Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([C:13](O)=[O:14])[CH2:4][N:3]1[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17].[Cl:29][C:30]1[C:31]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[N:32][CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1>>[Cl:29][C:30]1[C:31]([N:40]2[CH2:45][CH2:44][N:43]([C:13]([CH:5]3[CH2:4][N:3]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:26])[F:27])(=[O:18])=[O:17])[C:2](=[O:1])[N:6]3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:14])[CH2:42][CH2:41]2)=[N:32][CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(Cl)c1
Product: O=C(C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1)N1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1

Procedure:
In analogy to example 1, (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid (example 11) was coupled with 1-[3-chloro-5-(trifluoromethyl)pyrid-2-yl]piperazine to give the title compound as a colorless solid. MS: 663.5 ([M+H])
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17](O)=[O:18])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:28]1C=CN=C1)=O.N>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17](=[O:18])[NH2:28])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(=O)O
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(N)=O
Yield: 100.3 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carboxy-5-phenylisoxazole (0.6 g) was dissolved in tetrahydrofuran (6 ml) and carbonyldiimidazole (0.31 g) was added thereto under ice-cooling with stirring, followed by stirring of the mixture at room temperature for 30 minutes. Aqueous ammonia (1 ml) was added dropwise to the reaction mixture and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried using anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (0.60 g, quantitative) as a colorless powder.
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.O[C:12]1([C:22]2(C(O)=O)[CH2:30][C:26]3[N:27]=[CH:28][S:29][C:25]=3[CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19][C:18]2[N:17]=[CH:16][N:15]=[CH:14][C:13]1=2>N1C=CC=CC=1>[S:29]1[C:25]2[CH2:24][CH2:23][C:22](=[C:12]3[CH2:21][CH2:20][CH2:19][C:18]4[N:17]=[CH:16][N:15]=[CH:14][C:13]3=4)[CH2:30][C:26]=2[N:27]=[CH:28]1
Reactant: O=C(O)C1(C2(O)CCCc3ncncc32)CCc2scnc2C1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: c1ncc2c(n1)CCCC2=C1CCc2scnc2C1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
1.06 g of benzenesulphonyl chloride is added to a solution of 0.66 g of 5-(5-hydroxy-5,6,7,8-tetrahydroquinazoline-5-yl)-4,5,6,7-tetrahydrobenzothiazole-5-carboxylic acid and 20 ml of pyridine at 0° C. After 2 hours at 0° C., the reaction mixture is poured into ice-water—the resulting solid is filtered off, dried, dissolved in 1 ml of 2,4,6-trimethylpyridine and then heated to 140° C. After 90 minutes, the reaction mixture is cooled to room temperature, mixed with hot water, stirred for 10 minutes and then the water is decanted off. This “water-treatment process” is repeated twice more. The solid is then dried and purified by flash chromatography (SiO2 60F). The title compound is identified on the basis of e Rf.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].Cl[CH2:29][C:30]1[O:34][C:33]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=1>>[CH3:38][O:37][C:35]([C:33]1[O:34][C:30]([CH2:29][N:9]2[C:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[S:14][C:11]=3[C:12](=[O:13])[N:7]([OH:6])[C:8]2=[O:21])=[CH:31][CH:32]=1)=[O:36]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Reactant: COC(=O)c1ccc(CCl)o1
Product: COC(=O)c1ccc(Cn2c(=O)n(O)c(=O)c3sc4ccccc4c32)o1

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with methyl 5-chloromethyl-2-furoate and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 3.64 (s, 3H); 5.60 (s, 2H); 6.48 (d, J=3 Hz, 1H); 7.09 (d, J=3 Hz, 1H); 7.32 (dd, J=8 Hz, 1H); 7.44 (dd, J=8 Hz, 1H); 7.92 (d, J=9 Hz, 1H); 8.00 (d, J=8 Hz, 1H); Ret. time=2.33 min., m/z=373.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:43][C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=32)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(Br)c4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 608.0 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:20][C@H:19]2[C@H:11]([CH2:12][C:13]3[C:18]2=[CH:17][C:16]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[Cl:31])=[CH:15][C:14]=3[CH3:32])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>CO.[OH-].[OH-].[Pd+2]>[Cl:31][C:22]1[CH:23]=[C:24]([C:27]([F:30])([F:28])[F:29])[CH:25]=[CH:26][C:21]=1[C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([CH3:32])[CH:15]=1)[CH2:12][C@H:11]1[C@@H:19]2[CH2:20][NH:8][CH2:9][CH2:10]1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2Cl)cc2c1C[C@@H]1CCN(Cc3ccccc3)C[C@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2Cl)cc2c1C[C@@H]1CCNC[C@H]21
Temperature: 20 °C
Reaction time: 10 h
Yield: 80 %

