Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[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(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[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[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=3[N:6]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
To a solution of ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (4.00 g, 12.4 mmol) in N,N-dimethylformamide (30 mL) were serially added bromodiphenylmethane (3.38 g, 13.7 mmol) and potassium carbonate (1.90 g, 13.7 mmol), and the mixture was stirred at 60° C. for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to provide 4.50 g of the title compound Yield 74%.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:32])[C@H:16]([CH2:28][C:29](=[O:31])[NH2:30])[NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[OH:26])[CH2:11][CH2:10]1)C1C=CC=CC=1.CCOCC>[H][H].[C].[Pd]>[ClH:1].[OH:26][C:20]1[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C@H:16]([C:15]([N:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)=[O:32])[CH2:28][C:29](=[O:31])[NH2:30])=[O:27]
Reactant: [H][H]
Reactant: NC(=O)C[C@H](NC(=O)c1ccc(O)cc1O)C(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Product: NC(=O)C[C@H](NC(=O)c1ccc(O)cc1O)C(=O)N1CCNCC1
Yield: 77.4 %

Procedure:
Ethanolic solution (20 ml) of 1-benzyl-4-(2,4-dihydroxybenzoyl-L-asparaginyl)piperazine.hydrochloride (340 mg) was subjected to catalytic reduction in the presence of 10% palladium-carbon (300 mg) for 18 hours at room temperature and under atmospheric pressure in hydrogen stream. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a colorless oily product. This product was powdered with addition of ether and then collected by filtration to obtain 1-(2,4-dihydroxybenzoyl-L-asparaginyl)piperazine.hydrochloride (212 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1>C1COCC1>[CH3:1][N:2]([CH3:3])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: CCOC(=O)CN(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(C(=O)OC(C)(C)C)cc1)N(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Ethyl (dimethylamino)acetate (0.16 mL, 1.11 mmol) was dissolved in THF (10 mL) and cooled to −78° C. LiHMDS (1.2 mL, 1M solution in THF) was added. The reaction was allowed to stir about 30 minutes. Tert-butyl 4-(bromomethyl)benzoate (0.3063 g, 1.13 mmol) in THF (3 mL) was slowly added to the reaction. The reaction was allowed to stir overnight under nitrogen, slowly warming to room temperature. The reaction was quenched with saturated ammonium chloride and diluted with ethyl acetate. The resulting mixture was separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layer was dried with sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography. 1H NMR 600 MHz (CDCl3) δ 7.87 (m, 2H), 7.24 (m, 2H), 4.08 (m, 1H), 4.06 (m, 1H), 3.41 (dd, 1H, J=9.2, 6.0), 3.07 (dd, 1H, J=13.5, 9.3), 2.97 (dd, 1H, J=13.4, 5.8), 2.39 (s, 6H), 1.56 (s, 9H), 1.16 (m, 3H). MS: cal'd 322 (MH+), exp 322 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:13]([CH2:15][CH3:16])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:13]([N:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]1=[O:1])([CH2:15][CH3:16])[CH3:14]
Reactant: COC(=O)c1ccnc(O)c1
Reactant: CCC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(C)n1ccc(C(=O)OC)cc1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.8 %

