Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:17]=2)=[CH:11][N:10]=1)=S)C.[Cl-].O[NH3+].C([N:38](CC)C(C)C)(C)C.C(O)C>CO>[NH2:38][C:6]1[N:8]=[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([NH:23][C:24](=[O:25])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:17]=3)=[CH:11][N:10]2[N:5]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(F)c(NC(=O)OC(C)(C)C)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)nn3c2)ccc1F
Yield: 83.5 %

Procedure:
In the same manner as in Example 23-1 and using ethyl{[(5-{3-[(tert-butoxycarbonyl)amino]-4-fluorophenoxy}pyridin-2-yl)amino]carbonothioyl}carbamate (13.5 g, 30.0 mmol), hydroxylammonium chloride (14.7 g, 212 mmol), N,N-diisopropylethylamine (26.2 mL, 150 mmol), ethanol (75 mL) and methanol (75 mL) as starting materials, the title compound (9.00 g, 84%) was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CN=C1.[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)Cl)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[C:17]([Si:21]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](OCc1ccc([N+](=O)[O-])cc1)(c1ccccc1)c1ccccc1
Reaction time: 5 h

Procedure:
To a stirred solution of 4-nitrobenzyl alcohol, 12, (1.00 g, 6.50 mmol), and imidazole (0.97 g, 14.1 mmol) in DMF (10.0 ml), was added tert-butyl-diphenyl-chlorosilane (1.98 g, 7.20 mmol) over 10 min under N2 at room temperature. The reaction mixture was stirred for an additional 5 h, diluted with Et2O (75 ml), washed with H2O (5×15 ml), dried (MgSO4) and evaporated to dryness under vacuum. An oil was obtained which crystallised on standing and was recrystallised to a solid from EtOH (70%); yield: 2.36 g (93%). vmax /cm-1 (film): 2931, 2857 (CH2, asym., sym.), 1521, 1345 (NO2); 1H-NMR, dH : 1.06(9H, s, t-Bu), 4.92 (2H, s, CH2), 7.42-7.46 (5H, m, Ph), 7.63-7.65 (7H, m, Ph+Harom2+6), 8.23 (2H, d, J=8.23, Harom3+5); MS, (EI), (391.54); m/z: 334 (M - t-Bu, 100), 288 (M - t-Bu - NO2, 10), 256 (M - t-Bu - Ph, 20), 199 (Ph2SiOH+, 100); C23H25NO3Si.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:5]([C:20]#[N:21])[C:4]1=[O:22].[C:23](Cl)(=[O:26])[CH:24]=[CH2:25].CCN(C(C)C)C(C)C>ClCCl>[C:23]([N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]([CH3:2])[C:4](=[O:22])[C:5]=2[C:20]#[N:21])[CH2:19][CH2:18]1)(=[O:26])[CH:24]=[CH2:25]
Reactant: C=CC(=O)Cl
Reactant: Cn1c(=O)c(C#N)c(NC2CCNCC2)c2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N1CCC(Nc2c(C#N)c(=O)n(C)c3ccccc23)CC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-Methyl-2-oxo-4-(piperidin-4-ylamino)-1,2-dihydro-quinoline-3-carbonitrile hydrochloride salt (leg, 0.020 g, 0.07 mmole) in dichloromethane at −10° C. was added acryloyl chloride (1.1 eq, 0.007 g, 0.077 mmole) followed by the addition of N,N′-diisopropylethylamine (1.5 eq, 0.014 g, 0.011 mmole, 0.02 mL). The resulting solution stirred at −10° C. for 1 hour then warmed to RT and stirred for an additional 2 hours. The reaction was quenched into ice cooled water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 4-(1-Acryloyl-piperidin-4-ylamino)-1-methyl-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a yellow solid (0.004 g, 32% calc M+H 337, obs M+H 337).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:23]([CH:25]=[O:26])=[CH:24][C:16]=2[F:15])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C(=O)O)c(F)c1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)Nc2ccc(Cc3ccccc3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzylbenzenamine (0.100 g, 0.55 mmol), 2-fluoro-4-formylbenzoic acid (0.092 g, 0.55 mmol), N,N-diethylpropan-2-amine (0.10 ml, 0.65 mmol) in DMF (2.00ml) was added HBTU. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc, washed with water and dried over MgSO4. The solvent was evaporated and the residue was purified by flash chromatography in a EtOAc/Hexene system to give the title compound. MS (ESI) m/z: Calculated; 333.3: Observed; 332.1. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 10.05-10.10 (1H, m), 8.31-8.44 (2H, m), 7.80-7.85 (1H, m), 7.67-7.73 (1H, m), 7.56-7.62 (2H, m), 7.15-7.40 (6H, m), 3.99 (2H, s)
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][C:19]=1[CH2:20][CH3:21])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH3:22][C:23]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][C:19]=1[CH2:20][CH3:21])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([N+:30]([O-:32])=[O:31])[C:23]=2[CH3:22])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: C=CCOc1cc(Oc2ccc(C=O)cc2)ccc1CC
Product: C=CCOc1cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)ccc1CC

