Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:31])C(=O)C1.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:9]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:10][CH:11]=[C:12]([Br:31])[C:13]=1[F:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1c(OCc2ccccc2)ccc(Br)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-benzyloxy-6-fluorophenyl)-carbamic acid tert-butyl ester (2.35 g, 7.41 mmol) in DMF (20 mL) at 0° C. is added NBS (1.45 g, 8.15 mmol). The mixture is stirred at 0° C. for 30 min., and then at RT for 18 h. It is then poured into water, extracted with EtOAc, washed with water and brine, and dried with MgSO4. The solvent is removed to give the title compound and it is used in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[CH3:15][S-:16].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([S:16][CH3:15])[N:7]=1
Reactant: C[S-]
Reactant: CON(C)C(=O)c1ncc(Cl)nc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ncc(SC)nc1Cl
Reaction time: 5 h

Procedure:
To a solution of 55B (2 g, 8.47 mmol) in DMF (10 mL), 1 eq. of sodium methanethiolate was added to the solution. After 5 hours, 0.5 eq. of sodium methanethiolate was added to the suspension. The reaction was stirred overnight then diluted with EtOAc and washed with NaHCO3 (aq) and brine. The organic layer was concentrated and purified by flash chromatography to provide the title compound. MS (m/z) 248 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:20]([N:28]=C=O)(=[O:27])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([NH2:28])=[O:27])[CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2ccnn2-c2ccc(F)cc2)ccn1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)Nc1cc(-c2ccnn2-c2ccc(F)cc2)ccn1
Temperature: 50 °C
Yield: 73.4 %

Procedure:
To the solution of 4-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-pyridin-2-ylamine (83 mg, 0.33 mmol) in DCM (3.0 mL) is added benzoyl isocynate (96 mg, 0.65 mmol). The resulting mixture is heated at 50° C. for 1 hour. The solvent is then carefully removed in vacuum and to the residue are added K2CO3 (54 mg, 0.39 mmol) and ethanol (2 mL). The reaction mixture is then heated at 85° C. for 30 min. Solvent is again removed in vacuum and the residue is purified through a Silica column eluting with 0-100% EtOAc/Heptane to give the titled compound (72 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1.[C:28](Cl)(=[O:30])[CH3:29]>>[C:28]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)n1c(C(=O)c2cccc([N+](=O)[O-])c2)c(N)c2ccc(Cl)cc21
Reactant: CC(=O)Cl
Product: CCOC(=O)n1c(C(=O)c2cccc([N+](=O)[O-])c2)c(NC(C)=O)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-6-chloro-1-ethoxycarbonyl-2-(3-nitrobenzoyl)indole (step 1) and acetyl chloride. 1H-NMR (CDCl3) δ: 9.18 (1H, br s), 8.65-8.69 (1H, m), 8.38-8.42 (1H, m), 8.02-8.10 (1H, m), 7.98 (1H, s), 7.61-7.71 (2H, m), 7.18-7.25 (1H, m), 4.15 (2H, q, J=7.0 Hz), 2.24 (3H, s), 1.17 (3H, t, J=7.0 Hz)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([OH:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2Br)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([OH:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: OC(Cc1ccccc1Br)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: OC(Cc1ccccc1-c1ccccc1)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Temperature: 80 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
1-(4-Benzyl-morpholin-2-yl)-2-(2-bromo-phenyl)-1-phenyl-ethanol (0.50 g, 1.0 equiv. prepared according to Example 15a below) and phenylboronic acid (0.402 g, 3.0 equiv., available from Aldrich Chemical Company) were suspended in a mixture ethanol/water (2/1, 7.5 mL) and Pd(Ph3)4 (0.022 g, 0.04 equiv.), then K2CO3 (0.654 g, 4.30 equiv.) were added. The mixture was heated to 80° C. under nitrogen atmosphere. After 16 hours, the reaction was cooled down to room temperature and filtered through Celite, then extracted with ethyl acetate. The organic layers were combined, dried with MgSO4, filtered and concentrated in vacuo yielding a yellow oil, which was purified by column chromatography on silica gel (10% EtOAc:Hexane) to give 0.491 g (98%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-:20])[CH:6]=[CH:5]2
Reactant: Fc1ccc2cnccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 6-fluoroisoquinoline (2.64 g, 17.9 mmol) in CH2Cl2 (70 mL) cooled at 0° C., MCPBA is added (3.4 g, 19.69 mmol). The reaction mixture is stirred at RT for 16 h. After 1 h of stirring, a yellow white precipitate forms. The solvent is evaporated under reduced pressure. To the yellow solid is added CH2Cl2 (5 mL), and the solid is isolated by vacuum filtration. Rinsing the solid with CH2Cl2 yields a white solid, which is dried under vacuum to afford 3 g (100%) of 6-fluoro-isoquinoline N-oxide.
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1>C(NCC)C.CO>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:1]1[C:9](=[CH2:10])[CH:8]=[CH:12][CH:11]=1
Reactant: O=Cc1ccco1
Reactant: C1=CCC=C1
Solvent: CCNCC
Solvent: CO
Product: C=C1C=CC=C1c1ccco1

