Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-])=O.[OH-].[Na+].[C:17](=[S:19])=[S:18].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)(=O)C>[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]2[S:19][C:17](=[S:18])[NH:12][C:3]=2[CH:4]=1)([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: S=C=S
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc2sc(=S)[nH]c2c1
Temperature: 115 °C
Yield: 54.3 %

Procedure:
A solution of 4-chloro-3-nitro-phenylacetic acid (25.0 g, 0.116 mol) in 1N aqueous NaOH (143 mL, 0.143 mol) was added to preformed polysulfide solution (from 72.42 g, 0.301 mol of Na2S.9H2O, 26.87 g, 0.837 mol of S, and 74 mL of H2O) at 50° C. The resulting mixture was mechanically stirred as the temperature of the oil bath was gradually increased to 115° C. over 10 min. The mixture was stirred at that temperature for two hours then allowed to cool to room temperature over two hours. Carbon disulfide (13.9 mL, 0.231 mol) was added and the reaction flask was placed in a 50° C. oil bath. The reaction mixture was stirred at that temperature for 18 hours then cooled in an ice bath, stirred, and acidified by cautious addition of glacial acetic acid (50 mL). The mixture was filtered and the filter cake was washed with water. The solid was stirred with sodium carbonate (30.7 g, 0.29 mol) in water then filtered to remove sulfur. The filtrate was cooled in an ice-bath and gradually acidified to pH 3.3 by addition of 6N HCl (100 mL). The precipitate was collected, washed with ice-cold water (100 mL) and dried in vacuo to a pale brown solid (21.5 g, 82%). This crude product was recrystallized from ethanol to afford 5-carboxymethyl-2-thioxo-2,3-dihydrobenzothiazole as a pale brown solid (14.2 g).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH2:10]([N:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][NH2:16])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:3][C:2]1[N:1]=[C:8]([NH:16][CH2:15][CH2:14][CH2:13][N:12]([CH2:17][CH3:18])[CH2:10][CH3:11])[N:7]=[C:5]([NH:16][CH2:15][CH2:14][CH2:13][N:12]([CH2:17][CH3:18])[CH2:10][CH3:11])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCN(CC)CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCN(CC)CCCNc1nc(Cl)nc(NCCCN(CC)CC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following the procedure described in Japanese Patent Publication No. 39272/74, 50.0 ml of water was cooled to 3° C. and slowly 18.4 g (0.1 mole) of cyanuric chloride was added while maintaining 3°-5° C. by means of an external ice-water bath. Slowly 26.0 g (0.2 mole) of 3-(diethylamino)propylamine was added while maintaining 3°-12° C. by means of an ice-water bath. The resulting solution was stirred at ambient temperature for approximately eight hours and allowed to stand overnight. Slowly a 10 percent aqueous potassium carbonate solution was added to the reaction solution until it was slightly alkaline. The solid which precipitated was collected by filtration. The water wet filter cake was resuspended in water and dissolved by the addition of hydrochloric acid. Slowly 10 percent aqueous potassium carbonate was added until the mixture was slightly alkaline. The resulting solid was collected by filtration, washed with water and dried in vacuo to obtain 2-chloro-4,6-bis[3-(diethylamino)propyl]amino-1,3,5-triazine, a water-insoluble, white colored solid which melted at 119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9]Br>ClCCl.O>[Br:9][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[OH:8]
Reactant: Oc1cccc(Cl)c1
Reactant: BrBr
Solvent: ClCCl
Solvent: O
Product: Oc1cc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
A solution of 5.03 gm (39.1 mMol) 3-chlorophenol in 20 mL dichloromethane was cooled in an ice bath as 6.25 gm (39.1 mMol) bromine were added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was diluted with water, the phases separated, and the organic phase dried over magnesium sulfate. The residue was subjected to silica gel chromatography, eluting with 3:2 dichloromethane:hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 2.04 gm (25%) of 2-bromo-5-chlorophenol.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][SH:6].[O-]CC.[Na+].Cl.[NH:12]([C:16]1[S:17][CH:18]=[C:19]([CH2:21][Cl:22])[N:20]=1)[C:13]([NH2:15])=[NH:14]>C(O)C>[ClH:22].[NH:12]([C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:6][CH2:5][CH2:4][CH2:3][NH2:2])[N:20]=1)[C:13]([NH2:15])=[NH:14]
