Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.Cl.C(OC([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH:38][C:39]([NH:41][CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:40])[CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[CH:27][N:26]=1)=[O:24])=O)(C)(C)C.C(=O)([O-])O.[Na+]>CO>[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH:38][C:39]([NH:41][CH2:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:40])[CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[CH:27][N:26]=1)=[O:24]
Reactant: CN(C)CCCC(NC(=O)NCCc1ccccc1)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)CCCC(NC(=O)NCCc1ccccc1)c1ccc(C(=O)Nc2ccccc2N)nc1
Yield: 84 %

Procedure:
4.0 M hydrogen chloride-ethyl acetate solution (1.0 mL) was added to a solution of N-(2-t-butoxycarbonylaminophenyl)-5-[1-(3-dimethylaminopropyl)-3-phenethylureidomethyl]pyridine-2-carboxylic acid amide (Reference Compound No. 6-1, 31 mg, 0.060 mmol) in methanol (2.0 mL), and then the reaction mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution (30 mL) was added thereto, and then the whole was extracted with ethyl acetate (30 mL) three times. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 24 mg of the title compound as a yellow amorphous product. (Yield 84%)
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[S:10])[O:4][N:3]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[C:25]1([S:31]([O:1][C:2]2[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[S:10])[O:4][N:3]=2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Oc1cc(CCC(=S)OC(c2ccccc2)c2ccccc2)on1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1cc(CCC(=S)OC(c2ccccc2)c2ccccc2)on1)c1ccccc1

Procedure:
This benzhydryl 3-hydroxyisoxazol-5-ylmethylthioacetate was reacted with benzenesulphonyl chloride in the presence of triethylamine to give benzhydryl 3-benzenesulphonyloxyisoxazol-5-ylmethylthioacetate, which was treated with trifluoroacetic acid to afford the title compound as crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1I.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([O:24][CH3:25])[CH:16]=1>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][C:17]=1[O:24][CH3:25]
Reactant: COc1cc(F)ccc1B(O)O
Reactant: COC(=O)CNc1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CNc1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-ylamino)-acetic acid methyl ester and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow oil (73%). MS (ESI): m/z=291.113 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[N+:20]([O-:22])=[O:21])[C:13](OC)=[O:14])=[CH:4][CH:3]=1.[NH3:24]>CO>[N+:20]([C:19]1[CH:18]=[CH:17][C:12]([C:13]([NH2:24])=[O:14])=[CH:11][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:23])([O-:22])=[O:21]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cc2)c1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cc2)c1
Temperature: 80 °C
Yield: 22.8 %

