Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][NH:7][N:6]=1)=[O:4].[OH-].[Na+].[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O>O1CCOCC1>[C:17]([O:16][C:14]([NH:10][C:9]1[C:5]([C:3]([OH:2])=[O:4])=[N:6][NH:7][CH:8]=1)=[O:13])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)c1n[nH]cc1N
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)O
Temperature: 50 °C
Reaction time: 5 h
Yield: 86.8 %

Procedure:
To a mixture of 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (50.0 g, 355 mmol) in dioxane (500 mL) was added 2M aqueous NaOH solution (213 mL, 426 mmol), the mixture heated to 50° C. and stirred for 5 h. To this mixture was then added (BOC)2O (81.4 g, 373 mmol), using a dioxane rinse (100 mL) and the mixture heated at 50° C. for a further 5 h, then stirred at ambient for 14 h. The dioxane was removed in vacuo and water (1 L) added. The mixture was taken to pH 2 using conc. aqueous HCl solution and the solid formed collected by filtration and dried on the filter. The solid was dried further through azeotrope with toluene (x3) and in the vacuum oven to give 4-tert-butoxycarbonylamino-1H-pyrazole-3-carboxylic acid (70.0 g, 87%) as a violet solid.
Reaction SMILES: Br.[N:2]1([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[C:25]1([NH:31][C:32]([N:5]2[CH2:4][CH2:3][N:2]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:7][CH2:6]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(NN1CCNCC1)c1ccc(F)cc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NN1CCN(C(=O)Nc2ccccc2)CC1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of N-piperazinyl-p-fluorobenzamide hydrobromide (300 mg) and triethylamine (0.412 ml) in dichloromethane (6 ml) was added phenyl isocyanate (0.186 ml) at ambient temperature, and the reaction mixture was stirred at the same temperature for 1 hour. The precipitate was filtered, then washed with dichloromethane and water. The residue was dried to give N-(4-phenylcarbamoyl-1-piperazinyl)-p-fluorobenzamide (0.23 g).
Reaction SMILES: [C:1]1([C:7]([CH3:18])([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.N.[H][H]>[Ni]>[C:1]1([C:7]([CH3:18])([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CC(CCCC#N)(CCCC#N)c1ccccc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(CCCCN)(CCCCN)c1ccccc1
Temperature: 125 °C
Yield: 172.5 %

Procedure:
An autoclave was charged with 0.42 mol 100 g 5-phenyl-5methylnonanedinitrile, 10 g Raney nickel, and 9.86 mol 400 ml methanol. The reaction mixture was flushed with nitrogen and then charged with 8.9 mol 150 g ammonia. The reactor was then pressurized to 1500 psig with hydrogen and heated at 125° C. for two hours. The reactor was cooled, vented, the contents filtered, and the filtrate concentrated in a rotary evaporator. Another hydrogenation run was made under essentially the same conditions described above except that 0.46 mol 110 g of 5-phenyl-5methylnonanedinitrile was employed. The product of this run was concentrated as described above. Analysis of these concentrates by NMR and GLC indicated that complete hydrogenation of the nitrile groups to amino groups had been accomplished. The concentrates were then fractionally distilled under vacuum to give 180 g of 5-phenyl-5-methyl-1,9-nonanediamine for an 84 mol percent yield based on the 5-phenyl-5-methylnonanedinitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.O>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH2:1])=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cccc(Oc2ccc(C(F)(F)F)cc2)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 58.6 %

Procedure:
EX-656A) 3-Aminophenol (5.0 g, 45.8 mmol) and 4-bromo-α,α,α-trifluorotoluene (14.0 g, 62.2 mmol) were dissolved in anhydrous dimethylacetamide (20 mL), then anhydrous cesium carbonate (30 g, 92.3 mmol) and copper triflate benzene complex (200 mg) were added. The mixture was stirred and heated to 85° C. using a reflux condenser under an argon atmosphere. After 16 h, the mixture was diluted with water (120 mL), and the aqueous layer was extracted with diethyl ether (4×60 mL). The combined ether layers were washed with 3% HCl, 5% NaOH and water, then dried over anhydrous MgSO4. The ether was removed in vacuo, and the recovered oil purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:8) to give 6.8 g (59 %) of the desired 3-(4-trifluoromethylphenoxy)aniline product as a yellow oil, which solidified to a yellow powder, 98% pure by HPLC analysis. HRMS calcd. for C13H10F3NO: 254.0792 [M+H]+, found: 254.0798.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:7][C:8]1[N:13]=[C:12](Cl)[C:11]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:26][CH3:27])=[C:10]([CH3:28])[N:9]=1>CN1C(=O)CCC1.CCOC(C)=O>[NH2:7][C:8]1[N:9]=[C:10]([CH3:28])[C:11]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:26][CH3:27])=[C:12]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[N:13]=1
Reactant: CCCCCN
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(C(=O)OC)cc1OC
Temperature: 150 °C
Reaction time: 15 h

