Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]([CH3:23])[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:33]1[S:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>CN(C)C=O>[S:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[O:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]([CH3:23])[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]2[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=2[Cl:21])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)OCCOCc1c(Cl)cccc1Cl
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2nc3ccccc3s2)cc1)C(=O)OCCOCc1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
38.5 g of 2-(2,6-dichlorobenzyloxy)ethyl 2-(4-hydroxyphenoxy)-propionate were dissolved in 200 ml of dimethylformamide and 15.2 g of potassium carbonate were added to the solution. The mixture was stirred at 80° C. for 1 hour. A solution of 18.6 g of 2-chlorobenzothiazole in 50 ml of dimethylformamide was added dropwise at this temperature to the resulting mixture. After the addition, the mixture was stirred at the same temperature for 2 hours to complete the reaction. The reaction mixture was poured onto ice water, and the separated oily product was extracted with toluene. The toluene layer was washed successively with a 1% aqueous solution of sodium hydroxide and water, and then toluene was evaporated under reduced pressure to give 43.5 g of 2-(2,6-dichlorobenzyloxy)ethyl 2-[4-(benzothiazol-2-yloxy)phenoxy]propionate as a viscous oily product represented by the formula above.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11]O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:15]>C1C=CC=CC=1>[Cl:15][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2ncccc2c1
Solvent: c1ccccc1
Product: ClCc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Quinolin-6-yl-methanol (7.7 g, 48 mmol) was dissolved in benzene (3 mL) and SOCl2 (20 mL) was added at 0° C. The mixture was stirred at RT for 1 h, then heated to reflux and stirred an additional 1 h. The mixture was cooled to RT and the solid was filtered to give the 6-chloromethyl-quinoline.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:9][NH:10][CH2:11][CH2:12][OH:13]>C(=O)(O)[O-].[Na+]>[CH3:9][N:10]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH2:11][CH2:12][OH:13]
Reactant: Clc1ccncc1
Reactant: CNCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(CCO)c1ccncc1

Procedure:
A mixture of 4-chloropyridine hydrochloride salt (15.0 g) and 2-methylaminoethanol (30 mL) was refluxed for 48 hour. After cooling to rt the crude mixture was added slowly to saturated solution of sodium bicarbonate (150 mL). The product was extracted with EtOAc (3×100 mL), the combined EtOAc was washed with brine (50 mL), dried (Na2SO4) and removed in vacuo to give the desired product 2-[methyl(pyridin-4-yl)amino]ethanol as yellow solid (7.0 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:34][C:35]1[CH:36]=[N:37][C:38](S(C)(=O)=O)=[N:39][CH:40]=1>O1CCCC1.CC(N(C)C)=O.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:38]3[N:39]=[CH:40][C:35]([Cl:34])=[CH:36][N:37]=3)[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2c(OCCOc3ncc(Cl)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 0.08 h
Yield: 69.2 %

Procedure:
To 4-(tert-butyl)-N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Example 2) (196 mg) in tetrahydrofuran (2.5 ml) at room temperature under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 37 mg) and the mixture was stirred for 5 minutes. To the mixture was added a solution of 5-chloro-2-methylsulphonylpyrimidine (94 mg) in tetrahydrofuran (5 ml) and dimethylacetamide (0.5 ml) the mixture was stirred for a further 48 hrs. The reaction was diluted with water (200 ml) and extracted with dichloromethane (3×50 ml). The organic fractions were combined, washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (20 g) eluted with ether:hexane (4:1) to yield the title compound as a white solid (170 mg).
Reaction SMILES: N1C=C[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.COC(C)=C.[C:23]([O:27][C:28]([N:30]1[CH2:34][C@H:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH2:32][C@@H:31]1[C@@H:45]([OH:60])[C@@H:46]([NH:56][C:57](=[O:59])[CH3:58])[CH2:47][C:48]1[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[CH:49]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClCCl.CC(C)=O>[C:23]([O:27][C:28]([N:30]1[CH2:34][C@H:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[CH2:32][C@@H:31]1[C@H:45]1[O:60][C:3]([CH3:4])([CH3:2])[N:56]([C:57](=[O:59])[CH3:58])[C@H:46]1[CH2:47][C:48]1[CH:49]=[C:50]([F:55])[CH:51]=[C:52]([F:54])[CH:53]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(CO[C@@H]2C[C@H]([C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(C)=O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: c1ccncc1
Agent: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc(CO[C@@H]2C[C@H]([C@H]3OC(C)(C)N(C(C)=O)[C@H]3Cc3cc(F)cc(F)c3)N(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 1 h
Yield: 607.3 %

