Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5].[CH3:16][N:17]([C:19]1[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=1)[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:16][N:17]([CH3:18])[C:19]1[CH:24]=[C:23]([CH:22]=[CH:21][CH:20]=1)[C:25]([O:1][CH:2]([CH3:15])[CH2:3][C:4](=[O:5])[CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:26]
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: CC1=CCCC(C)(C)C1C(=O)CC(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1=CCCC(C)(C)C1C(=O)CC(C)OC(=O)c1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 67.1 %

Procedure:
To a solution of 3-hydroxy-1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-butanone (4.00 g, 92% pure, 17.5 mmol), 3-N,N-dimethylaminobenzoic acid (3.13 g, 19.0 mmol), and DMAP (1.85 g, 15.2 mmol) in CH2Cl2 (50 ml) was added N,N′-dicyclohexylcarbodiimine (DCC) (4.31 g, 20.9 mmol) in CH2Cl2 (15 ml). The reaction medium was stirred at room temperature for 70 h. Then, the mixture was acidified with concentrated HCl and extracted twice with ether and washed with water, saturated aqueous NaHCO3 and then with saturated aqueous NaCl. Finally, the organic phases were dried over Na2SO4, concentrated at 50-60°/0.03 mbar) and purified by flash-chromatography over SiO2 (cyclohexane/AcOEt=97:3). 4.20 g of product were thus obtained (yield: 68%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]([O:17]CC)=[O:16])[CH:11]=1.O.[OH-].[Li+]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1
Reactant: CCOC(=O)c1cc(CCOC2CCCCO2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(CCOC2CCCCO2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)isoxazole-3-carboxylate (1.77 g, 6.57 mmol) was dissolved in THF (20 ml). 1M lithium hydroxide monohydrate (6.57 ml) was added and the resulting mixture stirred at RT for 2 h. During the same day more of 1M lithium hydroxide monohydrate (19.71 ml in total) was added and the reaction mixture was stirred overnight. THF was evaporated, water was added and the pH was adjusted to 4 with citric acid solution. The mixture was extracted four times with ethyl acetate. The combined organic layers were dried and evaporated. LC-MS: [M+1]=242.24.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])([O:3][CH3:4])=[O:2].[CH3:17][O:18][C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][CH3:27])[N:20]=1>ClCCl>[CH3:17][O:18][C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH3:27])[C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([O:3][CH3:4])=[O:2])(=[O:12])=[O:13])=[O:16])[N:20]=1
Reactant: CNc1nc(C)nc(OC)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)N(C)c1nc(C)nc(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
To a solution of 2-carbomethoxybenzenesulfonyl isocyanate (22.4 g 93.0 mmol) in dichloromethane (100 mL) was added 2-methoxy-4-methyl-6-methylamino-1,3,5-triazine (10.7 g, 69.6 mmol), followed by a catalytic amount of 1,4-diaza[2.2.2]bicyclooctane. After stirring overnight at ambient temperature under a nitrogen atmosphere, the reaction mixture was concentrated in vacuo. The residue was triturated with diethyl ether and then washed with 1-chlorobutane to yield the title compound as a white powder (27.8 g, m.p. 126°-131° C.).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6](O)[C:7]3[S:13][CH2:12][CH2:11][CH2:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:17])=O>>[CH:1]1([C:4]2[N:5]=[C:6]([Cl:17])[C:7]3[S:13][CH2:12][CH2:11][CH2:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(C2CC2)nc2c1SCCC2
Product: Clc1nc(C2CC2)nc2c1SCCC2

Procedure:
A stirred solution of product from Step A (17 g) in phosphorus oxychloride (160 ml) was heated at reflux for 1 hour. Two-thirds of the phosphorus oxychloride was distilled from the reaction mixture and the residue poured into ice water to give 12.1 g of title compound which was dried and used in Step C without further purification or characterization.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[CH:6]=1.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CCOCC>[OH:19][C:13]1([C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=3[CH:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCCCC1
Reactant: COc1ccc2cc(Br)sc2c1
Solvent: O
Solvent: CCOCC
Product: COc1ccc2cc(C3(O)CCCCC3)sc2c1
Yield: 41.7 %

