Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](/[CH:25]=[C:26](/[C:28](=[O:33])[NH:29][CH2:30][CH2:31][CH3:32])\[CH3:27])[CH:23]=2)[NH:18][CH:17]=1)[C:8]([O:10][CH3:11])=[O:9].[CH2:34](Br)[CH:35]=[CH2:36].Cl>CN(C)C=O.O>[CH2:36]([N:18]1[C:19]2[C:24](=[CH:23][C:22](/[CH:25]=[C:26](/[C:28](=[O:33])[NH:29][CH2:30][CH2:31][CH3:32])\[CH3:27])=[CH:21][CH:20]=2)[C:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=2[O:4][CH3:3])=[CH:17]1)[CH:35]=[CH2:34]
Reactant: C=CCBr
Reactant: CCCNC(=O)/C(C)=C/c1ccc2[nH]cc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C(\C)C(=O)NCCC)ccc21
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
Sodium hydride (0.048 g of a 60% dispersion in oil) was added to a stirred solution of methyl E-3-methoxy-4-[5-[2-(propylcarbamoyl)-1-propenyl]indol-3-ylmethyl]benzoate (0.5 g) in N,N-dimethylformamide (5 ml), under an atmosphere of nitrogen. After 0.5 hr, allyl bromide (0.14 g) was added and stirring continued for 3 hr. The solution was acidified with 1M hydrochloric acid (10 ml), diluted with water (20 ml), extracted with ethyl acetate (twice), and the organic phase was washed with water (4 times), brine, and dried (MgSO4). The solvent was evaporated to give an oil which was purified by flash chromatography, eluting with 2:1:1 hexane:methylene chloride:ethyl acetate, to give methyl E-4[1-allyl-5-[2-(propylcarbamoyl)-1-propenyl]indol-3-ylmethyl)-3-methoxybenzoate (0.36 g, 66%) as a white foam; partial NMR (250 MHz, DMSO-d6) 0.87(t, 3H, CH2CH2CH3), 1.47(m, 2 H, CH2CH2CH3), 1.99(s, 3H, CCH3), 3.11(m, 2H, CH2CH2CH3), 3.83(s, 3H, OCH3), 3.90(s, 3H, OCH3), 4.06(s, 2H, ArCH2Ar'), 4.77(br d, J=5.3 Hz, 2H, NCH2CH:C), 5.00-5.16(m, 2H, olefinic H), 6.0(m, 1H, olefinic H), 7.94(br t, 1H, NHCO).
Reaction SMILES: C([CH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[C:4]([OH:6])=[O:5])C.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:30][C:31](C)=O>>[CH2:22]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:3][C:4]([O:6][CH2:30][CH3:31])=[O:5])=[CH:8][C:9]=1[O:14][CH3:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)=O
Reactant: BrCc1ccccc1
Reactant: CCC(C(=O)O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1ccc(OCc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 4-hydroxy-3-methoxyphenylacetic acid (25 g, 120 mmol), commercially available from Aldrich Chemical Company, in acetone (150 mL) was added potassium carbonate (50 g, 360 mmol) followed by benzyl bromide (23 g, 130 mmol). The reaction mixture was stirred at ambient temperature for 15 hours and then was concentrated under reduced pressure. The residue was partitioned between 500 mL of water and 500 mL of diethyl ether. The aqueous layer was extracted with 300 mL of diethyl ether and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give 32 g of the title compound as a yellow solid. The product was carried on to the next step without purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[C:5]([C:10]([F:13])([F:12])[F:11])[C:4]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[N:3]1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:32])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28]>ClCCl.[Ag]C#N>[Cl:32][C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]([F:19])([F:20])[C:15]([F:17])([F:18])[F:16])[C:5]=2[C:10]([F:12])([F:13])[F:11])=[O:8])=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Cl
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: N#C[Ag]
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4.24 g (12.8 mmol) of 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride in 25 ml of dichloromethane p.a. is added to a suspension of 2.38 g (12.8 mmol) of methyl 5-amino-2-chlorobenzoate and 2.57 g (19.2 mmol) of silver(I) cyanide in 50 ml of dichlormethane p.a., and the mixture is stirred at room temperature for 16 h. The suspension is then filtered through silica gel and the product is eluted using a mixture of cyclohexane and ethyl acetate (1:1). The organic phase is washed successively three times with 6N hydrochloric acid and twice with saturated sodium chloride solution. The organic phase is then dried over sodium sulphate, filtered and concentrated on a rotary evaporator under reduced pressure. This gives 5.75 g (93%) of methyl 2-chloro-5-({[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzoate.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[CH3:21])(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C1COCC1.CO.O[Li].O>O>[Cl:20][C:16]1[C:15]([CH3:21])=[C:14]([S:11]([NH:10][C:5]2([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]2)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C1(NS(=O)(=O)c2cccc(Cl)c2C)CCCC1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1S(=O)(=O)NC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.2 %

