Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)(=[O:22])=[O:21]
Reactant: O=C1CNCCN1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a mixture of 2-piperazinone (0.98 g, 9.79 mmol, Sigma-Aldrich, St. Louis, Mo.) and triethylamine (Aldrich, 2.0 mL, 14.35 mmol) in CH2Cl2 (20 mL) at 0° C. was added a solution of 2-thiophenesulfonyl chloride (1.79 g, 9.79 mmol, Sigma-Aldrich, St. Louis, Mo.) in CH2Cl2 (10 mL). After 30 min, the mixture was diluted with saturated aqueous NaHCO3 (10 mL) and stirred at room temperature for 3 d. The slurry was filtered and washed with water (3×5 mL) to give 4-(2-thiophenylsulfonyl)-2-piperazinone as a white powder (2.1 g).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[C:10]([NH:11][C:12]2[C:17]3[CH:18]([CH3:21])[CH2:19][CH2:20][C:16]=3[N:15]=[C:14]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[F:29])[N:13]=2)=[CH:9][CH:8]=[N:7][CH:6]=1)C.[OH-].[Na+]>CO>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]([F:29])=[C:22]([C:14]2[N:13]=[C:12]([NH:11][C:10]3[C:5]([C:4]([OH:30])=[O:3])=[CH:6][N:7]=[CH:8][CH:9]=3)[C:17]3[CH:18]([CH3:21])[CH2:19][CH2:20][C:16]=3[N:15]=2)[CH:27]=1
Reactant: CCOC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1C(C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CCc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(=O)O)c21
Temperature: 25 °C
Yield: 95.5 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluoro-phenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-nicotinic acid ethyl ester (180 mg, 0.42 mmol, 1 eq) in MeOH (5 ml) was added a 1N NaOH(aq) solution (634 μl, 0.63 mmol, 1.5 eq) and the reaction mixture was heated to reflux for 1 h. The solution was cooled to rt and concentrated in vacuo. Water (20 ml) was added to the crude material and the aqueous layer was acidified to pH 4. The solid was filtered, washed with water (2×5 ml) and dried overnight to give 4-[2-(5-chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-nicotinic acid, 49 (160 mg, 95%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH:23]([O:26][CH2:27][CH2:28]O)([CH3:25])[CH3:24].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:28][CH2:27][O:26][CH:23]([CH3:25])[CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: CC(C)OCCO
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)OCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
A mixture of 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (0.33 mmol), 2-isopropoxyethanol (0.65 mmol), diethyl azodicarboxylate (114 mg, 0.65 mmol) and triphenylphosphine (171 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was heated using microwave irradiation to a temperature between 85 and 120° C. for a 30 to 90 min period. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to provide Compound 7.
Reaction SMILES: [Na].[O:2]([CH2:9][C:10](=[O:12])[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCO>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:11][C:10](=[O:12])[CH2:9][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)COc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
Sodium (6.74 g, 293 mmol) was added to EtOH (808 mL) at 0° C. The mixture was stirred at 0° C. until the sodium was completely dissolved. Then phenoxy-2-propanone (53 mL, 266 mmol) was added dropwise. The mixture was stirred at 0° C. for 10 minutes and then diethyl oxalate (36 mL, 266 mmol) was added. Then the mixture was stirred at room temperature for 16 hours and the solvent was evaporated in vacuo. The residue was dissolved in H2O and the mixture was acidified with a 1M solution of HCl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by open column chromatography (silica; DCM) to yield 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (35.9 g, 54% yield) as an oil.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.CN(C)C=O.Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>O>[N:2]1([O:1][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: On1nnc2ccccc21
Reactant: CCCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOn1nnc2ccccc21
Temperature: 135 °C

