Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[CH:15]1(B(O)O)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1.[NH4+].[Cl-]>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][N:8]([CH:15]3[CH2:17][CH2:16]3)[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc2c1cnn2C1CC1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Methyl 6-bromo-1H-indazole-4-carboxylate (1.0 g, 3.92 mmol) was dissolved in 1,2-Dichloroethane (DCE) (14 mL) and stirred for 15 min. Next added cyclopropylboronic acid (0.674 g, 7.84 mmol) and sodium carbonate (0.831 g, 7.84 mmol). The reaction was stirred at RT (suspension). Copper (II) acetate (0.712 g, 3.92 mmol) and 2,2′-bipyridine (0.612 g, 3.92 mmol) were suspended in DCE (24 mL) with heating and the hot suspension was added to the reaction mixture. The contents were stirred with heating at 70° C. overnight. After cooling to RT, the reaction mixture was poured onto sat. NH4Cl and ice. Next added DCM and stirred for 10 min. The contents were filtered through Celite, washing with water and DCM. The layers were separated and the aq. layer was extracted with DCM (1×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (3-25% gradient ethyl acetate in hexanes) wherein the less polar product was observed to be the title compound, and was collected as a yellow solid (0.54 g, 46%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.20 (m, 4H), 3.81-3.90 (m, 1H), 3.95 (s, 3H), 7.86 (d, J=1.52 Hz, 1H), 8.30 (d, J=1.77 Hz, 1H), 8.32 (d, J=1.01 Hz, 1H); LC-MS (ES) m/z=295.1 [M+H]
Reaction SMILES: [CH2:1]([Si:4]([Cl:7])(Cl)Cl)[CH:2]=[CH2:3].N12CCCN=C1CCCCC2.[OH:19][C:20]([C:23]([OH:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[CH2:1]([Si:4]1([Cl:7])[O:26][C:23]([CH3:25])([CH3:24])[C:20]([CH3:22])([CH3:21])[O:19]1)[CH:2]=[CH2:3]
Reactant: CC(C)(O)C(C)(C)O
Reactant: C=CC[Si](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CC[Si]1(Cl)OC(C)(C)C(C)(C)O1
Reaction time: 12 h
Yield: 69.3 %

Procedure:
To a cooled (0° C.) solution of allyltrichlorosilane (4.9 mL; 34 mmol) in CH2Cl2 (50 mL) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (13 mL; 84 mmol). A solution of pinacol (4.0 g; 34 mmol) in CH2Cl2 (50 mL) was then added slowly and the resultant solution was warmed to room temperature and stirred for 12 hours. The solution was concentrated and the residue was treated with diethylether (100 mL). The mixture was stirred for 1 hour during which time the formation of a precipitate was observed. The mixture was then filtered and the filtrate was concentrated. The residue was distilled under reduced pressure to give 5.2 g (72%) of 2-allyl-2-chloro-4,4,5,5-tetramethyl-[1,3,2]dioxasilolane as a clear, colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[C:16]([CH3:18])[S:15][C:10]=2[NH:11][C:12](=[O:14])[N:13]=1.[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[CH3:21][N:11]1[C:10]2[S:15][C:16]([CH3:18])=[CH:17][C:9]=2[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:13][C:12]1=[O:14]
Reactant: Cc1cc2c(-c3ccccc3F)nc(=O)[nH]c2s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(-c3ccccc3F)nc(=O)n(C)c2s1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 12.4 g of 4-(o-fluorophenyl)-6-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 248 ml of dimethylformamide is added 2.58 g of 67% sodium hydride. After stirring at 50°C for 1 hour and cooling to room temperature, 20.45 g of methyl iodide in 61.4 ml of dimethylformamide is added dropwise thereto. The mixture is stirred at room temperature for 1 hour, then poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel using chloroform as an eluent to give 1-methyl-4-(o-fluorophenyl)-6-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 119° - 121°C (after recrystallization from chloroform-ethanol), and 3-methyl-4-(o-fluorophenyl)-6-methyl-3H-thieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 239° - 241°C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.CC[N:17](C(C)C)[CH:18]([CH3:20])[CH3:19].C(N)(C)C>>[CH:18]([NH:17][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)([CH3:20])[CH3:19]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CC(C)N
Product: CCOC(=O)c1cnc(SC)nc1NC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.4 %

