Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.N#N.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([NH:36][C@H:37]([C:45](Cl)=[O:46])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:44])[NH2:43])(=[O:35])=[O:34])[CH:27]=[CH:26]2>C(Cl)(Cl)Cl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([NH:36][C@H:37]([C:45]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:46])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:43])[NH2:44])(=[O:35])=[O:34])[CH:27]=[CH:26]2
Reactant: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)ccc2c1
Reactant: CCOC(=O)C1CCCCN1
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCCN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2.2 g of ethyl 2-piperidinecarboxylate and 4.1 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 500 ml of chloroform was added and the chloroform solution was washed twice with 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ethyl ether to give 2.9 g of powdery ethyl 1-[N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl]-2-piperidinecarboxylate. For analysis of the product, a portion of the product was converted to the flavinanate, M.P. 192°-3° C. I.R. (KBr): 3,210, 1,747, 1638 cm-1
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([O:22][CH:23]([CH3:25])[CH3:24])[CH2:21][CH2:20]3)=[C:15]([CH3:26])[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH:23]([O:22][C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:27])=[O:2])=[CH:6][CH:7]=3)=[CH:14][C:15]=2[CH3:26])[CH2:21][CH2:20]1)([CH3:25])[CH3:24]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OC(C)C)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1C1(OC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
Using General Procedure I; a solution of methyl{4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate (Compound 84, 100.0 mg, 0.28 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 60.0 mg (62%) of the title compound as a colorless solid.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=1[CH3:24])C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:16]1[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: Cc1c(O)ccc(F)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(O)ccc(F)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-(6-fluoro-3-hydroxy-2-methyl-phenyl)carbamate (500 mg, 1.46 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL). The reaction was stirred at room temperature overnight, then the solvent was removed in vacuo, to give the title compound as yellow oil (200 mg, 97%).
Reaction SMILES: [OH:1][C:2]([C:4]1[C:5]2[O:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[C:14](=[O:23])[C:6]=2[N:7]([CH3:13])[C:8]=1[CH2:9][C:10]([OH:12])=[O:11])=[O:3].Cl.[CH2:25](O)[CH3:26]>>[OH:3][C:2]([C:4]1[C:5]2[O:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[C:14](=[O:23])[C:6]=2[N:7]([CH3:13])[C:8]=1[CH2:9][C:10]([O:12][CH2:25][CH3:26])=[O:11])=[O:1]
Reactant: CCO
Reactant: Cn1c(CC(=O)O)c(C(=O)O)c2c1C(=O)c1ccccc1CO2
Agent: Cl
Product: CCOC(=O)Cc1c(C(=O)O)c2c(n1C)C(=O)c1ccccc1CO2
Yield: 89 %

Procedure:
5,10-Dihydro-3-hydroxycarbonyl-1-methyl-10-oxo-1H-[2]benzoxepino[4,3-b]pyrrole-2-acetic acid (360 mg, 1.14 mmol) is suspended in absolute ethanol (5 ml) and heated to reflux under nitrogen. Then concentrated HCl (75 μl) is added, and the mixture is heated at reflux for 30 minutes. The homogeneous solution is allowed to cool, and the product crystallizes. The solid is filtered and washed with ice-cold ethanol and dried to give 350 mg (89%) of ethyl 5,10-dihydro-3-hydroxycarbonyl-1-methyl-10-oxo-1H-[2]benzoxepino[4,3-b]pyrrole-2-acetate. M.P. 201°-202° (dec).
Reaction SMILES: S(=O)(=O)(O)O.C(O)(=O)C.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([N:20]([CH2:25][CH3:26])S(C)(=O)=O)[C:12]=1[O:27][CH2:28][CH3:29].[OH-].[Na+]>O>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][CH2:25][CH3:26])[C:12]=1[O:27][CH2:28][CH3:29]
Reactant: CCOc1c(Br)ccc(C(=O)O)c1N(CC)S(C)(=O)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCNc1c(C(=O)O)ccc(Br)c1OCC
Reaction time: 72 h
Yield: 68.5 %

