Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:37])[CH2:25][O:26][C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)=[O:21])[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][CH2:16][CH2:17][CH3:18].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>C1(C)C=CC=CC=1>[CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:37])[CH2:25][O:26][C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:38]1[CH:42]=[CH:41][N:40]=[CH:39]1)=[O:21])[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][CH2:16][CH2:17][CH3:18]
Reactant: c1c[nH]cn1
Reactant: C=C(COC(=O)CCCCCCCBr)COC(=O)NCCCCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: C=C(COC(=O)CCCCCCCn1ccnc1)COC(=O)NCCCCCCCCCCCCCCCCCC

Procedure:
1-Octadecylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane (from Preparation 11) (1.18 g) and imidazole (0.68 g) were stirred in toluene (20 ml) at 104° C. for 14 hours. The mixture was cooled and evaporated in vacuo. The residue was chromatographed on silica gel 60 (70-230 mesh, 40 g) with ether/chloroform/triethylamine (1:1:0.04) as eluent to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:14]([O:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[N:28]=[C:29]=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:29]([NH:28][C@H:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C@@H:22]2[O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:30])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: O=C=N[C@H]1CCCC[C@@H]1OCc1ccccc1
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)N[C@H]2CCCC[C@@H]2OCc2ccccc2)c1O
Yield: 27 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (109 mg, 0.49 mmol) and the crude (1S,2S)-(−)-2-benzyloxycyclohexyl isocynate in 2 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product (60 mg, 27% two steps). LC-MS (m/z) 454.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([Cl:23])=[O:19])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(Sc2ccc(Cl)cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccc(Sc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of acid from step 4 in CH2Cl2 (0.2M) was added oxalyl chloride (1.2 eq) and one drop of DMF. The mixture was stirred at rt for 3 h and the solvent evaporated. The crude acid chloride was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH2:8][CH:7]2[NH:9][CH:4]([CH2:5][CH2:6]2)[C:3]=1[C:10]1[C:11]([Cl:15])=[N:12][S:13][N:14]=1.C=O.[CH:18](O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:18][N:9]1[CH:7]2[CH2:6][CH2:5][CH:4]1[C:3]([C:10]1[C:11]([Cl:15])=[N:12][S:13][N:14]=1)=[C:2]([Cl:1])[CH2:8]2
Reactant: ClC1=C(c2nsnc2Cl)C2CCC(C1)N2
Reactant: O=CO
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1C2CCC1C(c1nsnc1Cl)=C(Cl)C2

Procedure:
A mixture of 3-chloro-2-(3-chloro-1,2,5-thiadiazol-4-yl)-8-azabicyclo[3.2.1]oct-2-ene (1.0 g, 3.8 mmol), formaldehyde (37% water solution, 10 ml) and formic acid (6.0 ml) was heated at reflux for 2 h. After cooling water was added (100 ml) and the water solution was made basic with potassium carbonate. The water solution was extracted with diethylether (3×50 ml). The organic extracts were dried over magnesium sulfate and evaporated. The residue was crystallized as the oxalate salt from acetone in 1.2 g yield.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][CH2:12][OH:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:13][CH2:12][CH2:11][C:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:10]=2[O:9][CH:8]=1
Reactant: COC(=O)CBr
Reactant: OCCc1coc2c(O)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c(CCO)coc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
7-hydroxy-3-(2-hydroxyethyl)benzofuran (1.09 g), methyl bromoacetate (0.86 ml) and potassium carbonate (930 mg) were added to DMF (50 ml) and the mixture was stirred at room temperature for 18 hours. After filtering the reaction solution, the filtrate was concentrated and added to water layer (150 ml), followed by extracting the resultant twice with ethyl acetate (20 ml). After combining the organic layers, the resultant was washed with saturated brine and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/1) using silica gel to obtain the desired compound (1.48 g, yield: 97%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][O:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCOCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:31]3[CH2:32][CH2:33][CH:28]([CH2:27][O:26][CH3:25])[CH2:29][CH2:30]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:21])[CH3:22]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: COCC1CCNCC1
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: COCC1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 200 mg, 0.604 mmol) and 4-(methoxymethyl)piperidine (117 mg, 0.906 mmol) in Dioxane (6 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (50 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6H) 1.59-1.75 (m, 2H) 1.98-2.12 (m, 2H) 3.31 (s, 3H) 3.41-3.58 (m, 3H) 3.97-4.15 (m, 2H) 6.35 (d, J=2.27 Hz, 1H) 7.40 (s, 1H) 7.60 (m, J=8.34 Hz, 2H) 7.99 (m, J=8.59 Hz, 2H) 8.08 (d, J=2.27 Hz, 1H) 10.88 (s, 1H). ESI-MS: m/z 424.2 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[C:10]([O:13]C)[CH:11]=[CH:12][C:7]=2[N:6]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:5][C:4]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3]1.C[S-].[Na+].C(O)(=O)C.O>CN(C=O)C>[O:30]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[N:6]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:5][C:4]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccc(N)cc2)c2ccc(OC)cc2S(=O)(=O)C1
Agent: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCCC1(CCCC)CN(c2ccc(N)cc2)c2ccc(O)cc2S(=O)(=O)C1
Yield: 67.6 %

