Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]([CH2:16][CH3:17])(P(=O)([O-])[O-])/[C:4](/[CH3:11])=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C([Li])CCC.[CH3:23][C:24]1([CH3:46])[CH2:33][CH:32]=[C:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[C:30]2[CH:29]=[C:28](/[C:41](/C)=[CH:42]/C=O)[CH:27]=[CH:26][C:25]1=2>C1COCC1.CCOCC>[CH3:11]/[C:4](/[CH:3]=[CH:16]/[CH:17]=[C:41](/[C:28]1[CH:27]=[CH:26][C:25]2[C:24]([CH3:23])([CH3:46])[CH2:33][CH:32]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[C:30]=2[CH:29]=1)\[CH3:42])=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)/C=C(\C)C(CC)(CC)P(=O)([O-])[O-]
Reactant: C/C(=C\C=O)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(C)/C=C/C=C(\C)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C
Reaction time: 1 h

Procedure:
To a cold (-78° C.) solution of diethyl-(E)-3-ethoxycarbonyl-2methylallylphosphonate [prepared in accordance with J. Or. Chem. 39: 821 (1974)] 264.0 mg, (1.00 mmol) in THF (2 ml) was added 26.0 mg (0.41 mmol, 0.65 ml) of n-butyllithium in hexanes (1.6M solution) followed immediately by the addition of (E)-3-(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalen-yl)-2-butenal (Compound X) 82.0 mg, 0.26 mmol) in THF (3 ml). After 1 hour, the reaction mixture was diluted with ether (60 ml), washed with water (5 ml), saturated aqueous NaCl (5 ml) and dried over MgSO4. After removal of the solvents under reduced pressure, the title compound was isolated as an oil by column chromatography (5% EtOAc/hexanes, followed by HPLC using 1% EtOAc/hexanes). 1H NMR (acetoned6): δ 7.36-7.43 (2H, m), 7.18-7.27 (4H, m), 7.17 (1H, d, J=1.7 Hz), 7.08 (1H, dd, J=11.2, 15.2 Hz), 6.46 (1H, d, J=11.2 Hz), 6.38 (1H, d, J=15.2 Hz), 5.98 (1H, t, J=4.7 Hz), 5.78 (1H, s), 4.10 (2H, q, J=7.1 Hz), 2.35 (3H, s), 2.33 (3H, s), 2.32 (2H, d, J=4.7 Hz), 2.12 (3H, s), 1.31 (6H, s), 1.22 (3H, t, J=7.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[C:17]([CH3:27])=[CH:16][C:15]([CH:12]4[CH2:13][CH2:14]4)=[CH:20][N:19]=3)[CH2:22][CH2:23]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: Cc1nc(Br)ccc1C(=O)O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2C)CC1
Yield: 57.1 %

Procedure:
Using 6-bromo-2-methylnicotinic acid (864 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (913 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (948 mg) was obtained.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17]([O:24][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([CH2:32]Br)=[CH:27][C:26]=1[Cl:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:24][C:25]1[C:26]([Cl:34])=[CH:27][C:28]([CH2:32][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:29][C:30]=1[Cl:31])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cc(CBr)cc(Cl)c1OCc1ccccc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2cc(Cl)c(OCc3ccccc3)c(Cl)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 h at this temperature and 2-benzyloxy-5-bromomethyl-1,3-dichloro-benzene (CAB02118, 1.73 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (75 mL) was added. The mixture was transferred into a separation funnel and washed with water (2×100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 1.76 g (78%).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])[NH:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:36])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:36]=[S:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:25])[F:26])[NH:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(N3CCSCC3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(N3CCS(=O)CC3)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
20.1 mg (0.0515 mmol) of the 7-thiomorpholin-4-yl-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Example 104 was dissolved in 2.3 ml of methylene chloride, and 9.8 mg (0.0566 mmol) of m-chloroperbenzoic acid was further added to the solution. The obtained mixture was stirred at 0° C. for 2 hours. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and was then concentrated. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1), so as to obtain 16.6 mg (79%) of 7-(1-oxothiomorpholin-4-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[CH2:28]1[O:40][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.O>CC#N>[CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][CH2:28][CH:29]([OH:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:24][CH:25]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(N)cc1)Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCC1CO1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CCCCCCCCCCC(O)CNc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)OCC)cc1
Temperature: 25 °C
Yield: 108 %