Procedure:
The product from Example 236C and 2-methyl-3-nitroaniline were processed as in Example 6A to provide the titled compound. MS (ESI−) m/z 423 (M−H)−.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([OH:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)C(C)C)C.Cl>C(Cl)Cl.CS(C)=O>[CH2:7]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
To a solution of 2.3 ml of oxalyl chloride in 40 ml of methylene chloride cooled at -65° C. is added a solution of 4.45 g of dimethylsulfoxide in 20 ml of methylene chloride over a period of 10 minutes, and the mixture is stirred at -60° C. for 10 minutes. To the mixture is added a solution of 5 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate in 50 ml of methylene chloride over a period of 10 minutes, and the resulting mixture is stirred at -60° C. for 20 minutes. To the mixture is added 10.3 g of diethylisopropylamine over a period of 10 minutes, and the temperature is raised from -60° C. up to -30° C. To the mixture is added 80 ml of 1N hydrochloric acid, and the mixture is stirred at room temperature. The methylene chloride layer is separated, washed with water, dried and concentrated under reduced pressure. The residue is purified by silicagel column chromatography (hexane: ethyl acetate=4:1 to 2:1), to give 2.6 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate as an oil.
Reaction SMILES: CC[O-].[Na+].[C:5]1([NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].C([O:15][C:16](=O)[C:17](=[N:23][O:24][CH3:25])[C:18](OCC)=[O:19])C.Cl>C(O)C.C(#N)C>[CH3:25][O:24][N:23]=[C:17]1[C:18](=[O:19])[NH:12][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][C:16]1=[O:15]
Reactant: CCOC(=O)C(=NOC)C(=O)OCC
Reactant: Nc1ccccc1N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: CON=c1c(=O)[nH]c2ccccc2[nH]c1=O
Temperature: 70 °C
Yield: 75.7 %

