Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].F[C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[C:11]#[N:12]>CN(C=O)C>[CH:2]([O:4][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:15]=1)[C:11]#[N:12])([CH3:3])[CH3:1]
Reactant: CC(C)O
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C#N)cc(C(F)(F)F)c1
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 131.3 %

Procedure:
To a mixture of propan-2-ol (102.96 g 1.76 moles) in DMF (3200 mL, 8 V) at 5° C. was added NaH (122 g, 5.08 moles). The mixture was stirred for 2 hours. To this mixture 3-fluoro-5-(trifluoromethyl)benzonitrile (400, 2.1 moles) was added dropwise. The temperature of the mass was increased to 25 to 30° C. and maintained at same temperature for 1 hour. Reaction was monitored by HPLC. After completion, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate and then concentrated under vacuum to give 530 g (2.31 moles; 110%) of 3-isopropoxy-5-(trifluoromethyl)benzonitrile, which was taken as such to next step with no further purification. HPLC purity—96.5% by area (a/a).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([NH:10][NH2:11])=O)[CH:5]=[CH:4][N:3]1[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17].[CH3:20][N:21]=[C:22]=[S:23]>CO.O>[SH:23][C:22]1[N:21]([CH3:20])[C:8]([C:6]2[CH:5]=[CH:4][N:3]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:2](=[O:1])[CH:7]=2)=[N:10][N:11]=1
Reactant: C[Si](C)(C)CCOCn1ccc(C(=O)NN)cc1=O
Reactant: CN=C=S
Solvent: CO
Solvent: O
Product: Cn1c(S)nnc1-c1ccn(COCC[Si](C)(C)C)c(=O)c1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 105.8 %

Procedure:
The title compound of Example 20.1 (19.0 g, 67.0 mmol) was stirred in methanol (150 mL) and heated to 60° C. Methyl isothiocyanate (5.04 mL, 73.7 mmol) was then added via a syringe. After stirring for 40 minutes, a solution on NaOH (2.95 g, 73.7 mmol) in water (30 mL) was added and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The aqueous residue was neutralized, extracted with chloroform, and the organic layer dried over sodium sulfate and concentrated. The residue was purified by silica gel using ethyl acetate to give the product (24.0 g, 56%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28]OC4C=CC=CC=4)[CH:22]=3)[O:20][C@@:6]1([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:7][O:8]2)(=[O:3])[CH3:2].[BrH:41].CC(O)=O>C(O)(=O)C>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][Br:41])[CH:22]=3)[O:20][C@@:6]1([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(COc4ccccc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Reactant: Br
Solvent: CC(=O)O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(CBr)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(phenoxymethyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (5.5 g, 9.54 mmol), in acetic acid (23.62 mL) under nitrogen atmosphere, was added 37% HBr/AcOH (47.7 mL). The reaction mixture was stirred at r.t. for 3 h. After the completion of the reaction as confirmed by TLC, the reaction mixture was cooled to 0° C. and quenched very slowly with saturated solution of potassium carbonate until effervescence ceases. The crude compound was extracted with ethyl acetate (2×300 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford crude compound which was purified by column chromatography (silica gel, 3:7 Ethyl acetate:Pet ether) to afford the title compound (4.28 g, 79%) as a white solid.
Reaction SMILES: C1(N)C=CC=CC=1.[N+:8]([C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([N+:21]([O-:23])=[O:22])[C:12]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[CH:26]=1)([O-:10])=[O:9].[Cl:39]Cl>ClCCl>[N+:21]([C:13]1[CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:37])([F:38])[C:33]([F:34])([F:35])[F:36])[C:26]=1[Cl:39])([O-:23])=[O:22]
Reactant: ClCl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Nc1cccc(OC(F)(F)C(F)(F)F)c1
Solvent: ClCCl
Solvent: Nc1ccccc1
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Nc1cccc(OC(F)(F)C(F)(F)F)c1Cl

Procedure:
When desired, the above described halogenation reaction can be carried out utilizing less than one molar quantity of halogenating agent, thereby effecting monohalogenation instead of dihalogenation. The monohalogenated product can be further halogenated if desired with the same or a different halogenating agent. For instance a benzenamine such as N-(2,6-dinitro-4-trifluoromethylphenyl)-3-(1,1,2,2,2-pentafluoroethoxy)benzenamine can be reacted with about a 0.5 molar amount of chlorine in dichloromethane at about 25° C. to give N-(2,6-dinitro-4-trifluoromethylphenyl)-2-chloro-3-(1,1,2,2,2-pentafluoroethoxy)benzenamine. The latter compound can be further halogenated, for instance by reaction with about a 0.5 to 1.0 molar amount of bromine in dichloromethane, to provide the corresponding dihalogenated derivative, for example N-(2,6-dinitro-4-trifluoromethylphenyl)-2-chloro-4-bromo-5-(1,1,2,2,2-pentafluoroethoxy)benzenamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8](O)=[O:9].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([Cl:20])=[O:9]
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(-c2ccccc2)cc1F
Reaction time: 2 h

