:21][C:20]=2[O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:16][N:15]=1)=[O:13])[CH3:10]>C(#N)C>[CH2:9]([NH:11][C:12]([C:14]1[C:18]([Br:1])=[C:17]([C:19]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:21][C:20]=2[O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:16][N:15]=1)=[O:13])[CH3:10]
Reactant: CCNC(=O)c1cc(-c2cc(CCc3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCNC(=O)c1noc(-c2cc(CCc3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Bromosuccinimide (207 mg, 1.16 mmol) was added to a suspension of 5-(2,4-Bis-benzyloxy-5-phenethylphenyl)-isoxazole-3-carboxylic acid ethylamide (564 mg, 1.06 mmol) in acetonitrile (20 mL). Ceric ammonium nitrate (290 mg, 0.53 mmol) was added and the reaction mixture was heated to reflux (affording homogeneous orange solution) and stirred for 30 minutes. The reaction mixture was allowed to cool to ambient temperature and acetonitrile was removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL) and the phases were separated. The organic phase was washed with saturated aqueous sodium chloride solution (50 mL) and dried over sodium sulphate. The mixture was filtered and the filtrate solvents were removed in vacuo to afford a yellow oil which was purified by flash chromatography on silica gel (20 g, IST) eluting with 10-30% ethyl acetate in hexane. This affords 5-(2,4-Bis-benzyloxy-5-phenethylphenyl)-4-bromo-isoxazole-3-carboxylic acid ethylamide as yellow oil (326 mg, 53%). LCMS:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]2)[C@@H:10]1[F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([C:34]([F:37])([F:36])[F:35])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O.[Cl-].[Na+].O>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([C@H:18]([OH:19])[C:34]([F:37])([F:36])[F:35])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[S:14]2)[C@@H:10]1[F:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H](F)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H](F)[C@H](OCc3ccccc3)[C@@H]([C@H](O)C(F)(F)F)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
To a solution of tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.352 g, 0.829 mmol) and TMSCF3 (0.290 g, 2.04 mmol) in anhydrous THF (15 mL) was added TBAF (1.0 M in THF, 0.050 mL, 0.050 mmol). After addition the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled at 0° C., and another batch of TBAF (1.0 M in THF, 1.5 mL, 1.5 mmol) was added. The mixture was stirred at room temperature for another 2 h, and then diluted with EtOAc (20 mL) and brine (50 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (20 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was purified and separated on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 2:3), affording tert-butyl ((3aR,5R,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a pale yellow solid (0.141 g, 34%). 1H NMR (400 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 6.14 (d, J=7.5 Hz, 1H), 5.09 (td, J=4.1, 46.4 Hz, 1H), 4.87 (d, J=10.8 Hz, 1H), 4.38-4.30 (m, 1H), 4.50 (d, J=10.8 Hz, 1H), 4.25-4.22 (m, 1H), 4.10-4.06 (m, 2H), 3.27 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[NH:15][C:14](=O)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[NH:13][C:10]2=[N:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]2[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ncc(-c3ccccc3)nc2[nH]1
Product: Clc1nc2nc(-c3ccccc3)cnc2[nH]1
Reaction time: 0.5 h

Procedure:
Reflux a solution of 5-phenyl-1,3-dihydro-imidazo[4,5-b]pyrazin-2-one (200 mg) in phosphorus oxychloride (10 mL) for 18 hours. After cooling, remove the excess POCl3 in vacuo, and triturate the residue in ice-water (200 mL). After stirring for 30 minutes, filter the precipitate to obtain 2-chloro-5-phenyl-1H-imidazo[4,5-b]pyrazine as a gray solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.O=[Pt]=O>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH2:8][NH2:9])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cccc(C#N)n1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CCC[C@H](CN)N1
Reaction time: 50 h

