Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=2)=[CH:5][C:4]=1[NH2:19].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=2)=[CH:5][C:4]=1[NH:19][S:27]([CH3:26])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1noc(C=Cc2ccc(OC)c(N)c2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1noc(C=Cc2ccc(OC)c(NS(C)(=O)=O)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methoxy-5-[2-(3-propyl-[1,2,4]oxadiazol-5-yl)-vinyl]-phenylamine (compound of Example 8; 0.08 g, 3.08 mmol) was dissolved in dichloromethane (10 mL) followed by addition of pyridine (0.047 mL, 0.60 mmol) and methanesulfonyl chloride (0.034 mL, 0.45 mmol) at room temperature. After stirring for 8 h, dichloromethane was evaporated and the reaction mixture was cooled to room temperature. The crude residue obtained was purified by column chromatography (silica gel, petroleum ether) to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.C(=O)([O-])[O-:23].[Na+].[Na+]>S(=O)(=O)(O)O>[F:21][C:2]([F:1])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][C:17]([NH2:18])=[O:23])[N:8]=1
Reactant: O=C([O-])[O-]
Reactant: N#CCCSCc1nccc(NC(N)=NCC(F)(F)F)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)CCSCc1nccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A solution of 3-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]propionitrile (850 mg.) in concentrated sulphuric acid (4 ml.) was kept at 20° for 16 hours then added dropwise to saturated aqueous sodium carbonate. The mixture was extracted with EtOAc (3×20 ml.) and the extract dried (MgSO4) and evaporated in vacuo to give 3-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]propionamide as an oil. The maleic acid salt was prepared in acetone (yield 720 mg; 60%), m.p. 168°-169° (decomp.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[C:24]([F:32])[CH:23]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.CO.[OH-].[Li+]>C1COCC1>[NH2:1][C:2]1[C:3]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:32])[CH:23]=2)=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCC(NC(=O)OC(C)(C)C)CC3)cnc2N)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To methyl 4-(3-amino-6-(4-((tert-butoxycarbonyl)amino)cyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (230 mg, 0.517 mmol) was added MeOH (2 mL), THF (2 mL) and then lithium hydroxide 1M aqueous solution (1.552 mL, 1.552 mmol). The reaction was stirred at room temperature for 1 h. The solvent was concentrated to residue, then THF (20 mL) was added and concentrated to residue. Then THF (20 mL) was added again and re-concentrated to residue to constant mass to give the desired product (which is 2:1 trans to cis ratio), used as is. Assume quantitative yield (0.517 mmol). LCMS (m/z): 431.2 (MH+), 0.78 min for both.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:21])([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:20].[Cl:20][C:19]1[C:14]([C:11]2([F:21])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ncccc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC1(c2ncccc2Cl)CCNCC1
Reaction time: 0.5 h
Yield: 194.2 %

Procedure:
3-Chloro-4′-fluoro-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.13 g, 0.41 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 2 mL). The mixture was stirred for 30 minutes and the solvent removed by evaporation under vacuum. The solid was triturated from ether to afford the title compound (0.10 g). LCMS m/z 215.28 [M+H]+. R.T.=1.87 min (Analytical Method 3).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][O-])=[O:5])[CH3:2].[K+].[Br-].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH:18]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:17][C:16]2=O.C(Cl)Cl.O.[NH2:46][NH2:47]>C(O)C>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][CH2:7][C:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH3:11])=[CH:21][CH:20]=2)[C:16](=[O:17])[NH:47][N:46]=1)[CH3:2]
Reactant: NN
Reactant: COc1ccc2c(c1)C(=O)OC2[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=C[O-]
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCc1n[nH]c(=O)c2cc(OC)ccc12
Yield: 37.6 %

