Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:27][C:28]1[N:29]=[C:30]([CH:33]=[CH:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([F:46])([F:45])([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[O:31][CH:32]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:23])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1)[CH2:27][C:28]1[N:29]=[C:30]([CH:33]=[CH:34][C:35]2[CH:36]=[CH:37][C:38]([S:41]([F:46])([F:42])([F:43])([F:44])[F:45])=[CH:39][CH:40]=2)[O:31][CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=CCCn2ccnn2)cc1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1coc(C=Cc2ccc(S(F)(F)(F)(F)F)cc2)n1)c1ccc(C=CCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
A solution of [4-(4-[1,2,3]triazol-1-yl-but-1-enyl)-phenyl]-carbamic acid tert-butyl ester (0.135 g, 0.43 mmol) in N,N-dimethyl formamide (3 ml) was treated with sodium hydride (0.012 g, 0.47 mmol) and stirred for 30 min at room temperature. After addition of 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole (0.149 g, 0.43 mmol) and stirring for 12 h the reaction was quenched by the addition of a sat. NH4Cl solution (8 ml). Extraction with ethyl acetate (3×10 ml), washing with water, drying over sodium sulfate and concentration in vacuo yielded crude [4-(4-[1,2,3]triazol-1-yl-but-1-enyl)-phenyl]-{2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazol-4-ylmethyl}-carbamic acid tert-butyl ester (0.27 g) which was used in the next step without any further purification.
Reaction SMILES: CN([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])C.[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[O:17]=[C:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11]
Reactant: CN(C)CC1CCCCC1=O
Reactant: O=C1CCCC1
Product: O=C1CCCCC1CC1CCCC1=O
Yield: 80 %

Procedure:
2-(2-oxo-cyclopentyl)methyl cyclohexanone is prepared from 2-(dimethylaminomethyl)-cyclohexanone and cyclopentanone according to the method described in Ann.Chim., 1963, 53 (6), 819 and is isolated as a colourless oil in 80% yield b.p. 92°/0.05 mm. 5,6,7,8-Tetrahydro-2,3-dihydro-1H-cyclopenta[b]quinoline is prepared from 2-(2-oxocyclopentyl)methylcyclohexanone according to the method described in Ann.Chim., 1963, 53, (6), 819 and is isolated in 65% yield as a colourless oil b.p. 80°/0.05 mm. The hydrochloride is prepared for characterisation by treating an ethereal solution of the base with ethereal HCl and is isolated as the hemihydrate as colourless needles from ethanol-ether m.p. 104° C (Found: C, 65.7; H, 7.8; N, 6.6. C12H16N.HCl.1/2H2O requires: C, 65.8; H, 7.8; N, 64%. 5,6,7,8-Tetrahydro-2,3-dihydro-1H-cyclopenta[b]-quinoline is converted to methyl 5,6,7,8-tetrahydro-2,3-dihydro-1H-cyclopenta[b]quinoline-5-carboxylate following the method described in Example 19 and this is converted to 5,6,7,8-tetrahydro-2,3-dihydro-1H-cyclopenta[b]quinoline-5-carboxamide following the method described in Example 22. The amide is converted to the title compound, following the procedure of Example 23, and is recrystallised from isopropanol, dissolved in ether and treated with an excess of ethereal HCl. The resultant solid is recrystallised from ethanol-ester to give the hydrochloride of the title compound as the monohydrate m.p. 118° C. (Found: C, 54.6; H, 6.3; N, 10.0. C13H16N2S.HCl H2O requires: C, 54.4; H, 6.6; N, 9.8%).
Reaction SMILES: [C:1]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH2:25]([NH:32][NH2:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)[Cl:35]>C1COCC1>[Cl-:35].[CH2:25]([N+:32]1[N:33]=[CH:11][C:10]2[C:9](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:1]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCCl
Reactant: O=Cc1ccccc1C(=O)c1ccccc1
Reactant: NNCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: [Cl-]
Product: c1ccc(C[n+]2ncc3ccccc3c2-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
Sixty-two grams (0.30 mole) of 2-benzoylbenzaldehyde in 140 mL of THF was treated with 81.5 g (0.59 mole) of potassium carbonate and 64 g (0.32 mole) of benzylhydrazine dihydrochloride. The mixture was stirred 30 minutes at 0° and 40 mL of methylene dichloride was added. The mixture was stirred at room temperature for one day, filtered and stripped in vacuo to provide 131 g of 2-benzyl-1-phenyl phthalazinium chloride.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[N:27]=[C:26]([C:28]2[C:36]3[C:31](=[N:32][C:33]([Cl:37])=[N:34][CH:35]=3)[NH:30][N:29]=2)[CH:25]=[CH:24][CH:23]=1.CCN(CC)CC.O>CN(C=O)C>[Br:21][C:22]1[N:27]=[C:26]([C:28]2[C:36]3[C:31](=[N:32][C:33]([Cl:37])=[N:34][CH:35]=3)[N:30]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:29]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Clc1ncc2c(-c3cccc(Br)n3)n[nH]c2n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncc2c(-c3cccc(Br)n3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of trityl chloride (8.5 g, 30.5 mmol) in DMF (80 mL) was added dropwise to the solution of 3-(6-bromo-pyridin-2-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine (from Example 30 supra) (8.0 g, 25.7 mmol) and Et3N (12 mL, 83.2 mmol) in DMF (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours then poured into water and extracted with ethyl acetate. The organic solution was dried with anhydrous Na2SO4. After filtration and concentration, the residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate, 20:1) to give 3-(6-bromo-pyridin-2-yl)-6-chloro-1-trityl-1H-pyrazolo[3,4-d]pyrimidine as a white powder. (Yield 3.8 g, 27%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CC#N.O>[CH3:9][NH:8][C:6]1[N:7]=[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=[C:4]([NH:10][C@@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]2)[N:5]=1
Reactant: C1CCNCC1
Reactant: CNc1nc(Cl)nc(N[C@H]2CC[C@@H](C(=O)O)CC2)n1
Solvent: CC#N
Solvent: O
Product: CNc1nc(N[C@H]2CC[C@@H](C(=O)O)CC2)nc(N2CCCCC2)n1
Temperature: 80 °C

