Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=O.S(Cl)([Cl:13])=O>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][Cl:13]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: O=S(Cl)Cl
Product: ClCc1cncc(Br)c1

Procedure:
A solution of 5-bromonicotinic acid (4 g, 0.02 mol) in thionyl chloride (25 mL) was heated under reflux for 4 h. The excess thionyl chloride was removed under reduced pressure to provide 5-bromonicotinyl chloride which was used without further purification. To 5-bromonicotinyl chloride (3.5 g, 13.6 mmol) was added glycine ethylester (2.1 g, 20.3 mmol) and diisopropyl ethyl amine (2.6 g, 20.1 mmol) in THF (70 mL) and the reaction mixture stirred at RT for 16 h. The reaction mixture was diluted with EtOAc and washed with brine solution. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure and the residue was purified by silica gel column chromatography using 25% EtOAc in hexane to provide ethyl 2-(5-bromonicotinamido)acetate 1.2 g (33%) as a brown solid. LCMS Method T: retention time 1.28 min; [M+1]=288.2
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2(O)[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH2:8]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1.COCCN(S(F)(F)F)CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[C:7]1([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13]1
Reactant: Cn1ncc([N+](=O)[O-])c1C1(O)CCC=CCC1
Agent: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1C1=CCC=CCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.9 %

Procedure:
To a solution of (Z)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)cyclohept-4-enol (1.35 g, 5.70 mmol) in dry DCM (60 mL) was added dropwise a solution of deoxo-Fluor® (50% in THF, 6.2 mL, 17.1 mmol) and the reaction mixture was stirred at room temperature for 90 min. The mixture was cooled to 0° C. and saturated aqueous NaHCO3 solution (70 mL) was added, dropwise initially, and extracted with DCM (100 mL). The organic layer was separated, dried over MgSO4, and concentrated under reduced pressure. Purification via silica gel column chromatography (15-20% EtOAc/hexane) gave 5-((1E,4Z)-cyclohepta-1,4-dienyl)-1-methyl-4-nitro-1H-pyrazole as a pale yellow oil (523 mg, 42%). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 5.90 (t, J=5.6 Hz, 1H), 5.88-5.79 (m, 1H), 5.71-5.63 (m, 1H), 3.82 (s, 3H), 3.14-3.08 (m, 2H), 2.62-2.55 (m, 2H), 2.44-2.37 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:10]=[O:11].N12CCC(CC1)C(O)C2>>[OH:11][CH2:10][C:2](=[CH2:3])[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: C=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: OC1CN2CCC1CC2
Product: C=C(CO)C(=O)OC(C)(C)C