Procedure:
methyl-1-(3-chloro-2-methylphenylsulfonamido)cyclopentanecarboxylate (550 mg, 1.65 mmol) was charged and dissolved through addition of THF (5 ml), and methanol (5 ml). LiOH.H2O dissolved in H2O (5 ml) was added thereto, followed by stirring for 12 hours at room temperature. After the stirring for 12 hours, the resultant solution was vacuum-evaporated, adjusted with 2N—HCl to pH 5-6, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Then, through vacuum distillation, the solvent was removed so as to obtain 1-(3-chloro-2-methylphenylsulfonamido)cyclopentanecarboxylic acid (516 mg, 1.62 mmol, 98%).
Reaction SMILES: O.[SH-].[Na+:3].C([S:11]([C:14]1[N:19]=[C:18]([N:20]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[S:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:17]=[C:16]([NH:38][C@H:39]([CH3:42])[CH2:40][OH:41])[N:15]=1)(=O)=O)C1C=CC=CC=1>CS(C)=O>[OH:41][CH2:40][C@H:39]([NH:38][C:16]1[CH:17]=[C:18]([N:20]([S:21]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)(=[O:22])=[O:23])[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:19]=[C:14]([S-:11])[N:15]=1)[CH3:42].[Na+:3]
Reactant: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCOCC2)nc(S(=O)(=O)Cc2ccccc2)n1
Agent: [Na+]
Agent: [SH-]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCOCC2)nc([S-])n1
Reaction time: 1.25 h

Procedure:
Sodium hydrosulfide hydrate (0.62 g) was added to a solution of the subtitle product of step iii) (2.5 g) in DMSO (5 ml) and the green solution stirred for 1.25 h. A further aliquot of sodium hydrosulfide hydrate (0.28 g) was added and stirred for 45 min. A further aliquot of sodium hydrosulfide hydrate (0.32 g) was added and stirred for 1.25 h before the addition of a final aliquot of sodium hydrosulfide hydrate (0.10 g) in DMSO (1 ml). The resulting reaction solution was diluted with DMSO (10 ml) and used directly in the following step. The subtitle compound was also kept as a stock solution for further reaction with alkyl halides, described in Examples 107-110.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:4]=1)#[N:2].C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([NH2:35])=[O:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:4]=1)#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1=C(C(N)=O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (696 mg, 1.45 mmol; Example 5A) and HATU (2 eq., 1104 mg, 2.9 mmol) were initially charged in dry DMF (35 ml) at 0° C., and after brief stirring (20 min) ammonium chloride (5 eq., 388 mg, 7.26 mmol) and DIEA (7 eq., 1314 mg, 10.16 mmol) were added. The mixture was stirred at RT for 4 h (monitored by HPLC). The mixture was then concentrated, and the residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (612 mg, 88% of theory).
Reaction SMILES: C([O:5][C:6](=[O:12])[C@@H:7]([CH3:11])[C@@H:8]([NH2:10])[CH3:9])(C)(C)C.C[O:14][C:15]([C:17]1[N:18]=[C:19]([C:35]#[N:36])[C:20]2[C:25]([C:26]=1[OH:27])=[CH:24][CH:23]=[C:22]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]=2)=O.C(N(CC)CC)C>CCO>[C:35]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[C:22]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:21]=2)[C:26]([OH:27])=[C:17]([C:15]([NH:10][C@@H:8]([CH3:9])[C@H:7]([CH3:11])[C:6]([OH:5])=[O:12])=[O:14])[N:18]=1)#[N:36]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: C[C@H](N)[C@H](C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)[C@H](C)C(=O)O
Temperature: 140 °C
Yield: 35.1 %