Procedure:
Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (900 g, 3.87 mol) ethanol (12 L), DIEA (876 mL, 5.05 mol), and isopropylamine (379 mL, 4.45 mol) were combined and mixed at ambient temperature for 4 h. An additional amount of isopropylamine (50 mL, 0.59 mol) was added and the mixture was stirred overnight at ambient temperature. The reaction was concentrated under reduced pressure and the crude product was diluted with water (2 L). The aqueous layer was extracted with chloroform (2×3 L). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (1042 g, 4.08 mol, >100% yield, contaminated with trace DIEA) as a pale brown oil that was used without further purification. MS (ESI) m/z 256.4 [M+1]+.
Reaction SMILES: [CH:1]([NH:3][NH:4][CH:5]=O)=O.C[Si](Cl)(C)C.CCN(CC)CC.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1>N1C=CC=CC=1>[N:4]1[N:3]=[CH:1][N:19]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:25]=2)[CH:5]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=CNNC=O
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(O)Cc1ccc(-n2cnnc2)cc1
Temperature: 100 °C
Yield: 92.9 %

Procedure:
Adapting a protocol by Catarzi et al (J. Med Chem., 2001, 44, 3157-3165), diformylhydrazine (352 mg, 4.0 mmol) and then dropwise trimethylsilyl chloride (2.53 mL, 20 mmol) and Et3N (1.30 mL, 9.3 mmol) were added to a suspension of 4-aminophenylacetic acid (201 mg, 1.33 mmol) in anhydrous pyridine. The mixture was heated at 100° C. overnight, volatiles were removed at reduced pressure and the resulting solid was treated with water (6 mL), collected, washed with H2O and dried in vacuo to provide 251 mg (93%) of 141JP01 as a light brown solid. LCMS m/z 204[M+H]+. 1H-NMR (DMSO-d6) δ 9.05 (s, 2H), 7.62 (d, 1H, J=8.6), 7.40 (d, 1H, J=8.2), 3.61 (s, 2H).
Reaction SMILES: N1C=CC=CC=1.[N:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[NH2:13][C:12]1[N:7]=[C:8]([NH:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH:9]=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(N)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(N)n1
Temperature: 0 °C
Yield: 50 %

Procedure:
Pyridine (0.130 mL, 1.60 mmol) was added to pyridine-2,6-diamine (350 mg, 3.21 mmol) in DCM (6.4 mL). The reaction mixture was cooled to 0° C., and then methanesulfonyl chloride (0.124 mL, 1.60 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (30-100% acetone/hexanes, linear gradient) to afford N-(6-aminopyridin-2-yl)methanesulfonamide (˜50% purity) that was used without further purification. MS ESI calc'd. for C6H10N3O2S [M+H]+ 188. found 188.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6]1)=[O:4].C[O-].[Na+]>C1(C)C=CC=CC=1>[C:21]([O:20][C:18]([N:7]1[CH2:8][CH2:9][C@@H:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.8 %

Procedure:
A mixture of (+)-(3R,4R)-4-(4-fluoro-phenyl)-piperidine-1,3-dicarboxylic acid 1-tert butyl ester 3-methyl ester (3.55 g, 10.5 mmol) and sodium methoxide (1.14 g, 21.1 mmol) in 100 ml anhydrous toluene was heated at reflux over night. After cooling to room temperature the reaction mixture was quenched with water and concentrated in vacuo. The residue was dissolved in a mixture of 100 ml 1,4-dioxane and 50 ml 2 M aqueous sodium hydroxide solution. After stirring at RT for 5 h the mixture was diluted with water and washed with two portions of tert-butyl methyl ether. The aqueous layer was cooled to 0° C., acidified to pH 1-2 with ice-cold 1 M aqueous hydrochloric acid solution and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography and crystallization from heptane/ethyl acetate 9:1 (30 ml) gave the title compound as white crystals (1.76 g, 52%, 97.5% ee).
Reaction SMILES: O[N:2]=[C:3]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:4]([CH3:12])[C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]2[C:4]([CH3:12])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[O:11][N:2]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(=O)C(C)C(=NO)c1ccc(OC)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1onc(-c2ccc(OC)cc2)c1C
Temperature: 25 °C
Yield: 74.9 %

Procedure:
Ethyl 4-(hydroxyimino)-4-(4-methoxyphenyl)-3-methyl-2-oxobutanoate (17.7 g, 63.4 mmol) and concentrated sulfuric acid (15 mL) were added to 180 mL of absolute ethanol and the mixture was refluxed for 20 hours. After the mixture cooled to room temperature, saturated sodium bicarbonate solution was added to neutralize the mixture. The product was extracted with EtOAc and the combined organic layer was dried over MgSO4 and concentrated to give 12.4 g of the title compound. MS: (+) m/z 262.45 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1I)[NH2:5].[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][C:8]=1[C:12]1[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=1[Cl:10]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(I)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
3-Chloro-4-iodoaniline (3.0 g, 11.8 mmol), (2-chloro-4-(trifluoromethyl)phenyl)boronic acid (3.2 g, 14.2 mmol), Pd(dppf)Cl2 (969 mg, 1.2 mmol), and K2CO3 (3.3 g, 23.7 mmol) were dissolved in 1,4-dioxane (40 mL) and water (10 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:12](=O)([O-])[O-].[K+].[K+].P(OC)(OC)(OC)=O>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COP(=O)(OC)OC
Product: COc1ccc(NC(C)=O)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 281.1 %

