Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C>[C:12]1([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: O=C1Cc2ccc(-c3ccccc3)cc2N1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
2.4 g of 6-bromo-2-indolinone are placed in 60 ml of dimethoxyethane, 1.9 g of phenylboric acid in 8 ml of ethanol and 0.3 g of tetrakistriphenylphosphine palladium are added and to this mixture 12 ml of 2N sodium carbonate solution are added dropwise at ambient temperature. The mixture is stirred for 6 hours at 85° C. After cooling the catalyst is filtered off, the solvent is eliminated and the residue is washed with 100 ml of water and 20 ml of 1N sodium hydroxide solution. The residue is purified through a silica gel column with petroleum ether/ethyl acetate (8:2) as eluant.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([CH2:17][O:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:29])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:29])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c[nH]c2c(COC(=O)c3ccccc3)cccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCC(=O)c1cnc2c(COC(=O)c3ccccc3)cccc2c1Cl

Procedure:
A solution of 3-butyryl-8-(benzoyloxymethyl)-4(1H)-quinolone (17.93 g) in phosphoryl chloride (150 ml) was heated at reflux for 1.5 hours, then the excess phosphoryl chloride evaporated. The residue was poured onto ice, extracted with dichloromethane, dried and evaporated to give 3-butyryl-4-chloro-8-(benzoyloxymethyl)quinoline. The crude product was used without further purification.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([Br:15])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:18][Mg+].[Br-]>C1COCC1>[Br:15][C:14]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4](=[O:5])[CH3:18])[C:11]=2[S:12][C:13]=1[CH3:16]
Reactant: CON(C)C(=O)c1cccc2c(Br)c(C)sc12
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cccc2c(Br)c(C)sc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
A solution of 3-bromo-2-methyl-benzo[b]thiophene-7-carboxylic acid methoxy-methyl-amide (2.02 g, 6.43 mmol) in THF (65 mL) is cooled to 0° C., treated with CH3MgBr (3.0 M, 2.4 mL, 7.1 mmol). The reaction is stirred at 0° C. for 10 min, then at rt for 10 min. It is cooled to 0° C., quenched with sat. NH4C (10 mL); diluted with H2O (20 mL); treated with 0.1 M HCl (20 mL); extracted with EtOAc (2×40 mL). The combined organic layers are dried with Na2SO4, filtered and concentrated. Purification of the crude material by chromatography gives the title compound (1.39 g, 5.18 mmol, 81%). 1H NMR (CDCl3): δ. 2.58 (s, 3H), 2.75 (s, 3H), 7.53 (t, J=7.9 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.99 (d, J=7.5 Hz, 1H) ppm. ES-MS (m/z): calcd for C11H9BrOS (M+1)+: 270.2. found: 270.0.
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([O:12][C:13](=[O:30])[CH2:14][CH2:15][C:16]([O:18][CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([OH:27])[C:21]([CH3:29])([CH3:28])[CH2:20]2)=[O:17])[CH2:6][C:5]1([CH3:32])[CH3:31].S([O-])([O-])=O.[Na+].[Na+].[C:39]([OH:43])([CH3:42])([CH3:41])[CH3:40]>>[OH:43][C:39]([CH3:42])([CH3:41])[CH2:40][O:27][N:22]1[C:21]([CH3:29])([CH3:28])[CH2:20][CH:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][C:13]([O:12][CH:7]2[CH2:6][C:5]([CH3:32])([CH3:31])[N:4]([O:3][CH2:40][C:39]([OH:43])([CH3:42])[CH3:41])[C:9]([CH3:11])([CH3:10])[CH2:8]2)=[O:30])[CH2:24][C:23]1([CH3:26])[CH3:25]
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(OCC(C)(C)O)C(C)(C)C2)CC1(C)C

Procedure:
Aqueous hydrogen peroxide is added to a mixture of bis(1-oxyl-2,2,6,6-tetramethylpieridin-4-yl)succinate and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-50° C. Excess peroxide is decomposed with aqeuous sodium sulfite solution. The organic layer is concentrated and the crude product is purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29](Cl)[CH:28]=2)[N:12]=1)=[O:10].NC1C(C2C=CC([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=CC=2)=NC(Br)=C(C(F)(F)F)N=1>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:13]([C:27]2[CH:32]=[CH:31][C:30]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[CH:29][CH:28]=2)[N:12]=1)=[O:10]
Reactant: CS(=O)(=O)Nc1ccc(-c2nc(Br)c(C(F)(F)F)nc2N)cc1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2cccc(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F
Product: CS(=O)(=O)Nc1ccc(-c2nc(C(=O)N[C@@H]3CCCC[C@H]3O)c(C(F)(F)F)nc2OCC(F)(F)F)cc1