Procedure:
To a solution (4.0 M) of 6-methyl-2-pyridinecarbonitrile in TFA was added PtO2 (0.1 eq) and the mixture was stirred for 50 h under H2 atmosphere at 50 psi. The reaction mixture was filtered and concentrated at reduced pressure to afford the title compound SS1. MS (ES) C7H16N2 required: 128, found: 129 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N+:9]([O-])[C:10]3[C:15]([C:16]=2[N+:17]([O-:19])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.[C:21]1([N:27]=C=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[NH:27]([C:8]1[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[C:16]([N+:17]([O-:19])=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1c(N2CCOCC2)c[n+]([O-])c2ccccc12
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1c(N2CCOCC2)c(Nc2ccccc2)nc2ccccc12

Procedure:
The 3-morpholino-4-nitroquinoline-N-oxide (3 g, 0.011 mol) was suspended in dimethylformamide (40 ml) and following addition of phenyl isocyanate (3.4 g, 0.029 mol), the mixture was added on an oil bath at 80°-90° C. for ca. 3 hours. The reaction mixture was totally charged into water and subjected to extraction with chloroform. The chloroform layer was washed with water and dried with anhydrous sodium sulfate. After the chloroform was distilled off under vacuum, the residue was subjected to recrystallization with ethanol. The resulting crystal was recovered by filtration under vacuum to obtain 2-anilino-3-morpholino-4-nitroquinoline in an amount of 2.95 g (yield, 77%).
Reaction SMILES: FC(F)(F)C(O)=O.N1C=CC=CC=1.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][OH:25])([O-:16])=[O:15].C1CCC(N=C=NC2CCCCC2)CC1.O.O.C(O)(=O)C(O)=O>C(OCC)(=O)C.C1C=CC=CC=1.C(OCC)(=O)C.C1C=CC=CC=1.CS(C)=O>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH:24]=[O:25])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=CCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
Trifluoroacetic acid (1.31 ml, 17 mmols) and 2.7 ml (33.3 mmols) of pyridine were added to a mixture of 5.51 g (33.3 mmols) of 2-(2-nitrophenyl)ethanol, 50 ml of dimethyl sulfoxide, 50 ml of benzene and 21 g (0.1 mol) of DCC. After stirring the mixture at room temperature for 4 hours, 300 ml of aqueous solution of 8.82 g (70 mmols) of oxalic acid dihydrate was added thereto. The resulting mixture was stirred at room temperature for 30 minutes and diluted with 500 ml of ethyl acetate. The organic layer was separated off, washed with saturated NaCl, dried over Na2SO4 and concentrated to obtain a yellow oil. The oil was subjected to silica gel column chromatography (95:5 benzene-ethyl acetate) to obtain 2-nitrophenylacetoaldehyde in the form of an unstable oil in an amount of 4.50 g (yield 81%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)([O-:30])=[O:29]>>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([S:37]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:39])=[O:38])=[CH:35][CH:36]=1)([O-:30])=[O:29]
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 89 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 4-nitrobenzenesulfonyl chloride under the conditions used in example 2 giving 89% of the title compound.
Reaction SMILES: [C:1]([N:6]=[C:7]=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCCl>[C:1]([NH:6][C:7](=[O:8])[O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OCc1ccccc1
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)OCc1ccccc1

Procedure:
A solution of methacryloyl isocyanate (11.1 g; 0.1 mol) in 1,2-dichloroethane (50 ml) was dropise added to dry benzyl alcohol (10.8 g; 0.1 mol) under nitrogen stream while cooling with ice. After completion of the addition, 1,2-dichloroethane was evaporated under reduced pressure. The residue (21.8 g) was recrystallized from a mixture of hexane and benzene to give benzyl N-methacryloylcarbamate as colorless needles. M.P., 109°-110° C.
Reaction SMILES: [C:1](=[O:16])([S:14][CH3:15])[O:2][O:3][CH:4]([O:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH:5]([CH3:7])[CH3:6].[C:17](O)(=O)C(C)(C)C>>[C:1](=[O:16])([S:14][CH3:15])[O:2][O:3][CH:4]([O:8][C:9](=[O:13])[C:10]([CH3:17])([CH3:11])[CH3:12])[CH:5]([CH3:7])[CH3:6]
Reactant: CSC(=O)OOC(OC(=O)C(C)C)C(C)C
Reactant: CC(C)(C)C(=O)O
Product: CSC(=O)OOC(OC(=O)C(C)(C)C)C(C)C