Procedure:
To Mg (0.22 g, 9.05 mmol) under argon in Et2O (20 ml) was added dropwise a solution of bromide (4) (2.00 g, 8.23 mmol) in Et2O (20 ml). The mixture was refluxed for 2 h, a solution of cyclohexanone (1.00 ml, 9.87 mmol) in Et2O (5 ml) was added and the mixture was refluxed for 2 h. It was poured into iced water. The solution was extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated under vacuum to give 8.00 g as an oil. Triturating from diisopropyl ether afforded 2-(1-hydroxycyclohexyl)-6-methoxybenzothiophene as a white powder (0.90 g, 65%).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:30]=[CH:31][C:32]=4[C:33](O)=[O:34])[C:20]=3[NH:21][C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=3[CH3:29])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[CH:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:30]=[CH:31][C:32]=4[C:33]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:34])[C:20]=3[NH:21][C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=3[CH3:29])=[O:14])[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(C4CCCCC4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(C4CCCCC4)CC3)cnc12
Yield: 55.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-(4-cyclohexylpiperidine-1-carbonyl)-7-(2,5-dimethylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (75 mg, 0.16 mmol) obtained in step 2 and ethanesulfonamide (84 mg, 0.80 mmol), the title compound (50 mg, 55%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4](=[CH2:16])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(#N)C.CO>[C:6]([NH:5][CH:4]([CH2:16][N:28]1[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:30][CH2:29]1)[C:3]([O:2][CH3:1])=[O:17])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=C(NC(=O)OCc1ccccc1)C(=O)OC
Solvent: CO
Solvent: CC#N
Product: COC(=O)C(CN1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To N-carbobenzyloxydehydroalanine methyl ester (2.0 g, 8.4 mmol) was added 4-tert-butoxycarbonylpiperazine (1.56 g, 1.0 eq), ferric chloride (0.220 g, 0.2 eq) in a 6:1 mixture of acetonitrile/methanol. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated under reduced pressure. EtOAc was added and the organic layer washed with a soldium sulfate solution. Upon removal of the solvent under reduced pressure, the crude material was purified by column chromatography (silica gel; CH2Cl2:MeOH 4:1) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:9]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([F:27])[CH:16]=3)[CH2:10]2)=[CH:4][CH:3]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:9]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:18]([C:19]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:20])=[C:17]([F:27])[CH:16]=3)[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccc(Cl)cc3)C2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccc(Cl)cc3)C2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.4 %

Procedure:
A mixture of 4-((1-((4-chlorophenyl)(phenyl)methyl)azetidin-3-yl)-methoxy)-5-cyclopropyl-2-fluorobenzoic acid (50 mg, 0.11 mmol), methanesulfonamide (15 mg, 0.16 mmol), EDCI (31 mg, 0.16 mmol) and DMAP (20 mg, 0.16 mmol) in DCM (20 mL) was stirred at 25° C. for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with HCl (2.0 M, 20 mL) and brine (50×2 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase Combiflash (35%-38% MeCN in 0.5% NH4HCO3) to give the target product (11.0 mg, 19%) as an off-white solid. LCMS (ESI) Method A: RT=5.83 min, m/z: 543.5 [M+H]+. 1H-NMR (500 MHz, MeOH-d4): δ 7.31-7.29 (m, 4H), 7.23-7.19 (m, 5H), 7.14-7.11 (m, 1H), 6.69-6.66 (m, 1H), 4.51 (s, 1H), 4.08 (d, J=6.5 Hz, 2H), 3.39-3.34 (m, 2H), 3.32-3.13 (m, 5H), 2.94-2.90 (m, 1H), 1.99-1.96 (m, 1H), 0.84-0.80 (m, 2H), 0.58-0.54 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:14])O[C:11](=[O:13])[CH:12]=2)=[CH:4][CH:3]=1.Cl.Cl.[CH2:17]([NH:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(=O)C>[CH2:17]([N:24]1[C:11](=[O:13])[CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([OH:14])=[N:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNCc1ccccc1
Reactant: O=C1C=C(c2ccc(Cl)cc2)C(=O)O1
Agent: Cl
Solvent: CC(=O)O
Product: O=c1cc(-c2ccc(Cl)cc2)c(O)nn1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 3-(4-chlorophenyl)-2,5-furandione (10.24 g, 66.9 mmol) in acetic acid (300 mL) was added benzylhydrazine dihydrochloride in one portion (19.6 g, 100 mmol). The reaction mixture was stirred at reflux for 14 h. Analysis by HPLC/MS indicated the reaction was complete. After cooling to room temperature, the resulting white suspension was filtered. The collected solid was washed with EtOAc (20 mL×2), and dried in a 50° C. vacuum oven for 16 h to yield 6.5 g of the desired product as a white solid. The filtrate was concentrated under reduced pressure, and the obtained residue was crystallized in EtOAc to afford additional 1.6 g of the title compound (8.1 g in total, 39% yield). HPLC/MS (method A): retention time=3.29 min, (M+H)+=313.1. 1H NMR (DMSO-d6, 500 MHz): δ 11.62 (s, 1H), 7.65 (d, J=10 Hz, , 2H), 7.51 (d, J=10 Hz, 2H), 7.23-7.38 (m, 5H), 7.04 (s, 1H), 5.11 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18](=[O:20])[NH2:19])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1(C)C=CC(S(O)(=O)=O)=C[CH:22]=1>C(O)C>[CH2:21]([O:16][C:15](=[O:17])[CH2:14][CH2:13][C@@H:12]([C:18](=[O:20])[NH2:19])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(N)=O

