Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:23]([NH:31][C:32]1[CH:44]=[C:43](Br)[CH:42]=[CH:41][C:33]=1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2)CCCCC1.CN(C)C(=O)C>[C:23]([NH:31][C:32]1[CH:44]=[C:43]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH:42]=[CH:41][C:33]=1[C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(Oc3ccccc3)cc2)cc1NC(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
60 mg of 4-phenoxyphenylboronic acid, 49 mg of sodium carbonate and 6 mg of polymer supported di(acetato) dicyclohexylphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate, and stirred at: 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, 6 mg of polymer supported di(acetato) dicyclohexylphenylphosphine palladium(II) was added and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex company, eluent; hexane: ethyl acetate=4:1] to obtain tert-butyl 2-(benzamido)-4-(4-phenoxyphenyl)benzoate.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21]C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:36][CH:37]=2)[C:5]=1[OH:21]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(COc2c(-c3ccc4c(c3)COC4=O)ccc(OC(F)F)c2O)cc1
Temperature: 80 °C
Yield: 42 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.25 mmol) in acetonitrile (5 mL), was added potassium carbonate (103.5 mg, 0.75 mmol) and 1-bromomethyl-4-methanesulfonyl-benzene (186.8 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (50 mg, 41%).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:15][C:8]2=[N:9][C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH3:4].NC1C=C(C)C=C(C)N=1.C(O)(=O)CC.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH:41]=[CH:40][CH2:39]2)=[CH:34][CH:33]=1>CN(C=O)C>[CH2:3]([C:5]1[N:15]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH:41]=[CH:40][CH2:39]3)=[CH:36][CH:37]=2)[C:8]2=[N:9][C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH3:4]
Reactant: COC(=O)C1(c2ccc(CBr)cc2)CC=CC1
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Agent: Cc1cc(C)nc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCC(=O)O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2(C(=O)OC)CC=CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (0.885 g, 22.1 mmol) in 50 ml of DMF at 0° C. was added a solution of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (3.57 g, 20 mmol, prepared from 2-amino-4,6-dimethylpyridine by nitration, hydrogenolysis to the diamine and condensation with propionic acid and polyphosphoric acid, as described in EP 400974 A2) in 10 ml of DMF dropwise and the reaction mixture was warmed to room temperature. After 20 minutes the reaction was cooled to 0° C. and a solution of the product of Step 4, above, (5 g, 17 mmol) in 10 ml of DMF was added dropwise. The reaction was then allowed to warm to room temperature and stirred overnight then the DMF was removed in vacuo. The residue was taken up in water and extracted three times with ethyl acetate. The combined organics were washed with saturated sodium chloride solution, dried with MgSO4, filtered, evaporated and chromatographed on silica gel with a gradient elution from 5:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate to yield 5.8 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.O>C1C=CC=CC=1>[CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c2ccccc2sc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: c1ccc2c(c1)Cc1ccccc1S2
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
A solution of thioxanthone (10 g) in 60 mL of benzene was treated with 5.0 g of LAH by stirring for 15 min. The mixture was heated and 100 mL of ether was added carefully. Reflux was continued for 90 min. The cooled mixture was neutralized with water. The solids were filtered off and the filtrate evaporated to dryness. Pure thioxanthene (9.1 g, 98%) was isolated by chromatography using 20% ethyl acetate/hexane; 1H NMR (CDCl3) δ3.82 (s, 3H), 7.21 (m, 4H), 7.33 (m, 2H), 7.46 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)=[C:30]([C:39]([F:42])([F:41])[F:40])[CH:29]=1>CN(C=O)C>[CH:36]1([CH2:35][O:34][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][O:1][C:2]3[CH:10]=[CH:9][C:8]4[NH:7][C:6]5[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=5[C:4]=4[CH:3]=3)=[CH:29][C:30]=2[C:39]([F:40])([F:41])[F:42])[CH2:38][CH2:37]1
Reactant: FC(F)(F)c1cc(CCl)ccc1OCC1CC1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(OCC4CC4)c(C(F)(F)F)c3)cc21
Reaction time: 16 h
Yield: 17.9 %