Procedure:
Dissolve 21 wt % NaOEt in EtOH solution (164 g, 0.507 mol) in 2B-3 ethanol (331 mL) and add 1,2-phenylenediamine (27.4 g, 0.253 mol). Stir the resulting mixture allow to stir at ambient temperature for approximately 30 minutes during which time all the solid material dissolves producing a dark amber solution. Add 2-methoxyimino-malonic acid diethyl ester (51.5 g, 0.253 mol). Heat the resulting mixture to 70° C. and stir under nitrogen for approximately 4 hours monitoring by HPLC analysis (Zorbax RX C18, 55% ACN/45% 0.1% TFA, 1 mL/min, 233 nm). Allow the reaction mixture to cool to ambient temperature. Lower the pH of the reaction mixture from 11.6 to 1.2 by the addition of 700 mL of aqueous 1N HCl solution. Concentrate the reaction mixture in vacuo to remove the ethanol. Filter the resulting amber slurry through a glass frit. Collect the solid and rinse with aqueous 1N HCl and dry under vacuum at 50° C. to afford 42 g (76% yield) of the title compound as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 11.1 (s, 1H), 10.9 (s, 1H), 7.22 (s, 4H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7; 159.4, 148.1, 128.5, 127.8, 125.8, 125.7, 122.8, 122.7, 63.1; IR (CHCl3) 3062, 2970, 2902, 1704, 1656, 1606, 1505, 1414, 1058, 1043, 754 cm−1; UV (EtOH) λmax 278 nm (ε 4623), 276 nm (ε 4618), 216 nm (ε 41495); HRMS (ES+) exact mass calc'd for C10H9N3O3 242.0542, Found 242.0553; Anal. calc'd for C10H9N3O3: C, 54.79; H, 4.14; N, 19.17. Found: C, 54.60; H, 4.15; N, 18.94.
Reaction SMILES: [CH:1]([N:4]=[CH:5][CH:6]=[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH:1]([NH:4][CH2:5][CH:6]=[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8])([CH3:3])[CH3:2]
Reactant: CC(=CC=NC(C)C)c1ccccc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(=CCNC(C)C)c1ccccc1-c1ccccc1
Reaction time: 5 h

Procedure:
A solution of 2.63 g of 1-isopropylimino-3-p-biphenylyl-2-butene (obtainable from 3-p-biphenylyl-2-butenal and isopropylamine) in 20 ml of absolute ether is added dropwise to a solution of 0.6 g of LiAlH4 in 20 ml of absolute ether. The mixture is then boiled for 5 hours, water is added carefully and the mixture is worked up in the customary manner to give 1-isopropylamino-3-p-biphenylyl-2-butene.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[N+:18]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:18][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:7][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)nc1C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(N)c(N)nc1C(=O)OCC
Temperature: 0 °C
Yield: 94.5 %

Procedure:
Diethyl 6-amino-5-nitro-2,3-pyridinedicarboxylate (5.00 g, 0.0176 mol) is suspended in 250 mL of absolute ethanol and the mixture cooled to 0° C. Palladium on carbon (50 g of 10% is added and the mixture is shaken under 50 psi hydrogen in a Parr apparatus for four hours. The catalyst is removed by filtration through a pad of Celite, and the filtrate is concentrated to yield 4.21 g (94.2%) of product as a yellow solid, melting point 143°-146.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)ccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(Cl)ccc1Cl)C2
Yield: 199.7 %

Procedure:
A mixture of 7-(2,5-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.0 g), aminoguanidine hydrochloride (0.43 g), concentrated hydrochloric acid (0.82 ml), water (0.82 ml) and ethanol (30 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue recrystallized from water to give 7-(2,5-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 120) (1.3 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])=[O:4].[C:12](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[O:10][CH3:12])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1scc(Br)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1scc(Br)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 129.3 %

Procedure:
Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (˜200 mL). The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on high vacuum, yielding 13.7 g (100%) of methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH+=251.0).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N:11]([CH3:21])[S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:22]1[S:23][CH:24]([CH2:27][N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)[CH2:25][N:26]=1)=[CH:5]2.C(P(CCCC)CCCC)CCC.[CH3:47][O:48][CH2:49][C@H:50](O)[CH3:51].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH3:47][O:48][CH2:49][C@H:50]([CH3:51])[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N:11]([CH3:21])[S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:22]1[S:23][CH:24]([CH2:27][N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)[CH2:25][N:26]=1)=[CH:5]2
Reactant: COC[C@@H](C)O
Reactant: CN(c1cc(O)cc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCSCC4)S3)cc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To a solution of N-{5-hydroxy-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylpyridine-2-sulfonamide (145 mg) in toluene (2 mL) and tetrahydrofuran (1 mL) were added tributylphosphine (0.22 mL), (2R)-1-methoxypropan-2-ol (0.057 mL) and 1,1′-(azodicarbonyl)dipiperidine (220 mg), and the mixture was stirred at 80° C. for 3 hr, and concentrated. The residue was diluted with ethyl acetate, and subjected to basic silica gel column chromatography (eluate: ethyl acetate), and the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-1:2) to give the title compound (80 mg, yield 48%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([NH:14][S:15]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2)(=[O:17])=[O:16])[C:11]([OH:13])=O.[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([NH:14][S:15]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2)(=[O:16])=[O:17])[C:11]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1)=[O:13]
Reactant: O=C(O)C(CCc1ccccc1Cl)NS(=O)(=O)c1cccc2[nH]ccc12
Reactant: COC(=O)C1CCNCC1
Product: COC(=O)C1CCN(C(=O)C(CCc2ccccc2Cl)NS(=O)(=O)c2cccc3[nH]ccc23)CC1