Reactant: N=C(N)Nc1nc(CCl)cs1
Reactant: NCCCS
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N=C(N)Nc1nc(CSCCCN)cs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Aminopropanethiol hydrochloride (2.54 g.) in ethanol (20 ml.) was added to a solution of sodium ethoxide (1 g. Na in 25 ml. ethanol) at 0° C. under a nitrogen atmosphere. The suspension was stirred at 0° C. for 2 hours and a solution of 2-guanidino-4-chloromethylthiazole hydrochloride (2.27 g.) in ethanol (25 ml.) was then added. The suspension was allowed to reach room temperature and stirred for 16 hours. Filtration of the suspension and acidification of the filtrate with concentrated hydrochloric acid gave a precipitate of 2-guanidino-4-[(3-aminopropyl)thiomethyl]thiazole hydrochloride, m.p. >350° C.
Reaction SMILES: [OH:1][C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:6]([CH3:7])[CH2:5]1)=O.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].N1CCCC1>ClCCl>[CH3:7][N:6]1[C@H:8]2[C:18]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:20]=3[C:10](=[CH:11][NH:12]4)[CH2:9]2)=[CH:19][C@@H:4]([C:2]([N:23]2[CH2:24][CH2:25][CH2:22][CH2:21]2)=[O:1])[CH2:5]1
Reactant: CCN(CC)CC
Reactant: CN1C[C@H](C(=O)O)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: ClCCl
Solvent: C1CCNC1
Product: CN1C[C@H](C(=O)N2CCCC2)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
30 g (111.80 mmol) lysergic acid is dissolved in 400 ml dichloromethane and cooled to 0°-5° C., 31.16 ml (223.61, 2 eq.) triethylamine and 18.66 ml (223.61 mmol, 2 eq.) pyrrolidine is added and within 15 minutes 1.5 equivalents propanephosphonic acid anhydride (50% in ethyl acetate). The reaction mixture is stirred for 1 hour at room temperature, then it is poured onto ice and extracted with dichloromethane, the organic layer is dried with Na2SO4, evaporated and the residue (28.6 g) is purified by chromatography on silica eluting with dichloromethane:methanol 9:1 to give ((6aR,9R)-7-Methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinolin-9-yl)-pyrrolidin-1-yl-methanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:31]=[CH:30][C:18]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]3)=[O:20])=[CH:17][CH:16]=2)=[N:12][CH:13]=1)=[O:6].[CH2:36]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)[C:37]1[CH:45]=[CH:44][C:43]2[O:42][CH2:41][O:40][C:39]=2[CH:38]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:36]([N:46]1[CH2:51][CH2:50][N:49]([C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:19]([C:18]3[CH:17]=[CH:16][C:15]([O:14][C:11]4[N:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]5[CH:32]=[CH:33][C:34]([Cl:35])=[C:2]([Cl:1])[CH:3]=5)=[CH:9][CH:10]=4)=[CH:31][CH:30]=3)=[O:20])[CH2:22][CH2:23]2)=[O:28])[CH2:48][CH2:47]1)[C:37]1[CH:45]=[CH:44][C:43]2[O:42][CH2:41][O:40][C:39]=2[CH:38]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCC(C(=O)O)CC3)cc2)nc1)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCC(C(=O)N4CCN(Cc5ccc6c(c5)OCO6)CC4)CC3)cc2)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzoyl}piperidine-4-carboxylic acid (7.96 g, 15.5 mmol) in DMF (160 mL) were added 1-piperonylpiperazine (3.75 g, 17.6 mmol), 1-hydroxybenzotriazole monohydrate (2.85 g, 18.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.56 g, 18.6 mmol) under ice cooling, and the resulting solution was stirred for overnight at room temperature. This reaction solution was concentrated under reduced pressure. To the residue were added water and ethyl acetate, and the resulting solution was vigorously stirred. The resulting precipitates were collected by filtration and recrystallized from a dichloromethane-methanol mixed solvent, to thereby yield 7.36 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.O[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])=[CH:5][CH:4]=1
Reactant: O=Cc1cccc(O)c1
Reactant: CN(C)c1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)c1ccc(COc2cccc(C=O)c2)cc1
Temperature: 25 °C