Procedure:
1,1-Dioxo-3,3-dibutyl-5-(4-aminophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 105; 918 mg, 2.13 mmol) was dissolved in DMF (dry, 20 ml). Sodium thiomethoxide (810 mg, 11.6 mmol) was added. The reaction mixture was treated at 100–120° C. for four hours then room temperature overnight. Acetic acid (3 ml) was added and the mixture was flushed with nitrogen (g) and the gas was lead through a flask containing sodium hypochlorite in order to destroy the methyl mercaptan formed. Water was added and the water layer was extracted two times with EtOAc. The combined organic layer was washed with brine, dried, filtered and evaporated under reduced pressure. The mixture contained DMF so toluene and brine was added (everything didn't dissolved). The water layer was extracted two times with toluene. The combined organic layers were washed once with brine. The separation funnel was washed with EtOAc in order to dissolve everything. The toluene and EtOAc solutions were combined, dried, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography using DCM:EtOAc, 7:3 as eluent to give the title compound 0.6 g (27%). M/z 417.4.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[Cl:12]([O-])(=O)=O.[Na+]>O>[OH:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: [O-][Cl+2]([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(Cl)c1
Temperature: 50 °C

Procedure:
2-Hydroxy-5-nitro pyridine (1 g, 7.14 mmol) was added portion wise to 4.5 mL of concentrated HCl under constant stirring and then heated to 50° C. To this was slowly added a solution of sodium chlorate (266 mg, 2.5 mmol) in water (4 mL). The reaction was maintained at the same temperature for an additional hour, and then cooled to 0° C. The precipitate obtained was filtered, washed thoroughly with water and dried to obtain 2-hydroxy-3-chloro-5-nitro pyridine.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:5][N:4]1CC)[CH3:2].Cl[O-].[Na+]>>[CH2:1]([N:3]1[CH2:7][CH:6]([NH:8][C:9](=[O:19])[C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCN1CC(NC(=O)c2ccc([N+](=O)[O-])cc2)CN1CC
Agent: [Na+]
Agent: [O-]Cl
Product: CCN1CC(NC(=O)c2ccc([N+](=O)[O-])cc2)C=N1

Procedure:
In accordance with the procedure of Example 2, N-(1,2-diethyl-4-pyrazolidinyl)-4-nitrobenzamide is reacted with sodium hypochlorite and the product is isolated.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[OH:23]>>[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:14]=1[O:23][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Product: O=[N+]([O-])c1c(F)cccc1Oc1ccc(C(F)(F)F)cc1Cl
Yield: 47 %

Procedure:
This material was prepared in 47% yield from 2,6-difluoronitrobenzene and 2-chloro-4-trifluoromethylphenol following the general procedure outlined in Example 104. The product was isolated as an oil which was characterized by IR and 1H NMR spectroscopy.
Reaction SMILES: [H-].[Na+:2].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH:11]([OH:18])[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[Cl:19][C:20]1[S:21][CH:22]=[CH:23][C:24]=1[CH2:25][Br:26]>C1CCCCC1.C(O)(C)C>[CH:7]1[C:8]([Cl:10])=[CH:9][C:4]([Cl:3])=[C:5]([CH:11]([O:18][CH2:25][C:24]2[CH:23]=[CH:22][S:21][C:20]=2[Cl:19])[CH2:12][N:13]2[CH:14]=[N:15][CH:16]=[CH:17]2)[CH:6]=1.[Br-:26].[Na+:2]
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: Clc1sccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCCCC1
Product: Clc1ccc(C(Cn2ccnc2)OCc2ccsc2Cl)c(Cl)c1
Product: [Br-]