Procedure:
A mixture of concentrated sulphuric acid (128 ml) and acetic acid (192 ml) was added with stirring to 4-bromo-3-ethoxy-2-(N-ethyl-N-methylsulphonylamino)benzoic acid (8.8 g) at 85° C. for 100 minutes and left to stand at ambient temperature for 3 days. After pouring onto excess water, the mixture was made neutral by the careful addition of sodium hydroxide solution with cooling&g, extracted with ethyl acetate, dried (anhydrous magnesium sulphate) and the solvent evaporated to give 4-bromo-2-ethylamino-3-ethoxybenzoic acid (4.74 g) as a brown solid, m.p. 129-139° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[Cl:11].[Cl:12][C:13]1[CH:14]=[C:15]([C:20](=O)[C:21]([F:24])([F:23])[F:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1.ClCCCl.C(=O)([O-])[O-].[K+].[K+]>C(N(CC)CC)C>[Cl:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:9])[CH:10]=[C:20]([C:15]2[CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]([Cl:12])[CH:14]=2)[C:21]([F:24])([F:23])[F:22])=[CH:7][C:2]=1[CH3:1]
Reactant: CC(=O)c1ccc(Cl)c(C)c1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Yield: 88.5 %

Procedure:
3.0 g of 4-chloro-3-methylacetophenone, 4.35 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 30 ml of 1,2-dichloroethane, 2.46 g of potassium carbonate and 0.18 g of triethylamine were fed and the mixture was refluxed by heating for 16 hours. The reaction solution was cooled to room temperature, and separated by adding 200 ml of ethyl acetate and iced water. The organic phase was washed with diluted hydrochloric acid and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent is a mixed liquid of hexane:ethyl acetate=9:1) to obtain 6.2 g of 1-(4-chloro-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one as brown liquid.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][O:6][CH:5]([C:10]3([NH:13][C:14](=O)OCC)[CH2:12][CH2:11]3)[C:4]=2[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[CH2:26]1[CH2:30]OC[CH2:27]1>>[S:1]1[C:9]2[CH2:8][CH2:7][O:6][CH:5]([C:10]3([NH:13][CH3:14])[CH2:12][CH2:11][CH2:30][CH2:26][CH2:27]3)[C:4]=2[CH:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: CCOC(=O)NC1(C2OCCc3sccc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CNC1(C2OCCc3sccc32)CCCCC1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of ethyl 1-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)cyclopropylcarbamate (1.1 g, 4.1 mmol) in dry THF (20 mL) at 0° C. under N2 was added LiAlH4 (152 mg, 4.0 mmol) in one portion. The resulting mixture was refluxed for 2 h and then cooled to room temperature. Water (5 mL) was added to quench the reaction. The reaction mixture was filtered and the filtrate was extracted with EtOAc (3×75 mL). The combined extract was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (700 mg, 84%).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:17]=[C:16]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH:21]2[CH3:25])=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C.[OH-].[Li+].C1COCC1>O>[CH3:14][N:10]([CH2:11][CH2:12][CH3:13])[C:8](=[O:9])[C:7]1[CH:6]=[C:5]([CH:17]=[C:16]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH:21]2[CH3:25])=[O:19])[CH:15]=1)[C:4]([OH:26])=[O:3]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)N2CCCC2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)N2CCCC2C)c1
Yield: 108.3 %

Procedure:
Stir a solution of N-methyl-5-(2-methylpyrrolidine-1-carbonyl)-N-propyl-isophthalamic acid ethyl ester (218 mg, 0.6 mmol), 1 N lithium hydroxide (2.4 mL, 2.4 mmol) and THF (2.4 mL) at room temperature overnight. Add 50 mL water and extract with dichloromethane (3×10 mL). Acidify the aqueous with 1 N HCl (3 mL) and extract with dichloromethane (3×10 mL). Dry (sodium sulfate) and concentrate to give the title compound (216 mg, 100%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21]C2C=CC=CC=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:36]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[Br:28])=[O:37])(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C=Nc1ccccc1Br
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2Nc2ccccc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2NC(=O)Nc2ccccc2Br)cc1
Yield: 23.8 %