Procedure:
To the crude solution of cis-4-(4-chloro-6-(methylamino)-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid (˜0.38 mmol) in CH3CN/H2O (1/1, 5 ml) was added piperidine (188 μL, 5 equivalents). The reaction mixture was heated at 80° C. overnight. The reaction solution was condensed and the crude was acidified and purified by RP-HPLC (Luna 5μ C8(2), 100×21 mm, 15-60% CH3CN/H2O, 0.1% TFA, 17 min) to give the product (34.9 mg). MS (ES+): m/e 335.22 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[O:5])[CH3:4].[C:9]1([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>O1CCCC1>[C:3]([CH:22]([C:19]1[CH:20]=[CH:21][C:16]([S:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:17][CH:18]=1)[C:23]#[N:24])(=[O:5])[CH3:4]
Reactant: CCOC(C)=O
Reactant: N#CCc1ccc(Sc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)C(C#N)c1ccc(Sc2ccccc2)cc1
Yield: 73.3 %

Procedure:
To a stirred suspension of 144 mg of 60% sodium hydride, in 10 ml of tetrahydrofuran at 0° C. under nitrogen atmosphere was added a mixture of 396 mg of ethyl acetate, 675 mg of 4-phenylthiophenylacetonitrile and 5 ml of tetrahydrofuran. Thirty minutes later, the ice bath was removed. Seventeen hours later, the tetrahydrofuran was distilled off in vacuo, and 10 ml of 2N hydrochloric acid and 20 ml of dichloromethane were added and separated, and the water layer was further extracted twice in 20 ml of dichloromethane. The organic layer and extract were combined, and dried by anhydrous magnesium sulfate, and concentrated in vacuo, and the residue was isolated and refined by silica gel chromatography (the eluent was a mixed solvent of hexane:ethyl acetate at a (v/v) rate of 4:1), and 587 mg of the title compound was obtained.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:8][C:9]([CH2:11][N:12]1[C:17]([CH3:18])=[CH:16][N:15]=[C:14](O)[C:13]1=[O:20])=[O:10])[CH3:7].O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:3][C:14]1[C:13](=[O:20])[N:12]([CH2:11][C:9]([O:8][CH2:6][CH3:7])=[O:10])[C:17]([CH3:18])=[CH:16][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cn1c(C)cnc(O)c1=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Cn1c(C)cnc(Cl)c1=O
Temperature: 60 °C