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyisobutoxy) S-methyl thiocarbonate (11) and replacing isobutyric acid with pivalic acid affords O-(1-pivaloyloxyisobutoxy) S-methyl thiocarbonate (15) as an oil.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:10][O:9][C:8]3[C:11]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:13]=[CH:14][C:7]=3[C:5]=2[N:6]=1.Br[CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:1][C:2]2[S:3][C:4]3[CH2:10][O:9][C:8]4[C:11]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=[CH:14][C:7]=4[C:5]=3[N:6]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1OCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1OCc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Yield: 17 %

Procedure:
Using ethyl [(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]acetate and bromodiphenylmethane, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 17%.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:52]=[CH:51][C:42]2[C:43](=[O:50])[C:44]([CH3:49])([CH3:48])[S:45](=[O:47])(=[O:46])[C:41]=2[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:52]=[CH:51][C:42]2[C:43](=[O:50])[C:44]([CH3:49])([CH3:48])[S:45](=[O:46])(=[O:47])[C:41]=2[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC1(C)C(=O)c2ccc(Br)cc2S1(=O)=O
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)C(C)(C)C2=O
Yield: 91 %

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 6-bromo-2,2-dimethyl-1-benzothiophen-3(2H)-one 1,1-dioxide (Intermediate 241), the title compound was obtained in 91% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C@@H:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=4[C@H:16]([OH:25])[CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:28](Br)[CH:29]=[CH2:30].CCOCC.[ClH:37]>C1COCC1.CCOCC>[ClH:37].[CH2:30]([O:25][C@H:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH2:19][CH2:20][C@@H:14]([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH2:15]1)[CH:29]=[CH2:28]
Reactant: O[C@@H]1C[C@H](CN2CCC(c3ccccc3)CC2)CCc2ccccc21
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCO[C@@H]1C[C@H](CN2CCC(c3ccccc3)CC2)CCc2ccccc21
Reaction time: 0.5 h