Procedure:
To a solution of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.069 g, 0.264 mmol) in DMF (1 mL) was added Cs2CO3 (0.086 g, 0.264 mmol) followed by 4-(chloromethyl)-1-(cyclopropylmethoxy)-2-(trifluoromethyl)benzene (0.070 g, 0.264 mmol). The reaction mixture was stirred for 16 h and filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to give the title compound as a light yellow oil (0.023 g). LCMS m/z=488.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 0.35-0.44 (m, 2H), 0.58-0.67 (m, 2H), 1.24-1.34 (m, 4H), 2.04-2.16 (m, 1H), 2.51 (dd, J=16.74, 11.05 Hz, 1H), 2.68-2.90 (m, 4H), 3.49-3.61 (m, 1H), 3.94 (d, J=6.44 Hz, 2H), 4.15-4.27 (m, 2H), 5.03 (s, 2H), 6.82 (dd, J=8.72, 2.40 Hz, 1H), 6.93-7.02 (m, 2H), 7.20 (d, J=8.84 Hz, 1H), 7.56 (dd, J=8.53, 1.96 Hz, 1H), 7.67 (d, J=1.89 Hz, 1H), 8.45 (bs, 1H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:32])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:20]=[CH:21][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][CH:24]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][N:6]=2)=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1ccc(CO)cn1)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.7 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared in Example 30B-b, 59 mg, 0.13 mmol) in diethyl ether (5 mL) was cooled to 0° C. and then treated with lithium aluminum hydride (8 mg, 0.20 mmol). The reaction was slowly warmed to 25° C. where it was stirred for 16 h. At this time, the reaction mixture was slowly diluted with water (5 mL) and then extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-phenoxy-phenyl)-propionamide (28 mg, 51%) as a yellow foam: FAB-HRMS m/e calcd for C26H28N2O3 (M+H)+ 417.2178. found 417.2163.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.ClC(Cl)C(Cl)Cl.[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Cl-].[Cl-].[Al+3].Cl>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
A 500 mL round bottom flask equipped with a magnetic stirrer bar and an inert atmosphere (nitrogen gas) was charged with 5.25 mL (48.3 mmol) of anisole, 4.83 g (48.3 mmol) of succinic anhydride, 125 mL 1,1,2,2-tetrachloroethane and 125 mL of nitrobenzene. The reaction vessel was cooled with an external ice bath and stirred for 30 minutes. Aluminum trichloride (14.2 g, 106.4 mmol) was added to the pale yellow solution, which then turned to a dark reddish brown color. The ice bath was removed, and the reaction was allowed to stir at room temperature for 36 hours. Reaction was again cooled with an external ice bath. Prepared acidic solution by pouring 1N hydrogen chloride solution into a 100 mL beaker filled with ice. This solution was added to the reaction mixture carefully, drop-wise at first until reaction became clear with white precipitate. After that point a 10 mL portion was carefully added to test for reactivity, and then the remained of the ice/acid mixture was added. A second 100 mL of ice/acid mixture was added, the external ice bath removed and the pale emulsion was stirred for 2 hours. A white precipitate was collected form the emulsion by suction filtration. This solid was dissolved in 300 mL of 0.3 M sodium hydroxide, washed with 100 mL of ethyl acetate, and acidified to ˜pH 1 with 1 M hydrochloric acid. The white precipitate that was collected upon vacuum filtration was washed with 3×100 mL de-ionized water and dried. The product (4.7 g, 47%) was isolated as a white solid, mp 149-150° C. Combustion analysis: Found: C, 63.52; H, 5.78%; C11H12O4 requires C, 63.45; H, 5.81%; 1H NMR (d6-DMSO): δ 12.2, s, 1H (COOH); δ 7.9 d, 2H (aryl H's); δ 7.0, d, 2H, (aryl H's); δ 3.8, s, 3H (OMe H's); δ 3.2, t, 2H (CH2 α to carbonyl); δ 2.5, t, 2H (CH2 α to COOH).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)(=[O:4])=[O:3].[CH:16]1([C:19]2[CH:20]=[C:21]([CH3:31])[C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][CH:24]=2)[CH2:18][CH2:17]1>>[CH:16]1([C:19]2[CH:20]=[C:21]([CH3:31])[C:22]([N:25]3[CH2:26][CH2:27][N:28]([C:11]([C:10]4[CH:9]=[CH:8][C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:15][CH:14]=4)=[O:13])[CH2:29][CH2:30]3)=[N:23][CH:24]=2)[CH2:18][CH2:17]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: CS(=O)(=O)NCc1ccc(C(=O)O)cc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CNS(C)(=O)=O)cc2)CC1
Yield: 38.8 %