Procedure:
Pentylamine (7.2 mL) was added to a solution of the product from step (iii) (5 g) in NMP (80 mL). The resulting solution was stirred at 150° C. for 15 h. The reaction mixture was allowed to cool, diluted with EtOAc and washed with water and brine. The organic phase was dried and evaporated under reduced pressure. The residue was suspended in diethyl ether (20 mL) and the solid was collected by filtration to give the subtitle compound as a colourless solid 1.2 g that was used without further purification.
Reaction SMILES: [CH2:1]([S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16]C)=[O:15])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([OH:16])=[O:15])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc(CSCCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(CSCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of methyl 3-(phenethylthiomethyl)benzoate (1.15 g, 4.02 mmol) in THF (4 mL) and MeOH (4.00 mL) was added 1 N aqueous NaOH solution (6 mL). The resulting mixture was stirred at rt for overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with 1 N HCl solution. The solid was filtered and vacuum dried to give the desired product (1.05 g, 95%) as a white solid. 1H NMR (DMSO-d6) δ 13.07 (s, 1H), 7.93 (s, 1H), 7.83-7.81 (m, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.29-7.25 (m, 2H), 7.20-7.17 (m, 3H), 3.84 (s, 2H), 2.91-2.78 (m, 2H), 2.63-2.59 (m, 2H). MS (ESI): 273.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].Cl.[CH3:14][O:15][C:16](=[O:26])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:18].C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>C(Cl)Cl>[CH3:14][O:15][C:16](=[O:26])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:18][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C

Procedure:
t-Boc-glycine (1.75 g, 1.00×10-2 mole), L-phenylalanine methyl ester hydrochloride (2.16 g, 1.00×10-2 mole), and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (2.47 g, 1.00×10-2 mole), and CH2Cl2 (50 ml) are stirred at room temperature for 16 hours. The reaction mixture is then washed in turn with 0.5 M aqueous HCl (2 times) and saturated aqueous NaHCO3 before being dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate gives 6a as an extremely viscous, almost colorless oil, which was shown to be homogeneous by TLC on silica gel plates and the structure corroborated by NMR. NMR (CDCl3) δ 1.42 (S, 9, t-boc), 3.02 (d,2, benzylic methylene), 3.59 (S, 3, ester), 7.13 (S, 5, aromatic).
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:16]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([C:36]3[NH:40][C:39]([C:41]4[N:46]=[CH:45][C:44]([CH:47]=[O:48])=[CH:43][CH:42]=4)=[CH:38][CH:37]=3)[CH2:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:18][CH2:17]1.O>O1CCCC1>[CH:16]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH:28]([C:36]3[NH:40][C:39]([C:41]4[N:46]=[CH:45][C:44]([CH:47]([OH:48])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])=[CH:43][CH:42]=4)=[CH:38][CH:37]=3)[CH2:29][CH:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH2:18][CH2:17]1
Reactant: CS(C)(=O)=O
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)CC(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reaction time: 1 h
Yield: 22.5 %

Procedure:
To a solution of dimethylsulfone (446 mg) in tetrahydrofuran (10 mL) was added dropwise lithium hexamethyldisilazide (1.6M tetrahydrofuran solution) (2.7 mL) at −78° C., and the mixture was stirred for 1 hr. To the reaction mixture was added dropwise a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (1 g) in tetrahydrofuran (5 mL), and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). The obtained pale-yellow amorphous solid was subjected to basic silica gel column chromatography to give a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). The pale-yellow amorphous solid was purified by preparative HPLC to give the title compound (270 mg, yield 22%) as a colorless amorphous solid. MS: 559 (MH+).
Reaction SMILES: [C:1]([N:9]1[CH2:15][CH2:14][CH:13](Br)[C:12](=[O:17])[C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:23]([NH2:26])(=[NH:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([N:9]1[CH2:15][CH2:14][C:13]2[N:26]=[C:23]([CH3:24])[NH:25][C:12]=2[C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([N:9]1[CH2:15][CH2:14][C:13]2[N:25]=[C:23]([CH3:24])[O:17][C:12]=2[C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=N)N
Reactant: O=C1c2ccccc2N(C(=O)c2ccccc2)CCC1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc2c([nH]1)-c1ccccc1N(C(=O)c1ccccc1)CC2
Product: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccccc1)CC2
Temperature: 25 °C
Yield: 4 %
Yield: 34 %