Procedure:
 In a typical procedure, t-butyl acrylate (III) is reacted with paraformaldehyde in the presence of 3-quinuclidinol to provide t-butyl hydroxymethylacrylate (IV). This is first treated with thionyl chloride in the presence of triethylamine and pyridine to provide the corresponding chloromethylacrylate, which is then reacted with (S,S)-α-α′-dimethyldibenzylamine to provide an acrylate of the formula (V). This is converted to a compound of the formula (IX) by the method set out in Tet. Lett., 1993, 34(8), 1323-6. A compound of the formula (IX) is then condensed with a lysine derivative of the formula (X) by a similar procedure to that described in EP-A-0358398 for the preparation of a compound of the formula (XI). A compound of the formula (XI) is then converted to a compound of the formula (II) using a solution of trifluoroacetic acid and anisole in dichloromethane.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([CH3:38])[C:17]2[CH:18]=[N:19][C:20]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N)CN>[Pd].CO>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([CH3:38])[C:17]2[CH:18]=[N:19][C:20](/[CH:30]=[CH:31]\[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(C#Cc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Solvent: NCCN
Product: Cc1ccccc1-c1cc(/C=C\c2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
A mixture of 100 mg (0.198 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-phenylethynyl-4-o-tolyl-pyridin-3-yl)-isobutyramide (Example 72), 10 mg (0.17 mmol) ethylenediamine and 1 mg 10% palladium on carbon in 2 ml methanol was stirred at room temperature under an atmosphere of hydrogen gas for 8 h. The reaction mixture was filtered and concentrated. Column chromatography afforded 28 mg (24%) of the title compound as an orange viscous oil.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[F:25][C:26]1[CH:35]=[CH:34][C:29]2[N:30]=[C:31]([NH2:33])[S:32][C:28]=2[CH:27]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:33][C:31]2[S:32][C:28]3[CH:27]=[C:26]([F:25])[CH:35]=[CH:34][C:29]=3[N:30]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nc2ccc(F)cc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2ccc(F)cc2s1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 1, 95.6 mg, 0.33 mmol) in methylene chloride (3.3 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.18 mL, 0.36 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of 6-fluoro-benzothiazol-2-ylamine (123 mg, 0.73 mmol) in tetrahydrofuran (1.7 mL) and N,N-diisopropylethylamine (0.14 mL, 0.79 mmol). This solution was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(6-fluoro-benzothiazol-2-yl)-propionamide (138.4 mg, 95%) as a white solid: mp 131-133° C; FAB-HRMS m/e calcd for C2H19FCl2N2OS (M+H)+437.0657, found 437.0665.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]=[N+]=[N-])=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1>[NH2:11][CH2:10][C:7]1[N:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])nc1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCc1ccc(CO)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
Add 6-azidomethyl-nicotinic acid methyl ester (2.3 g, 11.97 mmol) and tetrahydrofuran (100 mL) in a flask and cool to 0° C. Add 1M lithium aluminum hydride solution in tetrahydrofuran (17.95 mL, 17.95 mmol) slowly. Stir the mixture for 30 min. Quench the reaction with ice. Add 10 mL of saturated Rochelle's salt solution. Stir for 30 min. Filter, remove the solvent under reduced pressure to give 6-aminomethyl-pyridin-3-yl-methanol (1.6 g, 97% yield) as a yellow oil.
Reaction SMILES: [I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH:26]2[CH2:30][CH2:29][O:28][CH2:27]2)(=O)=O)=CC=1>CN(C=O)C>[I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Reactant: COc1nccc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(I)cn2C1CCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (0.100 g) in DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 36.1 mg), and the mixture was stirred at room temperature for 1 hr. Tetrahydrofuran-3-yl 4-methylbenzenesulfonate (221 mg) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (115 mg).
Reaction SMILES: C[O:2][CH:3]1[CH:7]([CH:8]=O)[CH2:6][CH:5](OC)O1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH:3]([C:7]1[CH:6]=[CH:5][N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=3)=[CH:15][CH:14]=2)[CH:8]=1)=[O:2]
Reactant: COC1CC(C=O)C(OC)O1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(C=O)c2)cc1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
A solution of 33.6 g (210 millimoles) of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde in 200 ml of glacial acetic acid was added dropwise to 40.6 g (200 millimoles) of 6-(4-aminophenyl)-4,5-dihydro-5-methylpyridazinone in 400 ml of glacial acetic acid at 80° C. After 2 hours, the reaction mixture was poured into saturated NaHCO3 solution and extracted with CH2Cl2. The extract was washed with water and saturated NaCl solution and dried over Na2SO4, the solvent was stripped off in a rotary evaporator, and the residue was then recrystallized from dimethylformamide (DMF)/water. 44.2 g of 6-[p-(3-formylpyrrol-1-yl)-phenyl]-4,5-dihydro-5-methylpyridazinone of melting point 191°-192° C. were obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:21][N:20]=[CH:19][N:18]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][N:27]2[C@H:32]([CH3:36])[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][N:27]2[C@H:32]([CH3:36])[C:33]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]3[S:21][N:20]=[CH:19][N:18]=3)(=[O:15])=[O:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:34]
Reactant: C[C@H](C(=O)O)n1ccc2c(F)cccc21
Reactant: O=S(=O)(Nc1ncns1)c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](C(=O)N1CCN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CC1)n1ccc2c(F)cccc21
Yield: 63.7 %

Procedure:
Synthesized according to general procedure 5, method B. The reaction was set up with 0.61 mmol 4-(piperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, 0.61 mmol (2R)-2-(4-fluoro-indol-1-yl)-propionic acid, 0.61 mmol HATU, 0.61 mmol N,N-diisopropyl ethyl amine and 2 mL (1:1) DMF:methylene dichloride to get (R)-4-{4-[2-(4-Fluoro-1H-indol-1-yl)propionyl]piperazin-1-yl}-N-[1,2,4]thiadiazol-5-yl benzenesulfonamide as a white solid (200 mg, 63% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=515.3; tR=3.16 min. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.56 (d, J=9.0 Hz, 2H), 7.47 (s, 1H), 7.37 (s, 1H), 7.15-7.09 (m, 1H), 6.94 (d, J=9.1 Hz, 2H), 6.84-6.79 (m, 1H), 6.54 (d, J=3.2 Hz, 1H), 5.87-5.82 (m, 1H), 3.66 (d, J=4.6 Hz, 2H), 3.58-3.53 (m, 2H), 3.17-3.09 (m, 4H), 1.59 (s, 3H).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([O:7][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCCCC1
Reaction time: 2 h