Procedure:
Using 4-(methanesulfonylaminomethyl)benzoic acid (138 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (156 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (100 mg) was obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[NH:11][C:10]2[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[N:8]=1)(=[O:6])=[O:5].[CH3:16]I.[Cl-].[Cl-].[Ca+2]>CO>[CH3:16][N:11]1[C:10]2[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[N:8]=[C:7]1[S:4]([CH3:3])(=[O:5])=[O:6]
Reactant: CS(=O)(=O)c1nc2c([nH]1)CCCC2
Reactant: CI
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Product: Cn1c(S(C)(=O)=O)nc2c1CCCC2

Procedure:
Sodium hydride (55.8 mg) (60% in mineral oil) was added to a solution of 2-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-benzimidazole (233 mg) and MeI (0.080 mL) in DMF(dry) (10 ml) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The reaction mixture was diluted with MeOH (2 mL), and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give 1-methyl-2-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-benzimidazole (200 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.OS(O)(=O)=O.[CH3:36]O>C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:36])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1
Reactant: CO
Reactant: Cc1c(NCc2ccc(Oc3ccc(CCC(=O)O)cc3)cc2)cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 76B (9.78 g, 24.1 mmoles) in MeOH (24 mL) was treated with concentrated H2SO4 (1 mL) and heated at reflux overnight. Reaction cooled and quenched with saturated NaHCO3. Reaction mixture diluted with ethyl acetate, washed with H2O, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 20% ethyl acetate:hexanes) to provide the title compound. MS (ESI−) m/z 419 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=3)[C:28](O)=[O:29])=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.Cl.CN.[CH3:35][N:36](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([C:28]([NH:36][CH3:35])=[O:29])[CH:31]=3)=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:18])([F:17])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-[5-(4-Chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylcarbamoyl]-nicotinic acid (120 mg, 260 μmol) and methylamine hydrochloride (140 mg, 2.6 mmol) were dissolved in DMF (3 mL). TBTU (125 mg, 390 μmol) and DIPEA (672 mg, 908 μl, 5.2 mmol) were added. The reaction mixture was stirred at room temperature for 20 h. The crude reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 10 g, 0% to 100% ethyl acetate in heptane) to deliver 34 mg (28%) of the title compound as white solid; LC-MS (UV peak area/ESI) 99.5%, 465.0928 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[N:8]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:7]=1)(=O)C.[OH-].[Na+]>C(O)C.O>[Cl:21][C:20]1[C:15]([N:8]2[C:9]([C:11]([Cl:12])([Cl:13])[Cl:14])=[CH:10][C:6]([CH2:5][OH:4])=[N:7]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)OCc1cc(C(Cl)(Cl)Cl)n(-c2ncccc2Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCc1cc(C(Cl)(Cl)Cl)n(-c2ncccc2Cl)n1
Reaction time: 1 h

Procedure:
36.9 g of [1-(3-chloropyridin-2-yl)-5-(trichloromethyl)-1H-pyrazol-3-yl]methyl acetate were dissolved in 100 ml of ethanol, and 20 g of NaOH (as a 40% solution in water) were added. After 1 h, the mixture was diluted with 300 ml of water, and the product was filtered off, washed with water and dried. This gave 30 g (95%) of the product as a white solid.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:34]=[N:35][CH:36]=[C:37]([Br:39])[CH:38]=5)=[CH:27][C:26]=4[NH:41][C:42]4[C:43]5[CH:51]=[CH:50][C:49]([CH:52]([CH3:54])[CH3:53])=[N:48][C:44]=5[N:45]=[CH:46][N:47]=4)=[CH:20][CH:19]=3)C3C(=CC=CC=3)C=2C=CC=1.O.[OH-].[Li+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:32][C:33]3[CH:34]=[N:35][CH:36]=[C:37]([Br:39])[CH:38]=3)=[O:40])=[CH:27][C:26]=2[NH:41][C:42]2[C:43]3[CH:51]=[CH:50][C:49]([CH:52]([CH3:54])[CH3:53])=[N:48][C:44]=3[N:45]=[CH:46][N:47]=2)=[CH:20][CH:19]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cncc(Br)c4)ccc3Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)ncnc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cncc(Br)c4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 70 °C
Yield: 51.7 %