Procedure:
A mixture of (2S,3S)-3-amino-2-methyl-butyric acid tert-butyl ester (20 mg, 0.12 mmol), 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (25 mg, 0.078 mmol), and triethylamine (0.050 mL) in EtOH (2 mL) was heated in a microwave reactor at 140° C. for 6 h. The resulting mixture was concentrated to dryness, and the residue was re-dissolved in CH2Cl2 and passed through a plug of silica gel. After evaporating the solvent, the residue was dissolved in CH2Cl2 (3 mL) and treated with trifluoroacetic acid (2 mL) for 2 h. The mixture was concentrated in vacuo, and the resulting residue was taken up in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH ˜2 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 11.1 mg of the title compound as a white solid. MS: (−) m/z 404.32 (M−1).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([SH:11])[N:8]2[N:12]=[C:13]([CH2:15][OH:16])[N:14]=[C:7]2[N:6]=1)=[O:4].CC(O[CH2:21][C:22]1[CH2:31][S:30][C@@H:25]2[C@H:26]([NH2:29])[C:27](=[O:28])[N:24]2[C:23]=1[C:32]([OH:34])=[O:33])=O.B(F)(F)F.CCOCC.ClCCl>S1(CCCC1)(=O)=O.ClCCl>[NH2:29][C@@H:26]1[C:27](=[O:28])[N:24]2[C@@H:25]1[S:30][CH2:31][C:22]([CH2:21][S:11][C:9]1[N:8]3[N:12]=[C:13]([CH2:15][OH:16])[N:14]=[C:7]3[N:6]=[C:5]([C:3](=[O:4])[NH:2][OH:1])[CH:10]=1)=[C:23]2[C:32]([OH:34])=[O:33]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(NO)c1cc(S)n2nc(CO)nc2n1
Agent: FB(F)F
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cc(C(=O)NO)nc4nc(CO)nn34)CS[C@H]12
Temperature: 0 °C
Reaction time: 20 h
Yield: 40.4 %

Procedure:
N-Hydroxy-2-(hydroxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine-5-carboxamide (190 mg) (0.79 mmol) and 193 mg (0.71 mmol) of 7-amino-cephalosporanic acid are suspended in 20 ml of sulpholane/dichloromethane (1:1 v/v). 4.2 ml of boron trifluoride diethyl etherate are added thereto at 0° C. The mixture is stirred at 0° C. for 2 hours and at room temperature for 20 hours. 80 ml of dichloromethane are added. The precipitated material is separated and dissolved in water. The mixture is adjusted to pH 4 by the addition of saturated aqueous sodium hydrogen carbonate solution. The precipitated product is filtered off under suction and washed in sequence with water, ethanol and diethyl ether. There are obtained 130 mg of (6R,7R)-7-amino-3-[[[5-(hydroxycarbamoyl)-2-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH3:25]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O:23][CH3:25])=[O:22])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CO
Product: COC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C

Procedure:
19.54 g of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylic acid are dissolved in 350 ml of MeOH, 0.97 g of paratoluenesulfonic acid is added and the mixture is then refluxed for 18 hours. After evaporation of the solvent, the residue is taken up with AcOEt and washed with saturated NaHCO3 solution and then with saturated NaCl solution. It is dried over MgSO4, the insoluble material is filtered off and the filtrate is then concentrated to dryness to give 18.53 g of the expected compound, m.p.=133° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:22]=[CH:21][C:8]2[O:9][C:10]3[CH:16]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:13][C:11]=3[O:12][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].I[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[N:36]1[C:45]2[C:40](=CC=CC=2)[CH:39]=[CH:38][CH:37]=1>[Cu]I.O.C(Cl)Cl>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH2:19][C:18]([NH:17][C:15]2[CH:14]=[CH:13][C:11]3[O:12][C:7]4[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH2:2][C:38]5[CH:37]=[N:36][CH:45]=[CH:40][CH:39]=5)[CH:22]=[CH:21][C:8]=4[O:9][C:10]=3[CH:16]=2)=[O:20])[CH:25]=1
Reactant: CC(=O)Nc1ccc2c(c1)Oc1ccc(NC(C)=O)cc1O2
Reactant: Ic1cccnc1
Reactant: c1ccc2ncccc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1cccnc1)Nc1ccc2c(c1)Oc1ccc(NC(=O)Cc3cccnc3)cc1O2
Temperature: 170 °C
Reaction time: 48 h