Procedure:
To a stirred solution of cyclohexanol (Aldrich, 10.2 g, 100 mmol) in methylene chloride (250 mL) at 0° C., Methane sulfonyl chloride (8.52 mL, 110 mmol) and triethyl amine (17.5 mL, 125 mmol) were added slowly and the mixture was stirred for 2 hrs. The reaction was quenched with water and the mixture was washed with 0.5 N HCl and brine solution. The organic layer was dried with sodium sulfate. Removal of solvent gave a yellow oil. 18.05 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26]([CH3:29])(=[O:28])=[O:27])(=[O:19])=[O:18])[CH:5]=[C:6]([CH:15]=1)[O:7][CH2:8][C:9]1([CH2:12][O:13][NH2:14])[CH2:11][CH2:10]1.[ClH:30].N1C=CC([C:36]([NH2:38])=[NH:37])=N1>CN(C)C=O>[ClH:30].[CH3:1][C:2]1[CH:3]=[C:4]([O:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26]([CH3:29])(=[O:28])=[O:27])(=[O:19])=[O:18])[CH:5]=[C:6]([CH:15]=1)[O:7][CH2:8][C:9]1([CH2:12][O:13][NH:14][C:36]([NH2:38])=[NH:37])[CH2:11][CH2:10]1
Reactant: N=C(N)c1cc[nH]n1
Reactant: Cc1cc(OCC2(CON)CC2)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCC2(CONC(=N)N)CC2)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of N-{1-[[5-methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}amine (3.5 g, 8.0 mmol), as prepared in the preceding step, in N,N-dimethylformamide (30 mL) was added 1H-pyrazole-carboxamidine hydrochloride (3.7 g, 25.0 mmol). The reaction mixture was stirred at ambient temperature overnight. N,N-Dimethylformamide was removed under high vacuum. Acetonitrile (50 mL) was added and the solid was removed by filtration. The filtrate was concentrated in vacuo and the residue was dried under high vacuum. The residue was partitioned between water (100 mL plus 5 mL brine) and diethyl ether (50 mL). The water solution was extracted with diethyl ether (50 mL). The combined diethyl ether solution was extracted with pH 5 water (30 mL). The combined water solution was adjusted to pH 8-9 by using 2N NaOH and extracted into ethyl acetate (3×100 mL). The ethyl acetate solution was washed with pH 7 buffer solution (5×60 mL) and brine (50 mL) and dried over Na2SO4. After removing the solvent, 0.6N HCl methanol (50 mL) was added and the solution was concentrated. The residual oil was crystallized from methanol/ethyl acetate (1:50) to give the title compound as white solid (3.6 g, 86%). 1H-NMR (300 MHz, DMSO-d6) δ11.07 (br s, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.09-8.14 (m, 2H), 7.97 (t, J=7.7 Hz, 1H), 7.65 (br s, 4H), 6.76 (s, 1H), 6.52 (s, 1H), 6.51 (s, 1H), 3.86 (s, 2H), 3.78 (s, 2H), 3.48 (s, 3H), 2.21 (s, 3H), 0.69 (m, 2H), 0.62 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C20H25N3O7S2: 484.1 (M+H), 506.1 (M+Na). Found: 484.0, 506.0.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].O>ClCCl>[C:11]([O:1][CH2:2][C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1)(=[O:13])[CH3:12]
Reactant: OCc1ncc2sccn12
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCc1ncc2sccn12
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.5 %

Procedure:
To a solution of 0.231 g (1.50 mmol) of the 5-Hydroxymethylimidazo[5,1-b]thiazole prepared in Preparation 10 in 8 ml of dichloromethane was added 0.156 ml (1.65 mmol) of acetic anhydride with ice-cooling, and the mixture was stirred at room temperature for 20 hours. To the reaction solution were added water and a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography using silica gel, eluting with a 30:1 mixture of chloroform and methanol to give 0.237 g (yield 81%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16]([C:18]1[N:22]([CH3:23])[C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:23][N:22]1[C:21]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]3[CH:15]=[CH:14][CH:13]=[CH:12]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:20][CH:19]=[C:18]1[C:16]#[N:17]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S(=O)(c1ccc(Br)cc1)n1cccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)n2cccc2)cc1
Reaction time: 16 h
Yield: 54.2 %