Procedure:
The title compound was prepared in analogy to example 4 (6-(3-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide) by substituting 5-bromo-3-(3-chloro-phenyl)-6-trifluoromethyl-pyrazin-2-ylamine by N-[4-(3-amino-6-bromo-5-trifluoromethyl-pyrazin-2-yl)-phenyl]-methanesulfonamide.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=[C:18]([C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[C:32](=NO)[CH2:31][CH2:30]5)[CH:17]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1CC[O:41]CC1.C(N(CC)CC)C>ClCCl>[N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)=[C:18]([C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[C:32](=[O:41])[CH2:31][CH2:30]5)[CH:17]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(CN1CCOCC1)N1CCCC(c2cc(-c3ccc4c(c3)CCC4=NO)c(-c3ccncc3)o2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCc2cc(-c3cc(C4CCCN(C(=O)CN5CCOCC5)C4)oc3-c3ccncc3)ccc21
Yield: 54.7 %

Procedure:
A solution of the product of Step 1 (140 mg, 0.32 mmol) in dry dichloromethane (10 ml) was treated with morpholine (0.031 ml, 0.35 mmol) and triethylamine (0.049 ml, 0.35 mmol) and heated at reflux for 3 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried, concentrated in vacuo and then purified by silica gel chromatography eluting with chloroform/ethanol/0.880 ammonia solution (98:1.8:0.2) to yield the title compound (85 mg, 55%); MS(ES+) m/e 486 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]([N:18]1[C:22]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:21][N:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CS(O)(=O)=O.[OH-].[Na+]>O>[CH2:11]([N:18]1[C:22]([CH:23]2[C:5]3[C:6](=[C:7]([CH3:8])[C:2]([CH3:1])=[C:3]([O:9][CH3:10])[CH:4]=3)[C:25](=[O:26])[CH2:24]2)=[CH:21][N:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)C=Cc1cncn1Cc1ccccc1
Reactant: COc1cccc(C)c1C
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(c(C)c1C)C(=O)CC2c1cncn1Cc1ccccc1
Temperature: 92.5 °C

Procedure:
A mixture of 2,3-dimethylanisole (2.0 g), 3-(3-benzyl-3H-imidazol-4-yl)-acrylic acid (3.4 g) and methanesulfonic acid (60 ml) is heated at 90-95° C. for 45 minutes. The cooled reaction mixture is poured into water and is made alkaline with sodium hydroxide solution. The product is extracted into ethyl acetate which is washed with water, dried with sodium sulfate and evaporated in reduced pressure. The crude product is purified by flash chromatography by eluting with methylene chloride-methanol solution. The yield is 1.1 g.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[N:32]=[C:31]2[NH:33][CH:34]=[C:35]([CH:36]=O)[C:30]2=[CH:29][CH:28]=1>CO.N1CCCCC1>[Cl:26][C:27]1[N:32]=[C:31]2[NH:33][CH:34]=[C:35](/[CH:36]=[C:7]3\[O:8][C:4]4[C:3]([CH2:12][N:13]5[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]5)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=4[C:6]\3=[O:9])[C:30]2=[CH:29][CH:28]=1
Reactant: O=Cc1c[nH]c2nc(Cl)ccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4nc(Cl)ccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.020 g, 0.057 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 6-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.009 g, 0.057 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 60° C. for 1 hour. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (95:5→90:10)) to obtain tert-butyl (Z)-4-({2-[(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.020 g, 69%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=3[CH3:24])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[S:25]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:26]4[CH2:27][CH2:28][CH2:29][S:25]4(=[O:31])=[O:30])=[CH:19][C:18]=3[CH3:24])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C)CC2)c(C)c1
Yield: 58.2 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodo-2-methylphenyl)methanone (487 mg) described in Preparation Example 154 and isothiazolidine 1,1-dioxide (136 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (279 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=O)[C:7](=[CH:17]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C(=O)(O)O.[NH2:28][C:29]([NH2:31])=[NH:30].C[O-].[Na+]>CO.C(Cl)Cl>[NH2:30][C:29]1[N:31]=[CH:17][C:7]2[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]3[CH:3]=[C:2]([Cl:1])[CH:23]=[CH:22][C:5]=3[C:6]=2[N:28]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2)c2cc(Cl)ccc2C1=O
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 8 h