Procedure:
The urea was synthesized from 2-[(4-acetamidophenyl)sulfonylamino]phenyl aniline(1 mmol) and 2-bromophenylisocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.12 g, 24%). EI-MS mn/z 501(M−H)−.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2
Yield: 71.6 %

Procedure:
Prepared from {5-dimethylamino-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M2) (284 mg, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (158 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:27][C:28]1[N:29]=[C:30]([CH:33]=[CH:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([C:43]([F:46])([F:45])[F:44])=[O:42])=[CH:37][CH:36]=2)[O:31][CH:32]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:23])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1)[CH2:27][C:28]1[N:29]=[C:30]([CH:33]=[CH:34][C:35]2[CH:36]=[CH:37][C:38]([S:41]([C:43]([F:46])([F:44])[F:45])=[O:42])=[CH:39][CH:40]=2)[O:31][CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=CCCn2ccnn2)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1coc(C=Cc2ccc(S(=O)C(F)(F)F)cc2)n1)c1ccc(C=CCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
A solution of [4-(4-[1,2,3]triazol-1-yl-but-1-enyl)-phenyl]-carbamic acid tert-butyl ester (0.157 g, 0.5 mmol) in N,N-dimethyl formamide (4 ml) was treated with sodium hydride (0.014 g, 0.5 mmol) and stirred for 30 min at room temperature. After addition of 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole (0.168 g, 0.5 mmol) and stirring for 12 h the reaction was quenched by the addition of a sat. NH4Cl solution (8 ml). Extraction with ethyl acetate (3×10 ml), washing with water, drying over sodium sulfate and concentration in vacuo yields crude [4-(4-[1,2,3]triazol-1-yl-but-1-enyl)-phenyl]-{2-[2-(4-trifluoromethane-sulfinyl-phenyl)-vinyl]-oxazol-4-ylmethyl}-carbamic acid tert-butyl ester (0.28 g) which was used in the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([Cl:14])[N:3]=1.[Cl:15]N1C(=O)CCC1=O>C(O)C>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH:11]([CH3:12])[CH3:13])[C:5]([Cl:15])=[C:4]([Cl:14])[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)CNc1cc(Cl)nc(N)[n+]1[O-]
Solvent: CCO
Product: CC(C)CNc1c(Cl)c(Cl)nc(N)[n+]1[O-]
Yield: 58.9 %

Procedure:
6.30 g of 2-amino-4-isobutylamino-6-chloropyrimidine 3-oxide are suspended in 110 ml of ethanol. 4.85 g of N-chlorosuccinimide are added. The reaction mixture is heated under reflux for 2 hours and then evaporated to dryness. The residue is taken up in 50 ml of water. The pH is adjusted to 8 by addition of concentrated sodium hydroxide solution. The precipitate formed is filtered on sintered glass, washed with water until neutral and dried under vacuum over phosphorus pentoxide. It is recrystallized from 150 ml of ethanol. 4.30 g of 2-amino-4-isobutylamino-5,6-dichloropyrimidine 3-oxide are obtained.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=[O:11])[C:5]=2[S:4][C:3]=1[Cl:12].[CH3:13][O:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])[C@H:16]1[CH2:27][C:28](=[O:31])[CH2:29]Br>>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:29][C:28](=[O:31])[CH2:27][C@H:16]3[C@H:15]([O:14][CH3:13])[CH2:20][CH2:19][CH2:18][N:17]3[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])[C:10](=[O:11])[C:5]=2[S:4][C:3]=1[Cl:12]
Reactant: O=c1[nH]cnc2c(Br)c(Cl)sc12
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2c(Br)c(Cl)sc2c1=O