Procedure:
According to general procedure B, 1-[(4-bromophenyl)sulfonyl]-1H-pyrrole (250 mg, 0.87 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 1-methyl-5-[4-(1H-pyrrol-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile (81 mg, 30%) was provided after purification. MS (ESI) m/z 311. HPLC purity 100.0% at 210-370 nm, 11.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[I:12]I.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Ag+2]>[I:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH:3]=[CH:4]2
Reactant: II
Reactant: O=c1ccc2ccccc2[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Product: O=c1ccc2cc(I)ccc2[nH]1

Procedure:
A solution of 2-[1H]-quinolone (2.0 g) and silver sulphate (2.14 g) in concentrated sulphuric acid (15.0 cm3) was stirred at room temperature during the addition of iodine (3.5 g). After heating at 50° for 24 hours the mixture was poured onto ice, the solution was neutralised with solid sodium carbonate and the solid was filtered off. This material was chromatographed on silica (Merck "MK 60.9385") eluting with chloroform to affford a residue which was recrystallised from methanol to give 6-iodo-2-[1H]-quinolone, m.p. 261°, (0.8 g).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH2:10]Cl)([CH3:9])[CH3:8])=[CH:3][CH:2]=1.[Na].[CH3:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1>>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH3:9])([CH3:8])[CH2:10][N:21]2[CH:22]=[CH:23][N:24]=[C:20]2[CH3:19])=[CH:3][CH:2]=1
Reactant: C[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Reactant: Cc1ncc[nH]1
Agent: [Na]
Product: Cc1nccn1C[Si](C)(C)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound is prepared by applying the procedure of Example 23 to (1,1'-biphenyl-4-yl)chloromethyldimethylsilane and the sodium salt of 2-methylimidazole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[CH3:29])=[C:5]([SH:30])[CH:4]=1)#[N:2].CC1(C)C2C=CC=CC=2I([C:41]([F:44])([F:43])[F:42])O1>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[CH3:29])=[C:5]([S:30][C:41]([F:44])([F:43])[F:42])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CC1(C)OI(C(F)(F)F)c2ccccc21
Solvent: ClCCl
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2SC(F)(F)F)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
Under argon, (4S)-4-(4-cyano-2-sulfanylphenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (45 mg, purity 50%, 53 μmol) was dissolved in dichloromethane (1 ml). At −78° C., 3,3-dimethyl-1-(trifluoromethyl)-1,3-dihydro-1λ3,2-benziodoxole (26 mg, 79 μmol; 1.5 eq.) was added, and the mixture was stirred for 2 h. The reaction solution was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Kromasil C18 column, 20×50 mm; mobile phase: acetonitrile/water+0.1% TFA). After lyophilization, the title compound was obtained as a solid (11.4 mg, 44% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([NH2:28])[C:24]=1[C:25]([OH:27])=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:28][C:23]1[C:24](=[C:19]([Cl:18])[CH:20]=[CH:21][CH:22]=1)[C:25]([OH:27])=[O:26])=[O:6]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1C(=O)O)c1cccc(F)c1
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
15.9 parts of 3-fluorobenzoyl chloride and 10.1 parts of triethylamine are introduced simultaneously, from 2 feeds, into a solution of 17.1 parts of 6-chloroanthranilic acid in 200 parts of methylene chloride at from 25° to 30° C. The reaction mixture is subsequently stirred for 30 minutes, and is extracted once with 1 N hydrochloric acid and then with water. The organic solution is dried and concentrated, giving 29 parts of N-(3'-fluorobenzoyl)-6-chloroanthranilic acid of melting point 216°-219° C.; yield: 98.6% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:4]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1c([N+](=O)[O-])cnn1CCc1ccccc1
Yield: 31.2 %

Procedure:
430 mg (2.5 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.41 ml (3 mM) of (2-bromoethyl)benzene and 1.6 g (5.0 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for a day. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=5:1), to obtain 218 mg (31.2%) of the title compound and 506 mg (65.5%) of the compound of Preparative Example 1.