Procedure:
A slurry prepared from 7.0 g (0.023 mole) of 2,7-bis(acetylamino)dibenzodioxin, 12.0 g (0.059 mole) of 3-iodopyridine, 9.8 g (0.051 mole) of copper (I) iodide, 12.9 g (0.093 mole) of potassium carbonate, and 230 ml of quinoline was heated with stirring at 170° C. for 48 hours. The reaction mixture was cooled to room temperature, 100 ml of methylene chloride and 100 ml of water were added, and a precipitate was separated by filtration. To the filtrate was added 100 ml of water and the organic layer was separated from the aqueous layer. The organic layer was concentrated and dried under reduced pressure to give 23.5 g of a crude product which was used without purification in the next reaction.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]#N)[CH2:12][CH2:11]1.C(O)(C(F)(F)F)=[O:22].CC#N>CCOCC.C(Cl)Cl>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])=[O:22])[CH2:12][CH2:11]1
Reactant: CN1CCN(CCCC#N)CC1
Reactant: Cc1ccccc1I
Reactant: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccccc1C(=O)CCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 10 mL oven-dried flask was added Mg turnings (116 mg, 4.0 mmol) which were activated under vacuum by the use of a heat-gun. Under inert atmosphere was added a mixture of 2-iodotoluene (0.65 g, 3.0 mmol) in Et2O (3 mL) and the reaction mixture was allowed to reflux for 1 hour. A solution of compound 14 (0.33 g, 2.0 mmol) in CH2Cl2 (3 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H2SO4 (6 mL, 2 M) and stirred at rt for 2 hours followed by addition of NaOH (8 mL, 2 M). Addition of THF (15 mL) was followed by extraction with CH2Cl2 (3×20 mL). The organic phases were dried (MgSO4) and evaporated to dryness to produce 0.26 g of crude 15. The crude product was subjected to preparative HPLC [eluent: Buffer A: 0.1% TFA; Buffer B: 80% CH3CN+0.1% TFA] to produce an analytically pure sample of compound 15. LC-MS [M+H]+ 260 (cald. 260.4).
Reaction SMILES: C(C1CCC2C(=CC=C(C3C=C([F:20])C(F)=C(F)C=3)C=2)C1)CC.[CH2:23]([CH:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[C:32]=2F)[CH2:27]1)[CH2:24][CH3:25]>FC(F)(F)S(OC1C=C2C(=CC=1)CC(CCC)CC2)(=O)=O>[CH2:23]([CH:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][C:30]([F:20])=[C:31]([OH:37])[CH:32]=2)[CH2:27]1)[CH2:24][CH3:25].[CH2:23]([CH:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=2)[CH2:27]1)[CH2:24][CH3:25]
Reactant: CCCC1CCc2c(ccc(O)c2F)C1
Reactant: CCCC1CCc2cc(-c3cc(F)c(F)c(F)c3)ccc2C1
Agent: CCCC1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Product: CCCC1CCc2cc(O)c(F)cc2C1
Product: CCCC1CCc2cc(O)ccc2C1

