Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:12][C@@H:13]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@@H:14]1Br)(=[O:11])[CH3:10]>C1(C)C=CC=CC=1.C(#N)C.[O-2].[Zn+2].[Cl-].[Zn+2].[Cl-]>[C:9]([O:12][C@@H:13]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:14]1[O:8][C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: Cc1ncccc1O
Agent: [Cl-]
Agent: [O-2]
Agent: [Zn+2]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1C
Temperature: 60 °C
Reaction time: 18 h

Procedure:
6 g (73.7 mmol) of zinc oxide, 2.6 g (19 mmol) of zinc chloride and 4 g of 4 Å molecular sieve are mixed. This mixture is desiccated perfectly and 2 g (18.3 mmol) of 2-methyl-3-pyridinol and 6.6 g (18.6 mmol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide in 40 ml of toluene and 40 ml of acetonitrile are then added. The mixture is stirred at 60° C. for 18 hours and then filtered. The filtrate is concentrated under reduced pressure and the evaporation residue is purified by chromatography on silica gel using an ethyl acetate/hexane mixture (7/3 then 100% ethyl acetate; v/v) as the eluent to give the expected product in the form of a beige solid (yield=7%).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[SH:22][CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].[Cl-].[Na+]>CN(C)C=O>[CH2:27]([O:26][C:24](=[O:25])[CH:23]([S:22][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1)[CH3:29])[CH3:28]
Reactant: CCOC(=O)C(C)S
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Sc1cc(C)c(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 111.3 %

Procedure:
To a solution of methyl 4-chloro-2-methyl-5-nitrobenzoate (2.52 g) in N,N-dimethylformamide (20 ml) were added potassium carbonate (3.04 g) and ethyl 2-mercaptopropionate (2.2 g), and the mixture was stirred at 80° C. for 4 hours. After the reaction was complete, to the mixture was added a saturated aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure to give methyl 4-[(2-ethoxy-1-methyl-2-oxoethyl)thio]-2-methyl-5-nitrobenzoate (4.0 g). Subsequently, the title compound was obtained in a similar manner to Reference Example 2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(OCC)(=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[S:32]([CH3:31])(=[O:34])=[O:33])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cccc(NCc2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)N(Cc1cccnc1)c1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
A 3.2 g. portion of 3-(3-nitrophenylaminomethyl)pyridine was dissolved in 15 ml. of toluene, and 2.7 g. of potassium carbonate and 1.6 ml. of methanesulfonyl chloride were added. The mixture was heated to a gentle boil and stirred overnight under reflux. Twenty-five ml. of water and 25 ml. of ethyl acetate were added, and the organic phase was dried and evaporated under vacuum. The residue was triturated with diethyl ether, filtered and dried to obtain 2.4 g. of the desired product, m.p. 131°-133°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=O)=[CH:16][CH:15]=2)[CH:10]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:36][CH2:37][C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39].C(N(CC)CC)C.F[B-](F)(F)F.O=C1C=CC=CN1OC(N(C)C)=[N+](C)C>CN(C)C=O>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:10]1[CH:11]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21](=[O:23])[NH:36][CH2:37][C:38](=[O:39])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]1
Reactant: NCC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)NCC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
A solution of 150 mg (0.32 mmol) of (3RS,4RS)-[4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-phenyl]-acetic acid and 55 mg (0.32 mmol) of 2-amino-1-phenyl-ethanone in 5 ml of dimethylformamide was treated in sequence with 44.6 μl (0.32 mmol) of triethylamine and 96 mg (0.32 mmol) of O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU) and the mixture was stirred at room temperature for 18 hours. For the working-up, the reaction was evaporated in an oil pump vacuum, the residue was taken up in 20 ml of methylene chloride and washed with 5 ml of water. The organic phase was dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude material was chromatographed on silica gel using a 95:5 mixture of methylene chloride and methanol as the eluent. There were obtained 120 mg (64% of theory) of tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[(2-oxo-2-phenyl-ethylcarbamoyl)-methyl]-phenyl}-piperidine-1-carboxylate as a colourless oil; MS: 615 (M+Na)+.
Reaction SMILES: [OH-].[K+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:5]=2[O:4]1.O.[OH:16][CH2:17][CH:18](CO)[OH:19]>>[OH:4][C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][C:10]=1[O:11][CH2:3][CH:18]([OH:19])[CH2:17][OH:16]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Reactant: OCC(O)CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC(O)CO)c(O)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
0.3 mol (19.8 g) of 85% by weight potassium hydroxide pellets is dissolved in 210 ml of glycerol, and 0.25 mol (41.75 g) of 3,4-methylenedioxynitrobenzene is then added, with stirring. After heating for one and a half hours in the region of 110° C., the reaction medium is poured into 1.5 liters of iced water. The mixture is filtered in order to remove a small quantity of starting material. The filtrate is acidified to pH=4 with hydrochloric acid and then treated with 10 g of vegetable charcoal. After stirring for a few minutes at ambient temperature and removal of the vegetable charcoal by filtration, the solution is left to stand overnight at 0° C. and the expected product which has crystallized is then filtered off. After recrystallization from ethanol and drying in vacuo, the product melts at 148° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH:20]1([N:26]([CH3:35])[C:27](N2C=C[N+](C)=C2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:27](=[O:28])[N:26]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH3:35])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)C1CCCCC1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C1CCCCC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(cyclohexyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptane, 1:5) (80%, white crystals). HPLC-MS m/z=395.2 (M+1), Rt: 5.7 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([O-])=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[NH2:1])[CH:9]=[CH:10]1
Reactant: O=[N+]([O-])c1cccc2cc[nH]c12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cccc2cc[nH]c12
Yield: 99 %