Procedure:
Step B of example 3 was repeated with the following exceptions: NaH (about 6.4 g), cyclohexane (about 75.6 g), 1-(2,4-dichlorophenyl)-2-(1-imidazolyl)ethanol (about 41.2 g), and isopropanol (228 g) were employed. The cyclohexane solution of 2-chloro-3-bromomethylthiophene was then added to the reactor containing the imidazoyl mixture and the contents stirred at reflux for 4 hours, yielding a solution of crude tioconazole and solid sodium bromide. Processing continued in accordance with example 3. The crude reaction yield is ca. 25.3% based on 2-chloro-3-methylthiophene.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]#[N:20])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CCC#N)NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CCc1nnn[nH]1)NC(=O)OCc1ccccc1
Temperature: 82.5 °C
Yield: 75 %

Procedure:
Into the same device as used in Example 1 were placed 77.3 g (0.28 mole) of methyl (2S)-2-benzyloxycarbonylamino-4-cyanobutyrate, 27.3 g (0.42 mole) of sodium azide, 57.7 g (0.42 mole) of triethylamine hydrochloride and 280 ml of toluene. Thereafter, the mixture was heated to a temperature of 82 to 83° C. to undergo a reaction for 24 hours. Subsequently the same procedure as in Example 1 was repeated, and crystals were collected by filtration. Further, the crystals were recrystallized from methanol and water, filtered and dried, giving 67.7 g (0.21 mole) of methyl (2S)-2-benzyloxycarbonylamino-4-(tetrazole-5-yl)butyrate (yield 75.8% based on methyl (2S)-2-benzyloxycarbonylamino-4-cyanobutyrate). The reaction is illustrated below with chemical formulas: ##STR27##
Reaction SMILES: [N:1]([CH2:4][C:5]1([F:21])[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:1][CH2:4][C:5]1([F:21])[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:9][CH2:10]1
Reactant: [N-]=[N+]=NCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 60 h

Procedure:
To a solution of benzyl 4-(azidomethyl)-4-fluoropiperidine-1-carboxylate (1.5 g, 5.1 mmol) in THF (10 mL) at RT was added water (0.92 mL, 0.92 mmol) and triphenylphosphine (4.3 g, 15.4 mmol). The reaction mixture was stirred for 60 h, concentrated, dissolved in HCl (1M) and extracted with Et2O four times. The aqueous layer was basified to pH 11 and extracted with EtOAc twice. The organic layer was dried over Na2SO4, filtered and concentrated. The crude mixture was chromatographed on silica gel (CH2Cl2 to 80:20:2 CH2Cl2:MeOH:NH4OH) to give benzyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate. M.S. (M+1): 267
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].CCN(CC)CC>C1COCC1>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:18]=[CH:19][C:10]3[N:9]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])[CH:7]=[CH:6][CH:5]=4)[CH2:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[CH:25][CH:24]=1
Reactant: Nc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from 4-(3-amino-phenyl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 70) by treatment with methanesulfonyl chloride and Et3N in THF at 23° C. Obtained as a light yellow solid (24 mg).
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>CN(C=O)C.CCN(CC)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC[C@@H](C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-pent-4-yn-2-ol (68 mg, 0.82 mmol) (see Example 78 below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (100 mg, 0.27 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (31 mg, 0.03 mmol) and CuI (6 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was concentrated and the residue was chromatographed on a silica gel column with neat CH3CN then THF and finally MeOH as elution solvent. The resulting (R)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was triturated with Et2O and then recrystalized from superheated EtOH. (Yield 18 mg, 20%).
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:12][CH:11]=1)[CH3:2].[CH2:29]([I:31])[CH3:30].[CH2:32](O)[CH3:33]>>[I-:31].[I-:31].[CH2:27]([N+:3]([CH2:29][CH3:30])([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:11]=[CH:12][C:13]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N+:22]([CH2:32][CH3:33])([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:14][CH:15]=1)[CH3:28]
Reactant: CCI
Reactant: CCN(CC)CCCCCSc1ccc(SCCCCCN(CC)CC)cc1
Reactant: CCO
Product: CC[N+](CC)(CC)CCCCCSc1ccc(SCCCCC[N+](CC)(CC)CC)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
First, 510 mg of 1,4-bis(5-diethylaminopentylthio)benzene was dissolved in 5 ml of absolute ethanol, and after adding 960 μl of ethyl iodide, the mixture was refluxed for 4 hours, then cooled and evaporated under a reduced pressure to remove the ethanol. After adding 5 ml of acetone, the mixture was stirred at a room temperature for 3 hours and allowed to stand in a freezer overnight. The resulting crystal was collected by filtration, washed with acetone and dried under a reduced pressure to obtain 519 mg of the title compound as a light gray crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:23]=1[S:32]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1cc(Cl)c(Cc2cnc3ccccc3c2)c(Cl)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2cnc3ccccc3c2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(3,5-dichloro-4-quinolin-3-ylmethyl-phenyl)4-trifluoromethyl-benzenesulfonamide was synthesized (80%) from 3,5-dichloro-4-quinolin-3-ylmethyl-phenylamine (230), 2-chloro-4-trifluromethylbenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.49 (br s, 1H), 8.78 (d, J=1.9 Hz, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.19 (s, 1H), 7.98 (d, J=7.0 Hz, 1H), 7.96 (d, J=7.7 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 781 (s, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H), 7.24 (s, 2H), 4.34 (s, 2H). MS (EI): m/z 543 (M−H).
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCCC1.[O:16]=[C:17]1[S:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18]1.CO>C(OCC)C.CN(C1C=CC=CN=1)C>[CH3:1][O:23][C:22]([CH:19]1[CH2:18][C:17](=[O:16])[S:21][CH2:20]1)=[O:24]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CC(C(=O)O)CS1
Agent: CN(C)c1ccccn1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1CSC(=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
225 g (1.09 mol) of dicyclohexylcarbodiimide (DCC) are added in portions, while cooling with ice, to a solution of 160 g (1.095 mol) of tetrahydro-5-oxo-3-thiophenecarboxylic acid, 70 g (2.19 mol) of methanol and 4 g (32.8 mmol) of dimethylaminopyridine (DMAP) in 2.5 litres of diethyl ether. After 4 hours' stirring at room temperature, the dicyclohexylurea is filtered off and the filtrate is extracted with 500 ml of 2N hydrochloric acid and 500 ml of saturated sodium hydrogen carbonate solution, is washed with water and is dried over sodium sulfate. There are obtained 149 g of solid product having a melting point of 33°-35° C.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[C:4]([N+]([O-])=O)[C:3]=1[N+:19]([O-])=O.[H][H].[NH3:24]>[Pd].C(O)C>[NH2:19][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:2]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:24])[CH:9]=1)=[O:7]
Reactant: N
Reactant: [H][H]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1
Temperature: 45 °C
Yield: 72.2 %