Procedure:
PHOSPHOROUS OXYCHLORIDE (2.8 ML, 30 MMOL) WAS ADDED TO A STIRRED MIXTURE OF 1-ETHOXYCARBONYLMETHYL-3-HYDROXY-6-METHYLPYRAZINONE (5.3 G, 25 MMOL) IN DRY TOLUENE (50 ML) UNDER ARGON. THE RESULTING MIXTURE WAS HEATED TO 60° C. AFTER 64 H, THE MIXTURE WAS COOLED AND WATER AND ETHYL ACETATE WERE ADDED. THE ORGANIC LAYER WAS DRIED (NA2SO4) AND EVAPORATED IN VACUO. THE RESIDUE WAS PURIFIED BY FLASH COLUMN CHROMATOGRAPHY ON SILICA GEL (50% ETOAC/HEXANES) TO GIVE THE TITLE COMPOUND AS A CRYSTALLINE SOLID:
Reaction SMILES: [N:1]1([C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:9]=3[S:8](=[O:21])(=[O:20])[N:7]=2)[CH:5]=[CH:4]N=C1.[CH:22](N)(C)C>>[CH:5]([NH:1][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:17])[F:18])=[CH:15][C:9]=2[S:8](=[O:20])(=[O:21])[N:7]=1)([CH3:22])[CH3:4]
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2ccc(C(F)(F)F)cc21
Reactant: CC(C)N
Product: CC(C)NC1=NS(=O)(=O)c2cc(C(F)(F)F)ccc2N1

Procedure:
3-(Imidazol-1-yl)-7-trifluoromethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide was treated with isopropylamine according to the general procedure Method A to give the title compound; m.p. 287-289° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[OH:24][CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27](=O)[O:26]1.CN(C)C=O>C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH:27]4[C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:25](=[O:24])[O:26]4)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: O=C1OC(O)c2ccccc21
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Solvent: CCO
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C4OC(=O)c5ccccc54)CC3)cc21
Yield: 99 %

Procedure:
A mixture of 1-ethyl-1,4-dihydro-6-fluoro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid 0.5 g, 3-hydroxyphthalide 0.24 g and dimethylformamide 5 ml was heated at 100°-110° C. for 3 hours under stirring. After cooling, ethanol was added, and the insoluble matters were collected by filtration. The precipitates obtained were washed with ethanol and dried. 0.70 g (99%) of 1-ethyl-1,4-dihydro-6-fluoro-4-oxo-7-(4-phthalidyl-1-piperazinyl)quinoline-3-carboxylic acid was obtained as colorless powders.
Reaction SMILES: C([Li])CCC.[C:6]1([CH2:12][CH2:13][CH2:14][C:15]#[CH:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:17][Si:18]([CH3:27])([CH3:26])[C:19]1[O:23][CH:22]=[C:21](C=O)[CH:20]=1.[C:28]([O:31][C:32](=O)C)(=[O:30])[CH3:29]>CCCCCC.O1CCCC1.O>[C:28]([O:31][CH2:32][CH:16]([C:21]1[CH:20]=[C:19]([Si:18]([CH3:17])([CH3:26])[CH3:27])[O:23][CH:22]=1)[C:15]#[C:14][CH2:13][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:30])[CH3:29]
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: C#CCCCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCC(C#CCCc1ccccc1)c1coc([Si](C)(C)C)c1
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (a 1.6M solution in hexane; 0.9 ml, 1.44 mmol) was added dropwise to a solution of 5-phenyl-1-pentyne (198.1 mg, 1.38 mmol) in tetrahydrofuran (4 ml) at 0° under argon. After 30 minutes, a solution of 5-trimethylsilyl-3-furaldehyde (231 mg, 1.38 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued for 1 hour and acetic anhydride (0.4 ml) was added. After 2 hours, the mixture was poured into water and extracted thoroughly with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was flash chromatographed on silica using 5% ethyl ether/hexane. Fractions with Rf of about 0.33 on evaporation gave the title ester as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([NH2:28])=[S:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][C:30](OC(C)=O)=O.ClCC=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[S:27][CH:29]=[CH:30][N:28]=4)=[CH:24][CH:25]=3)[CH2:18][CH2:19]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(C(N)=S)cc3)CC2)CC1
Reactant: CC(=O)OC(C)=O
Agent: O=CCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(-c4nccs4)cc3)CC2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of the product of Example 12.24, Step 1 above (151 mg; 0.374 mmol) in DMF (3 ml) was treated with Ac2O (1 ml) and chloroacetaldehyde (587 mg; 50% aq. solution; 3.74 mmol). The solution was stirred at 80° C. for 1 hr. The reaction was partitioned between iPrOAc (50 mL) and aq. sodium bicarbonate (20 mL). The organic was washed three more times with aq. sodium bicarbonate (3×10 mL). The organic was dried over magnesium sulfate, filtered and evaporated to a brown semi-solid. The solid was digested (refluxing MTBE). The nearly homogenous solution was allowed to stand at −10° C. for 1 hr, causing the deposition of a tan solid. The supernatant was drawn off and the solid rinsed with MTBE. All volatiles were removed and light tan solid was chromatographed (PTLC; 40:1 CH2Cl2/MeOH), affording the title compound.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:5]([O:19][CH3:20])=[C:6]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22](=[O:23])[NH:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])([CH3:13])[CH3:11])[CH:7]=[C:6]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:5]=1[O:19][CH3:20]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
NaOH (199 mg, 4.97 mmol) was added to an ice-bath cooled solution of N-[3-amino-5-(1,1-dimethylethyl)-2-methoxyphenyl]-methane sulfonamide (for reference procedure see for example WO2010026096, which is incorporated herein by reference in its entirety; 500 mg, 1.84 mmol). The ice bath was removed and complete dissolution of reagents occurred. 2,2,2-trichloroethyl chloroformate (380 μL, 2.76 mmol) was added and the reaction mixture was warmed to RT and stirred for 90 min. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-60% EtOAc in cyclohexane, to afford the title compound (620 mg, 75%) as a white solid. LCMS (Method 1): Rt 3.98 min, m/z 445, 447, 449 [MH+].
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4]([O:38][CH3:39])[CH:3]=1.FC1C=CC(B(O)O)=C(OC)C=1>C(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:32][CH2:33][S:34]([CH3:37])(=[O:35])=[O:36])=[C:4]([O:38][CH3:39])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Agent: COc1cc(F)ccc1B(O)O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(F)ccc1-c1ccncc1NCCS(C)(=O)=O