Procedure:
Combine 3-fluorobiphenyl-4-carboxylic acid 10.46 g (0.048 mol), 432 mL of methylene chloride, 7 drops of dimethylformamide, and 5.44 mL (0.062 mol, 1.3 equiv) of oxalyl chloride. After 2 h, evaporate the solvent to afford 3-fluorobiphenyl-4-carbonyl chloride as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][C:34]([CH:36]1[CH2:40][CH:39]([NH:41][CH3:42])[CH2:38][N:37]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:35]>>[CH3:32][O:33][C:34]([CH:36]1[CH2:40][CH:39]([N:41]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:31])([F:29])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH3:42])[CH2:38][N:37]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:35]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNC1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Product: COC(=O)C1CC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CN1C(=O)OC(C)(C)C

Procedure:
4-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-Methylamino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester following General Procedure C.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Br:19])[CH:16]=3)[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.C(O)(=O)CC>Br>[BrH:19].[Br:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][NH:10][CH2:18]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(Br)cc3C2)cc1
Agent: Br
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: Brc1ccc2c(c1)CNC2
Yield: 176.8 %

Procedure:
In 25 ml of 47% hydrobromic acid was suspended 5.0 g of 2-(p-toluenesulfonyl)-5-bromoisoindoline, and 4.0 g of phenol and 15 ml of propionic acid were added to the suspension, after which the resulting mixture was heated under reflux for four hours. The reaction mixture was concentrated under reduced pressure, and ethanol was added to the residue obtained, after which the resulting crystals were collected by filtration, to obtain 3.5 g of 5-bromoisoindoline hydrobromide. The hydrobromide obtained was suspended in 50 ml of methylene chloride, and 2.8 g of triethylamine was added to the suspension, after which 2.4 g of carbobenzoxy chloride was dropwise added thereto with ice-cooling. Thereafter, the resulting mixture was stirred at room temperature for one hour. The reaction mixture was added 50 ml of water and the pH was adjusted to 1 with 6N hydrochloric acid. Thereafter, the organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium chloride. The solvent was then removed by distillation under reduced pressure. To the residue thus obtained was added n-hexane, and the resulting crystals were collected by filtration to obtain 3.8 g of colorless, crystalline 2-benzyloxycarbonyl-5-bromoisoindoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:21])=[O:6]
Reactant: COc1ccc(C(=O)O)c(OC)c1OC
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c(OC)c1OC
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2,3,4-trimethoxybenzoic acid (7.3 g) was dissolved in methanol (73 ml), mixed with sulfuric acid (15 ml), and stirred for 3 hours while heating at 80° C. The resultant was allowed to stand for cooling, evaporated under reduced pressure for removing the solvent, and the residue was added to cold water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water and then with a saturated aqueous sodium chloride solution, dried over sodium sulfate anhydride, and evaporated under reduced pressure for removing the solvent to give Compound IIbt-a (6.8 g, 87%) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[NH:12][C:11](=[O:13])[C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[N:12]=[C:11]([O:13][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nn(-c2ccc(F)cc2)[nH]c1=O
Reactant: FC(F)(F)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccc(F)cc2)nc1Oc1ccnc(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
To a solution of 2-(4-fluorophenyl)-2,3-dihydro-5-methyl-4H-1,2,3-triazol-4-one (i.e. the product of Step C, 3.1 g, 16 mmol) in N,N-dimethylformamide (70 mL) was added anhydrous potassium carbonate (6.2 g, 45 mmol) under an atmosphere of nitrogen. 4-Chloro-2-trifluoromethyl-pyridine (2.9 g, 16 mmol) was added and the mixture was heated to 100° C. for 20 h. The reaction mixture was diluted with water, then extracted with diethyl ether. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel eluting with 0 to 20% ethyl acetate in hexanes to obtain the title compound (4.2 g) as a viscous light yellow oil that solidified upon standing to form an off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:22])[CH2:20]Cl)[C:10]2[CH:23]=[CH:24][CH:25]=[CH:26][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:22])[CH2:20][NH:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]2[CH:23]=[CH:24][CH:25]=[CH:26][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C1[C@H]2CCC[C@H]2N(C(=O)CCl)c2ccccc2N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CNCc2ccccc2)c2ccccc2N1Cc1ccccc1
Yield: 30 %