Procedure:
0.2 g (0.596 mmol) of (±)-cis-7-[(4-phenylpiperdin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol dissolved in 5 ML THF were added dropwise to a suspension of 0.029 g (0.715 mmol) of NaH (60% dispersion in mineral oil) in 10 mL THF. After 30 min at room temperature, 0.12 mL of allyl bromide were added and the reaction mixture was refluxed 8 h. After cooling, the reaction mixture was quenched by addition of MeOH and the solvent was removed in vacuo. The residue was taken up in 1 N NaOH and extracted with CH2Cl2; the organic phase was dried and the solvent was removed in vacuo. The resulting crude product was purified by chromatography, eluting with a mixture CH2Cl2/MeOH 100:2 respectively, yielding an oil which was dissolved in Et2O; the solution was brought to acidic pH with Et2O/HCl and the solvent was removed in vacuo. The resulting solid was triturated with Et2O, yielding 65 mg of the title product. m.p. 126-128° C.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[C:13]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].N(C(C)(CC)C([O-])=O)=NC(C)(CC)C([O-])=O.N(C(C)(C)C(OC)=O)=NC(C)(C)C(OC)=O>C(O)(C)C.O>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[CH2:23])=[CH:24][CH:25]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C=Cc1ccc(OC(C)(C)C)cc1
Agent: CCC(C)(N=NC(C)(CC)C(=O)[O-])C(=O)[O-]
Agent: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Solvent: O
Solvent: CC(C)O
Product: C=Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In 400 mL of isopropanol, 56.7 g of p-acetoxystyrene and 26.4 g of p-tert-butoxystyrene were dissolved, then 8.3 g of 2,2′-azobis(methyl 2-methylpropionate) (V-601: trade name of a product from Wako Pure Chemicals Ind., Ltd.) was added, followed by reacting at 80° C. for 6 hours under nitrogen gas flow. After the reaction, said reaction solution obtained was poured into 10 L of water for precipitation, followed by filtering off deposited crystal. The thus obtained crystal was added to 450 mL of methanol, followed by charging 234 g of a 15% aqueous tetramethylammonium hydroxide solution and reacting under reflux for 4 hours while stirring. The thus obtained solution was cooled to room temperature, then neutralized by adding drop-wise 12.9 g of glacial acetic acid. The neutral solution was poured into 10 L of water for precipitation, followed by filtering off deposited crystal and drying under reduced pressure, to obtain 42.6 g of poly(p-hydroxystyrene/p-tert-butoxystyrene) as a white powder crystal. The thus obtained crystal was named polymer A1. A composition ratio of p-hydroxystyrene unit and p-tert-butoxystyrene unit in polymer A1 was found to be about 7:3 from the measurement results by 13CNMR. Weight average molecular weight (Mw) of polymer A1 was about 9,500 and distribution (Mw/Mn) thereof was about 1.75 from the measurement results by gel permeation chromatography using polystyrene as a standard.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[CH2:13][CH2:14]C2C3C(=CC=CC=3)C=N2)=[CH:3][N:2]=1.O.[NH2:25]N>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[CH2:13][CH2:14][NH2:25])=[CH:3][N:2]=1
Reactant: NN
Reactant: C1=NC(CC/C=C/c2cncc3ccccc23)c2ccccc21
Solvent: O
Solvent: CCO
Product: NCC/C=C/c1cncc2ccccc12

Procedure:
To a refluxing solution of 1.75 g of (E)-1-[4-(4-isoquinolinyl)-3-butenyl]-1H-isoindole-1,3-(2H-dione in 80 mL of ethanol was added 1.1 mL of hydrazine hydrate and the reaction was stirred at reflux for 17 hours. The solvent was removed in vacuo and the residue was triturated with chloroform. The extract was concentrated to yield 1 g of (E)-4-(4-isoquinolinyl)-3-buten-1-amine as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:39][C@@H:40]([NH2:51])[C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1>O.CN(C=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C@@H:10]([C:14]([NH:51][C@@H:40]([C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=[CH:43][CH:42]=2)[CH3:39])=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)[C@@H]1CC(=O)N(Cc2ccccc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
A 20 ml DMF solution of 1.16 g of 1-benzyl-5-oxopyrrolidine-3-carboxylic acid was mixed with 2.0 g of WSC hydrochloride and 859 mg of HOBt and stirred at room temperature for 30 minutes. 1.1 g of (1R)-1-naphthylethylamine was added thereto successively and stirred at 60° C. After completion of the reaction, this was mixed with 100 ml of water, extracted with ethyl acetate and washed with 1 M hydrochloric acid. The organic layer was concentrated, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) and then recrystallized from ethyl acetate-hexane to obtain 856 mg and 831 mg of (3R)-1-benzyl-N-[(1R)-1-(1-naphthyl)ethyl]5-oxopyrrolidine-3-carboxamide and (3S)-1-benzyl-N-[(1R)-1-(1-naphthyl)ethyl]5-oxopyrrolidine-3-carboxamide (stereoisomers un-verified). Both of the thus obtained compounds were respectively subjected to reduction in the same manner as in Example 84, made into salt with fumaric acid and recrystallized from ethanol-ethyl acetate to obtain (1R)—N-{[(3S)-1-benzylpyrrolidin-3-yl]methyl}-1-(1-naphthyl)ethanamine fumarate and (1R)—N-{[(3R)-1-benzylpyrrolidin-3-yl]methyl}-1-(1-naphthyl)ethanamine fumarate.