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methanesulfonyl-ethyl)-amine (example 158, intermediate b) and 4-fluoro-2-methoxyphenyl-boronic acid (CAS RN 179899-07-1) and using a gradient of CH2Cl2:methanol (100:0 to 85:15) for the chromatographic purification. Colorless foam (55%). MS (ESI): m/z=325.10 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].O>CC(O)C.[Co]>[Cl:1][C:2]1[CH:9]=[C:6]([CH2:7][NH2:8])[CH:5]=[N:4][CH:3]=1
Reactant: N#Cc1cncc(Cl)c1
Agent: [Co]
Solvent: CC(C)O
Solvent: O
Product: NCc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 80.6 %

Procedure:
A mixture of 5-chloro-nicotinonitrile (63.8 mg, 461 μmol), 2-propanol (9.2 mL; not dry), and CaSO4 (−325 mesh) (920 mg, 6.76 mmol) was treated with a suspension of Raney Cobalt 2700 in 2-propanol under air (2 mL) (prepared by diluting 2 mL of the commercial water slurry with 15 mL 2-propanol, centrifuging, decanting, and repeating with 2×15 mL 2-propanol, then resuspending with 2 mL 2-propanol). The flask was then sealed and evacuated until bubbles formed, and the evacuated flask was flushed with H2 gas via balloon pressure. After 11 h stirring at rt under balloon H2 pressure, a NMR spectrum of a worked-up reaction aliquot indicated 80% conversion to the title compound. The reaction was then filtered, the filter cake was washed with 2-propanol (3×10 mL), and the combined clear colorless filtrates were concentrated briefly under rotary evaporation at 50° C. The residue was taken up in DCM and concentrated again to afford the volatile crude title compound (53 mg, 81%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:31][NH2:32]>CO>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:32][CH3:31])=[CH:6][CH:7]=2)=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:13][CH3:14])=[CH:25][CH:26]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)c(OC)c1
Reactant: CN
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc(O)c(OC)c1
Temperature: 85 °C
Yield: 48 %