Procedure:
Operating analogously to what described in example 113 starting from potassium 2-ethoxycarbonyl-ethenolate (771 mg, 5 mmoles), (5-methoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-triphenyl-phosphonium bromide (2.53 g, 5 mmoles), prepared as described in example 36, CH2Cl2 (20 ml) and hydrazine monohydrate (250 mg, 5 mmoles) in ethanol (20 ml), 0.52 g of the title compound were obtained.
Reaction SMILES: C=O.[OH-].[Na+].[C:5]([Si:9]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:10][CH:11]1[CH:15]([CH:16]=[O:17])[O:14][CH:13]([N:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH:12]1[O:26]C(=O)C)([CH3:8])([CH3:7])[CH3:6].[C:42](O)(=[O:44])C>O1CCOCC1>[C:5]([Si:9]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:10][CH:11]1[C:15]([CH2:42][OH:44])([CH2:16][OH:17])[O:14][CH:13]([N:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH:12]1[OH:26])([CH3:7])([CH3:6])[CH3:8]
Reactant: CC(=O)OC1C(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(C=O)OC1n1ccc(=O)[nH]c1=O
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)[Si](OC1C(O)C(n2ccc(=O)[nH]c2=O)OC1(CO)CO)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Hydroxymethylation of the 5′-aldehyde is performed as per the method of Cannizzaro which is well documented in the literature (Jones, G. H., et. al., J. Org. Chem. 1979, 44, 1309-1317). These conditions are expected to additionally remove the 2′-O-acetyl group. Generally, Briefly, formaldehyde (2.0 eq., 37% aq.) and NaOH (1.2 eq., 2 M) is added to a solution of Compound 10 in 1,4-dioxane. After stirring at room temperature for several hours, this mixture is neutralized with acetic acid, evaporated to dryness, suspended in methanol, and evaporated onto silica gel. The resulting mixture is added to the top of a silica gel column and eluted using an appropriate solvent system to give Compound 11.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][CH3:16])[C:3]=1[C:4]#[N:5].[S:17](Cl)(=[O:20])(=[O:19])[NH2:18]>>[S:17]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][CH3:16])[C:3]=1[C:4]#[N:5])(=[O:20])(=[O:19])[NH2:18]
Reactant: CSCCCCOc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Product: CSCCCCOc1cccc(NS(N)(=O)=O)c1C#N
Yield: 66 %

Procedure:
Prepared as in Example 197a from 2-amino-6-(4-(methylthio)-butoxy)benzonitrile (Example 233b) and sulfamoyl chloride in 66% yield. MS 316 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C@H:3]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(C(C)C)C(C)C.Cl.[CH3:31][C:32]1[CH:41]=[C:40]([CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=2)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1>CN(C)C=O>[CH3:31][C:32]1[CH:41]=[C:40]([CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47]([S:50]([NH:1][C@H:2]3[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C@H:3]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=[O:52])=[O:51])=[CH:46][CH:45]=2)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To the stirred solution of 687 mg (2.4 mol) of di-tert-butyl cis-4-aminopyrrolidine-1,3-dicarboxylate (prepared according to J. Med. Chem. 2001, 44, 1192-1201) was added 2.1 mL of Hunig's base in 10 mL of N,N-dimethylformamide and 922 mg of 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride. The solution was stirred at room temperature overnight. The N,N-dimethylformamide was removed in vacuo, and the residue was dissolved in 100 mL of chloroform. The chloroform solution was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified using flash chromatography on silica gel eluting with ethyl acetate/hexane to provide 929 mg (65% yield) of di-tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-1,3-dicarboxylate. MS: 598.4 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][S:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)(=[O:34])=[O:33])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: O=S(=O)(Cl)c1ccccn1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNS(=O)(=O)c2ccccn2)no1

Procedure:
Method same as for preparation 10 using tert-butyl (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (210 mg, 057 mmol) and 2-pyridinesulphonylchloride (J. Med. Chem; 1997, 40, 1149) (170 mg, 0.96 mmol) as starting materials.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Br:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:14])=[CH:15][CH:16]=2)[N:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(Cn2nccc2Br)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(c1ccc(Cn2nccc2Br)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
4-((5-bromo-1H-pyrazol-1-yl)methyl)benzoic acid (200 mg, 0.71 mmol), pyrrolidine (61 mg, 0.85 mmol) and EDC-HOBt (452 mg, 2 mmol) were combined in CH2Cl2 and stirred for 4 h at room temperature. The mixture was evaporated in vacuuo and the residue dissolved in ethyl acetate and washed with water. The separated organic layer was dried and concentrated affording the product as an oil (231 mg, yield 99%), which was used in next step without further purification. LCMS (m/z): 334.2 [M+H]+
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]=[C:10]([OH:16])[CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(F)c2c(c1)CCC(=O)N2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1cc(F)c2nc(O)ccc2c1
Yield: 77.3 %

Procedure:
To a solution of 8-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl acetate (718 mg) in toluene (8 mL) was added DDQ (1.2 g). The resultant solution was heated at 70° C. over 48 h. After aqueous work-up with EtOAc, the crude product was purified by a flash silica column chromatography to afford the pure product (550 mg) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:21][O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:2]=2[O:1][CH2:4][CH:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:2]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCCC2)cc1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Product: O=C(OCC1CCCCC1)c1ccc(C(F)(F)F)cc1OCC1CCCCC1
Yield: 198.2 %