Procedure:
To a solution of ethyl{(4-aminobenzyl)[4-(trifluoromethyl)benzyl]amino}(oxo)acetate (38 mg, 0.10 mmol) and 1,2-dodecylene oxide (22 mg, 0.12 mmol) in 1.0 mL CH3CN were added at once magnesium perchlorate (27 mg, 0.12 mmol) under inert atmosphere. The reaction mixture was stirred 24 at rt. 2 mL of H2O were added and the resulting mixture was extracted with EtOAc (2×5 mL), dried over MgSO4, filtered and the solvents were evaporated under vacuum to give a slightly yellow oil (61 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:7]=1.CO.[NH4+].[Cl-]>[Fe].O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ccncc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(F)cc1Nc1ccncc1
Temperature: 80 °C
Yield: 65.7 %

Procedure:
To a mixture of (5-fluoro-2-nitro-phenyl)-pyridin-4-yl-amine (375 mg, 1.61 mmol) in a 3:1 mixture of MeOH:water (40 mL) were added NH4Cl (516 mg, 9.65 mmol) and iron powder (359 mg, 6.43 mmol) and the reaction mixture heated at 80° C. for 2 h. After cooling to RT, the solid was filtered through a pad of Celite® and washed with additional MeOH. The filtrate was concentrated in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was dried and concentrated in vacuo to afford the title compound as a dark beige solid (215 mg, 66%). LCMS (Method C): RT 1.32 min [M+H]+ 204.09
Reaction SMILES: [CH:1]1([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2C=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C=CC=CC=2)CCCCCC1.Cl[CH:30]([O:32]C(Cl)Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:1]1([C:8]2[CH:9]=[CH:12][C:13]([CH:30]=[O:32])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: ClC(Cl)OC(Cl)Cl
Reactant: O=Cc1ccccc1C1CCCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: c1ccc(C2CCCCCC2)cc1
Solvent: ClCCl
Product: O=Cc1ccc(C2CCCCCC2)cc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Cycloheptylbenzaldehyde can be manufactured as follows: 200 ml of titanium tetrachloride are added dropwise, whilst stirring, to a solution of 200 g of cycloheptylbenzene in 600 ml of absolute methylene chloride under a nitrogen atmosphere at -10°C, and thereafter 132.5 g of dichloromethyl ether are added similarly at 0°C. The reaction mixture is then stirred for a further 30 minutes at 10°C and poured onto 3 kg of ice, and the whole is extracted twice with 500 ml of methylene chloride. The organic phases are washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. Distillation of the evaporation residue in a high vacuum yields 4-cycloheptyl-benzaldehyde in the fraction boiling at 120-130°C/0.8 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7](CC2C=CC(C)=CC=2)[C:8]2[C:16]3[S:15][C:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:13][C:12]=3[C:11]([O:26][CH3:27])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40]>C(#N)C>[Cl:44][C:43]([Cl:46])([Cl:45])[CH2:42][O:41][C:39](=[O:40])[N:7]([C:8]1[C:16]2[S:15][C:14]([NH:17][C:18](=[O:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:13][C:12]=2[C:11]([O:26][CH3:27])=[CH:10][CH:9]=1)[CH2:6][C:5]1[CH:36]=[CH:37][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)c2sc(NC(=O)c3ccccc3)nc12
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc(N(Cc2ccc(C)cc2)C(=O)OCC(Cl)(Cl)Cl)c2sc(NC(=O)c3ccccc3)nc12
Temperature: 80 °C
Yield: 40.4 %