Procedure:
Methyl N-(4-chlorophenyl)-4-nitroisophthalamate (220 mg) obtained in step A was dissolved in 10 mL of a methanol solution of 7 mols of ammonia. After the reactor was sealed, the solution was heated for 36 hours at 80° C. with stirring. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The resulting solid was dried under reduced pressure to obtain 48 mg (23%) of 4-nitro-3-N-(4-chlorophenyl)-isophthalamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:22][Si](C)(C)C)([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.CO.[OH-].[Na+]>O>[CH:5]1[C:6]([F:8])=[CH:7][C:2]([F:1])=[C:3]([C:9]([OH:22])([CH2:10][N:11]2[N:12]=[CH:13][N:14]=[CH:15]2)[CH2:16][N:17]2[N:18]=[CH:19][N:20]=[CH:21]2)[CH:4]=1
Reactant: C[Si](C)(C)OC(Cn1cncn1)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(Cn1cncn1)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A mixture of 7.5 g (0.02 mol) of 2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazole-1-yl)-2-(trimethylsilyloxy)propane, 40 ml of methanol, 3 ml of water and 0.1 g of sodium hydroxide was stirred at room temperature for 1 h. After adding 300 ml of water the solution was concentrated to a volume of 50 ml with vacuum distillation. The obtained suspension was cooled to 0° C. and filtered. The obtained product was 6.12 g, water content was 11.5%. After drying at 80° C. 5.35 g of title compound was obtained. Yield: 87.4%. Mp.: 139–141° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].[NH2:27][CH:28]([CH:32]1[CH2:34][CH2:33]1)[CH2:29][CH2:30][OH:31]>>[CH:32]1([CH:28]([NH:27][C:24]([C:7]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:21])[F:23])[CH:14]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)=[O:26])[CH2:29][CH2:30][OH:31])[CH2:34][CH2:33]1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: NC(CCO)C1CC1
Product: N#Cc1ccc2c(c1)cc(C(=O)NC(CCO)C1CC1)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 3-amino-3-cyclopropylpropan-1-ol in a manner similar to that described in Example 11.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:25])[C@@H:14]([NH2:24])[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:25])[C@@H:14]([NH:24][C:35](=[O:37])[CH3:36])[CH2:15][C:16]2[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=2)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)COC1(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Dissolve (R)-4-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (920 mg, 2.38 mmol) in dry tetrahydrofuran (20 ml) under an atmosphere of nitrogen. Add to the resulting solution triethylamine (400 μl, 2.87 mmol) and acetic anhydride (235 μL, 2.49 mmol). After 1 hour, dilute with ethyl acetate and wash with water (twice), 0.1 N hydrochloric acid, and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography 0:100 to 70:30 ethyl acetate:hexanes) to give the desired compound as a white solid (738 mg, 72% yield).
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:26]2[CH2:38][CH2:37][C:36]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([Cl:39])[CH:34]=4)[NH:29][C:28]=3[CH2:27]2)([F:25])[C:11]([N:13]([CH2:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=[O:20])[CH3:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.C1COCC1>C1COCC1>[C:1]1([S:7]([C:10]([CH:26]2[CH2:38][CH2:37][C:36]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([Cl:39])[CH:34]=4)[NH:29][C:28]=3[CH2:27]2)([F:25])[C:11]([N:13]([CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:18]([CH2:19][OH:20])[CH:17]=2)[CH3:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(Cc1cccc(C(=O)O)c1)C(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Agent: B
Solvent: C1CCOC1
Product: CN(Cc1cccc(CO)c1)C(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Yield: 84.2 %

Procedure:
To 61 mg (0.107 mmol) of (RS,SR)-3-({[2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-acetyl]-methyl-amino}-methyl)-benzoic acid (from example 73) in 3 mL of THF at 0° C., 160 μL (0.107 mmol, 1 eq) of BH3.THF (1M in THF) were added, and the reaction mixture stirred for an additional hour, and then partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with EtOAc/heptane 2:1 yielded 50 mg (84%) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N-(3-hydroxymethyl-benzyl)-N-methyl-acetamide as a white solid, MS: 555 (M).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].[Si:18]([O:25][CH2:26][CH:27]1[C:31]([CH2:32]Br)=[CH:30][CH2:29][CH2:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Si:18]([O:25][CH2:26][CH:27]1[C:31]([CH2:32][N:7]2[C:8]([S:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:17])[NH:5][C:6]2=[O:16])=[CH:30][CH2:29][CH2:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC=C1CBr
Reactant: CCc1c(Sc2ccccc2)[nH]c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(Sc2ccccc2)n(CC2=CCCC2CO[Si](C)(C)C(C)(C)C)c(=O)[nH]c1=O