Procedure:
According to the method of Example 4, 0.662 g (0.0025 mole) of 7-bromo-6-chlorothieno[3,2-d]pyrimidin-4(3H)-one and 1.24 g (0.0037 mole) of allyl trans-3-methoxy-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate were combined to give the title compound: yield 0.90 g (69%); 1H-nmr (CDCl3) delta 1.3-2.1 ppm (multiplet, 4H, OCHCH2CH2CH2N), 2.7-3.1 (multiplet, 4H, COCH2CH and NCH2), 3.3 (broad singlet, 1H, CH2CHNCO), 3.4 (singlet, 3HOCH3), 4.0 (broad doublet, 1H, CHOCH3), 4.6 (broad doublet, 2H, CH2CH=CH2), 4.9-5.1 (multiple peaks, 2H, NCH2CO), 5.3 (triplet with fine splitting, 2H, CH2 =CH), 5.9 (octet, 1H, CH=CH2), 7.2 [singlet, 0.15H, thieno H (some of the 6-chloro analog, an impurity)], 8.0 [broad singlet, 0.15H, (N=CH--N from the 6-chloro analog)], 8.1 (broad singlet, 1H, N=CH--N).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH:30]=[CH:29][N:28]=[CH:27]1.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1)=[O:13])=[CH:5]2
Reactant: NCCCCCn1ccnc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCCCCn1ccnc1)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
A mixture of 0.90 g of 5-chloroindole-2-carboxylic acid and 0.74 g of 1,1'-carbonyldiimidazole in 25 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then 0.70 g of 1H-imidazole-1-pentanamine in 25 ml of tetrahydrofuran was added and stirring was continued for 16 hours. The mixture was heated at reflux for 5 hours, 5 ml of water was added and heating was continued for one hour longer. The mixture was concentrated, then one ml of 5N sodium hydroxide and about 25 ml of dichloromethane was added with shaking. The organic layer was separated and filtered and gave 1.2 g of the compound of the Example as white crystals, mp 214°-216° C.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(O[C@@H:23]1[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[C@@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]1[O:25][C:26](=[O:28])[CH3:27])(=O)C>ClCCl.C1(C)C=CC=CC=1>[C:26]([O:25][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[O:40][C@H:23]1[O:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:28])[CH3:27]
Reactant: COC(=O)c1ccc(Cc2ccccc2O)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a suspension of methyl 4-(2-hydroxybenzyl)benzoate (0.053 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (0.26 g) in dichloromethane (1 mL) and toluene (3 mL) was added boron trifluoride-diethyl ether complex (0.083 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) to give 2-(4-methoxycarbonyl-benzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.067 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.CS(O[CH2:22][CH:23]([Cl:25])[Cl:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:3]([O:16][CH2:22][CH:23]([Cl:25])[Cl:24])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: CS(=O)(=O)OCC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(Br)c(OCC(Cl)Cl)c2CC[C@@H]1C
Temperature: 110 °C
Reaction time: 48 h
Yield: 45.9 %

Procedure:
A 40-mL resealable tube was charged with 1-[(2S)-6-bromo-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (90 mg, 0.32 mmol), 2,2-dichloroethyl methanesulfonate (82 mg, 0.42 mmol), potassium carbonate (135 mg, 0.96 mmol), and N,N-dimethylformamide (10 mL). The resulting mixture stirred for 48 h at 110° C. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (eluting with petroleum ether/ethyl acetate, 10:1 then 1:2) to afford 1-[(2S)-6-bromo-5-(2,2-dichloro ethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (56 mg, 46%) as light yellow oil. MS (ESI, pos. ion) m/z 31, 383 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[CH:5][CH:4]=1.[NH2:21][CH2:22][C:23]([OH:25])=[O:24]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:21]([CH2:22][C:23]([OH:25])=[O:24])[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CCC(=O)c2ccccc2)cc1
Reactant: NCC(=O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc(-c3ccccc3)n2CC(=O)O)cc1
Temperature: 100 °C