Procedure:
30.7 g (0.1 mol) of this crude chlorodinitrobenzophenone, 0.31 g of 5% Pd/C (a product of Nippon Engelhardt K.K.) and 200 ml of ethanol were charged in a closed glass vessel equipped with a thermometer and a stirrer. While vigorously stirring the mixture at 45±2° C., hydrogen was introduced thereinto and 11.76 l(0.525 mol) of hydrogen was absorbed in 7 hours. The reaction mixture was cooled to 30±2° C. and 11 g of 28% aqueous ammonia was added thereto. Hydrogen was introduced at the same temperature and 3.84 l (0.17 mol) of hydrogen was absorbed in 5 hours. After the completion of the reaction, the temperature of the reaction mixture was raised to 75° to 80° C. The catalyst and contaminants were removed by filtering the reaction mixture with heating. The filtrate was cooled to precipitate 3,3'-diaminobenzophenone as a yellow crystal. The crystal was recovered by filtration, washed with a 50% aqueous ethanol solution, and dried to give 15.3 g (yield 72.2% based on the crude chlorodinitrobenzophenone) of a product with m.p. of 148° to 149.5° C. This product was recrystallized from water to give pure 3,3'-diaminobenzophenone as a light yellow needle crystal with m.p. of 149° to 150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[N:7]=[C:6]2[CH2:25]O.S(Cl)([Cl:29])=O.C(OCC)(=O)C.CCCCCC>ClCCl>[Cl:29][CH2:25][C:6]1[C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cn2nc(CO)c3cc(OC)c(OC)cc32)cc1OC
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(CCl)c3cc(OC)c(OC)cc32)cc1OC
Temperature: 25 °C

Procedure:
In 1500 ml of dichloromethane was dissolved 184.0 g of 5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-3-hydroxymethyl-1H-indazole at room temperature, followed by stirring under cooling with ice. To the solution was added dropwise 75.4 ml of thionyl chloride over 20 minutes. One minute later, the spot of the starting material on a thin layer chromatogram (ethyl acetate:hexane=2:1) disappeared. The reaction mixture was warmed to room temperature, and 3500 ml of dichloromethane was added thereto. The mixture was washed with 1000 ml of a saturated sodium Hydrogencarbonate aqueous solution, dried over sodium sulfate, filtered, and the evaporation of the solvent gave 189.7 g of a colorless solid. This solid was used in the subsequent reaction without further purification.