Procedure:
Mix 4-(dimethylamino)benzyl alcohol (3.35 g. 22 mmol), 3-hydroxybenzaldehyde (2.69 g, 22 mmol), triphenylphosphine (5.8 g, 22 mmol) and diethylazadicarboxylate (3.83 g, 22 mmol) in tetrahydrofuran (25mL). Stir at room temperature under anhydrous atmosphere until the reactionis done. Concentrate the solution in vacuo and dilute with a small quantityof ethyl ether. Filter any precipitate and concentrate the filtrat in vacuo. Purify by silica gel chromatography to give 3-(4-(dimethylamino)-benzyloxy) benzaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>>[OH:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)cn1
Product: Cc1ccc(O)c([N+](=O)[O-])n1
Temperature: 6 °C

Procedure:
To 40 ml. of ice cold concentrated sulfuric acid was added 10.9 g. of 3-hydroxy-6-methylpyridine. Maintaining the temperature at 6° C., 4.7 ml. of fuming nitric acid was added dropwise with stirring. The mixture was allowed to warm to room temperature overnight. Ice (200 g.) was added with stirring. After the ice had melted, the precipitate was collected, washed with water and dried to give 3-hydroxy-6-methyl-2-nitropyridine, m.p. 103°-105° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1([CH3:22])[CH:15]=[CH:14][C:13]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:12]=2[O:11]1.[CH2:23]([O:30][C:31]([NH:33][C@H:34]([C:36]([OH:38])=[O:37])[CH3:35])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:23]([O:30][C:31]([NH:33][C@@H:34]([CH3:35])[C:36]([O:38][C@H:14]1[C:13]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:12]=2[O:11][C:10]([CH3:22])([CH3:9])[C@@H:15]1[Br:1])=[O:37])=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)C=Cc2cc(C#N)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1Br
Yield: 29.2 %

Procedure:
N-Bromosuccinimide (6.408 g) was added to a solution of 2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (5.55 g) and N-benzyloxycarbonyl-L-alanine (6.69 g) in chloroform (60 ml). After being stirred under reflux for 16 hours, the mixture was poured into saturated aqueous sodium bicarbonate and diluted with chloroform. The organic layer was separated, washed successively with 5% aqueous sodium thiosulfate, water, and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was dissolved in diisopropyl ether and allowed to stand at ambient temperature. The resulting precipitates were collected by filtration, washed with diisopropyl ether, and dried to give (3R,4S)-4-{(2S)-2-benzyloxycarbonylaminopropionyloxy}-3-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (4.26 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C(=O)O)c1C
Product: Cc1cccc(C(=O)Cl)c1C

Procedure:
As described for Reference Example 26, 3.0 g of 2,3-dimethylbenzoic acid is reacted with 40 ml of thionyl chloride to give 3.2 g of the product as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH2:4][CH:3]1[CH2:20][NH:21][C:22](=[O:42])[CH:23]([NH:34]C(OC(C)(C)C)=[O:36])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1.[ClH:43]>C(OCC)(=O)C>[OH2:36].[ClH:43].[ClH:43].[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH2:4][CH:3]1[CH2:20][NH:21][C:22](=[O:42])[CH:23]([NH2:34])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1.[OH2:36].[OH2:36].[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH2:4][CH:3]1[CH2:20][NH:21][C:22](=[O:42])[CH:23]([NH2:34])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1.[ClH:43].[ClH:43]
Reactant: CN1c2ccccc2C(c2ccccc2F)=NCC1CNC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1c2ccccc2C(c2ccccc2F)=NCC1CNC(=O)C(N)Cc1c[nH]c2ccccc12
Product: O
Temperature: 0 °C