Procedure:
Add p-toluene sulfonic acid pyridine salt (0.245 g, 1 mmol) and 2-methoxypropene (4.6 mL, 49 mmol) to a solution of (2R,4R)-2-[(1S,2S)-2-acetylamino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-4-(4-methoxy-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (5.64 g, 10.55 mmol) in dichloromethane (25 mL) and acetone (25 mL). Stir 60 min and concentrate under reduced pressure. Dissolve residue in ethyl acetate and wash with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry magnesium sulfate and purify on silica gel with hexanes/ethyl acetate mixtures to give the desired compound as a foam (3.49 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[NH:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:20]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: C1CCCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1nc(N2CCCCCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloroquinazoline (1.0 g) in tetrahydrofuran (10 mL) were added triethylamine (2.1 mL) and perhydroazepine (0.745 mL) with ice cooling and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water (20 mL) and the resulting mixture was concentrated. The residue was extracted with methylene chloride three times. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with hexane-diethyl ether (10:1) to give the title compound (991 mg) having the following physical data.
Reaction SMILES: S(OC1CC2C3C(=CC=CC=3)NC=2CC1)(C1C=CC(C)=CC=1)(=O)=O.C(N)C.[C:28]([NH:31][CH:32]1[CH2:44][C:43]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][C:35]=2[CH2:34][CH2:33]1)(=O)[CH3:29].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:28]([NH:31][CH:32]1[CH2:44][C:43]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][C:35]=2[CH2:34][CH2:33]1)[CH3:29]
Reactant: CC(=O)NC1CCc2[nH]c3ccccc3c2C1
Agent: CCN
Agent: Cc1ccc(S(=O)(=O)OC2CCc3[nH]c4ccccc4c3C2)cc1
Agent: [Al+3]
Product: CCNC1CCc2[nH]c3ccccc3c2C1

Procedure:
Following the procedure given in Example 18 and using 25 g. of 3-tosyloxy-1,2,3,4- -tetrahydrocarbazole and 90 g. of ethylamine there was otained 3 g. of 3l -(ethylaino)-1,2,3,4-tetraydrocarbazole which melted at 128°-129°C. (corr.). Alternatively this compound can be prepared by reduction of 3-acetamido-1,2,3,4-tetrahydrocarbazole (Example 2) with lithium aluminum hydride following a procedure similar to that described in Example 260 below.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccccc1
Yield: 45.4 %

Procedure:
As described for Example 9, 0.314 g (1.0 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.155 g (1.1 mmol) of benzoyl chloride and 0.111 g (1.1 mmol) of triethylamine in 10 ml of dichloromethane for 1.5 hours at room temperature. The product is recrystallized from dichloromethane-hexane to give 0.19 g of crystals, m.p. 219°-221° C. Anal. Calc'd for C28H22N2O2 : C,80.4; H,5.3; N,6.7. Found: C,79.6; H,5.5; N,6.7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28].O>CN(C=O)C>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:23][CH:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28])[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: CCCCC(CC)CBr
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)Cn1c2ccc(Br)cc2c2cc(Br)ccc21

Procedure:
To a solution of 3,6-dibromocarbazole (3.0 g, 8.95 mmol) in 25 mL of dried DMF was added potassium carbonate (2.47 g, 17.9 mmol). The mixture was stirred and degassed for 1 h, after which 1-bromo-2-ethylhexane (2.70 g, 13.4 mmol) was added dropwise, followed by refluxing for 2 days. The reaction mixture was poured into 100 mL of distilled water and extracted with chloroform. The combined organic layer was dried with anhydrous magnesium sulfate. After removal of the solvent and unreacted 2-ethylhexyl bromide under reduced pressure, the residue was purified by column chromatography on silica gel using hexane and ethyl acetate as the eluent to afford 3,6-dibromo-9-(2-ethylhexyl)-carbazole as a waxy solid. Yield: 3.02 g (77.2%), M.P.: 62.4-63.6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[C:6]([CH3:16])[C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[C:6]([CH3:16])[C:3]=1[C:4]#[N:5]
Reactant: Cc1c(C#C[Si](C)(C)C)ccc(N)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N)c(C#N)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
A mixture of 1.4 grams (0.006 mole) of 2-amino-5-(trimethylsilylethynyl)-6-methylbenzonitrile and 0.9 gram (0.006 mole) of potassium carbonate in 50 mL of methanol was stirred at ambient temperature for one hour. The reaction mixture was then concentrated under reduced pressure to a residue. The residue was taken up in about 75 mL of water, and the solution was extracted with two 200 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.0 gram of 2-amino-5-ethynyl-6-methylbenzonitrile. The NMR spectrum was consistent with the proposed structure. This reaction was repeated several times.
Reaction SMILES: [Mg].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=O.[F:11][C:12]1[C:20]([CH3:21])=[C:19]([F:22])[CH:18]=[CH:17][C:13]=1C(Cl)=O.OS(O)(=O)=O>C1(C)C=CC=CC=1.O.C(O)C.C(Cl)(Cl)(Cl)Cl>[F:11][C:12]1[C:20]([CH3:21])=[C:19]([F:22])[CH:18]=[CH:17][C:13]=1[C:4]([CH2:3][C:2]([O:8][CH2:9][CH3:10])=[O:7])=[O:6]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Cc1c(F)ccc(C(=O)Cl)c1F
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CC(=O)c1ccc(F)c(C)c1F
Reaction time: 8 h