Procedure:
Dissolve 7-nitroindole in ethanol and add ammonium formate (10 equivalents) and a catalytic amount of 10% palladium on carbon. Heat the mixture to reflux for 1 hr before cooling, filter through celite, and evaporate to provide the product as a purple solid (99%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=[NH:7])[NH:5][NH2:6].[NH2:15][C:16](=S)[C:17](OCC)=[O:18]>C(O)C>[NH2:15][C:16]1[C:17](=[O:18])[NH:7][C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=2[CH3:1])=[N:5][N:6]=1
Reactant: CCOC(=O)C(N)=S
Reactant: Cc1c(C(=N)NN)cccc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1c(-c2nnc(N)c(=O)[nH]2)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-3-nitrobenzimidohydrazide (2.10 g, 10.81 mmol) and ethyl 2-amino-2-thioxoacetate (3.60 g, 27.0 mmol) in ethanol (100 mL) was heated at reflux for 8 hr, during which period product precipitated. Upon cooling to rt, the product, 6-amino-3-(2-methyl-3-nitrophenyl)-1,2,4-triazin-5(2H)-one (2.18 g) was collected as a white solid by suction filtration and dried under vacuum. This product was 88% pure by HPLC. It was used in the next step without further purification.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:43])[F:44])[CH:37]=4)(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc(C(F)(F)F)c1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 95 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-3-(trifluoromethyl)benzenesulfonamide (26 mg, 0.040 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 21 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(trifluoromethyl)benzenesulfonamide (percentage yield: 95%), was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:30]([Cu])#[N:31]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:30]#[N:31])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc4c(c3)OCO4)cc2c1O
Reactant: N#C[Cu]
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4c(c3)OCO4)cc2c1O

Procedure:
Prepared in analogy to example 31g from 6-(benzo[1,3]dioxol-5-yloxy)-1-bromo-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and CuCN. ESI MS (m/z): 407 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:36][CH:37]2[CH2:42][CH2:41][N:40]([CH:43]3[CH2:46][O:45][CH2:44]3)[CH2:39][CH2:38]2)[C:34]=1[Cl:35])[C:30]#[N:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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.[Fe+2]>[Cl:35][C:34]1[C:33]([O:36][CH:37]2[CH2:42][CH2:41][N:40]([CH:43]3[CH2:44][O:45][CH2:46]3)[CH2:39][CH2:38]2)=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:19][CH2:20]2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: N#Cc1cc(N)c(Cl)c(OC2CCN(C3COC3)CC2)c1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(OC4CCN(C5COC5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 60 °C
Yield: 49.3 %