Procedure:
About equal molar amounts of furfural and cyclopentadiene are reacted in the presence of diethylamine catalyst and about 33% methanol solvent according to the method suggested by C. Schmidt, Chem, Ber., Volume 90, p. 1352, 1957. A viscous dark material is separated from the water layer.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:21]#[N:22])[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.C[Si]([N:27]=[N+:28]=[N-:29])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[C:4]([C:21]2[NH:29][N:28]=[N:27][N:22]=2)[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(C#N)cc(Br)cc32)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnn[nH]4)cc(Br)cc32)cc1
Yield: 34.1 %

Procedure:
A stirred solution of 6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carbonitrile (0.79 g, 2.1 mmol), trimethylsilyl azide (0.484 g, 4.20 mmol) and dibutyltin oxide (0.105 g, 0.420 mmol) in toluene (10 ml) was heated at 110° C. for 1 h in the microwave (biotage initiator). The resulting cream coloured solid was collected by filtration, washed with toluene and dried in vacuo at 65° C. to give the title compound as a near colourless solid (0.3 g). The mother liquor was evaporated and the residue triturated with cyclohexane (10 ml) to give a further quantity of the title compound as a pale yellow solid (0.38 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:16])[C:9]([C:11]2[CH:15]=[CH:14][NH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.CC1C=CC(S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[N+](CC)(CC)(CC)CC.[Cl-].O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:16])[C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: O=C(C(=O)c1cccc(Br)c1)c1cc[nH]c1
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(C(=O)c1ccn(CC(F)(F)F)c1)c1cccc(Br)c1
Temperature: 80 °C
Yield: 159.9 %

Procedure:
To a solution of 1-(3-bromophenyl)-2-(1H-pyrrol-3-yl)ethane-1,2-dione (93 mg, 0.33 mmol) in DMF (5.0 mL) was added 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (170 mg, 0.66 mmol), K2CO3 (100 mg, 0.73 mmol) and Et4NCl (5.5 mg, 0.033 mmol) at room temperature. After heating at 80° C. for 3 days, the reaction mixture is cooled, diluted with H2O, EtOAc. The two layers are separated and the aqueous layer is extracted with EtOAc. The combined organic extracts are washed with 1N HCl aqueous H2O, brine, dried (MgSO4) and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane: 20/80) to give the title compound (190 mg, 65%) as a solid. mp: 105-106° C. MS (+) ES: 418 (M+CH3COO)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:10][C:9](=[O:22])[NH:8][C:7]=2[N:23]=1.[H-].[Na+].[N+](C1C=C(S(O[CH2:39][C@@H:40]2[CH2:42][O:41]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:10][C:9](=[O:22])[N:8]([CH2:39][C@@H:40]3[CH2:42][O:41]3)[C:7]=2[N:23]=1
Reactant: COc1ccc2c(n1)NC(=O)CN2C(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)N(C[C@@H]1CO1)C(=O)CN2C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 130.6 %