Procedure:
To a solution of methyl 2-hydroxyisonicotinate (306 mg, 2 mmol) in N,N-dimethylformamide (20 mL) was added 2-bromobutane (330 mg, 2.4 mmol) and cesium carbonate (652 mg, 2 mmol), then stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography with dichloromethane/methanol=40:1 to give methyl 1-sec-butyl-2-oxo-1,2-dihydropyridine-4-carboxylate (334 mg, 80%). LRMS (M+H+) m/z: calcd 209.11. found 209.
Reaction SMILES: CN1CCOCC1.ClC(OCC)=O.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:27][CH2:28][S:29][CH3:30])[CH2:23][C:24](O)=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[OH:25][CH2:24][CH2:23][C@@H:22]([NH:21][C:19](=[O:20])[O:18][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:27][CH2:28][S:29][CH3:30]
Reactant: CSCC[C@@H](CC(=O)O)NC(=O)OC(C)(C)C
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CSCC[C@@H](CCO)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
N-methylmorpholine (3.63 ml) and ethyl chloroformate (3.01 ml) were added to a solution of (R)-3-((tert-butoxycarbonyl)amino)-5-(methylthio)pentanoic acid (7.92 g) in THF (79.2 ml) at −10° C. After stirring at −10° C. for 15 minutes, the generated insoluble matter was filtered off. An aqueous solution of sodium borohydride (1.55 g) (15 ml) was added to the filtrate at −10° C., and the mixture was stirred at −10° C. for 1 hour. A saturated aqueous ammonium chloride solution was added thereto, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added thereto to separate the organic layer. The organic layer was washed with a 0.5 N aqueous potassium hydrogensulfate solution, water, a 0.5 N aqueous sodium hydroxide solution and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/ethyl acetate) to obtain the title compound as a light-yellow, oily substance (7.18 g).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1ccc(COc2ccccc2)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(COc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-phenoxymethyl-pyridin-2-yl)-methanol described in Preparation Example 187 (167 mg, 0.776 mmol) in tetrahydrofuran (4 mL) were added phthalimide (126 mg, 0.856 mmol), triphenylphosphine (244 mg, 0.930 mmol) and diethyl azodicarboxylate (424 μL, 0.931 mmol, 40% toluene solution) at 0° C., and the solution was stirred at room temperature for 30 minutes. The reaction solution was partitioned with water and ethyl acetate. The organic layer was separated, washed with brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (heptane/ethyl acetate=1/1), and the title compound (383 mg, quantitatively) was obtained as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[CH:25]=[C:26]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CCc1cc(O)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(OC)cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Yield: 94.7 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (300 mg) in acetonitrile (10 mL) were added ethyl 3-(3-hydroxy-5-methoxyphenyl)propanoate (270 mg) and cesium carbonate (510 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (450 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:18](O)[CH3:19])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:18][CH2:19][Cl:23])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(O)N(Cc1ccc(Cl)cc1)Cc1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: ClCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)nc1

Procedure:
This compound was prepared in a manner analogous to that set forth in Step C of Example 1, using 6.0 grams (0.0193 mole) of 2-{[(6-chloro(3-pyridyl)methyl][(4-chlorophenyl)methyl]amino}ethan-1-ol, 2.4 grams (0.0203 mole) of thionyl chloride and four drops (catalyst) of pyridine in 75 mL of chloroform. The crude product was purified with column chromatography on silica gel. Elution was accomplished using 15% ethyl acetate in hexane then 30% ethyl acetate in hexane as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 5.7 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: O.NN.[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[CH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][NH:18]2.[OH-].[K+]>C(O)COCCO>[NH:18]1[C:19]2[C:15](=[C:14]([CH2:13][CH2:12][CH2:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[OH:4])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: O=C(CCc1cccc2[nH]ccc12)c1ccccc1O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Oc1ccccc1CCCc1cccc2[nH]ccc12
Temperature: 140 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
22.6 ml of hydrazine hydrate and then 11.6 g of 1-(2-hydroxyphenyl)-3-(1H-indol-4-yl)-1-propanone were slowly added with stirring to 50 ml of diethyleneglycol and then 20 ml of 78% potassium hydroxide were added thereto. The mixture was heated at 140° C. under an inert atmosphere for 30 minutes and the water and excess hydrazine hydrate were distilled at 210° C. with stirring over two hours and the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried, filtered and evaporated to dryness. The residue was chromatographed over silica and eluted with methylene chloride to obtain 8.613 g of 2-[3-(1H-indol-4-yl)-propyl]-phenol melting at ≅89° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:32])O[C:20](=[O:31])[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:9]1)(=[O:3])[CH3:2].C[Si](C)(C)[NH:35][Si](C)(C)C.CO>C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:32])[NH:35][C:20](=[O:31])[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1cc(C2=C(c3ccccc3[N+](=O)[O-])C(=O)OC2=O)c2ccccc21
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCCn1cc(C2=C(c3ccccc3[N+](=O)[O-])C(=O)NC2=O)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A solution of 0.411 g of 3-[1-(3-acetoxypropyl)-3-indolyl]-4-(2-nitrophenyl)furan-2,5-dione in 50 ml of chloroform was treated with a mixture of 1.53 g of 1,1,1,3,3,3-hexamethyldisilazane and 0.3 g of methanol and the mixture was heated at 60° C. for 1 hour. A further 1.53 g of hexamethyldisilazane and a further 0.3 g of methanol were added and the heating was continued overnight before adding further 1.53 g of hexamethyldisilazane and 0.3 g of methanol. The mixture was heated for a further 1 hour. The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with 5% methanol in dichloromethane to give 130 mg of 3-[1-(3-acetoxypropyl)-3-indolyl]-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione, m.p. 77°-78° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:14])[C:5]2[C:10]([C:11](=[O:13])[N:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:14][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:13])[N:12]=[C:3]1[CH2:2][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: Cn1c(CCl)nc(=O)c2ccccc21
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1c(COc2ccc(C=O)cc2)nc(=O)c2ccccc21
Yield: 62 %