Procedure:
A suspension of 15.98 g of N-Benyloxycarbonyl-L-isoglutamine in 500 mL of absolute ethanol containing 0.54 g of p-toluenesulfonic acid is refluxed for 12 hours until TLC indicated that the reaction is complete. The solution is concentrated to a small volume and addition f ether gave a solid. The solid is filtered and recrystallized to give 16.0 of N-Benyloxycarbonyl-L-isoglutamine ethyl ester, 16.
Reaction SMILES: CO[C:3](=O)[C@@H:4]1[CH2:8][C:7](=[CH:9][CH2:10][CH3:11])[CH2:6][N:5]1[C:12](OCC1C=CC=CC=1)=O.C[O:24][C:25](=O)[C@@H:26]1CC(=C)CN1C(OCC1C=CC=CC=1)=O>>[CH2:9]([C@@H:7]1[CH2:6][N:5]2[C@H:4]([CH2:3][C:25](=[O:24])[CH2:26][CH2:12]2)[CH2:8]1)[CH2:10][CH3:11]
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Reactant: CCC=C1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Product: CCC[C@H]1C[C@H]2CC(=O)CCN2C1
Yield: 24 %

Procedure:
In a similar manner to the procedures described in Preparative Examples 8(ii)′, 8(iii)′, 8(iv)′, 8(v)′ and 8(vi)′ above, reactions were conducted in turn, using (S)-1-benzyloxycarbonyl-4-propylideneproline methyl ester [prepared as described in Preparative Example 25′ above] instead of (S)-1-benzyloxycarbonyl-4methylideneproline methyl ester, to give the title compound as a brown oil (yield: 24%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:13](=[CH2:16])[C:14]#[N:15]>O>[NH2:15][C:14]1[CH:13]=[CH:16][N:4]([CH2:3][CH2:2][OH:1])[N:5]=1
Reactant: NNCCO
Reactant: C=C(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccn(CCO)n1
Reaction time: 17 h

Procedure:
2-Hydroxyethylhydrazine (7.6 g.) was added slowly to a solution of potassium carbonate (13.8 g.) in water (40 ml.). The mixture was cooled to 0°, then 2-chloroacrylonitrile (8.75 g.) was added slowly with vigorous stirring. Stirring was continued for a further 17 hours and the mixture was then continuously extracted with EtOAc for 20 hours. On evaporation of the solvent, 3-amino-1-(2-hydroxyethyl)pyrazole was obtained, (7.7 g.; 60%), b.p. 170°/0.5 mm.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][OH:12])=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][CH:11]=[O:12])=[CH:7][CH:8]=1
Reactant: OCC#Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccccc1
Solvent: ClCCl
Product: O=CC#Cc1ccc(C(F)(F)F)cc1
Yield: 84 %