Procedure:
2-Hydroxy-4-trifluoromethyl-benzoic acid (246 mg, 1.19 mmol) was reacted with toluene-4-sulfonic acid cyclohexylmethyl ester (640 mg, 2.34 mmol) as described above to give the title compound (470 mg, 99%) after purification by column chromatography.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[C:9]([CH3:15])[C:8]=1[CH3:16].Cl[C:18]1[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=1>CN(C)C=O>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][C:18]2[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH:23]=2)=[C:9]([CH3:15])[C:8]=1[CH3:16]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COCOc1c(C)cc(O)c(C)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1c(C)cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c(C)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
6.11 g of sodium hydride (55% by weight) were suspended in 300 ml of N,N-dimethylformamide, followed by the addition of 27.5 g of 4-methoxymethoxy-2,3,5-trimethylphenol. The resulting mixture was stirred at room temperature for one hour. To the reaction mixture, 40.1 g of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate were added in small portions and the mixture was stirred at 120° C. for 2 hours. The reaction mixture was concentrated by evaporation. Water was added to the concentrate, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography through a silica gel column (eluting solvent: n-hexane/ethyl acetate=5/1), whereby 57.0 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:13]=2)[N:8]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:7]=1[CH2:36][C:37]([O:39]CC)=[O:38])=[O:5])[CH3:2].[OH-].[Na+]>CCO>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)[CH:13]=2)[N:8]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=2)[C:7]=1[CH2:36][C:37]([OH:39])=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc12

Procedure:
The title compound was prepared in accordance with step (d) Example 2 from 2-ethoxycarbonylmethyl-1-(4-isopropoxyphenyl)-5-(4-trifluoromethylphenoxy)indole-3-carboxylic acid ethyl ester (265 mg, 0.47 mmol; see step (c) above), NaOH (aq, 2 M, 2.5 mL) and EtOH (15 mL). Yield 176 mg (70%), mp 158° C.
Reaction SMILES: CC(C)=O.[OH:5][CH2:6][CH:7]([CH2:9][OH:10])[OH:8].[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.S(=O)(=O)(O)O.C(N(CC)CC)C>[CH2:13]([O:5][CH2:6][CH:7]([OH:8])[CH2:9][OH:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: OCC(O)COCc1ccccc1
Reaction time: 3 h
Yield: 84 %

Procedure:
Into a mixed solution of acetone (800 ml) and glycerin (199 g, 2.16 mol) was added 98% sulfuric acid (6.9 g) at about 25° C., and the mixture was stirred for 3 hours. To this reaction solution was added triethylamine (18.0 g), and the solvent was distilled off under reduced pressure. Into a solution prepared by suspending sodium hydroxide (98.5 g) in toluene (526 ml) was dropped the above-described concentration residue at 55 to 75° C. Into this reaction solution, benzyl chloride (229 g, 1.81 mol) was dropped at 95 to 105%, and the mixture was reacted for 5 hours while distilling components of lower boiling points off. After completion of the reaction, water (366 ml) was added, and the liquid was partitioned. To the resultant toluene layer was added 98% sulfuric acid (22.9 g) and water (571 ml), and the mixture was stirred at about 50° C. for 5 hours stirred, then, the toluene layer was concentrated under reduced pressure. To the residue was added heptane (267 ml), methanol (534 ml) and water (267 ml), and the mixture was liquid-partitioned. The aqueous layer was liquid-partitioned by further adding heptane (267 ml), and the resulting aqueous layer was concentrated under reduced pressure to remove methanol. To the concentrated liquid was added sodium chloride (46 g), and the mixture was extracted twice with ethyl acetate (267 ml). The resultant ethyl acetate solution was concentrated under reduced pressure to obtain a title compound (277 g, yield 84%).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([OH:23])[CH2:20][NH:21][CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)(Cl)Cl.[C:28](Cl)(=[O:30])[CH3:29]>C(N(CC)CC)C>[C:28]([N:21]([CH3:22])[CH2:20][CH:19]([OH:23])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCOCC(O)CNC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOCC(O)CN(C)C(C)=O
Reaction time: 8 h