Procedure:
To a stirred solution of 300 mg (0.59 mmol) N-{7-[bis-(4-methyl-benzyl)-amino]-4-methoxy-benzothiazol-2-yl}-benzamide in 10 ml acetonitrile was added dropwise 0.60 ml (4.46 mmol) 2,2,2-trichloroethyl chloroformate and the reaction mixture heated at 80° C. for 72 h. The mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate/hexane) afforded 138 mg (40%) (2-benzoylamino-4-methoxy-benzothiazol-7-yl)-(4-methyl-benzyl)-carbamic acid 2,2,2-trichloro-ethyl ester as a yellow solid. ES-MS m/e (%):584 (M{37Cl, 37Cl, 37Cl}+H+, 5), 582 (M{37Cl, 37Cl, 35Cl}+H+, 32), 580 (M{37Cl, 35Cl, 35Cl}+H+, 100), 578 (M{35Cl, 35Cl, 35Cl}+H+, 92).
Reaction SMILES: CC(C)=O.[Cl:5]([O-:9])(=[O:8])(=[O:7])=[O:6].CS[C:12]1[S:16][CH:15]=[CH:14][S+:13]=1.C(OCC)C.[CH2:22]([O:24][C:25](=[O:33])[C@H:26]([CH2:29][CH2:30][S:31][CH3:32])[NH:27][CH3:28])[CH3:23]>C(OCC)(=O)C>[Cl:5]([O-:9])(=[O:8])(=[O:7])=[O:6].[S:16]1[CH:15]=[CH:14][S:13][C:12]1=[N+:27]([CH3:28])[CH:26]([C:25]([O:24][CH2:22][CH3:23])=[O:33])[CH2:29][CH2:30][S:31][CH3:32]
Reactant: CCOC(=O)[C@H](CCSC)NC
Reactant: CSc1scc[s+]1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCSC)[N+](C)=c1sccs1
Temperature: 25 °C
Yield: 222.1 %