Procedure:
To a stirred solution of 4-(1-(4-(2-Chloroethoxy)phenyl)-1-(4-hydroxyphenyl)-but-1-en-2-yl)-2-methoxyphenol (88 mg, impure) in 10 mL MeOH was added 2 mL CH3NH2 (aq). After the mixture was heated at 85° C. for 24 h., the solvent was removed in vacuo, EtOAc was added, the mixture was washed with water and brine, dried over Na2SO4, filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography (CH2Cl2/MeOH(NH3 gas)=10/1) to give the desired product (42 mg, 48% yield, Z/E=1/1) as a white solid. m/z=420[M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C1C=CC=CC=1.C(N(CC)C#CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[C:39](=[CH:45][C:46]1[CH:51]=[C:50]([O:52][CH3:53])[C:49]([O:54][CH3:55])=[C:48]([O:56][CH3:57])[CH:47]=1)[NH:38][CH2:37][CH2:36]2>N1C=CC=CC=1>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])/[C:39](=[CH:45]/[C:46]1[CH:51]=[C:50]([O:52][CH3:53])[C:49]([O:54][CH3:55])=[C:48]([O:56][CH3:57])[CH:47]=1)/[N:38]([C:14](=[O:16])[CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:37][CH2:36]2
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Reactant: COc1cc2c(cc1OC)C(=Cc1cc(OC)c(OC)c(OC)c1)NCC2
Agent: CC#CN(CC)CC
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C/c1cc(OC)c(OC)c(OC)c1)N(C(=O)Cc1cc(OC)c(OC)c(OC)c1)CC2

Procedure:
To a suspension of 24 parts of 3,4,5-trimethoxybenzeneacetic acid in 25 parts of benzene is added 7 parts of N,N-diethyl-1-propyne-1-amine, followed by a solution of 12 parts of 3,4-dihydro-6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methylene]isoquinoline [Ber. deut. chem. Ges., 55, 2989 (1922)] in 60 parts of pyridine. The resultant mixture is stirred at room temperatures for 18 hours, whereupon it is consecutively washed with aqueous 5% potassium carbonate, approximately 0.2% hydrochloric acid, and water, then dried over anhydrous sodium sulfate and stripped of solvent by vacuum distillation. The residue, crystallized from methanol, affords (Z)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-(3,4,5-trimethoxybenzeneacetyl)-1-[(3,4,5-trimethoxyphenyl)methylene]isoquinoline melting at 148°-150°.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=2[S:11](=[O:14])(=[O:13])[NH2:12])[CH2:18][CH2:17]1
Reactant: NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(c2ccc(C(N)=O)cc2S(N)(=O)=O)CC1

Procedure:
165 Grams of 4-chloro-3-sulfamoylbenzoic acid-amide (0.7 mole) were stirred with 0.3 l of N-methylpiperazine for 1 hour at 130° C. Subsequently the reaction mixture was diluted with 2 l of water, and the crystalline precipitate was suction-filtered. The crude product (150 g with a degradation point of 301° C.) was dissolved in 3 l of 0.5N HCl and, after the solution had been decolorized with activated charcoal, the said product was precipitated in a crystalline state, at pH 8, by means of 2N ammonia.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:9]2[C@:24]3([C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:34])[C:16]3([CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][CH2:17]3)[N:15]3[C@H:10]2[C:11](=[O:47])[O:12][C@@H:13]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:14]3[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:48](N(CC)CC)C.[C:55](=[O:58])(O)[O-:56].[Na+]>CS(C)=O.CO>[Cl:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([C@@H:9]2[C:24]3([C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:34])[C:16]3([CH2:21][CH2:20][C:19]([CH3:22])([CH3:23])[CH2:18][CH2:17]3)[N:15]3[C@H:10]2[C:11](=[O:47])[O:12][C@@H:13]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C@H:14]3[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=1)[C:55]([O:56][CH3:48])=[O:58]
Reactant: O=C([O-])O
Reactant: CCN(CC)CC
Reactant: CC1(C)CCC2(CC1)N1[C@H](c3ccccc3)[C@H](c3ccccc3)OC(=O)[C@H]1[C@H](c1cc(Cl)cc(Br)c1)[C@@]21C(=O)Nc2cc(Cl)ccc21
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)c1cc(Cl)cc([C@H]2[C@@H]3C(=O)O[C@@H](c4ccccc4)[C@@H](c4ccccc4)N3C3(CCC(C)(C)CC3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 90 °C
Yield: 13 %

Procedure:
The compound (3.14 g, 4.30 mmol) obtained in Step 1 above was dissolved in dimethyl sulfoxide (40 ml) and methanol (40 ml), triethylamine (0.71 ml, 5.16 mmol) and a 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (351 mg, 0.43 mmol) were added and the resulting mixture was stirred under heating at 90° C. for 2 days under carbon monoxide atmosphere. Saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [n-hexane:ethyl acetate=1:1 (v/v)] to give 0.40 g (13%) of the title compound as a yellow solid.