Procedure:
5 g of 1-hexadecyloxy-3-methylamino-propan-2-ol are dissolved in 30 cc. of anhydrous chloroform. At first 3 g of triethylamine and separately thereafter 2.4 g of acetylchloride are added dropwise with cooling and the mixture is stirred for 8 hours. The chloroform solution is washed with 2% hydrochloric acid and water, is evaporated and the residue is dissolved in 100 cc. of methanol. A solution of 0.6 g of sodium hydroxide in a little methanol is added to the methanol solution and the mixture is stirred at room temperature for one hour. The solvent is evaporated in a vacuo and the residue is triturated in chloroform. The chloroform solution is washed with 2% hydrochloric acid and water, is dried over sodium sulfate and is evaporated.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:41]([NH:43][CH3:44])[CH3:42])[CH:38]=[CH:39][CH:40]=1>ClCCl>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([N:43]([CH3:44])[CH:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=2)[CH3:42])=[O:8])[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(C(OC(C)=O)C(=O)O)cc(OC)c1OC
Reactant: CNC(C)c1cccc(OC)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1cccc(C(C)N(C)C(=O)C(OC(C)=O)c2cc(OC)c(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
A solution of α-acetoxy-3,4,5-trimethoxyphenyl-acetic acid (7.1 g) in dichloromethane (50 ml) was reacted with 1,1′-carbonyldiimidazole (4.06 g) at room temperature for 30 minutes. The solution was refluxed for 30 minutes, after which 1-(3-methoxyphenyl)-N-methylethylamine (4.13 g) dissolved in dichloromethane (10 ml) was added. The mixture was stirred at room temperature for 2 hours, after which it was washed with aqueous hydrochloric acid (20 ml, 1M) followed by aqueous sodium hydrogen carbonate (20 ml, 0.5 M). The organic phase was dried and concentrated to dryness, leaving crude 2-(3,4,5-trimethoxyphenyl)-2-acetoxy-N-methyl-N-[1-(3-methoxyphenyl)ethyl]acetamide (7.27 g).
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17]>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:11]([NH:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])=[O:12])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NS(=O)(=O)c1ccccc1
Yield: 83.5 %

Procedure:
The title compound was prepared in 83.5% yield from benzenesulfonyl isocyanate and 3,4-dichloroaniline following the procedure of Example 1, m.p. 194°-195° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(SCCCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(SCCCCOCc2ccccc2)cc1

Procedure:
A mixture of 4-(4-nitrophenylthio)-1-butanol (10 mmol) and potassium carbonate (20 mmol) in acetone (100 mL) is treated with a solution of benzylbromide (11 mmol) in acetone (50 mL). When the addition is completed the mixture is heated at reflux temperature for 18 hrs, cooled, filtered, and the filtrate is concentrated to obtain the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([S:20]([F:25])([F:24])([F:23])([F:22])[F:21])[CH:13]=1.[OH2:26].NN>C(O)C>[NH2:3][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([S:20]([F:25])([F:21])([F:22])([F:23])[F:24])[CH:13]=1.[C:16]([C:15]1[CH:18]=[CH:19][C:12]([NH:3][C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O-:26])=[O:11])=[CH:13][C:14]=1[S:20]([F:21])([F:22])([F:25])([F:23])[F:24])#[N:17]
Reactant: N#Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1S(F)(F)(F)(F)F
Reactant: O
Agent: NN
Solvent: CCO
Product: N#Cc1ccc(N)cc1S(F)(F)(F)(F)F
Product: N#Cc1ccc(NC(=O)c2ccccc2C(=O)[O-])cc1S(F)(F)(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
610 mg (1.63 mmol) of 4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-pentafluorosulfanylbenzonitrile (prepared in example 6) were dissolved in 30 ml of ethanol and admixed with 100 mg (1.956 mmol) of hydrazine hydrate (100%). The mixture was stirred at room temperature overnight. Afterward, the reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography (preparative HPLC; Purospher STAR RP-18e (10 μm); eluent: 5/95→95/5 [45 min.] acetonitrile/water (0.5% trifluoroacetic acid)). 4-Amino-2-pentafluorosulfanylbenzonitrile (1H NMR (500 MHz; d6-dmso) δ [ppm]=7.65 (s, 1H); 7.2 (s, 1H, 6.8 (m, 3H)) and N-(4-cyano-3-pentafluorosulfanylphenyl)phthalamate (1H NMR (500 MHz; d6-dmso) δ [ppm]=11.3 (s, 1H); 8.6 (s, 1H); 8.2 (d, 1H); 8.1 (d, 1H); 7.95 (d, 1H); 7.75 (m, 1H); 7.7 (m, 2H); 4.2 (q, 2H); 1.15 (t, 3H)) were obtained.