Procedure:
1-Benzoyl-4-bromo-1,2,3,4-tetrahydro-benzo[b]azepin-5-one (67.5 g, 200 mmol) from Example E5.7, acetamidine hydrochloride (92.7 g, 980 mmol) and potassium carbonate (136.0 g, 980 mmol) were suspended in acetonitrile (2.0 liters) and heated at reflux for 17 h under nitrogen. Additional acetamidine hydrochloride (18.5 g, 200 mmol) and potassium carbonate (27.7 g, 200 mmol) were added and the reaction mixture was heated at reflux for a further 6 h. Additional acetamidine hydrochloride (18.5 g, 200 mmol) and potassium carbonate (27.7 g, 200 mmol) were added again and the reaction mixture was heated at reflux for a further 6 h. On cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was taken up in dichloromethane (1.4 liters), washed with water (500 ml), dried over sodium sulfate, filtered and reduced in vacuo. The crude products were purified by flash chromatography on silica gel (eluant; 45% EtOAc:45% acetonitrile: 10% methanol) to yield the title compound (26.7 g, 34%) and 6-benzoyl-2-methyl-5,6-dihydro-4H-1-oxa-3,6-diaza-benzo[e]azulene (3.3 g, 4%).
Reaction SMILES: ClC[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCCN2CCOCC2)cc1
Temperature: 62.5 °C
Reaction time: 17.5 h
Yield: 2180.8 %

Procedure:
A 50 L jacketed reactor equipped with a reflux condenser and temperature probe was charged with 4-(3-chloropropyl)morpholine (2.44 kg, 0.54 mol), 4-bromophenol (2.27 kg, 0.54 mol, 1.0 equiv.), powdered potassium carbonate (6.331 kg, 1.88 mol, 3.50 equiv.), and DMF (12.2 L) and stirred. The reaction mixture was then heated to 60-65° C. and stirred overnight. After 17.5 h, the reaction mixture was cooled to 20-25° C. The reaction mixture was charged to a different reactor equipped with bottom valve for the work-up. While maintaining a temperature between 20-30° C., DI water (48.7 L) was charged to the reactor. The phases were separated. The aqueous layer was extracted with MTBE (3×24.4 L). To the combined organics, DI water (18.3 L) and then 6M sodium hydroxide (18.2 L) were added. The mixture was stirred for 2-5 minutes and the phases were separated. The organic phase was washed with water (24.4 L) and brine (24.4 L), dried over magnesium sulfate, filtered, and concentrated to give 3370 g of a yellow oil (89% crude yield, 99.4% AUC by HPLC).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH3:10])=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[Br:15]Br.O>C(Cl)(Cl)Cl>[Br:15][C:4]1[CH:3]=[C:2]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[S:1][CH:5]=1
Reactant: COC(=O)Cc1cccs1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cc(Br)cs1
Temperature: 25 °C
Yield: 41.2 %

Procedure:
To a solution of methyl 2-(thiophen-2-yl)acetate (5 g, 32 m mol) and anhydrous AlCl3 (10.7 g, 80 mmol) in CHCl3 (50 ml) was added dropwise bromine (1.8 ml, 34 mmol) at 0˜5° C. over 30 min. When the addition was complete, the mixture was allowed to warm to room temperature overnight. Then it was poured into icy water (50 ml), extracted with EtOAc (30 ml×3). The combined organic phase was dried over Na2SO4, filtered and concentrated. Purification by column chromatography (PE/EtOAc=10/1) gave the product (3.1 g, 41%) as light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>C(OCC)(=O)C.[Pd]>[N:15]1[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[NH:12][C:11]=1[S:10][C:7]1[CH:8]=[CH:9][C:4]([NH:1][C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:23]=2)=[S:29])=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: O=[N+]([O-])c1ccc(Sc2nc3ccccc3[nH]2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3nc4ccccc4[nH]3)cc2)ccc1Cl
Yield: 5 %

Procedure:
2-(4--Nitrophenylthio)benzimidazole (5.0 mmoles, 1.37 g) was reduced in ethyl acetate over 1.37 g 5% Pd/C, filtered and condensed and then reacted with 4-chloro-3-trifluoromethylphenylisothiocyanate (5.0 moles, 1.0 g) according to procedure C to yield the title compound 0.12 g, 5% product. Mass Spec (FD) 479. Calculated for C21H14ClF3N4S2 : C, 52.66; H, 2.95; N, 11.70. Found: C, 52.85; H, 3.18; N, 10.47.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12](O)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[K+].[Br-]>C(Cl)(Cl)Cl.CO>[C:13]1([C:12]2[NH:11][C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2nc(-c3ccccc3)[nH]c2c1
Yield: 70 %