Procedure:
In 20 ml of methylene chloride were dissolved 2.21 g (11.0 mmol) of 3-[4-(trifluoromethyl)phenyl]-2-propyn-1-ol, and 7.43 g (17.5 mmol) of Dess-Martin reagent were added to the solution under ice-cooling for 1.7 hours. Benzene was added to the resulting mixture and the insolubles were removed by filtration, followed by concentration of the filtrate to obtain 1.83 g (yield: 84%) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](C2CCOCC2)=[C:6]([N+:8]([O-])=O)[CH:7]=1.[C:17]([OH:20])(=O)[CH3:18]>[Fe]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:6]2[CH2:18][CH2:17][O:20][CH2:4][CH2:5]2)=[C:6]([CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)ccc1C1CCOCC1
Reactant: CC(=O)O
Agent: [Fe]
Product: Nc1cc(Br)ccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
A 3-neck flask was charged with 5-bromo-2-(tetrahydropyran-4-yl)nitrobenzene (see Working Example 18-1) (3.54 g, 11.8 mmol) and 10% aqueous acetic acid solution (65 mL), after which electrolytic iron (6.56 g, 118 mmol) was added and this was refluxed with stirring for 15 minutes. After this was allowed to cool to room temperature, the insoluble material was filtered off through Celite, and this same layer was further washed with 10% aqueous acetic acid solution (65 mL). The filtrate and the wash solutions were combined and then successively extracted with ethyl acetate (approx. 50 mL, 4 times), washed with distilled water (30 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and further drying under reduced pressure yielded the title compound (2.72 g, 85.4% yield) as a pale yellow solid.
Reaction SMILES: [ClH:1].C([O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][NH:23][C:24]([NH2:26])=[NH:25])[CH2:18][CH2:17]1)=[O:15])=[O:6])C.CO.[OH-].[Na+]>O>[ClH:1].[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C@H:16]1[CH2:17][CH2:18][C@H:19]([CH2:22][NH:23][C:24]([NH2:26])=[NH:25])[CH2:20][CH2:21]1)=[O:15])([OH:6])=[O:4]
Reactant: CCOC(=O)c1ccccc1NC(=O)[C@H]1CC[C@H](CNC(=N)N)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Nc2ccccc2C(=O)O)CC1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To N-(o-ethoxycarbonylphenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride (25.4 g, 0.063 mole) (which is prepared in the same manner as described in Example 1) is added methanol (130 ml), and the mixture is heated to 50° C., and thereto is added a solution of NaOH (7.16 g, 0.179 mole) in water (65 ml), and the mixture is stirred at 50°-60° C. for 45 minutes. The reaction mixture is ice-cooled, and the white precipitates are separated by filtration, suspended in methanol (100 ml) and dissolved by adding thereto 4N-hydrochloric acid (21 ml). After evaporation of the solvent under reduced pressure, the residue is recrystallized from water-methanol (4:1), and the crystals thus obtained are again recrystallized from water-methanol (3:1) to give N-(o-carboxyphenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride (19.3 g) as white crystals. The physical data of this compound are identical with those of N-(o-carboxyphenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride as obtained in Example 3.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[CH3:8][O:9][CH2:10][C:11](=O)[CH3:12].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:8][O:9][CH2:10][CH:11]([NH:7][C:4]1[NH:3][C:2]([CH3:1])=[N:6][N:5]=1)[CH3:12]
Reactant: Cc1nnc(N)[nH]1
Reactant: COCC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCC(C)Nc1nnc(C)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.3 %

Procedure:
To a solution (40 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and 1-methoxypropan-2-one (2.7 g) in acetic acid was added sodium cyanoborohydride (8.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (1.4 g, 32%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][C:18]1[C:28]2[C:29]3[C:21]([C:22](=O)[C:23](=O)[C:24]=3[CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:19]=1.[OH-].[K+]>CO>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2=[C:29]3[C:28]=1[CH:27]=[CH:26][CH:25]=[C:24]3[C:23]1[C:22]2=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8](=[O:9])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Reactant: O=C1C(=O)c2ccc(Br)c3cccc1c23
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(c2ccccc2)=C2C(=C1c1ccccc1)c1ccc(Br)c3cccc2c13
Temperature: 65 °C