Procedure:
To a three-necked 100 ml flask equipped for reflux and fitted with a mechanical stirrer was added 10.0 g (0.066 mol) of p-acetamidophenol, 2.0 g (0.014 mol) of potassium carbonate, and 20 ml (0.17 mol) of trimethyl phosphate. The mixture was heated to 90° C. for three hours then allowed to stand overnight before quenching with 50 ml of water. Extraction into methylene chloride and removal of residual starting material via a base wash with 6% sodium hydroxide solution gave on concentration in vacuo 6.5 g (60%) of p-acetamidoanisole.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:24]1(B(O)O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:32]2[C:33]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:29]=[CH:30][CH:31]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(Cl)cc3)c2c1O
Reactant: OB(O)c1cccc2ccccc12
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)c2snc(-c3ccc(Cl)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-bromo-3-(4-chloro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 1-naphthylboronic acid: MS (m/z) 461.0 (M+1).
Reaction SMILES: N[C:2]1[C:3]([C:14]2[C:15]([Cl:34])=[C:16]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:17]=[CH:18][C:19]=2[Cl:20])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.N([O-])=[O:36].[Na+]>C(O)(C(F)(F)F)=O>[Cl:34][C:15]1[C:14]([C:3]2[C:2](=[O:36])[NH:13][C:6]3[N:7]=[C:8]([S:11][CH3:12])[N:9]=[CH:10][C:5]=3[CH:4]=2)=[C:19]([Cl:20])[CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=1
Reactant: O=N[O-]
Reactant: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(N)nc2n1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(=O)[nH]c2n1
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a solution of N-[3-(7-amino-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-6-yl)-2,4-dichloro-phenyl]-3-trifluoromethyl-benzamide (1.7 g, 3.24 mmol) in TFA (15 mL) is slowly added NaNO2 (783 mg, 11.35 mmol) at 0° C. with stirring for 20 minutes. The solvents are evaporated and diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give the crude product. The crude product is purified by flash silica gel column, eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH(NH3, 2N)(93/7%), to give the title intermediate as a solid (1.64 g, 96.5%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=1.CN[C@@H]1CCCC[C@H]1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.[Cu]I>[F:21][C:18]1[CH:19]=[C:20]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:15]=[CH:16][C:17]=1[F:22]
Reactant: Fc1ccc(I)cc1F
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(ccn2-c2ccc(F)c(F)c2)c1
Temperature: 110 °C
Yield: 91.6 %

Procedure:
A mixture of methyl indole-5-carboxylate 24a (2 g, 11.4 mmol), 1-iodo-3,4-difluoro-benzene 24b (1.5 mL, 12.5 mmol), CuI (0.22 g, 1.14 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.54 mL, 3.43 mmol), and K3PO4 (6.06 g, 28.5 mmol) in toluene (12 mL) was heated at 110° C. for 7 hours. The reaction mixture was diluted with CH2Cl2 and filtered. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 20% EtOAc/heptane) to give 24c (3.0 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=2)=[S:22])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Product: Fc1cc(NC(=S)Nc2ccc(Cl)c(C(F)(F)F)c2)cc(C(F)(F)F)c1