Procedure:
1-Methyl-2-[2-((1,1-dimethylethoxy)carbonyl)amino-3-(1H-indol-3-yl)propanoyl]aminomethyl-5-(2'-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine (50 mg, 0.08 mmole) was dissolved in 2 ml of ethyl acetate, cooled to 0° C. and treated with hydrogen chloride gas for 1 hour. The solvent and excess hydrogen chloride were removed under reduced pressure to give the product as a foam which was 96% pure by HPLC.
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].CO[C:7]1[CH:8]=[C:9]([NH:17][C:18]([NH2:20])=[NH2+:19])[CH:10]=[C:11](OC)[C:12]=1OC.[Cl:21]C1C=C(C=CC=1)N.N#CN.[N+]([O-])(O)=O>O>[N+:1]([O-:4])([O-:3])=[O:2].[Cl:21][C:7]1[CH:8]=[C:9]([NH:17][C:18]([NH2:20])=[NH2+:19])[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1cc(NC(N)=[NH2+])cc(OC)c1OC
Agent: N#CN
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: NC(=[NH2+])Nc1cccc(Cl)c1

Procedure:
The 3-chlorophenylguanidinium nitrate starting material was prepared by the method described for 3,4,5-trimethoxyphenylguanidinium nitrate in Example 1 from 3-chloroaniline (10.35 g, 81.2 mmol), cyanamide (10.2 ml of a 50% w/v solution in water) and concentrated nitric acid (6 ml, 85.3 mmol) to give the desired product as a pale brown solid (12.5 g) m.p. 172-174°. δH (d6 DMSO) 9.75 (1H, br s), 7.52 (4H, br s), 7.45 (1H, t, J 7.8 Hz), 7.35-7.29 (2H, m) and 7.21 (1H, d, , 8.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][NH2:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(ON)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To 69a (6.93 g, 20 mmol) in 40 mL of DCM was added hydrazine hydrate (2.91 mL, 60 mmol). The mixture was stirred at room temperature for 4 h, cooled in an ice bath for 30 minutes, then filtered. The solid was rinsed with 10 mL of DCM and the filtrate was evaporated. After cooling in the fridge, more solid precipitated and the oil was dissolved in 10 mL of DCM and filtered. The filtrate was evaporated to give 4.31 g (99% yield) of 69b.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[K+].[CH2:29](OS(OCC)(=O)=O)[CH3:30].[NH4+].[OH-]>O.CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)=[N:11][C:10]([C:23]([F:24])([F:25])[F:26])=[N:9]2)=[CH:6][CH:7]=1)[CH3:30]
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(O)cc2)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(-n2nc(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A mixture of 1-(4-hydroxy-phenyl)-5-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole (4 g, 10.4 mmol), KOH (1.5 g, 26.8 mmol) and DMF (40 ml) was stirred at room temperature for 1 h. Then diethylsulfate (1.6 ml, 12.2 mmol) was added, the reaction mixture stirred at room temperature for 13 h, NH4OH (20 ml) added and the mixture poured into water (1 l). The precipitate was filtered, washed several times with water and dried. Recrystallization from ethanol yielded a white solid (3.7 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10](Cl)[C:4]=2[CH:3]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)C.O>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]([N:24]3[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][OH:18])[CH2:22][CH2:23]3)[C:4]=2[CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: Cc1ccc2c(c1)C(Cl)c1ccccc1CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(N1CCN(CCO)CC1)c1ccccc1CO2
Temperature: 80 °C
Yield: 79 %