Procedure:
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione (0.16 g, 0.66 mmol) and (5-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide (0.20 g, 0.66 mmol) in dimethylformamide (10 ml) were heated at 50° C. for overnight in the presence of sodium bicarbonate (66 mg, 0.79 mmol). After the concentration of dimethylformamide, [(5-t-butyldimethylsilyloxymethyl cyclopent-1-en-1-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidinedione was obtained by the separation of the column chromatography. And then, this compound in THF (10 ml) was reacted with n-tetrabutylammoniumfluoride at room temperature for 1 hr. After the concentration of THF, the residue was separated by column chromatography to give a desirable product (35 mg).
Reaction SMILES: [Br:1][CH2:2]/[C:3](/[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[CH:4]/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11]>C(O)C>[Br:1][CH2:2]/[C:3](/[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11]
Reactant: Fc1ccc(/C(=C\c2ccccc2Cl)CBr)cc1
Solvent: CCO
Product: Fc1ccc(/C(=C/c2ccccc2Cl)CBr)cc1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
77.2 g of E-1-bromo-2-(4-fluorophenyl)-3-(2-chlorophenyl)-prop-2-ene are heated at 180° C. for one hour. The reaction mixture is cooled to room temperature and 200 ml of ethanol are added. Thereafter, 10 g of active carbon are added and the mixture is heated to 50° C. and filtered while hot. 26.9 g (35%) of Z-1-bromo-2-(4-fluorophenyl)-3-(2-chlorophenyl)-prop-2-ene of melting point 73°-75° C. are obtained from ethanol.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH2:24]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27]>>[CH2:24]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:2]([CH2:3][C:4]2[CH:5]=[C:6]([C:10]3[CH:11]=[CH:12][C:13]([CH2:16][CH:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:14][CH:15]=3)[CH:7]=[CH:8][CH:9]=2)[CH3:1])=[O:34])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Product: CCCCOc1ccc(C(=O)N(C)Cc2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 500 mg (1.5 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione with 290 μl (1.5 mmol) of 4-butoxybenzoyl chloride, and after purification, 550 mg (83%) of 4-20 butoxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzamide are obtained in the form of a white solid with a melting point of 116° C.
Reaction SMILES: [F-].[Cs+].[Cl:3][C:4]1[C:9]([CH:10]=[O:11])=[C:8]([F:12])[C:7]([Si](C)(C)C)=[C:6]([F:17])[CH:5]=1>CN(C)C=O.CCCCCCC.O>[Cl:3][C:4]1[CH:5]=[C:6]([F:17])[CH:7]=[C:8]([F:12])[C:9]=1[CH:10]=[O:11]
Reactant: C[Si](C)(C)c1c(F)cc(Cl)c(C=O)c1F
Agent: [Cs+]
Agent: [F-]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(F)cc(F)cc1Cl
Reaction time: 0.17 h
Yield: 40.5 %

Procedure:
CsF (approximately 0.2 g) was added to a mixture of crude 6-chloro-2,4-difluoro-3-(trimethylsilyl)benzaldehyde (10.5 g, approximately 42 mmol) in dimethylformamide (15 mL)/H2O (2 mL). After stirring for 10 min the reaction was diluted with heptane and H2O. The phases were separated and the aqueous extracted with further heptane. The combined organic layers were washed with H2O, dried over MgSO4 and concentrated in vacuo to a yellow oil. Purification by column chromatography (1:4 EtOAc:heptane) followed by trituration with pentane gave the title compound as a white solid (3.0 g, 17.0 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:21])[CH:9]([CH3:20])[CH2:10][N:11](C)[C:12](=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:21])[CH:9]([CH3:20])[CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(CN(C)C(=O)OC(C)(C)C)C(=O)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNCC(C)C(O)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 46.3 %

Procedure:
A solution of tert-butyl 3-(3-chlorophenyl)-2-methyl-3-oxopropyl(methyl)carbamate (2.8 g, 9.4 mmol) in THF (20 mL) was added slowly to a suspension of LAH (537 mg, 14.1 mmol) in THF (10 mL). The mixture was then stirred at 50° C. for 4 h. The mixture was cooled to 0° C. and 4 g of ice was added into the reaction. The mixture was stirred for 30 min at room temperature, diluted with ethyl acetate, dried over Na2SO4, filtered and concentrated to give the crude product. The residue was purified by chromatography to obtain pure 1-(3-chlorophenyl)-2-methyl-3-(methylamino)propan-1-ol (930 mg, 32%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:28][CH2:29][CH2:30]C.C(I)CC>C1COCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:13]([CH2:28][CH2:29][CH3:30])=[CH:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCI
Product: CCCc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
To a solution of 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-1H-indole (1.6 g, 4.4 mmol, synthesized as described in Example 22A) in THF (10 mL), under N2, at −78° C., was added n-BuLi (2.5 M solution in hexanes, 2.15 mL, 5.37 mmol) dropwise. After stirring at −78° C. for 30 min, propyl iodide (1.1 g, 6.6 mmol) was added. After 30 min, the −78° C. bath was removed. The solution was warmed to rt. 5% HCl (10 mL) was then added and the mixture was partitioned between EtOAc and water. The organic phase was washed with water and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (20-70% EtOAc-hexanes gradient) to afford the title compound (0.79 g, 71% yield): MS (ES) m/z 406 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:17]1([C:23]2[O:27][N:26]=[CH:25][C:24]=2[CH2:28][CH2:29][C:30](O)=[O:31])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][C:24]2[CH:25]=[N:26][O:27][C:23]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (1.25 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (1.00 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.80 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.08 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-3-(5-phenyl-4-isoxazolyl)propionamide (1.89 g, yield 93%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 139–140° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[CH3:6][C:7]1[C:12]([CH3:13])=[C:11]([N+]([O-])=O)[CH:10]=[CH:9][N:8]=1.CCOCC>C(OC(=O)C)(=O)C>[C:1]([O:4][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:6])[C:12]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: Cc1nccc([N+](=O)[O-])c1C
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)Oc1ccnc(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
Anhydrous potassium acetate (49 g, 0.5 mol) was added to a solution of 2,3-dimethyl-4-nitropyridine (45.6 g, 0.3 mol) prepared in Step 2 in 300 ml of acetic anhydride and then refluxed under stirring for 16 hours. The reaction mixture was cooled to room temperature and then 400 ml of anhydrous ether was added thereto. The reaction mixture was stirred for 1 hour, filtered with Celite, and then concentrated under reduced pressure to give 4-acetoxy-2,3-dimethylpyridine (45 g, 91%). The resulting residue was added to 250 ml of water, refluxed under stirring for 4 hours, and then left overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give 32.6 g of 2,3-dimethyl-4-hydroxypyridine as a liquid form. The liquid product was dissolved in 120 ml of concentrated sulfuric acid and heated to 60° C. A mixture of 90% nitric acid (40 ml) and sulfuric acid (30 ml) was slowly added to the reaction mixture for 45 minutes, while maintaining the temperature at 60-65° C. The reaction mixture was heated for 2 hours at 65° C. and then for 30 minutes at 75° C. The reaction mixture was cooled to room temperature and then added to ice water. The resulting solution was brought to pH 5˜6 with ammonium hydroxide to give a pale yellow solid. The resulting solid was filtered, washed with cold water, and then dried at 80˜90° C. to give 34.5 g of the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[N:8]=1)[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH:20][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:7]1[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 72.8 %