Procedure:
To 100 ml of acetone, 2.0 g of 2-methylthio-1,3-dithiolium perchlorate was dissolved, and 50 ml of an ethyl ether solution containing 2.3 g of N-methyl methionine ethyl ester was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 6 hours, and then the solvent was distilled off. The residue was washed with ethyl acetate, whereby 7 g (yield: 54%) of N-(1,3-dithiol-2-ylidene)-N-methyl-N-(3-methylthio-1-ethoxycarbonylpropyl)ammonium perchlorate (Compound No. 6) was obtained as oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][OH:13])[C:9]#[N:10])=[C:4]([CH3:14])[CH:3]=1.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O.[BH4-].[Na+].NCCNCCN>CO>[C:19]([O:18][C:16](=[O:15])[NH:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:14])[CH2:11][CH2:12][OH:13])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1cc(Br)ccc1C(C#N)CCO
Agent: NCCNCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Br)ccc1C(CCO)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
To a solution of 2-(4-bromo-2-methyl-phenyl)-4-hydroxy-butyronitrile (27.3 g, 0.1074 mol) in MeOH (750 mL) at 0° C. was added (BOC)2O (46.9 g, 0.2149 mol), followed by NiCl2.6H2O (2.55 g, 0.01074 mol) and sodium borohydride (27.83 g, 0.7359 mol). The mixture was stirred at room temperature for 24 hours, and diethylenetriamine (12 mL, 0.1074 mol) was added. The reaction mixture was stirred for 30 minutes, then solvent was evaporated under reduced pressure. The resulting crude material was partitioned between NaHCO3 (10% aqueous solution) and EtOAc. The organic phase was washed with water and brine; dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 6/4) to give 30.3 g (79% yield) of [2-(4-bromo-2-methyl-phenyl)-4-hydroxy-butyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([CH:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28]([O-])=O)C.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:28]([NH:4][S:1]([NH2:5])(=[O:3])=[O:2])[C:27]1[CH:25]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NS(N)(=O)=O
Reactant: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: NS(=O)(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
The condensed sulfamide having an allyloxycarbonyl protecting group obtained as Sample No. 3 of Example 1 is dissolved in benzene (10 vol.), and triphenylphosphine (0.3 Eq.), sodium 2-ethylhexanoate (1.5 Eq.) in ethyl acetate, and palladium tetrakistriphenylphosphine (0.02 Eq.) are added thereto successively. The mixture is stirred at room temperature for 30 minutes. The reaction mixture is diluted with ethyl acetate, washed with water, dried, and concentrated in vacuo. The residue is recrystallized from toluene to give benzylsulfamide having the same physical constants as that obtained in Reference Example 1. Pale yellow crystals. Yield: 64%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH3:18])[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccc(F)cc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2ccc(F)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-(4-chloro-phenyl)-piperazine.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:10]2[CH2:11][C:12](=[O:14])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)O.CO.C(OC(C)C)(=O)C>COCCOC.O>[OH:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH3:3])[C:10]=1[CH2:11][CH2:12][OH:14]
Reactant: COc1cccc2c1CC(=O)O2
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)OC(C)C
Product: COc1cccc(O)c1CCO
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
7.18 g (189 mmol) of sodium borohydride was added to a solution of 10.76 g (65.5 mmol) of 4-methoxy-3H-benzofuran-2-one in 150 mL of ethyleneglycol dimethyl ether and stirred. While cooled on an ice-water bath, a solution of 5.25 mL (9.66 g, 94.5 mmol) of concentrated sulfuric acid in 21 mL of ethyleneglycol dimethyl ether was added dropwise thereto over 30 minutes. This mixture was heated and stirred on a 50° C. water bath for 49 minutes and then, while being stirred on an ice-water bath, 32 mL (25.3 g, 790 mmol) of methanol was added dropwise thereto for 6 minutes. This mixture was heated and stirred on a 50° C. water bath for 53 minutes, allowed to stand at room temperature overnight, 300 mL of isopropyl acetate and 200 mL of water were added therein and then the mixture was stirred for 5 minutes, transferred into a separatory funnel and settled. The aqueous layer was separated and discarded and after the organic layer was washed with 100 mL of water twice, the solvent was evaporated. The residue was crystallized from ethyl acetate-hexane and the obtained crystals were dried in vacuo at 30° C. and 3.12 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=[N:5][NH:6][C:7]1[CH:8]=[N:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[NH2:4].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=O)=[CH:21][CH:20]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O1CCOCC1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:23]([C:22]3[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[N:4][C:3]([C:2]([F:1])([F:15])[F:16])=[N:5]2)=[CH:8][N:9]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NN=C(N)C(F)(F)F)cn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(OC)nc2)cc1
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A mixture of 2,2,2-trifluoro-N′-(6-methoxypyridin-3-yl)ethanehydrazonamide (0.2 g, 0.854 mmol), 4-methoxybenzoyl chloride (175 mg, 1.02 mmol), pyridine (0.083 mL, 1.02 mmol), and 4-dimethylaminopyridine (125 mg, 1.02 mmol) in dioxane (2 mL) was refluxed with stirring overnight. After cooling, the solvent was removed under reduced pressure. ethyl acetate-tetrahydrofuran (9:1) and water was poured into the residue and the organic layer was separated, washed with 0.1 N hydrochloric acid, water, and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 2-methoxy-5-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]pyridine (57 mg, 19.1% yield).
Reaction SMILES: [N:1]([C@@:4]1([OH:23])[C@@H:8]([CH2:9][O:10]C(=O)C)[O:7][C@@H:6]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[S:19])[NH:17][C:15]2=[O:16])[CH2:5]1)=[N+:2]=[N-:3]>O1CCOCC1.[NH4+].[OH-].CCOCC>[N:1]([C@@:4]1([OH:23])[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[S:19])[NH:17][C:15]2=[O:16])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=S)[nH]c2=O)C[C@@]1(O)N=[N+]=[N-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cn([C@H]2C[C@@](O)(N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=S
Reaction time: 18 h