Procedure:
A stirred suspension of 10 g (0.032 mol) of 8-chloro-3,4-dihydro-4-(dimethylaminomethylene)-1-phenyl-5H-2-benzazepin-5-one and 8.5 g (0.047 mol) of guanidine carbonate in 250 ml of methanol was treated at room temperature, under argon, with 5.1 g (0.094 mol) of sodium methylate in one portion. Methylene chloride (150 ml) was added after 10 min and stirring was continued. The same quantities of sodium methylate and guanidine carbonate were added two more times at 2 hr intervals and stirring was continued overnight. After diluting with 250 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Crystallization of the residue from ethanol gave light tan crystals: mp 209°-210° C. Recrystallization of a sample from methylene chloride/ethyl acetate gave off-white prisms: mp 210°-211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:11])[CH2:9][O:10][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H](O)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2cccc(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a mixture of (S)-1-(3-Chloro-phenyl)-ethane-1,2-diol (9.83 g, 0.057 mol) and triethylamine (11.8 ml, 0.086 mol) a solution of TsCl (10.87 g, 0.057 mol) in dichloromethane (50 mL) was added at 0° C. over 30 min. The mixture was stirred at 0° C. for 4 h. Precipitate formed was removed by filtration, the filtrate was washed with water (50 mL), dried over Na2SO4 and evaporated. The residue was dissolved in CH2Cl2 (200 mL), filtered through a SiO2 pad and evaporated. Colorless oil, 16.34 g (0.050 mol, 88%).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[C:10]([I:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH2:21]>CCOCC>[I:17][C:10]1[C:9]([O:8][CH2:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH2:19])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]
Reactant: C=C(CBr)c1ccccc1
Reactant: O=Cc1cccc(O)c1I
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C(COc1cccc(C=O)c1I)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6.72 g (0.28 mmol) of sodium hydride are dissolved in 660 ml of ether and 120 ml of dimethylformamide under argon, and 64.1 g (0.26 mol) of 3-hydroxy-2-iodobenzaldehyde in 65 ml of ether are slowly added. After the mixture has been stirred at room temperature for 15 minutes, 61 g (0.28 mol) of 3-bromo-2-phenyl-1-propene, dissolved in 60 ml of ether, are added dropwise and the mixture is stirred overnight.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)[CH:27]=[O:28]>>[C:19]1([N:12]([C:6]2[CH:7]=[CH:8][C:9]([CH:27]=[O:28])=[CH:10][CH:11]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A Vilsmeier's reagent was prepared by adding dropwise phosphoryl trichloride (POCl3) (46 g) to N,N-dimethylformamide (22 g) with stirring in an ice bath. Thereto there was added a solution (200 ml) of N,N,N-triphenylamine (50 g) in N,N-dimethylformamide while continuing cooling in the ice bath. The stirring was continued for about one hour, and then the bath temperature was raised to about 90° C. While maintaining that temperature, the stirring was continued further for two hours. At the conclusion of the reaction the reaction system was cooled to room temperature, and then the reaction product was poured into ice water. The thus obtained aqueous solution was neutralized with an alkali to separate out a yellow precipitate. The precipitate was filtered off, dried and then recrystallized from ethyl alcohol. Thus, p-(N,N-diphenylamino)benzaldehyde (43 g) was obtained.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH2:17][C:18]([OH:20])=[O:19])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Pd]>[CH2:1]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH2:17][C:18]([OH:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(=O)O)c(C(=O)c2ccccc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(CC(=O)O)c(Cc2ccccc2)c1

Procedure:
A solution of 2-benzoyl-4-methoxyphenylacetic acid (13.0 g, 0.048 mol), prepared by the method of J. Med. Chem. 1981, 24, 998, in glacial acetic acid (600 mL) was treated under argon with 4.3 g. of 10% Pd/C and hydrogenated at 50 psi for 17 hours. The mixture was filtered using celite® and the filtrate was concentrated and reconcentrated from toluene and methylene chloride to give 14.2 of the title compound: 1H NMR (400 MHz, CDCl3) δ 3.52 (s, 2H), 3.75 (s, 3H), 4.0 (s, 3H), 6.7 (m, 2H), 7.15 (m, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:13]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>>[CH:13]1([NH:22][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[O:12])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: NC1CCc2ccccc21
Product: O=C(NC1CCc2ccccc21)c1ccc2c(c1)OCO2

Procedure:
Prepared in a similar manner to example 4 using benzo[1,3]dioxole-5-carboxylic acid and indan-1-ylamine. MS (M+H, 282.2).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C[O:16][C:17](=O)[C@H:18]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:19][C:20]1[C:21]([CH2:29]Cl)=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2>>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([N:1]2[CH2:29][C:21]3[C:22]4[CH:23]=[N:24][NH:25][C:26]=4[CH:27]=[CH:28][C:20]=3[CH2:19][C@@H:18]([NH:31][C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:33])[C:17]2=[O:16])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](NC(=O)OCc3ccccc3)C2=O)CC1