Procedure:
8 ml of ethnol and 1 ml of carbon tetrachloride are added to 3.6 g of magnesium turnings. After initiation of the reaction, a mixture of 22.2 g of ethyl malonate, 15 ml of ethanol and 60 ml of toluene are added at 50° C. The mixture is warmed for 1 hour at 50°-60° C. and then cooled to -5°--10° C. A solution of 25.7 g of 2,4-difluoro-3-methyl-benzoyl chloride (from 2,4-difluoro-3-methylbenzoic acid and thionyl chloride) in 15 ml of toluene is added dropwise at this temperature. The mixture is then allowed to come to room temperature. After standing overnight, a mixture of 60 ml of water and 10 ml of H2SO4 is added dropwise. The phases are separated, and the organic phase is washed with water, dried and concentrated. 50 ml of water and 2.0 g of p-toluenesulphonic acid are added to the oily residue. The mixture is refluxed for 4.5 hours, the phases are separated, and the organic phase is dried and concentrated in vacuo. 33.9 g of the title compound remain as a crude oil.
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:15])=O)[C:4]=2[N:3]=1.C([O-])(=O)C.[NH4+:20]>[NH4+].[OH-].CO>[CH3:1][C:2]1[NH:20][C:13](=[O:15])[C:12]2[C:4](=[C:5]([C:6]([OH:7])=[O:8])[CH:9]=[CH:10][CH:11]=2)[N:3]=1
Reactant: Cc1nc2c(C(=O)O)cccc2c(=O)o1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2c(C(=O)O)cccc2c(=O)[nH]1
Temperature: 80 °C
Yield: 16325.3 %

Procedure:
2-Methyl-4-oxo-4H-3,1-benzoxazine-8-carboxylic acid (51.5 g; 251.26 mmol) was dissolved in NH4OH (360.0 ml; 6.98 V; 28% solution). Ammonium acetate (77.5 g; 1.005 mmol) was added, and the reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with MeOH (40 mL) then heated for 72 h at 80° C. in a pressure bottle. The reaction mixture was concentrated on the rotary evaporator then cooled on ice and filtered. The solid was dried under vacuum to provide the desired product (33.5 g, 65% yield).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23](Cl)[C:22]=1[NH2:32])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([N:20]1[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:32]=[C:1]1[OH:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Oc1nc2cnc3ccccc3c2n1Cc1ccccc1
Temperature: 50 °C
Yield: 70.2 %