Procedure:
In this example, 3.7 g of crude crystals of 2-methyl-11-chloro-6,11-dihydrodibenz[b,e]oxepin obtained from 3.6 g of 2-methyl-6,11-dihydrodibenz[b,e]oxepinone-11 in the same manner as in Example 1 are dissolved in 60 ml of toluene and the solution is dropwise added to a solution of 9.8 g of 1-(2-hydroxyethyl)piperazine in 20 ml of toluene, followed by heating for 2 hours at 80° C. After completion of the reaction, 30 ml of water is added thereto, and the pH of the solution is adjusted to 2.0 with concentrated hydrochloric acid. Then, a toluene layer is discarded, and 20 ml of ethyl ether is added to an aqueous layer, followed by readjusting the pH of the solution to 10.5 with a 10 N sodium hydroxide aqueous solution. The aqueous layer is discarded, and the ethyl ether layer is dehydrated and concentrated under reduced pressure. The residue is purified through silica gel chromatography. Concentration of the main fractions gives 4.0 g of 2-methyl-11-[4-(2-hydroxyethyl)-1-piperazinyl]-6,11-dihydrodibenz[b,e]oxepin [compound 37] in an oily free base in a yield of 79%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][NH2:12].[CH3:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH2:15]1>>[CH3:11][N:12]1[C:8](=[O:10])[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:28]1[C:27]1[CH:30]=[CH:31][C:24]([O:23][CH2:22][CH2:21][CH2:20][N:16]2[CH2:17][CH2:18][CH2:19][C@H:14]([CH3:13])[CH2:15]2)=[CH:25][CH:26]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: C[C@H]1CCCN(CCCOc2ccc(C=O)cc2)C1
Reactant: CN
Product: C[C@H]1CCCN(CCCOc2ccc(-c3nc4cccnc4c(=O)n3C)cc2)C1

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 3-aminopyridin-2-carboxylic acid, methylamine and 4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}benzaldehyde. The resulting compound was recrystallized from diethyl ether-heptane to give a colorless acicular crystal (m.p. 83.5-88.5° C.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1.O[CH:39]1[CH:44]2[CH2:45][CH2:46][N:41]([CH2:42][CH2:43]2)[CH2:40]1>O1CCCC1>[N:41]12[CH2:46][CH2:45][CH:44]([CH2:43][CH2:42]1)[CH:39]([O:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1)[CH2:40]2
Reactant: Oc1ccon1
Reactant: OC1CN2CCC1CC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OC2CN3CCC2CC3)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.2 %

Procedure:
A solution of 9.18 g of triphenylphosphine in 100 ml of tetrahydrofuran was cooled to 5° C. 6.10 g of diethyl azodicarboxylate were then added dropwise to the cooled solution, after which 2.98 g of 3-hydroxyisoxazole and 4.45 g of 3-hydroxyquinuclidine were added, and the resulting mixture was stirred at room temperature for 24 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to afford 5.18 g (yield 76.2%) of the title compound as a colorless powder, melting at 80°-81° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=3)[CH2:11][CH2:10][N:9]=2)=[CH:4][C:3]=1[O:19][CH3:20].C(=O)([O-])[O-].[Na+].[Na+].[F:27][C:28]([F:41])([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>O1CCOCC1>[F:41][C:28]([F:27])([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=4)[CH2:11][CH2:10][N:9]=3)=[CH:4][C:3]=2[O:19][CH3:20])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: COc1cc(C2=NCCc3ccc(Cl)cc32)ccc1N
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(C2=NCCc3ccc(Cl)cc32)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
28.7 mg of 1-(4-amino-3-methoxyphenyl)-7-chloro-3,4-dihydroisoquinoline are dissolved in 400 μl of dioxane, and 300 μl of a 0.33 molar solution of sodium carbonate are then added. 480 μl of a 0.25 molar solution of 4-trifluoromethoxybenzenesulfonyl chloride in dioxane are added to this mixture. The whole is stirred at RT for 16 h and the reaction mixture is loaded, at neutral pH, onto a cartridge containing 400 mg of diatomaceous earth and 300 mg of alumina. The product is eluted with 12 ml of dichloromethane. The eluate is concentrated and the residue is purified by flash chromatography on silica gel. 34 mg of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.ON1[C:23]2C=CC=C[C:22]=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:42][NH:43][C:44]1=[N:45][C:46](=[O:56])[S:47]/[C:48]/1=[CH:49]\[CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C=O)C.O.C(N(CC)CC)C>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([N:53]1[CH2:54][CH2:55][CH:50](/[CH:49]=[C:48]2/[C:44]([NH:43][CH2:42][C:22]#[CH:23])=[N:45][C:46](=[O:56])[S:47]/2)[CH2:51][CH2:52]1)=[O:7]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(=O)c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
2,4-Bis(trifluoromethyl)benzoic acid (1.20 g) was added to a solution of 1-hydroxybenzotriazole (0.76 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.07 g), (5Z)-4-(methylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (1.5 g), triethylamine (1.3 mL) in DMF (50 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (1.7 g).