Procedure:
A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9) (57.6 mg, 0.162 mmol), 3-amino-4-chloro-5-((1-(oxetan-3-yl)piperidin-4-yl)oxy)benzonitrile (50 mg, 0.162 mmol), palladium(II) acetate (9.67 mg, 0.043 mmol), xantphos (9.40 mg, 0.016 mmol), DPPF (9.01 mg, 0.016 mmol) and cesium carbonate (138 mg, 0.422 mmol) in dioxane (1 ml) was evacuated and back filled with nitrogen three time and was heated at 60° C. for 2 h. The reaction mixture was filtered through a pad of celite, the filtrate was concentrated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 0-6% 2 N ammonia in methanol/dichloromethane). Compound from ISCO was suspended in methanol (1 ml) and the white precipitate was collected by filtration. 2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg) was obtained as a white solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:22].[CH3:23][C:24]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:29])[CH2:25][C:26](O)=[O:27]>>[CH3:29][C:24]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:23])[CH2:25][C:26]([NH:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:22])=[O:27]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: Nn1nc(-c2ccc(C(F)(F)F)cc2)c2ccccc2c1=O
Product: CC(C)(CC(=O)Nn1nc(-c2ccc(C(F)(F)F)cc2)c2ccccc2c1=O)c1ccccc1

Procedure:
The product of Example 147A and 3-methyl-3-phenylbutanoic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.37-11.43 (m, 1H), 8.39-8.48 (m, 1H), 7.95-8.01 (m, 2H), 7.94-7.97 (m, 2H), 7.82-7.85 (m, 2H), 7.71-7.75 (m, 1H), 7.43-7.46 (m, 2H), 7.29-7.33 (m, 2H), 7.15-7.21 (m, 1H), 2.63 (s, 2H), 1.47 (s, 6H); MS (APCI+) M/Z 466 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:25]4[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]4=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)nc1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cc1ccc(=O)n(-c2ccc(-n3cnc(CNC(=O)c4ccc(Cl)s4)c3)cc2)c1
Temperature: 130 °C
Yield: 14.5 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 (56 mg, 0.13 mmol), 2-hydroxy-5-methylpyridine (45 mg, 0.41 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K2CO3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was heated at 130° C. overnight. The mixture was then purified by HPLC to give the titled compound (8 mg). MS 425.0 and 427.0 (M+H, Cl pattern).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:4][CH:3]=3)=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNCC1CCCCC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCC4CCCCC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-cyclohexylmethyl-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].Cl.C(NCC)C>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:16]([CH2:17][CH3:18])[CH2:14][CH3:15])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCNCC
Agent: Cl
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 79.2 %

Procedure:
To a solution of 132.6 g of o-nitrobenzenesulfonyl chloride in 700 ml of tetrahydrofuran was added 88.5 g of diethylamine at 5°-15°. The reaction mixture was stirred at room temperature for 1 hour before the precipitated diethylamine hydrochloride was removed by filtration. The filtrate was evaporated to dryness in-vacuo and the residue dissolved in 1-chlorobutane. The 1-chlorobutane solution was washed with water, dried over magnesium sulfate and evaporated in-vacuo to give 122.4 g of o-nitro-N,N-diethylbenzenesulfonamide as a dark oil.
Reaction SMILES: Br[C:2]1[N:3]([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:16][C:15]=3[S:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])=[O:24])[CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][N:6]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.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>[C:31]1([C:2]2[N:3]([CH2:7][C:8]3[CH:9]=[C:10]([C:14]4[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:16][C:15]=4[S:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])=[O:24])[CH:11]=[CH:12][CH:13]=3)[CH:4]=[CH:5][N:6]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3Br)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3ccccc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 90 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
To a solution of 3-[3-(2-bromoimidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (58.5 mg, 0.115 mmol; see Example 11(b)) in toluene (5 mL) and ethanol (0.5 mL) was added phenyl boronic acid (55.9 mg, 0.458 mmol), Pd(PPh3)4 (7.9 mg, 6.88 μmol), NaOH (0.46 mL, 0.688 mmol, 1.5 M aq), and the reaction mixture was stirred for 4 h at 90° C. Another portion of phenyl boronic acid (20.0 mg, 0.164 mmol) and Pd(PPh3)4 (2.0 mg, 1.7 μmol) were added and the reaction was stirred overnight at 90° C. The reaction mixture was diluted with EtOAc (30 mL) and washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using EtOAc:hexane (8:2) as eluent to give the sub-title compound in 49% yield (28.4 mg, 0.056 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.Cl.[CH2:13]([O:15][C:16](=[O:20])[CH2:17][CH2:18][NH2:19])[CH3:14]>CN(C=O)C.O>[CH2:13]([O:15][C:16](=[O:20])[CH2:17][CH2:18][NH:19][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:14]
Reactant: CCOC(=O)CCN
Reactant: Cc1cccc([N+](=O)[O-])c1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNc1c(C)cccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 76.6 %