Procedure:
methyl 1-{4-(2-chlorophenyl)-2-[(1H-indol-4-ylsulfonyl)amino]butanoyl}piperidine-4-carboxylate is prepared from 4-(2-chlorophenyl)-2-[(1H-indol-4-ylsulfonyl)amino]butanoic acid and methyl piperidine-4-carboxylate in same manner Example 106 is synthesized. ESI MS Calc. 517.1; Found: 518.5 (M+H)+.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(=O)([O-])O.[Na+].[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:26][C:27]3[N:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][CH:28]=3)=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17]2)=[CH:13][CH:12]=1>CS(C)=O.O>[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:26][C:27]3[N:32]=[C:31]([C:33](=[N:3][OH:2])[NH2:34])[CH:30]=[CH:29][CH:28]=3)=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17]2)=[CH:13][CH:12]=1
Reactant: COc1ccc2c(Cc3cccc(C#N)n3)c(-c3ccccc3)[nH]c2c1
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(Cc3cccc(C(N)=NO)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 50 °C
Reaction time: 1.25 h
Yield: 105.6 %

Procedure:
To a solution of hydroxylammonium chloride (891 mg) in dimethylsulfoxide (5 mL) was added sodium hydrogen carbonate (1.29 g), and this mixture was stirred at 50° C. for 75 minutes. Then, a solution of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carbonitrile (435 mg) in dimethylsulfoxide (1.4 mL) was added dropwise thereto, followed by stirring at 50° C. for 24 hours. The reaction mixture was left to be cooled and diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (504 mg). 1H-NMR (CDCl3) δ ppm: 3.86 (3H, s), 4.40 (2H, s), 5.63 (2H, br s), 6.43-6.69 (1H, br), 6.77 (1H, dd, J=2.2, 8.8 Hz), 6.91 (1H, d, J=2.2 Hz), 7.09-7.15 (1H, m), 7.31-7.40 (2H, m), 7.40-7.49 (2H, m), 7.49-7.60 (3H, m), 7.66-7.74 (1H, m), 8.06 (1H, br s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)(=[O:17])=[O:16])[C@@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:37])C=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N+:23]([O-:37])[CH:22]=[CH:21]3)(=[O:16])=[O:17])[C@@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1ccc2cnccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1ccc2c[n+]([O-])ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
340 mg of (S)-6-(4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline was dissolved in 20 mL of dichloromethane, and 244 mg of m-chloroperbenzoic acid was added at 0° C. The reaction solution was stirred at room temperature for 16 hours and then concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate:methanol=8:1) to obtain 320 mg of the compound of interest as a colorless oil (91%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:14]=1)=O.[C:15]([NH2:23])(=[S:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1>[O:13]1[C:8]2[CH:7]=[CH:6][C:5]([C:3]3[N:23]=[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[S:22][CH:2]=3)=[CH:14][C:9]=2[CH2:10][CH2:11][CH2:12]1
Reactant: NC(=S)c1ccccc1
Reactant: O=C(CCl)c1ccc2c(c1)CCCO2
Solvent: C1COCCO1
Product: c1ccc(-c2nc(-c3ccc4c(c3)CCCO4)cs2)cc1
Yield: 94.1 %