Procedure:
A solution of the product of Example 231E (96 mg, 0.1187 mmol) in 1,4-dioxane (2 mL) was treated with a solution of lithium hydroxide monohydrate (10.0 mg, 0.2374 mmol) in water (1 mL) at ambient temperature, then heated at 70° C. for 30 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (30 mL), adjusted the aqueous pH to 5 with 1N aqueous hydrochloric acid, and separated the layers. The organic phase was washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Purification of the residue by silica gel chromatography eluting with 5% methanol/methylene chloride afforded the title compound as a light yellow solid (36 mg, 2%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 3.12-3.30 (m, 1 H) 5.61 (s, 2 H) 6.64 (d, J=8.09 Hz, 2 H) 6.90 (dd, J=6.43, 1.29 Hz, 1 H) 7.15 (d, J=8.46 Hz, 2 H) 7.65 (dd, J=8.09, 1.84 Hz, 1 H) 7.81 (dd, J=7.91, 2.39 Hz, 1 H) 7.97 (s, 1 H) 8.43 (d, J=1.84 Hz, 1 H) 8.48-8.51 (m, 2 H) 8.59 (s, 1 H) 8.88 (d, J=1.84 Hz, 1 H) 10.18 (s, 1 H) 10.51 (s, 1 H); MS (ESI+) m/z 586/588 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][N:22]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[CH2:21][N:22]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nccn1-2

Procedure:
In the manner given in Example 33, 2',5-dichloro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone (4.76 g., 10.0 mmol) is dissolved in 60 ml. of ethanol, treated with 1.00 ml. of hydrazine hydrate and heated to 73° C. for 2 hours. After filtration of the reaction mixture, the mother liquids are concentrated and the residue is recrystallized from ethyl acetate/hexane mixtures to give 8-chloro-6-(o-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine of melting point 178°-180° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)=O.[OH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[S:34])[NH2:33])[CH2:27][CH2:26]1>>[CH3:15][C:11]1([CH3:16])[CH2:10][CH2:9][C:8]([CH3:17])([CH3:18])[C:7]2[CH:6]=[C:5]([C:3]3[N:33]=[C:32]([N:28]4[CH2:29][CH2:30][CH2:31][CH:25]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][OH:19])[CH2:26][CH2:27]4)[S:34][CH:2]=3)[CH:14]=[CH:13][C:12]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CBr)ccc21
Reactant: NC(=S)N1CCCC(NCCCCO)CC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCC(NCCCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as already described starting from 508 mg (1.15 mmol) of 2-bromo-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone and the product from step c. The purification was carried out by means of preparative HPLC. The product is in the form of the hydrochloride.
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:25])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].CO>C(Cl)(Cl)Cl>[NH2:8][C:7]1[C:6]2[C:5](=[CH:12][C:11]([N:13]3[CH2:17][CH2:16][N:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[CH3:24])[C:14]3=[O:25])=[CH:10][CH:9]=2)[NH:3][N:2]=1
Reactant: Cc1ccncc1N1CCN(c2ccc(C#N)c(F)c2)C1=O
Reactant: NN
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: Cc1ccncc1N1CCN(c2ccc3c(N)n[nH]c3c2)C1=O
Temperature: 170 °C
Yield: 17.6 %

Procedure:
Hydrazine hydrate (5 mL) was added to solution of 2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitrile (I-123a: 163 mg) in 2-methoxymethanol (10 mL). The resulting mixture was heated to 170° C. and maintained for 22 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ice water and ethylacetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by preparative HPLC afforded 30 mg of the product (17.6% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[OH:8])[CH:2]=1.CN1C(C(C2C=CC=CN=2)O)=CN=C1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)=[O:8])[CH:2]=1
Reactant: OC(c1ccc(C(F)(F)F)cc1)c1cccnc1
Agent: Cn1cncc1C(O)c1ccccn1
Product: O=C(c1ccc(C(F)(F)F)cc1)c1cccnc1

Procedure:
The title compound was prepared analogously to the method in Intermediate 25: step b using pyridin-3-yl(4-(trifluoromethyl)phenyl)methanol (Intermediate 26: step a) in place of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.CC(O)=O.[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17].O>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[C:18](/[C:16]#[N:17])\[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Cl)cc21
Reactant: CCOC(=O)CC#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)/C(C#N)=C1\CCc2ccc(Cl)cc21
Temperature: 100 °C
Yield: 64.5 %

Procedure:
To a solution of 6-chloro-indan-1-one (commercially available, 16 g, 0.1 mol) in Benzene (500 ml), AcOH (160 ml) CH3COONH4 (80 g) and ethyl cyanoacetate (14.4 g, 0.13 mol) were added. The mixture was heated to 100° C. and stirred overnight with a Dean stark water trap. Then ethyl acetate was added and the mixture washed with water. The residue was first purified by FC followed by crystallization from ethanol to obtain the title compound (16.2 g, y=64.5%).