Procedure:
To a solution of cis-3-benzyl-6-(2-chloro-4-trifluoromethyl-phenyl)-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene (25 mg, 0.055 mmol) in MeOH (1.5 mL) was added Pd(OH)2 (5.0 mg, 20 wt %) and catalytic amount of acetic acid. The reaction mixture was stirred at 20° C. for 10 h under H2 atmosphere, filtered through celite and concentrated in vacuo. The residue was chromatographed in silica gel column (CH2Cl2/MeOH 95/5) to give the title compound (16 mg, 0.044 mmol): MS (ES) 366.1 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.Cl.[CH2:10]([N:17]1[CH2:22][CH2:21][O:20][CH:19]([C:23](O)=O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH4+].[OH-]>O>[C:11]1([CH2:10][N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][C:3]=4[N:8]=3)[CH2:18]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccncc1N
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CN2CCOC(c3nc4cnccc4[nH]3)C2)cc1
Yield: 21.8 %

Procedure:
A mixture of 3,4-pyridinediamine (1.7 g, 15.58 mmol), 4-benzylmorpholine-2-carboxylic acid hydrochloride (4.82 g, 18.69 mmol) and polyphosphoric acid (40 mL, 15.58 mmol) was refluxed for 12 hours. Then water (70 mL) and NH4OH were added thereto, and the resulting mixture was extracted with CH2Cl2 (10% CH3OH) (3×80 mL). The combined organic solution was washed with brine (2×100 mL), dried, and evaporated in vacuo to afford the title compound (1.0 g). LC-MS (ES) m/z=295 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10][S:11][C:12](S(C)=O)=[CH:13][N+:14]([O-:16])=[O:15].C[O-].[Na+]>CO>[CH3:10][S:11][C:12]1[NH:2][CH:3]=[C:4]([CH2:5][CH2:6][CH2:7][CH3:8])[C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: CCCCC(=O)CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1c[nH]c(SC)c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 48.5 %

Procedure:
1-Amino-2-hexanone hydrochloride (5.8g) was dissolved in methanol (100 ml) and mixed with a solution of 1-methylthio-1-methylsulphinyl-2-nitroethylene (6.8g) in warm methanol (100 ml). A solution of sodium methoxide in methanol (from 1.7g sodium) was added dropwise, with stirring, over 2 hours at 60°, and the mixture was evaporated to dryness. The residue was triturated with water, and the solid was filtered off and dried, to give 2-methylthio-3-nitro-4-n-butylpyrrole (3.9g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](Br)[C:3]=1[O:10][CH3:11].[N+:12]([O-])(O)=O>S(=O)(=O)(O)O.C(O)C.[Pd]>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:10][CH3:11])=[CH:2][C:7]=1[NH2:12]
Reactant: COc1c(Br)cc(F)cc1Br
Reactant: O=[N+]([O-])O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: COc1ccc(F)c(N)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
To a stirred mixture of 2,6-dibromo-4-fluoroanisole (52.5 g, 0.185 mol) in 98% sulfuric acid (152 mL) at 15° C. was added, dropwise over 0.5 h, a solution of nitric acid (9.2 mL) and sulfuric acid (152 mL) with external ice-bath cooling. The mixture was stirred at 20° C. over 4 h, then was poured into ice water (1 kg) and extracted with dichloromethane (3×150 mL). The combined extracts were dried (Na2SO4) and evaporated in vacuo to give a brown oil. Chromatography on silica with 1-50% ether in hexane gradient elution gave an off-white solid, a solution of which in ethanol (250 mL) was hydrogenated at 20° C. and 4 bar over 10% palladium on carbon (3.5 g) for 18 h. Catalyst was removed by filtration and the filtrate was evaporated in vacuo to give a residue which was partitioned between saturated aqueous NaHCO3 (300 mL) and dichloromethane (3×100 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica with 20-50% ether in hexane gradient elution gave the title compound (15.3 g, 59%) as an oil.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:38])[C:14]2[CH:19]=[C:18]([CH2:20][C:21]3[C:22](=[O:33])[C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[C:25](=[O:28])[C:26]=3[CH3:27])[CH:17]=[CH:16][C:15]=2[O:34]C(=O)C)[CH:7]=1>CO>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:38])[C:14]2[CH:19]=[C:18]([CH2:20][C:21]3[C:22](=[O:33])[C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[C:25](=[O:28])[C:26]=3[CH3:27])[CH:17]=[CH:16][C:15]=2[OH:34])[CH:7]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3)c2)=C(C)C1=O
Agent: CS(=O)(=O)O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccnc3)c2)=C(C)C1=O
Yield: 82 %