Procedure:
4-Amino-1-N-Boc-piperidine (110 mg, 0.55 mmol) and 2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionic acid methyl ester (150 mg, 0.34 mmol) was converted into the title compound in a manner analogous to the preparation of [9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-acetic acid methyl ester. Crude product was obtained as a dark foam in quantitative yield. Material was carried forward without further purification. 1H NMR (300 MHz, CDCl3): δ=8.05 (m, 1H), 7.35 (m, 6H), 7.15 (m, 1H), 6.27 (m, 1H), 5.28 (m, 1H), 5.15 (s, 2H), 4.87 (d, J=16.5, 1H), 4.63 (m, 1H), 4.47 (m, 1H), 4.24 (m, 1H), 3.99 (m, 1H), 3.49 (m, 1H), 3.04 (m, 1H), 2.83 (m, 2H), 2.63 (m, 1H), 1.90 (m, 1H), 1.74 (m, 2H), 1.58 (s, 9H). MS m/e (M−H)−=532.1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][S:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:16][C:15]2[CH:17]=[CH:18][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(N)cc1
Reactant: O=Cc1ccc(F)cc1
Product: CSc1ccc(N=Cc2ccc(F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-fluorobenzaldehyde and 4-methylthioaniline as starting materials, the title compound was obtained as a pale yellow needle-like crystals (yield 87%).
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:15][O:16][C:17]1[C:31]([O:32][CH3:33])=[CH:30][C:20]2[NH:21][C:22]([C:24]3[C:28]([NH2:29])=[CH:27][NH:26][N:25]=3)=[N:23][C:19]=2[CH:18]=1.[F:34][C:35]1[CH:36]=[CH:37][C:38]([O:44][CH3:45])=[C:39]([CH:43]=1)[C:40](O)=[O:41]>CN(C=O)C>[CH3:33][O:32][C:31]1[C:17]([O:16][CH3:15])=[CH:18][C:19]2[NH:23][C:22]([C:24]3[C:28]([NH:29][C:40](=[O:41])[C:39]4[CH:43]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=4[O:44][CH3:45])=[CH:27][NH:26][N:25]=3)=[N:21][C:20]=2[CH:30]=1
Reactant: COc1ccc(F)cc1C(=O)O
Reactant: COc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1OC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3n[nH]cc3NC(=O)c3cc(F)ccc3OC)[nH]c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of EDC (44 mg, 0.23 mmol) and HOBt (31 mg, 0.23 mmol) in DMF (5 ml) was added 3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.19 mmol) and 5-fluoro-2-methoxy-benzoic acid (36 mg, 0.21 mmol) and the mixture stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid partitioned between DCM (20 ml) and saturated aqueous sodium bicarbonate (20 ml). A precipitate was formed which was removed by filtration and oven dried to yield N-[3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-5-fluoro-2-methoxy-benzamide (64 mg, 81%). (LC/MS: Rt 2.64, [M+H]+ 412).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:23][CH2:22][N:21]([C:24]4[C:29]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:20][C:12]=3[N:13]=[C:14](S(C)(=O)=O)[N:15]=2)=[CH:5][CH:4]=1.[O-:36][CH2:37][CH3:38].[Na+]>O1CCOCC1.C(O)C>[CH2:37]([O:36][C:14]1[N:15]=[C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:35])[F:34])=[CH:8][CH:7]=2)[C:11]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:20][C:12]=2[N:13]=1)[CH3:38]
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1S(C)(=O)=O)C2
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1S(C)(=O)=O)C2
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)-7-(3-(methylsulfonyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4-amine (150 mg, 0.27 mmol) was suspended in dioxane (5.0 mL) and ethanol (2.0 mL), sodium ethoxide (20 mg, 0.28 mmol) was added and the mixture was stirred at at 80° C. for 2 hrs. Solvent was removed and the residue was purified by flash chromatography over silica gel and then by preparative TLC to obtain the product as a white solid (102 mg).
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][Cl:20]>CN(C)C=O>[Cl:20][CH2:19][CH2:18][CH2:17][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:2]([CH3:1])=[CH2:3])[C:5]1=[O:13]
Reactant: ClCCCBr
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a stirred solution of 8.5 parts of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one in 45 parts of N,N-dimethylformamide are added portionwise 1.7 parts of a sodium hydride dispersion 78%. After stirring for 1 hour at room temperature, the whole is cooled to 0-5° C and 8.65 parts of 1-bromo-3-chloropropane are added dropwise (slowly). Upon completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured into crushed ice and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 5.5 parts (44%) of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)2H-benzimidazol-2-one; mp. 115° C.