Procedure:
A mixture of 1-(4-methoxy-phenyl)-4-phenyl-butane-1,4-dione (2.90 g, 10.8 mmol) and glycine 4 (1.62 g, 21.6 mmol) in 100 mL of glacial acetic acid is heated at 100° C. The reaction is monitored by TLC, when the starting material is consumed, the mixture is washed with 5% H2SO4 (200 mL) and then extracted with ethyl acetate (2×200 mL). The organics are combined, dried over sodium sulfate, filtered and concentrated to yield [2-(4-Methoxy-phenyl)-5-phenyl-pyrrol-1-yl]-acetic acid as a green solid (3.40 g, crude), characterized by LCMS (Obs: 308.54, Cal: 307.34).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O.C(N(CC)CC)C>CO>[C:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCCCCCCC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCCCC(=O)O
Temperature: 60 °C
Reaction time: 12 h
Yield: 72.9 %

Procedure:
NH2—(CH2)7—COOH (5.00 g, 31.4 mmol), (BOC)2O (7.52 g, 34.5 mmol) and triethylamine (3.48 g, 34.5 mmol) were dissolved in 200 mL of methanol, and the mixture was stirred at 60° C. for 12 hours. After the reaction completed, methanol was removed under reduced pressure, and the obtained material was redissolved in 100 mL of ethyl acetate. Then, the resultant solution was subjected to separation using 0.2 mol/l HCl (twice) and water (twice), and dehydrating was carried out with anhydrous sodium sulfate. After that, recrystallization with hexane at 4° C. and collection using a glass filter (G6) were performed, thereby obtaining Boc-NH—(CH2)7—COOH (5.93 g, 22.9 mmol, yield: 73%).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:6]([NH2:7])=[CH:5][C:4]=1F)#[N:2].[CH2:14]([N:16]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]1)[CH3:15].C(N(C(C)C)CC)(C)C>>[CH2:14]([N:16]1[CH2:20][CH2:19][CH:18]([O:21][C:4]2[C:3]([C:1]#[N:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:6]([CH:5]=2)[NH2:7])[CH2:17]1)[CH3:15]
Reactant: CCN1CCC(O)C1
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC(Oc2cc(N)c([N+](=O)[O-])cc2C#N)C1
Temperature: 140 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To 183 mg of 4-cyano-3-fluoro-6-nitroaniline (which was synthesized following J. Med. Chem. 1994, 37, 467) and 201 mg of 1-ethyl-3-pyrrolidinol, 0.5 ml of diisopropylethylamine was added and stirred for 3 hours at 140° C. The reaction liquid was cooled to room temperature, and concentrated after addition of chloroform-methanol (1/1). The residue was separated and purified on preparative thin-layer chromatography [Kieselgel™ 60F254, Art.5744 (Merck); chloroform/methanol=4/1] to provide 114 mg of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([NH2:28])[C:9]([F:27])=[C:10]([N:14]3[CH2:18][CH2:17][CH:16]([NH:19]C(OC(C)(C)C)=O)[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:29])[C:5]([C:30]([OH:32])=[O:31])=[CH:4]1)[CH3:2].[ClH:33]>C(O)(=O)C>[ClH:33].[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([NH2:28])[C:9]([F:27])=[C:10]([N:14]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:29])[C:5]([C:30]([OH:32])=[O:31])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(N)c(F)c(N3CCC(NC(=O)OC(C)(C)C)C3)c(F)c21
Agent: Cl
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2c(N)c(F)c(N3CCC(N)C3)c(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A near solution of 4.5 g (10 mmole) of 1-ethyl-5-amino-6,8-difluoro-7-[3-(t-butoxycarbonylamino)-1-pyrrolidinyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 10 ml of 6.0 M hydrochloric acid and 100 ml of glacial acetic acid is heated at 60° C. for four hours and then stirred at room temperature for 18 hours. The solvent is removed in vacuo, the residue triturated with ethanol/ether (1:1), filtered, washed with ether, and dried in vacuo to give the title compound.