Procedure:
3'-Azido-5'-O-acetyl-4-thiothymidine (0.25 g; 0.76 mMol, Example 11) was dissolved in a mixture of 5 mL of dioxane and 5 mL of conc. NH4OH and stirred for 18 hrs. The solvent was removed in vacuo and the residue applied to a silica gel column followed by elution with CHCl3 /EtOAc (3:1 v/v). The appropriate fractions were combined and the solvent removed in vacuo to yield a yellow oil which was dissolved in Et2O, forming crystals upon concentration: 0.16 g (0.56 mMol; 74%).
Reaction SMILES: CO.O1CCCC1.[CH:8](=[N:15][N:16]1[CH2:20][CH2:19][N:18]([C@@:21]2([C:48]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=3)=[O:49])[S:27][C@H:26]3[N:23]([C:24](=[O:47])[C:25]3([N:30]=CC3C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=3)[O:28][CH3:29])[CH2:22]2)[C:17]1=[O:61])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>[Cl-].N(C(=O)C[N+](C)(C)C)N.O.C(Cl)Cl>[NH2:30][C:25]1([O:28][CH3:29])[C:24](=[O:47])[N:23]2[C@@H:26]1[S:27][C@@:21]([N:18]1[CH2:19][CH2:20][N:16]([N:15]=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:17]1=[O:61])([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=1)=[O:49])[CH2:22]2
Reactant: COC1(N=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@@H]21
Agent: C[N+](C)(C)CC(=O)NN
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC1(N)C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
In a mixed solvent consisting of 15 ml of methanol, 6 ml of tetrahydrofuran, 1.5 ml of water and 6 ml of methylene chloride was dissolved 740 mg of (3R,5R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-6-(3,5-di-tert-butyl-4-hydroxybenzylideneamino)-6-methoxy-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane. Thereto was added 240 mg of a Girard reagent (2-hydrazino-N,N,N-trimethyl-2-oxoethanaminium chloride). The mixture was stirred at room temperature for 1 hour. To the reaction mixture were added 30 ml of methylene chloride and 10 ml of water. The resulting mixture was adjusted to pH 7.0 with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: benzene/ethyl acetate=5/1 to 1/1) to obtain 320 mg (yield: 60.6%) of (3R,5R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-6-methoxy-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]([OH:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:17]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:8][C:9]([OH:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(C)(O)CNC1CCCCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(O)CN(Cc1ccccc1)C1CCCCC1
Temperature: 80 °C
Yield: 75 %

Procedure:
To ethyl 3-(cyclohexylamino)-2-hydroxy-2-methylpropanoate (6.7 g, 29.2 mmol) in 50 ml of acetonitrile at room temperature, was added benzyl bromide (5.2 ml, 43.8 mmol) dropwise, followed by K2CO3 (12 g, 87.6 mmol). The reaction mixture was heated at 80° C. for 18 h. It was then diluted to EtOAc, washed by brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=100:1 to 10:1) to give 7 g product (75%). [M+H] calc'd for C19H29NO3, 320; found 320.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13](OCC)=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH2:13][OH:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24]
Reactant: CCOC(=O)c1c(-c2ccccc2F)c2cc(Cl)ccc2[nH]c1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2F)c1CO
Reaction time: 0.5 h

Procedure:
A solution of 3.5 g (0.01 mol) of ethyl 6-chloro-4-(2-fluorophenyl)quinolin-2(1H)-one-3-carboxylate,* in 50 ml of tetrahydrofuran was added to a suspension of 1 g (0.022 mol) of lithium aluminum hydride in 50 ml of tetrahydrofuran. After stirring for 30 min at -20° to 0°, the hydride was hydrolized by addition of 5 ml of water. The mixture was then partitioned between methylene chloride and 2N hydrochloric acid. The methylene chloride layer was washed with water dried and evaporated. Crystallization of the residue from ethanol/chloroform yielded 6-chloro-4-(2-fluorophenyl)-3-hydroxymethylquinolin-2(1H)-one, with mp 282°-286°.