Procedure:
1,1′-Carbonyldiimidazole (2.9 g, 18 mmol) was added to a solution of N4-benzyl-2-chloroquinoline-3,4-diamine (5.0 g, 18 mmol) in tetrahydrofuran (THF) (50 mL), and the reaction was heated at 50° C. for three days. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the presence of starting material, and additional 1,1′-carbonyldiimidazole (1.5 g, 9.2 mmol) was added. The reaction was stirred for several hours at 80° C., and additional 1,1′-carbonyldiimidazole (2.9 g, 18 mmol) was added. The reaction was stirred for one hour at 80° C. and overnight at 50° C. A solid was present and was isolated by filtration, washed with diethyl ether, and dried under vacuum to provide 3.48 g of 1-benzyl-1H-imidazo[4,5-c]quinolin-2-ol as a fluffy, white solid. Diethyl ether was added to the filtrate, and the resulting mixture was stirred for 20 minutes. A solid was present and was isolated by filtration and dried under vacuum to provide 0.95 g of 1-benzyl-4-chloro-1H-imidazo[4,5-c]quinolin-2-ol as a fluffy, beige solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:43]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH:42]=[N:41][N:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:43]([CH2:44][CH:45]([CH3:46])[CH3:47])[CH:42]=[N:41][N:40]=5)=[O:57])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CC(C)C)cc2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CC(C)C)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methylthio]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.7 g) was dissolved in dichloromethane (50 ml). The solution was cooled to −78° C., and a solution of 3-chloroperbenzoic acid (0.39 g) in dichloromethane (5 ml) was added dropwise to the solution. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (extraction solvent: ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-((4-isobutyl-4H-1,2,4-triazol-3-yl)methylsulfinyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 33) (0.57 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.S(OC)(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:28](OCC)[CH3:29]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]=[CH:9][C:10]([O:12][CH2:28][CH3:29])=[O:11])=[O:7])=[CH:13][CH:14]=1
Reactant: CCOCC
Reactant: O=C(O)C=CC(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CCOC(=O)C=CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4.22 g of 3-(4-chlorobenzoyl)-acrylic acid in 40 ml of dimethylformamide were added 3.68 g of dimethyl sulfate and 1.36 g of potassium carbonate, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added diethyl ether. The mixture was washed, in turn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate. The diethyl ether was removed from the mixture by evaporation, and the residue was recrystallized from hexane to give 2.68 g of ethyl 3-(4-chlorobenzoyl)acrylate.
Reaction SMILES: C(OC([N:6]1[C:10]2[S:11][C:12]([C:14](OCC)=[O:15])=[CH:13][C:9]=2[C:8]([NH:19][C:20](=[O:34])[C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[N:7]1)C)C.C[Al](C)C.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]([CH3:48])[NH2:47])=[CH:42][CH:41]=1.Cl>C(OCC)(=O)C.P(O)(O)([O-])=O.[K+].O1CCCC1.C1(C)C=CC=CC=1>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]([CH3:48])[NH:47][C:14]([C:12]2[S:11][C:10]3[NH:6][N:7]=[C:8]([NH:19][C:20](=[O:34])[C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[C:9]=3[CH:13]=2)=[O:15])=[CH:42][CH:41]=1
Reactant: CCOC(=O)c1cc2c(NC(=O)c3ccc(N4CCN(C)CC4)cc3)nn(C(C)OCC)c2s1
Reactant: CN(N)c1ccc(Cl)cc1
Agent: C[Al](C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NN(C)c5ccc(Cl)cc5)cc34)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-(1-ethoxyethyl)-3-[4-(4-methylpiperazin-1-yl)benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylate (0.5 g, 1.03 mmol, 1 eq.) and toluene (5 mL) are placed in a dry 20 mL round-bottomed flask under argon. The suspension is stirred at a temperature in the region of 0° C., and a solution of trimethylaluminum (1.54 mL, 3 eq.) is then added dropwise to avoid rises in temperature. Once the addition is complete, the mixture is left stirring for 30 minutes at a temperature in the region of 25° C., followed by addition of a solution of N-(4-chlorophenyl)-N-methylhydrazine (0.480 g, 3.09 mmol, 3 eq.). The reaction mixture is then heated to a temperature in the region of 50° C. until the starting material has totally disappeared. After 2 hours 30 minutes, the mixture is allowed to return to a temperature in the region of 25° C., and is then diluted with ethyl acetate. A few drops of monopotassium phosphate are added thereto, until the evolution of gas has ceased, and the mixture is then left stirring for one hour. The solvent is then evaporated off and then the residue is dissolved in a mixture of dichloromethane and methanol. This solution is placed directly onto silica gel for purification by chromatography, eluting at the start with a methanol/dichloromethane mixture (10/90 by volume). Ethoxyethyl intermediate: LC/MS RT=3.41 min.; M+H+ 596.1. M−H− 594.2. After evaporation, the solid obtained is placed directly in 5 mL of tetrahydrofuran and 2 mL of 5 N hydrochloric acid at a temperature in the region of 50° C. N-{5-[N′-(4-Chlorophenyl)-N′-methylhydrazinocarbonyl]-1H-thieno[2,3-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide is thus obtained (119 mg, 22% for the two steps). MS: ES m/z=524
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[NH:6][CH3:7])[CH:2]=[CH2:3].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18](Br)[CH:19]=[CH2:20]>O>[CH2:18]([N:6]([CH3:7])[C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[CH2:1][CH:2]=[CH2:3])[CH:19]=[CH2:20]
Reactant: C=CCc1ccccc1NC
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCc1ccccc1N(C)CC=C

Procedure:
2-Allyl-N-methylaniline (14.7 g, 0.10 mol) is heated to 80° C. in the presence of 2 M sodium carbonate solution (75 ml) and allyl bromide (14.1 g, 0.116 mol) for 6 hours. The mixture is diluted with water and extracted with ether twice (150 and 75 ml portions). The extracts are washed with water and brine, dried over potassium carbonate, and concentrated to an oil. The oil is distilled on a Kugelrohr apparatus to provide pure N,2-diallyl-N-methylaniline.