Procedure:
To a solution of (3aR*,10aS*)-9-benzyl-4-(chloroacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]-cyclopenta[e][1,4]diazepin-10(1H)-one (1.0 g, 2.7 mmol) and benzylamine (1.45 g, 13.6 mmol) in ethanol (30 mL) was added potassium carbonate (560 mg, 4.1 mmol), and the mixture was refluxed for 17 hours. The solvent was distilled off. To the residue was added water, which was subjected to extraction with dichloromethane. The extract was washed with water, dried and, then, the solvent was distilled off. The residue was purified by silica-gel column chromatography (ethyl acetate-hexane 1:1), followed by crystallization from diethyl-ether to give 0.36 g (yield 30%), m.p. 95-98° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:15]([CH3:21])[CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C([Li])CCC.[C:29](OCC)(=[O:31])[CH3:30]>O1CCCC1>[C:19]([CH:18]([CH2:17][CH2:16][CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:8][CH:7]=2)[CH:10]=1)[CH3:21])[C:29](=[O:31])[CH3:30])#[N:20]
Reactant: CC(CCCC#N)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)C(C#N)CCC(C)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 2.5 grams (0.008 mole) of 5-[3-(4-trifluoromethylphenyl)phenyl]hexanenitrile in 20 mL of tetrahydrofuran was cooled to about -78 ° C., and 3.2 mL (0.008 mole) of n-butyllithium (2.5 molar in hexane) was added dropwise. Upon completion of addition, the reaction mixture was stirred at -78 ° C. for 30 minutes, and then 1.1 grams (0.012 mole) of ethyl acetate was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 60 hours. The reaction mixture was partitioned between ethyl acetate and aqueous dilute hydro-chloric acid. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 25% ethyl acetate in hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.9 gram of 3-cyano-2-oxo-6-[3-(4-trifluoromethylphenyl)phenyl]heptane. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([OH:4])=[O:3].[Cl:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].CC[O-].[Na+]>>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([Cl:7])[C:1](=[O:6])[C:2]([OH:4])=[O:3])[CH3:13]
Reactant: CCOC(=O)CCl
Reactant: O=C(O)C(=O)O
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(Cl)C(=O)C(=O)O

Procedure:
by ester condensation, e.g. by the reaction of oxalic acid or its diethylester with ethyl chloroacetate in the presence of sodium ethylate, α-chloro-β-keto-succinic acid ethyl ester is obtained in accordance with the following reaction scheme:
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.[CH3:47][N:48]([CH3:56])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]O>>[Cl:46][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][N:48]([CH3:56])[CH3:47])=[C:27]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: CN(C)CCCCCCO
Agent: c1ccc2[nH]ccc2c1
Product: CN(C)CCCCCCOc1c2[nH]c3ccc(Cl)cc3c2cc2c1[nH]c1ccc(Cl)cc12

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is 6-dimethylamino-1-hexanol. 1H-NMR (400 MHz, CDCl3) δ ppm 8.35 (s, 1 H), 8.20 (s, 2 H), 8.08 (s, 2 H), 7.41-7.32 (m, 4 H), 4.28 (t, J=6.4 Hz, 2 H), 2.31 (t, J=7.2 Hz, 2 H), 2.23 (s, 6 H), 2.00-1.90 (m, 2 H), 1.65-1.42 (m, 6 H); MS (ESI) m/z 466.2 (M−H)−; MS (ESI) m/z 468.1 (M+H)+
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:31]=[CH:30][C:15]([CH2:16]/[C:17](=[C:22](\[CH:27]([CH3:29])[CH3:28])/[C:23]([O:25][CH3:26])=[O:24])/[C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=1)=O)(C)(C)C.Cl.ClCCl.CO>CO>[CH3:21][O:20][C:18](=[O:19])/[C:17](/[CH2:16][C:15]1[CH:30]=[CH:31][C:12]([O:11][CH2:10][CH2:9][NH2:8])=[CH:13][CH:14]=1)=[C:22](/[CH:27]([CH3:28])[CH3:29])\[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)/C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)=C(\C(=O)OC)C(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)/C(Cc1ccc(OCCN)cc1)=C(\C(=O)OC)C(C)C
Reaction time: 20 h
Yield: 100.4 %