Procedure:
Methanesulfonic acid (0.00732 g, 0.0762 mmol) was added to a methanol solution (2 ml) of N-(pyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.0327 g, 0.0726 mmol), and the solvent was removed by distillation. The obtained residue was recrystallized from a mixed solvent of methanol, hexane and toluene (1:2:0.2) to obtain the titled compound (0.030 g, 0.0595 mmol, 82%).
Reaction SMILES: C(C1C=CC=CC=1[C:10]1[C:11]([Cl:21])=[C:12]([C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:13]([NH2:15])=O)(=O)N.[OH-].[Na+].[C:24]([OH:27])(=O)[CH3:25]>>[Cl:21][C:11]1[CH:10]=[CH:18][CH:17]=[C:16]([O:19][CH3:20])[C:12]=1[C:13]1[NH:15][C:24](=[O:27])[C:25]2[C:13](=[CH:12][CH:11]=[CH:10][CH:18]=2)[N:15]=1
Reactant: CC(=O)O
Reactant: COc1ccc(-c2ccccc2C(N)=O)c(Cl)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(Cl)c1-c1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Yield: 14 %

Procedure:
N (2 carbamoylphenyl)-2-chloro-6-methoxybenzamide (13 g, 42.7 mmol) was suspended in 100 mL of a 2 N NaOH solution and heated to reflux. After refluxing for 3 hours, another 25 mL of a 2 N NaOH solution was added, and the reaction was refluxed for another hour. The mixture was cooled to room temperature and acidified with acetic acid to pH 5. The formed precipitate was collected by filtration. The product was purified over alumina using EtOAc as an eluent giving 1.7 g (5.9 mmol, 14%) of 2-(2-chloro-6-methoxy-phenyl)-3H-quinazolin-4-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[O:3]1.[N+:17]([O-])([OH:19])=[O:18]>FC(F)(F)C(O)=O>[CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[CH:7]=[C:8]([N+:17]([O-:19])=[O:18])[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[O:3]1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cccc2c1OC(C)(C)C2
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc([N+](=O)[O-])cc2c1OC(C)(C)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of ethyl 2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (1 g, 4.54 mmol) in trifluoroacetic acid (7 mL) at 0° C. was slowly added nitric acid (1.36 mL). The reaction was stirred at 0° C. for one hour and then at room temperature for 30 minutes. The reaction was added to ice and the resultant solid was collected by filtration, and washed with water to provide ethyl 2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7-carboxylate (674) as a yellow solid (1.02 g, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:19][C:20]1[N:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1.C(O)(=O)C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:22]3[C:23]([CH3:26])=[CH:24][N:25]=[C:20]([Cl:19])[N:21]=3)[S:7][C:6]=2[CH:10]=1
Reactant: Brc1ccc2ccsc2c1
Reactant: Cc1cnc(Cl)nc1
Agent: CC(C)[N-]C(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CC(=O)O
Solvent: CCc1ccccc1
Product: Cc1cnc(Cl)nc1-c1cc2ccc(Br)cc2s1
Temperature: -75 °C
Reaction time: 0.67 h
Yield: 38.6 %

Procedure:
A solution of 6-bromobenzo[b]thiophene (5.00 g, 23.5 mmol) in THF (50 mL) is cooled to −70° C. Lithium diisopropylamide (12.9 mL of a 2 M solution in heptane/THF/ethylbenzene, 25.8 mmol) is added dropwise over 5 minutes. After stirring for 40 minutes at −75° C., the mixture is removed from the cold bath and allowed to warm to 0° C. over 15 minutes and then recooled to −35° C. 2-Chloro-5-methylpyrimidine (3.02 g, 23.5 mmol) is added to the mixture as a solid in one portion and the resultant mixture is allowed to stir for 30 minutes at −35° C. Acetic acid (1.55 g, 25.8 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.60 g, 24.7 mmol) are added in one portion to the mixture before it is allowed to stir at room temperature for 16 hours. Then the mixture is concentrated under reduced pressure, suspended in warm dichloromethane, eluted through a pad of silica in dichloromethane (1 L) and concentrated under reduced pressure. The crude material is subjected to chromatography on silica gel, eluting with dichloromethane in hexanes 50-100%. The resulting material is sonicated in ether (100 mL) and filtered to provide the title compound as an orange solid (3.08 g, 39% yield).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[OH-].[Na+]>>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:4]=3[CH2:3][CH:2]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C:8]=2[CH:9]=1
Reactant: CN1CCNCC1
Reactant: Fc1ccc2c(c1)C(Cl)Cc1ccc(C(F)(F)F)cc1S2
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(C2Cc3ccc(C(F)(F)F)cc3Sc3ccc(F)cc32)CC1