Procedure:
Syntheses were performed in the same manner as (7-2) and (7-3), with the exception of using the 2-propyl-5-fluoro-1,2,3,4-tetrahydro-6-naphthol and the 2-propyl-7-fluoro-1,2,3,4-tetrahydro-6-naphthol obtained in (10-1) above instead of the 2-propyl-1,2,3,4-tetrahydro-6-naphthol in (7-2), and yielded 35 g of 2-propyl-5-fluoro-6-(3,4,5-trifluorophenyl)-1,2,3,4-tetrahydronaphthalene, and 53 g of 2-propyl-7-fluoro-6-(3,4,5-trifluorophenyl)-1,2,3,4-tetrahydronaphthalene respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 1.8 mmol of benzoyl chloride in 3 ml of DMF were added. The reaction solution was then stirred at RT for a further 20 h. The crude product was purified using chromatographic methods.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH2:24]O)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.C(P(CCCC)CCCC)CCC.[NH:50]1[CH:54]=[N:53][CH:52]=[N:51]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(OCC)(=O)C.O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH2:24][N:50]4[CH:54]=[N:53][CH:52]=[N:51]4)[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2cc(CO)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: c1nc[nH]n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(COc2cc(Cn3cncn3)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 85.1 %

Procedure:
To a mixture of {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}methanol (0.50 g), tributylphosphine (0.61 g), 1H-1,2,4-triazole (0.21 g) and tetrahydrofuran (80 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.75 g) at room temperature, and the mixture was stirred for 15 hrs. Ethyl acetate was added to the reaction mixture. The ethyl acetate layer was washed successively with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 1-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}methyl)-1H-1,2,4-triazole as crystals (0.47 g, yield 85%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(N([CH2:22][CH3:23])CC)C>C(Cl)(Cl)Cl>[O:16]1[CH2:23][CH2:22][CH2:13][CH2:14][CH:15]1[O:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][S:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: NCCCCO
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=S(=O)(NCCCCOC1CCCCO1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 16 g of pyridine-3-sulfonyl chloride prepared as described by B. I. Alo, O. B. Familoni, F. Marsais and G. Queguiner, J. Heterocyclic Chem. 1992,29, 61-4 in 250 mL of chloroform was added to a solution of 8 g of 4-amino-1-butanol and 40 mL of triethylamine in 250 mL of chloroform at 0° C. The mixture was stirred overnight while warming to ambient temperature, the concentrated under reduced pressure to dryness. The residue was stirred with 500 mL of ethyl acetate, filtered and concentrated to dryness. To a solution of the crude N-(4-hydroxybutyl)pyridine-3-sulfonamide (28 g) in 200 mL of dichloromethane was added 30 mL of 3,4-dihydro-2H-pyran and 3 g of p-toluenesulfonic acid monohydrate. The reaction was stirred overnight, shaken with 100 mL of saturated sodium bicarbonate, dried over MgSO4, and concentrated to dryness. Chromatography of the residue over silica gel, eluting with ethyl acetate gave 20 g of N-(4-(2-tetrahydropyranyloxy)butyl)pyridine-3-sulfonamide as a thich amber oil.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[NH2:2].C([O:14][C:15]([C:17]1[CH:18]=[N:19][C:20]2[C:25]([C:26]=1Cl)=[CH:24][CH:23]=[CH:22][C:21]=2[F:28])=O)C.[OH-].[Li+].Cl>C(O)CCC.O.O1CCCC1>[F:28][C:21]1[C:20]2[NH:19][CH:18]=[C:17]3[C:15](=[O:14])[N:1]([C:3]4[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=4)[C:6]([OH:8])=[O:7])[N:2]=[C:26]3[C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: NNc1cccc(C(=O)O)c1
Reactant: CCOC(=O)c1cnc2c(F)cccc2c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.2 %

Procedure:
3-Hydrazinobenzoic acid (1.91 g, 0.013 mol) was added in one portion to a stirred solution of 4-chloro-8-fluoro-quinoline-3-carboxylic acid ethyl ester (2.93 g, 0.011 mol) in n-butanol (60 ml) at room temperature. The solution was heated to reflux for 16 h, cooled to room temperature and the resulting yellow solid filtered, washed with tert-butyl methyl ether and then dried. The solid was redissolved in a solution of tetrahydrofuran water (2:1; 21 ml) and lithium hydroxide (1.27 g, 0.031 mol) was then added. After stirring at room temperature for 16 h, concentrated hydrochloric acid (3 ml) was added dropwise to the mixture to precipitate a yellow solid which was filtered and dried under vacuum to give the title compound (intermediate 3) (2.32 g, 63%) as a bright yellow solid.