Procedure:
1-Methyl-2-fluoro-3-nitro-benzene (465 mg, 3 mmol) was dissolved in DMF (6 mL) and 3-aminopropionic acid ethyl ester hydrochloride salt (735 mg, 4.6 mmol) was added followed by TEA (1.5 mL, 10.7 mmol). The reaction mixture was heated in the microwave at 130° C. for 1 h, cooled, diluted with water (100 mL) and extracted with dichloromethane (2×50 mL). The combined organic fractions were washed with 1 N HCl (30 mL), water (30 mL) and brine (30 mL), dried and evaporated to provide 3-(2-methyl-6-nitrophenylamino)-propionic acid ethyl ester (580 mg, 77% yield) which was used directly. This intermediate (101 mg, 0.4 mmol), ammonium formate (252 mg, 4 mmol) and Pd/C (5%, 5 mg) were combined in a reaction vial and methanol (1 mL) was added. The mixture was agitated at room temperature for 4 h, diluted with dichloromethane (5 mL) and filtered, and the mother liquors were concentrated to provide the crude product 3-(2-amino-6-methylphenylamino)-propionic acid ethyl ester which was used directly. This intermediate (37 mg, 0.17 mmol) was dissolved in dichoromethane (1 mL) and carbonyldiimidazole (34 mg, 0.21 mmol) was added. The resulting mixture was agitated at room temperature overnight then purified directly by preparative HPLC using an acetonitrile/water/formic acid gradient providing the intermediate 3-(7-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propionic acid ethyl ester (21 mg, 51% yield) which was used directly. This intermediate was dissolved in DMF (1 mL), and K2CO3 (69 mg, 0.5 mmol) was added followed by (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (137.7 mg, 0.4 mmol), prepared as described previously. The resulting mixture was heated at 65° C. overnight, cooled, filtered and the solution was treated directly with Amberlyst® A26 (OH—) (650 mg, 0.87 mmol). This reaction mixture was agitated overnight and the resin was filtered and washed with several portions of methanol. The product was eluted by treating the resin with a 20% solution of formic acid in methanol (2×2 mL) and washing with methanol (2 mL). The combined eluant and final wash was evaporated and the residue was purified by preparative HPLC using an acetonitrile/water/formic acid gradient providing the title compound (9 mg, 15% yield). LCMS (ESMS): m/z 378 (M+H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:10]([CH2:22][C:23]([OH:25])=[O:24])[CH2:9][CH2:8][CH2:7]2.[CH2:26](O)[CH3:27]>>[CH2:26]([O:24][C:23](=[O:25])[CH2:22][CH:10]1[C:11]2[C:6](=[CH:5][C:4]([OH:3])=[C:13]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=2)[CH2:7][CH2:8][CH2:9]1)[CH3:27]
Reactant: CCO
Reactant: O=C(O)CC1CCCc2cc(O)c(C(=O)c3ccccc3)cc21
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)CC1CCCc2cc(O)c(C(=O)c3ccccc3)cc21

Procedure:
Analogously to the description in Example 2, 5.5 g of 6-hydroxy-7-benzoyl-1,2,3,4-tetrahydro-naphthalene-acetic acid ethyl ester and 20 ml of 2 N sodium hydroxide solution in 250 ml of ethanol give 6-hydroxy-7-benzoyl-1,2,3,4-tetrahydro-1-naphthylacetic acid in the form of yellow crystals of melting point 118°-120° C (from ether-petroleum ether).