Procedure:
To a solution of dimethyl 2-{4-[2-(t-butoxycarbonylamino)ethoxy]benzyl}-3-isopropylmaleate (287 mg, 0.659 mmol) in methanol (6 mL) was added 5 M hydrochloric acid (5.9 mL) at room temperature, and the mixture was left standing at room temperature for 20 h. The residue obtained by concentrating the mixture under reduced pressure was dissolved in ethyl acetate, and a saturated aqueous sodium hydrogen carbonate solution was added. After separating the phases, the organic layer was concentrated and the residue thus obtained was subjected to LH-20 (dichloromethane-methanol 1:1) to give 222 mg of the title compound as oil (quantitative).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:52])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][C:27]=4[C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:41][C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][C:50]=2[F:51])[NH:47][CH:46]=[CH:45]3)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:53]([O-:55])=[O:54].[NH2:56][CH2:57][C@H:58]1[CH2:63][CH2:62][C@H:61]([OH:64])[CH2:60][CH2:59]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C:27]2[CH2:28][C:29]([CH3:32])([CH3:33])[CH2:30][CH2:31][C:26]=2[CH2:25][N:22]2[CH2:21][CH2:20][N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:12]([NH:11][S:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:56][CH2:57][C@H:58]5[CH2:63][CH2:62][C@H:61]([OH:64])[CH2:60][CH2:59]5)=[C:3]([N+:53]([O-:55])=[O:54])[CH:4]=4)(=[O:10])=[O:9])=[O:52])=[C:14]([O:41][C:42]4[CH:43]=[C:44]5[C:48](=[CH:49][C:50]=4[F:51])[NH:47][CH:46]=[CH:45]5)[CH:15]=3)[CH2:24][CH2:23]2)=[CH:39][CH:38]=1
Reactant: NC[C@H]1CC[C@H](O)CC1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(Cl)c([N+](=O)[O-])c4)c(Oc4cc5cc[nH]c5cc4F)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC[C@H]5CC[C@H](O)CC5)c([N+](=O)[O-])c4)c(Oc4cc5cc[nH]c5cc4F)c3)CC2)=C(c2ccc(Cl)cc2)C1

Procedure:
A mixture of EXAMPLE 240A (153 mg), trans-4-(aminomethyl)cyclohexanol (73.5 mg) and N-ethyl-N-isopropylpropan-2-amine (0.16 mL) in dioxane (2 mL) was heated at 100° C. for 20 hours and concentrated. The residue was dissolved in dimethylsulfoxide-methanol (1:1) and purified by HPLC, eluting with 40%-65% acetonitrile in 0.1% TFA water over 40 minutes to provide the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 11.22 (s, 2H), 8.56-8.62 (m, 2H), 7.85 (dd, 1H), 7.51 (d, 1H), 7.38 (t, 1H), 7.29-7.36 (m, 4H), 7.12 (d, 1H), 7.03 (d, 2H), 6.66 (dd, 1H), 6.41 (s, 1H), 6.09 (d, 1H), 4.51 (d, 1H), 3.24 (t, 2H), 3.03 (s, 4H), 2.74 (s, 2H), 2.16 (d, 6H), 1.95 (s, 2H), 1.83 (d, 2H), 1.74 (d, 2H), 1.56 (dd, 1H), 1.38 (t, 2H), 0.95-1.16 (m, 4H), 0.92 (s, 6H).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH2:32])(=[O:31])=[O:30]>C1C=CC=CC=1>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:31])(=[O:30])[NH2:32])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(OCC2CCCCC2)c1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
A benzene (30 ml) solution containing 3.00 g (12.8 mmol) of 3-cyclohexylmethoxybenzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.43 g (14.1 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 n hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were recrystallized from acetonitrile to obtain 2.80 g (yield: 56.0%) of the title compound NMR (CDCl3) δ: 1.00-1.39 (5 H, m), 1.68-1.90 (6 H, m), 3.82 (2 H, d J=7 Hz), 4.95 (2 H, s), 7.10 (1 H, ddd, J=8 Hz, 2 Hz, 1 Hz), 7.25 (1 H, ddd, J=8 Hz, 8 Hz, 1 Hz), 7.38 (1 H, dd, J=8 Hz, 8 Hz), 7.45-7.50 (2 H, m), 7.62 (1 H, ddd, J=8 Hz, 8 Hz, 2 Hz), 7.96 (1 H, dd, J=8 Hz, 2 Hz), 8.53 (1 H, dd, J=8 Hz, 1 Hz), 10.03 (1 H, s)
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][S:31]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH2:37]2)(=[O:33])=[O:32].N1CCCCC1>C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][S:31]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])/[C:37]/2=[CH:17]\[C:14]1[NH:13][C:9]2[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH2:4][N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[C:7](=[O:19])[C:8]=2[C:15]=1[CH3:16])(=[O:32])=[O:33]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c(C)c2C1=O
Temperature: 25 °C
Yield: 79.4 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j (60 mg, 0.21 mmol) and 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 64c (67 mg, 0.19 mmol) were dissolved in 3 ml of ethanol, and added with 52 μl of piperidine the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-2-((5-(2,6-dichlorobenzylsulfonyl)-2-oxoindolin-3-ylidene)methyl)-5-(2-(diethylamino)ethyl)-3-methyl-5,6,7,8-tetrahydro pyrrolo[3,2-c]azepin-4(1H)-one 70 (95 mg, yield 79%) as an orange solid.