Procedure:
The title compound was synthesized according to the procedure used in example 2 starting with 3-Fluoro-5-(trifluoromethyl)-aniline and 4-Chloro-3-(trifluoromethyl)-phenylisothiocyanate. Yield: 98 mg (47%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([CH3:33])([CH3:32])[C:28](OC)=[O:29])=[N:25][CH:26]=2)=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([CH3:33])([CH3:32])[CH2:28][OH:29])=[N:25][CH:26]=2)=[N:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1ccc(-c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cn1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CO)c1ccc(-c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
To a solution of Example 84 (120 mg, 0.2 mmol) in THF (10 mL) at −78° C. was added DIBAl-H (1.0M/toluene, 0.6 mL, 0.6 mmol). The resulting solution was stirred at −78° C. for 1 h. The reaction mixture was then poured into a vigorously stirred Rochelle salt solution/EtOAc (1:1). Upon clarification of the organic layer, the layers were separated, dried over MgSO4, filtered, concentrated and purified on silica gel to afford the title compound (95.7 mg). LC/MS: m/e 456.1 (M+H)+. 1H NMR (500 MHz, acetone-d6): δ 1.35 (s, 6H), 3.73 (d, J=5.5 Hz, 2H), 4.08 (t, J=5.5 Hz, 1H) 7.40 (m, 3H), 7.58 (d, J=7.5 Hz, 1H), 7.82 (dd, J=3, 9 Hz, 1H), 8.25 (m, 2H), 8.39 (dd, J=2.5, 8.5 Hz, 1H), 8.47 (d, 2.5J=2.5 Hz, 1H), 9.21 (s, 1H).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[Br:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[C:10]([N:15]([CH2:18][C:19](=O)[CH3:20])[CH:16]=O)=[CH:9][CH:8]=1.C(OCC)(=O)C.N>C(O)(=O)C>[Br:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[C:10]([N:15]2[CH:18]=[C:19]([CH3:20])[N:5]=[CH:16]2)=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: COc1nc(Br)ccc1N(C=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1nc(Br)ccc1-n1cnc(C)c1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
A suspension of ammonium acetate (267 g) and N-(6-bromo-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide (199 g) in glacial acetic acid (400 mL) was stirred at 130° C. for one hour and 10 minutes. The reaction solution was brought back to room temperature. Ethyl acetate and ice water were added to the reaction solution, and the mixture was ice-cooled. Then, concentrated aqueous ammonia (500 mL) was added dropwise and then the organic layer was separated. The resulting organic layer was sequentially washed with water and brine and dried over anhydrous magnesium sulfate. Then, the organic layer was purified by short silica gel column chromatography (carrier: Wakogel™ C-200 manufactured by Wako Pure Chemical Industries, Ltd.; elution solvent: ethyl acetate). The eluted fraction was concentrated. The resulting residue was triturated with ethyl acetate and tert-butyl methyl ether and dried under reduced pressure to obtain 107.7 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]4[CH:17]=[C:18]([NH:21][C:22](=[O:30])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[Cl:29])[CH:19]=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[C:10]([C:31]([NH2:33])=[O:32])=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][N:35](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:14]2[CH2:13][CH2:12][C:11]3[C:10]([C:31]([NH2:33])=[O:32])=[N:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:34]#[N:35])=[CH:3][CH:4]=4)[C:16]=3[C:15]=2[CH:17]=1)=[O:30]
Reactant: CN(C)C=O
Reactant: NC(=O)c1nn(-c2ccc(Br)cc2)c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Temperature: 100 °C

Procedure:
1-(4-Bromophenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (5.2 g) and Zn(CN)2 (0.9 g) were dissolved in 100 ml DMF under N2. Then Pd(Ph3P)4 (1.38 g) was added. The reaction mixture was heated up to 100° C. under N2 for 12 hours. After the reaction is completed by HPLC, the solvent was evaporated, and the residue was suspended in ethyl acetate and water. After filtration, and washing with water and ethyl acetate, the filtrate of the organic layer was separated and dried with Na2SO4. After filtration and evaporation of solvent, the residue was triturated with ether. Solid obtained was filtered and washed with ether, then dried under vacuum. The desired compound (3.4 g) was obtained and characterized by 1H NMR, LC-MS (468, M+1), and CHN analysis. IKK-2 resin IC50≦1 μM.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[OH:13][C:14]1[CH:22]=[CH:21][C:17]2[CH:18]=[CH:19][O:20][C:16]=2[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[O:20]1[C:16]2[CH:15]=[C:14]([O:13][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:22]=[CH:21][C:17]=2[CH:18]=[CH:19]1
Reactant: Oc1ccc2ccoc2c1
Reactant: OC(CCl)CCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OC(CCc1cccnc1)COc1ccc2ccoc2c1
Temperature: 120 °C
Yield: 24.9 %

Procedure:
##STR16## (±)-α-(Chloromethyl)-3-pyridinepropanol (0.339 g, Example 2a)) was dissolved in anhydrous N,N-dimethylformamide (5 ml) and added to a suspension of 6-hydroxybenzofuran (0.245 g, Bull. Soc. Chim. Fr., 1973, 2355) and cesium carbonate (0.596 g) in anhydrous N,N-dimethylformamide (5 ml) which had been heated previously for one hour at 120° C. The mixture was then heated at 120° C. for 7 hours before being cooled to room temperature. The mixture was then poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:ethanol (19:1) and recrystallised from ethyl acetate:hexane to give the title compound (0.129 g).