Procedure:
A solution of 2-chloro-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethan-1-one (9b) (250 mg, 1.19 mmol) and thiobenzamide (180 mg, 1.3 mmol) in dioxane (10 mL) was refluxed for 15 hours, then the reaction mixture was concentrated. The residue was diluted with dichloromethane (20 mL), washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/cyclohexane 60/40) to afford the desired thiazole (9c) as a white solid (330 mg, 1.12 mmol, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:6]=[CH:7][C:8](=[O:12])[C:9]=1[O:10][CH3:11])=[O:5].[Cl:13][C:14](=[CH2:19])[CH:15]=[CH:16]OC>C1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[C:6]2[C:7](=[CH:16][CH:15]=1)[C:8]([O:12][C:3](=[O:2])[CH3:9])=[C:9]([O:10][CH3:11])[C:3]([O:2][CH3:1])=[C:4]2[O:5][C:4](=[O:5])[CH3:6]
Reactant: C=C(Cl)C=COC
Reactant: COC1=C(OC)C(=O)C=CC1=O
Solvent: c1ccccc1
Product: COc1c(OC)c(OC(C)=O)c2cc(Cl)ccc2c1OC(C)=O
Reaction time: 12 h
Yield: 203.1 %

Procedure:
A benzene (8 ml) solution of 2,3-dimethoxybenzo-1,4-quinone (1.0 g, 5.9 mmol) and 3-chloro-1-methoxy-1,3-butadiene (1.4 g, 12.0 mmol) is stirred for 30 hours under an inert atmosphere. After this time, the reaction mixture is concentrated and then dissolved in pyridine (8 ml). Acetic anhydride (3.0 g) is added, and the solution is stirred for 12 hours under an inert atmosphere. The contents are diluted ten-fold with water and extracted with ethyl acetate. The organics are then washed with water, brine, and then dried over sodium sulfate. Concentration, followed by flash chromatography (hexane/ethyl acetate 3:1) affords 2.03 g (93%) of a compound of the formula ##STR5##
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=O.C(N1CCOCC1)C.[CH2:24]([O:28][C:29](=[O:37])[NH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH2:25][CH2:26][CH3:27].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([O:28][C:29](=[O:37])[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([C:3](=[O:5])[CH2:2][NH:1][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:33][CH2:32]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCOC(=O)NC1CCNCC1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)NC1CCN(C(=O)CNC(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 150 mg Z-Gly-OH in 5 ml DMF were added 0.4 ml N-ethylmorpholine, 144 mg piperidin-4-yl-carbamic acid butyl ester and 236 mg TOTU. After stirring for 12 h it was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%), saturated NaHCO3 and 0.1 M HCl. The crude product thus obtained after evaporation of the solvent was directly used in the next step. Yield: 287 mg.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:11][C:12]([O:14]CC)=[O:13].O>CN(C=O)C>[CH:3]1([O:9][CH2:11][C:12]([OH:14])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)CBr
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COC1CCCCC1
Reaction time: 0.08 h
Yield: 31.7 %

Procedure:
To a solution of compound NaH (719 mg, 29.94 mmol) in DMF (10 mL) was added cyclohexanol (1 g, 9.98 mmol) at 0° C. After stirring for 5 minutes, ethyl 2-bromoacetate (2 g, 11.98 mmol) was added and the mixture stirred for another 16 h. Once complete, the mixture was treated with water (50 mL) and washed with ethyl acetate (2×20 mL). The water layer was treat with 2N HCL until pH 3. The water layer was extracted with ethyl acetate (2×20 ml) and the combined organic layers washed with brine (30 mL), dried over Na2SO4 and concentrated to give the desired product (500 mg, 27.8%) as colorless oil which was used in next step without further purification.