Procedure:
1,3-Diphenylacetone (17.5 g, 83 mMole) was dissolved in methanol (240 mL) and heated to 65° C. To the solution was added 5-bromoacenaphthenequinone (2), (20 g, 75 mMole). The resulting well-stirred suspension was then treated with 1M-methanolic KOH (100 mL, 100 mMole) at a fast drip rate, whereupon the dark colored product precipitated immediately. The mixture was then stirred at 65° C. for 1 hour, cooled and filtered. The black solid was washed well with methanol, ether and dried. Yield of product (3), (31 g).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:29])([C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[CH2:5][CH:6]=[CH:7][C@H:8]1[C@H:15]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:14][C@H:13]2[C@@H:9]1[CH2:10][C:11](=[O:23])[O:12]2>CO>[F:29][C:4]([F:3])([CH:24]([OH:28])[CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][CH2:7][C@H:8]1[C@H:15]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:14][C@H:13]2[C@@H:9]1[CH2:10][C:11](=[O:23])[O:12]2
Reactant: CCCC(=O)C(F)(F)CC=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCC(O)C(F)(F)CCC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Reaction time: 0.17 h

Procedure:
Sodium borohydride (0.800 g) was added to the solution of (1S,5R,6R,7R)-6-(4,4-difluoro-5-oxo-octenyl)-7-tetrahydropyranyloxy-2-oxabicyclo[3.3.0]-octan-3-one (5) (5.48 g) in methanol at 0° C., and stirred for 10 minutes. The reaction product was treated with a usual manner, and the obtained crude product was subjected to column chromatography to give a titled compound (6). Yield: 5.46 g (99.5%)
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br.[N:10](N)([CH3:12])[CH3:11].Cl.[OH-].[Na+]>CCOCC>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:10]([CH3:12])[CH3:11]
Reactant: C=CCCCCCCBr
Reactant: CN(C)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: C=CCCCCCCN(C)C

Procedure:
HOSiPcOSi(CH3)2(CH2)8N(CH3)2 Compound XXII A solution of CH2═CH(CH2)6Br, (CH3)2NNH2 and ether was stirred, the reaction mixture was worked up with HCl, NaNO3, and NaOH, and the resulting CH2═CH(CH2)6N(CH3)2 was isolated and distilled. A solution of this compound, (CH3)2SiHCl, CHCl3, H2PtCl6xH2O and isopropanol was warmed and the CH3OSi(CH3)2(CH2)8N(CH3)2—HCl formed was isolated. Next, a suspension of this intermediate, CH3SiPcOH and pyridine was partially distilled, and the CH3SiPcOSi(CH3)2(CH2)8N(CH3)2 obtained was isolated and recrystallized. Finally, a solution of this compound and CH2Cl2 was irradiated with light and the product was isolated, chromatographed, and recrystallized: MS-HRFAB exact mass, m/z: calculated for C44H45N9O2Si2 (M+H)+, 788.3313; found, 788.3300, 788.3290.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:16][CH2:15][CH2:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1CCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
2-(2-Hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (229 mg) obtained from Referential Example 77 and triethylamine (209 μL) were dissolved in methylene chloride (5 mL) To the resultant solution, methanesulfonyl chloride (116 μL) was added at room temperature, followed by stirring for 30 minutes. The residue obtained by removal through evaporation of the reaction solvent under reduced pressure was partitioned between water and methylene chloride. The organic layer was sequentially washed with water and saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, to thereby give the title compound in the form of crystals (288 mg, 93%).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([S:8][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1ccc(SCc2ccccc2)cc1
Yield: 68.2 %

Procedure:
A mixture of 37.2 g of benzylmercaptan, 36.3 g of 4-fluorobenzonitrile and 42 g of potassium carbonate in 700 ml of 2-butanone is refluxed for 7 hours. The solvent is evaporated off under vacuum and the residue is taken up with water and petroleum ether. The crystals formed are filtered off and washed with water and petroleum ether to give 46 g of 4-benzylthiobenzonitrile in the form of crystals melting at 85° C.