Procedure:
Phenylmethyl 6-(methyloxy)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate (11 g, 35.1 mmol) was dissolved in DMF (300 ml) at room temperature under argon to give a yellow solution. The solution was then cooled with an ice bath and treated with sodium hydride (1.685 g, 42.1 mmol). The solution was allowed to warm to room temperature. After 20 minutes (2S)-2-oxiranylmethyl 3-nitrobenzenesulfonate (9.56 g, 36.9 mmol) was added. After 1 h all the starting material was consumed so the reaction was treated with a saturated solution of NaHCO3 (350 ml) and the aqueous layer was extracted with DCM (3×400 ml). The combined organic layers were dried over MgSO4, filtered and evaporated to afford a light brown oil (16.93 g). The product was used as crude in the next step.
Reaction SMILES: [F:1][C:2]([F:43])([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=2[N+:25]([O-])=O)=[O:12])=[CH:5][CH:4]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:43])([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=1)[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=2[NH2:25])=[O:12])=[CH:7][CH:8]=1
Reactant: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(CCOC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)c(N)c1
Yield: 71.5 %

Procedure:
5.11 g (8.38 mmol) of 2-(2,4-dinitrophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)-phenoxy]methyl}phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-di-methyl-formamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 200 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 3.30 g of 2-(2,4-diaminophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: C(OCC1CS[C@@H]2C(NC(=O)C(C3N=C(N[C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)SC=3)=NOC(C)C)C(=O)N2C=1C(O)=O)(=O)C.C(O)=[O:53]>O>[C:32]1([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[OH:53])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=CO
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
A mixture of 3.62 g of the product of Example 16 and 16 ml of 50% aqueous formic acid was held at 60° C. for 20 minutes and was then cooled at 20° C. 16 ml of water were added and the mixture was stirred and vacuum filtered. The precipitate was rinsed and dried to obtain 1.23 g of triphenylcarbinol. The filtrate was evaporated to dryness under reduced pressure and the residue was taken up in ethanol which solution was evaporated to dryness under reduced pressure. The residue was taken up in water and the mixture was stirred and then cooled to induce crystallization. The mixture was vacuum filtered and the gummy crystals were rinsed with water and dried to obtain 1.68 g of raw product.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]([C:10]2[N:22]([CH3:23])[C:13]3=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([S:3]([C:4]1[C:5]([C:10]2[N:22]([CH3:23])[C:13]3=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:32])[CH3:2]
Reactant: CCSc1cccnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1cccnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 13.4 %

Procedure:
To a mixture of 2-(3-ethylsulfanyl pyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.62 g) and chloroform (10 ml) was added m-chloroperbenzoic acid (purity: not less than 65%) (0.79 g) while ice-cooling, and then the mixture was stirred at room temperature for 5 hours. To the reaction mixture was poured saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 2-(3-ethylsulfinyl pyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (87 mg), which is hereinafter referred to as “the present compound 2”, and 2-(3-ethylsulfonylpyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.49 g), which is hereinafter referred to as “the present compound 3”.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:31]#[N:32])(C)C.CN(C)C(Cl)=O>C(OCC)(=O)C.O>[C:31]([C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[CH:6][N:1]=1)#[N:32]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)/C=C/c1ccncc1
Agent: CN(C)C(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 45 h
Yield: 73.7 %