Procedure:
The title compound (364 mg, 65%) was prepared from 2-chloromethyl-1-methyl-4-oxo-1,4-dihydroquinazoline (416 mg, 2.0 nmmol) and 4-hydroxybenzaldehyde (244 mg, 2.0 mmol) in the presence of K2CO3 (276 mg, 2.0 mmol) as base by a similar procedure to that described in preparation 13.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[C:4]([F:15])[CH:3]=1.[C:16]([CH:19]=[C:20]=[O:21])(=[O:18])[CH3:17]>CCOC(C)=O>[F:15][C:4]1[CH:3]=[C:2]([NH:1][C:20](=[O:21])[CH2:19][C:16](=[O:18])[CH3:17])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1=[O:14]
Reactant: Nc1ccc(N2CCOCC2=O)c(F)c1
Reactant: CC(=O)C=C=O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1ccc(N2CCOCC2=O)c(F)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 61.4 %

Procedure:
A mixture of 4-(4-amino-2-fluorophenyl)morpholin-3-one (2.51 g, 11.9 mmol) and acetyl ketene (2.51 g, 29.9 mmol) in EtOAc (40 mL) was stirred at 80° C. for 24 h. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:4) to give the title compound as a yellow solid (2.15 g, 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[S:38]([CH3:37])(=[O:40])=[O:39])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCNCc4ccccc4)cc3)cc2)CC1
Reactant: CS(=O)(=O)Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCN(Cc4ccccc4)S(C)(=O)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-{4′-[4-(2-benzylamino-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and methane sulfonyl chloride.
Reaction SMILES: [C:1]1([S:11]([O-:14])(=[O:13])=[O:12])[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([O-:10])(=[O:9])=[O:8])[CH:2]=1.[Na+:15].[Na+].[N+:17]([O-])([O-:19])=[O:18].[Na+]>S(=O)(=O)(O)O>[N+:17]([C:5]1[CH:6]=[C:1]([S:11]([O-:14])(=[O:13])=[O:12])[CH:2]=[C:3]([S:7]([O-:10])(=[O:9])=[O:8])[CH:4]=1)([O-:19])=[O:18].[Na+:15].[Na+:15]
Reactant: O=[N+]([O-])[O-]
Reactant: O=S(=O)([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c1

Procedure:
In accordance with the above flowchart, a disodium benzene-1,3-disulfonate (1) is treated with sodium nitrate in concentrated sulfuric acid at 65° C. for several hours producing disodium 5-nitrobenzene-1,3-disulfonate (2), which is then reacted with thionyl chloride in dimethylformamide at reflux with crystallization from a boiling mixture of chloroform and carbon tetrachloride to give 5-nitro-1,3-benzenedisulfonyl chloride (3).
Reaction SMILES: [S:1]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=O)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(Cl)(=O)C([Cl:26])=O>ClCCl.CN(C)C=O>[S:1]([NH:17][CH2:18][CH2:19][C:20]([Cl:26])=[O:22])([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: CN(C)c1cccc2c(S(=O)(=O)NCCC(=O)O)cccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)c1cccc2c(S(=O)(=O)NCCC(=O)Cl)cccc12
Temperature: 0 °C