Procedure:
9 G. of 10-chloro-8-fluoro-10,11-dihydro-3-trifluoromethyldibenzo[b,f]thiepin are treated with 11 g. of N-methylpiperazine and stirred for 10 minutes at 105°-110° C. The cooled mixture is treated with 2N sodium hydroxide and extracted with ether. The ether solution is washed neutral with water and shaken with dilute methanesulfonic acid. The acidic solution is made alkaline with sodium hydroxide and extracted with ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated in a vacuum, and there is obtained 1-{8-fluoro-10,11-dihydro-3-trifluoromethyl-dibenzo[b,f]thiepin-10-yl]-4-methylpiperazine as a yellow oil which is converted into the methanesulfonate having a melting point of 224°-226° C. by treatment with methanesulfonic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.Cl>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:4]=1[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(OC)c([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [K+]
Solvent: CCC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1OC
Reaction time: 3 h

Procedure:
A 7.00 g portion of 2,4-dimethoxy-5-nitrobenzoic acid was dissolved in 2-butanone, and 9.90 g of potassium carbonate and 3.6 ml of dimethyl sulfate were added, followed by 3 hours of heating under reflux. After completion of the reaction, the reaction solution was poured into 1N hydrochloric acid aqueous solution, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 5.45 g of methyl 2,4-dimethoxy-5-nitrobenzoate.
Reaction SMILES: CN(C)C=O.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=[O:18].[Br:19]N1C(=O)CCC1=O>O>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:17]=[C:16]([Br:19])[CH:15]=[CH:14][C:13]1=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1ccccn1-c1ccccn1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc(Br)cn1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
Under ice-cooling, 15 ml of a dimethylformamide solution containing 1.50 g of 1-(2-pyridyl)-1,2-dihydropyridin-2-one was incorporated with 1.60 g of N-bromosuccinic acid imide. The mixture was stirred at room temperature for 2 hours, and then diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane=1:3), to give 1.13 g of the title compound as a pale brown powder.
Reaction SMILES: [C:1]([C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][C:5](OCC)=[O:6])#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:2][CH2:1][C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][CH2:5][OH:6]
Reactant: CCOC(=O)CC(C#N)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC(CCO)(c1ccccc1)c1ccccc1
Yield: 79.1 %

Procedure:
To a solution of ethyl 3-cyano-3,3-diphenylpropionate (reference compound 2-1) (1.2 g) in tetrahydrofuran (30 ml) was added lithium aluminum hydride (0.44 g) portionwise with ice-cooling and stirring. After completion of dropwise addition, the mixture was heated and stirred at 60° C. for 3 hours. The reaction mixture was then cooled with ice again, and water (1 ml), 15% aqueous sodium hydroxide solution (3 ml) and water (1 ml) were added in the order mentioned. The resulting precipitate was filtered off and the filtrate was extracted using ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was washed with ethyl acetate to provide the title compound (0.82 g) as colorless powder.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[C:15]1([C:21]2[CH2:25][C:24]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[O:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:28]3[CH2:27][CH2:26][C:24]4([O:23][N:22]=[C:21]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH2:25]4)[CH2:30][CH2:29]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: c1ccc(C2=NOC3(CCNCC3)C2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)CC(c3ccccc3)=NO4)nn2)n1

Procedure:
The object product (95 mg, 35%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (150 mg), 3-phenyl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene hydrochloride (200 mg) and potassium carbonate (140 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].CCOCC>C(COC)OC.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.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:23]1[O:22][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccco1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: COCCOC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.45 g) in dimethoxyethane (4 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.035 g) was stirred at room temperature for 30 minutes and then heated to 80° C. Furan-2-boronic acid (0.125 g) and aqueous sodium carbonate solution (2 ml, 1M) were added and the mixture heated under reflux for 3 hours. The cooled reaction was poured into ether and water. The organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up the minimum amount of dichloromethane and silica gel (10 g) added. The solvent was removed and the residue applied to a column of silica gel (75 g) which was eluted with hexane containing increasing proportions of dichloromethane. Combination and evaporation of suitable fractions gave the title compound as an very light pink crystalline solid 195-6° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[F:9][CH:10]([F:20])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1>>[F:9][CH:10]([F:20])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])=[CH:14][CH:13]=1
Reactant: Cc1ccccc1I
Reactant: C#Cc1ccc(OC(F)F)cc1
Product: Cc1ccccc1C#Cc1ccc(OC(F)F)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 12, step 3 starting from 1-Iodo-2-methyl-benzene (0.15 g, 0.69 mmol), and 1-Difluoromethoxy-4-ethynyl-benzene (0.116 g, 0.69 mmol), and was obtained as a light brown oil, (0.141 g, 79%), identified by NMR and mass spectral analyses. MS (EI+): 258 (M+).