Procedure:
A solution of (±) cis-2-ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (1.0 g, 0.005 mol) in dry toluene (20 ml) was treated with 3,4-dichloroaniline (0.81 g, 0.005 mol) and a catalytic amount of p-toluenesulfonic acid (5 ml of an anhydrous 0.1M solution of p-toluenesulfonic acid in benzene). The mixture was heated under nitrogen at 60° C. for 3 h. The reaction was worked up as described in Preparation 5. Purification on a silica gel column using 1% ethanol in chloroform as eluant afforded the title compound as a solid (1.33 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[CH:19]=[CH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C1COCC1.O.[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:28][CH:29]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C=Cc2cc(Cl)ccc2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCc2cc(Cl)ccc2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 84.8 %

Procedure:
To a solution of 4-[2-[2-(4-chlorophenyl)sulfonylamino-5-chlorophenyl]vinyl]benzoic acid (54 mg; prepared in Example 5.) in THF (4 ml), platinum oxide hydrate (3 mg) was added. The mixture was stirred for 2 hours at room temperature in a stream of hydrogen. The reaction mixture was filtered and the filtrate was concentrated under the reduced pressure. To the residue, methylene chloride was added. The mixture was stirred. The precipitate was collected by filter to give the title compound (46 mg) having the following physical data.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[CH2:9]([O:11][C:12]([C:14]1[C:15](Cl)=[N:16][C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][C:20]([Cl:30])=[CH:19][CH:18]=2)=[O:13])[CH3:10]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1[C:15]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[N:16][C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][C:20]([Cl:30])=[CH:19][CH:18]=2)=[O:13])[CH3:10]
Reactant: O=C1CCCN1
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(N2CCCC2=O)nc2ccc(Cl)cc2c1-c1ccccc1
Reaction time: 0.5 h
Yield: 6.5 %

Procedure:
To a solution of pyrrolidin-2-one (0.054 ml, 0.69 mmol) in THF in a microwave vessel under nitrogen, was added NaH (28 mg, 0.69 mmol) portion wise at 25° C. The reaction mixture was stirred for 30 min followed by the addition of a solution of 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B, 200 mg, 0.58 mmol) in 2 ml THF at 25° C. Then the resulting reaction mixture was stirred for 1 h at 60° C. in a microwave. After cooling, reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude residue which was purified by flash column chromatography (eluting with 20% ethyl acetate in hexane) to obtain 6-chloro-2-(2-oxo-pyrrolidin-1-yl)-4-phenyl-quinoline-3-carboxylic acid ethyl ester (15 mg, 7%) as an off white solid. LC-MS: 395 (M+H)+.