Procedure:
tert-Butyl (E)-3-(4-pyridyl)acrylate (0.88 g, 4.3 mmol) was dissolved in ethyl acetate (4 ml), and 3-chloroperbenzoic acid (ca. 77%, 0.95 g, 4.3 mmol) was added thereto. The reaction mixture was stirred at room temperature for 45 hrs and subjected to a silica gel (40 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (4:1) were collected and concentrated. The residue was dissolved in nitroethane (5 ml), and trimethylsilyl cyanide (0.63 g, 6.3 mmol) and N,N-dimethylcarbamoyl chloride (0.68 g, 6.3 mmol) were added thereto. The reaction mixture was stirred at room temperature for 20 hrs and combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to silica gel (30 g) column chromatography. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected and concentrated to give the titled compound (0.73 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>C1COCC1>[NH2:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[CH:8][CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1cccnc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ncccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of methyl 2-aminonicotinate (4 g) and 2M aqueous sodium hydroxide solution (35 mL) in THF (50 mL) was stirred at room temperature overnight. The reaction mixture was neutralized with 1M hydrochloric acid, and extracted with ethyl acetate. The aqueous layer was acidified with 1M hydrochloric acid, and extracted with THF. The organic layers were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (1.78 g) as a white solid.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:26])[CH:11]=[C:12]([CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[O:13][CH:14]=1)C1C=CC=CC=1.S(=O)(=O)(O)O>C(O)(=O)C>[OH:8][C:9]1[C:10](=[O:26])[CH:11]=[C:12]([CH2:15][NH:16][S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[O:13][CH:14]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1O
Temperature: 80 °C
Yield: 85.7 %

Procedure:
N-(5-Benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (7-01) (2.0 g, 5.39 mmol) was dissolved in acetic acid (25.0 mL) and sulfuric acid (0.058 mL) was added, then the reaction mixture was heated up to 80° C. for 24 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under vacuum. It was then diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. It was then purified by washing with hexane to get N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (8-01) (1.3 gm, 85.53%) as a brown solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][NH:8][CH3:9].Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[N:14]=[C:13]([S:25][CH2:26][CH3:27])[C:12]=1[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)=[O:29].CCCCCC>CN(C=O)C.O>[CH3:7][N:8]([CH3:9])[C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[N:14]=[C:13]([S:25][CH2:26][CH3:27])[C:12]=1[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)=[O:29]
Reactant: CNC
Reactant: CCSc1nc2cc(C(F)(F)F)ccc2c(Cl)c1C(=O)NCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc2cc(C(F)(F)F)ccc2c(N(C)C)c1C(=O)NCc1cccc(F)c1
Yield: 60 %

Procedure:
60 mg (0.45 mmol) K2CO3 and 0.7 ml (1.36 mmol, 2M in THF) dimethylamine were added at RT to a solution of 200 mg (0.45 mmol) 4-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-7-(trifluoromethyl)-quinoline-3-carboxamide (example 122) in DMF (3 ml) and the mixture was then heated in a closed vessel for 150 min at 80°. Then it was diluted with water and extracted with EE. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 17:3) of the residue yielded 120 mg (0.27 mmol, 60%) 4-dimethylamino-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-7-(trifluoromethyl)-quinoline-3-carboxamide. MS: m/z 452.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][N:22]([C:29]([CH:26]2[CH2:28][CH2:27]2)=[O:30])[CH2:23][CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)C1CC1
Product: CCN(Cc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6,5′-dimethoxy-biphenyl-3-yl)-acetic acid methyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11]O)[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][C:40]=1[SH:49]>ClCCl.O>[Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][S:49][C:40]3[CH:41]=[CH:42][C:43]4[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:39]=3)[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1
Reactant: Sc1ccc2ccccc2n1
Reactant: OCc1cn2c(Br)cnc(N3CCOCC3)c2n1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Brc1cnc(N2CCOCC2)c2nc(CSc3ccc4ccccc4n3)cn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of compound 1e (10 g, 30.45 mmol) and DIPEA (10.23 g, 79.30 mmol) in dichloromethane (200 mL) was cooled in an ice bath and MsCl (7.3 g, 63.48 mmol) was added dropwise. Upon complete addition, the reaction mixture was stirred for 3 h at room temperature and concentrated under reduced pressure. To the residue was added CH3CN (150 mL), followed by potassium carbonate (6.57 g, 47.6 mmol) and quinoline-2-thiol (5.62 g, 34.9 mmol). The resulting mixture was stirred overnight at 60° C. and allowed to cool to rt. Water (300 mL) was then added. The solids were collected by filtration. The crude product was recrystallized from DCM/ethyl ether (1:2 v/v) to obtain compound 78a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C20H18BrN5OS: 457.1 (M+H). found: 457.0