Procedure:
Prepared from 4-nitrophenylenediamine and benzoic acid in a manner similar to that of Example 9b. Yield: 70%; Rf (9/1 chloroform/methanol): 0.45; IR (KBr): 3290, 1500, 1330, 1290 cm−1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[S:11](N)([NH2:14])(=[O:13])=[O:12]>O1CCOCC1>[S:11]([NH:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8])(=[O:13])(=[O:12])[NH2:14]
Reactant: Cc1sc(N)c(C#N)c1C
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: Cc1sc(NS(N)(=O)=O)c(C#N)c1C
Temperature: 25 °C
Yield: 19.7 %

Procedure:
To a solution of 2-amino-4,5-dimethylthiophene-3-carbonitrile (Example 4b) (1.0 g, 6.57 mmol) in 1,4-dioxane (50 mL) was added sulfamide (3.87 g, 40.30 mmol). The reaction mixture was heated to reflux for 24 hr, after cooled to room temperature, the solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel eluting with EtOAc/Hexanes (2:3) to give 300 mg of product as a dark red oil. 1H NMR (400 MHz, DMSO-d6) δ 2.09 (3, 3H), 2.26 (s, 3H), 7.32 (s, 2H), 10.17 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH:19]3[CH2:21][CH2:20]3)[C:9]2=[O:22])[CH:3]=1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C(C)=CC=CC=1>[CH:19]1([C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:10]2[CH2:11][CH2:12][N:8]([C:4]3[CH:3]=[C:2]([CH:23]4[CH2:25][CH2:24]4)[N:7]=[CH:6][N:5]=3)[C:9]2=[O:22])[CH2:21][CH2:20]1
Reactant: OB(O)C1CC1
Reactant: O=C1N(c2cc(Cl)ncn2)CCN1c1cnccc1C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=C1N(c2cc(C3CC3)ncn2)CCN1c1cnccc1C1CC1
Yield: 38.9 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(6-chloropyrimidin-4-yl)-3-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-38a: 140 mg, 0.44 mmol) was reacted with cyclopropyl boronic acid (46 mg, 0.533 mmol), Pd(PPh3)4 (26 mg, 0.02 mmol), potassium carbonate (123 mg, 0.888 mmol) and xylene (10 mL) in seal tube at 125° C. for 14 hours. Purification by column chromatography on silica gel (1% methanol in chloroform) afforded 55 mg of the product (38.73% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]CC(Cl)(Cl)Cl)[N:30]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:18]=[CH:17][C:9]3[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=3[C:7]=2[C:19]#[N:20])=[O:35])[N:30]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3)c(C#N)c2s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (150 mg, 0.462 mmol) produced in Example 12(ii) in dimethylsulfoxide (2 mL) were added 2,2,2-trichloroethyl (3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)carbamate (190 mg, 0.485 mmol) and triethylamine (70 μL, 0.508 mmol), and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=70/30→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/diethyl ether to give the title compound (155 mg, 59%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][CH2:18][NH2:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O1CCCC1.[CH:32]1[C:41]2[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=2[CH:35]=[CH:34][C:33]=1[CH2:42][C:43](Cl)=[O:44]>O>[CH2:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:17][CH2:18][NH:19][C:43](=[O:44])[CH2:42][C:33]2[CH:34]=[CH:35][C:36]3[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=3[CH:32]=2)=[CH:4][C:3]=1[O:2][CH3:1])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Reactant: O=C(Cl)Cc1ccc2c(c1)CCCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCNC(=O)Cc2ccc3c(c2)CCCC3)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
8.01 g (31.2 mmol) of crude 2-(3-methoxy-4-benzyloxyphenyl)ethylamine, 3.78 g (37.4 mmol) of triethylamine and 80 ml of tetrahydrofuran were mixed and cooled to 0° C. and then (5,6,7,8-tetrahydronaphthalen-2-yl)acetyl chloride was added dropwise thereto. The mixture was stirred at 0° C. for 30 minutes and further at room temperature for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochloric acid and then saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1) to give 8.3 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetamide.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].O.CCOCC>C1C=CC=CC=1>[CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])=[S:19]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1c(C)cc([N+](=O)[O-])cc1C(=O)N(C)C
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: COc1c(C)cc([N+](=O)[O-])cc1C(=S)N(C)C
Yield: 85.2 %

Procedure:
To a solution of 3-dimethylcarbamoyl-4-methoxy-5-methylnitrobenzene (1.10 g) in benzene (11 ml) is added phosphorus pentasulfide (3.08 g), and the resultant mixture is refluxed for 1 hour. After sooling, the reaction mixture is mixed with icy water and shaken with ether. The organic layer is washed with water, dried over Glauber's salt and concentrated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with benzene, methylene chloride and then methylene chloride/2% methanol in order. The eluted fractions are concentrated under reduced pressure and the residue is washed with isopropyl ether to give 3-dimethylthiocarbamoyl-4-methoxy-5-methyl-nitrobenzene (1.0 g) as crystals melting at 138°-139° C.