Procedure:
970 mg(3 mmol) dansyl beta alanin were dissolved in 5 mL dried dichloromethane and stirred under argon flux at 0° C. Then 0.6 mL (6.6 mmol) oxalyl chloride was added drop wise at 0° C., and subsequently, a few drops of dried dimethylformamide were added which lead to gas development. The mixture was stirred at room temperature for 100 min. The solvents were removed by using a rotary evaporator and then the remainder was twice evaporated with dichloromethane. The crude product was used directly in the next step.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:19][C@H:20]([C:28]([NH2:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([NH:19][C@H:20]([C:28]([NH2:30])=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:14])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(N)=O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline was reacted with L-phenylalanine amide using the procedure described in Method 12 to yield N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide. To a solution of NaH (60% mineral oil—prewashed with THF) in THF at 0° C. was added N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide and the reaction was stirred at 0° C. for 45 minutes. Toluene-4-sulfonyl chloride was added and the reaction was stirred for 16 hours at room temperature. The reaction mixture was extracted with EtOAc (3×50 mL) and 0.2 N HCl (50 mL), and the combined organic layers were washed successively with sat. NaHCO3 (50 mL), and sat. NaCl (2×50 mL), dried over MgSO4, filtered, and concentrated to yield the title compound as an oil.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[CH3:10].I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:21])[CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:10]
Reactant: ICC1CCCC1
Reactant: CCOC(=O)Cc1cccc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 93.4 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of 0.31 M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3-chloro-phenyl)-acetic acid ethyl ester (1.28 g, 6.48 mmol) in tetrahydrofuran/hexamethylphosphoramide (16.1 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 g, 7.13 mmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.70 g, 93%) as a yellow oil: EI-HRMS m/e calcd for C16H21ClO2 (M+) 280.1230, found 280.1238.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5]2.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:15])[CH:21]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCn1ccc2cc(Br)ccc21
Reactant: OB(O)c1cccc(Cl)c1
Product: CCCCn1ccc2cc(-c3cccc(Cl)c3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-butyl-1H-indole (Step 1 of Example 29) and 3-chlorophenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (APCI, [M+H]+) m/z 284. 1HNMR (400 MHz, DMSO-d6): δ 7.85 (s, 1H), 7.69 (s, 1H), 7.63 (d, 1H, J=8.36 Hz), 7.55 (d, 1H, J=8.55 Hz), 7.47-7.41 (m, 3H), 7.34 (d, 1H, J=7.94 Hz), 6.48 (d, 1H, J=3.05 Hz), 4.19 (t, 2H, J=7.01 Hz), 1.73 (p, 2H, J=7.16 Hz), 1.25 (h, 2H, J=7.46 Hz), and 0.88 ppm (t, 3H, J=7.31 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH2:16][CH:15]=[CH2:14]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCOc1ccc(C(=O)O)cc1

Procedure:
The reaction of ethyl 4-hydroxybenzoate and 4-bromo-1-butene in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 4-But-3-enyloxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.57 (s, —CO2H); 7.89 (d, J=6.9, 2 arom. H); 7.00 (d, J=6.9, 2 arom. H); 5.86 (m, —CH═CH2); 5.19, 5.08 (2 d-like, CH═CH2); 4.00 (t, J=6.6, OCH2—CH2—CH═CH2); 2.50 (m, OCH2—CH2—CH═CH2). 13C-NMR (100 MHz, d6-DMSO): 166.95 (—C═O); 162.08; 134.66; 131.32 (2 arom. C); 122.92; 117.14; 114.22 (2 arom. C); 66.92; 32.90.