Procedure:
A mixture of 1-hydroxybenzotriazole (30.6 g), N,N-dimethylformamide (150 ml), 1-chlorooctane (32.7 g) and potassium carbonate (50 g) was heated at 135° C. for 0.5 hr. while stirring. The reaction mixture was poured into water and the resulting mixture was extracted with benzene. The benzene extract was dried and stripped of solvent by rotary evaporation and distillation to a pot temperature of 100 C. at a pressure of less than 0.1 mm of mercury. The product, n-octyl 1-benzotriazolyl ether was obtained as a clear yellow oil residue. The elemental analysis was as follows:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][NH:10][C:5]2=[C:4]([CH3:11])[CH:3]=1.[H-].[Na+].I[CH2:15][CH2:16][CH3:17].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][N:10]([CH2:15][CH2:16][CH3:17])[C:5]2=[C:4]([CH3:11])[CH:3]=1
Reactant: CCCI
Reactant: Cc1cc(Cl)nc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1ccc2nc(Cl)cc(C)c21

Procedure:
A solution of 5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridine (5 mmol) in dry DMF (10 mL) cooling on an ice bath was treated with NaH (60 mmol) under N2. After stirring at room temperature for 45 minutes iodopropane (10 mmol) was added. The mixture was allowed to react for further 3 hrs. Upon cooling on an ice bath it was treated with H2O (3 mL). The mixture was then extracted with diethyl ether (4×50 mL). The ether layers were combined, washed with brine, dried on MgSO4 and filtered. The solvent was evaporated to give 5-chloro-7-methyl-1-propyl-1H-pyrrolo[3,2-b]pyridine as orange oil. 1H-NMR (DMSO-d6) δ: 0.85 (t, 3H, J=7.6 Hz, CH3), 1.75 (m, 2H, CH2), 4.28 (t, 2H, J=7.6 Hz, CH2), 6.48 (d, 1H, J=3.2 Hz, Ar—H), 6.97 (s, 1H, Ar—H), 7.66 (d, 1H, J=3.6 Hz, Ar—H). MS (ESI+) m/z 209.0648 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5]Cl.[C:7](=[O:12])([O:10]C)[O:8][CH3:9]>>[C:7](=[O:10])([O:8][CH3:9])[O:12][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: COC(=O)OC
Reactant: ClCCCCCl
Product: COC(=O)OCCCCCl
Reaction time: 2 h
Yield: 13.8 %

Procedure:
The reaction conditions of Example 37 are substantially repeated employing 1,4-dichlorobutane (190.52 g, 1.5 moles), dimethyl carbonate (135.0 g, 1.5 moles) and 30.0 g of DOWEX® MWA-1 beads. After 2 hours at 150° C., distillation gives 34.5 g (13.8 percent yield based on 1,4-dichlorobutane) of 4-chlorobutyl methyl carbonate, b.p. 66° C.-67° C. (0.5 torr).
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:24][C:14]2=[C:15]3[C:20](=[CH:21][CH:22]=[C:13]2[O:12][CH2:11]1)[N:19]=[C:18]([CH3:23])[CH:17]=[CH:16]3)C1C=CC=CC=1>C(Cl)Cl>[CH3:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]3[O:12][CH2:11][C@@H:10]([CH2:9][OH:8])[O:24][C:14]3=2)[N:19]=1
Reactant: Cc1ccc2c3c(ccc2n1)OCC(COCc1ccccc1)O3
Solvent: ClCCl
Product: Cc1ccc2c3c(ccc2n1)OC[C@@H](CO)O3
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of (2R)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino [2,3-f]quinoline (0.74 g, 2.3 mmol) in CH2Cl2 (16 mL) being cooled in an ice-bath, FeCl3 (1.9 g, 12 mmol) was added. After 1 h, the ice-bath was removed and the reaction mixture was stirred for another 17 h. CHCl3 (30 mL) and 1 N NaOH (50 mL) were added to result in a suspension which was then filtered. The filtered solid was washed with CH3OH (50 mL). The combined organic layers were concentrated in vacuo. Purification on SiO2, eluted with (10:1) CHCl3:iPrOH gave 0.45 g (84%) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH:11]([OH:16])[CH2:12][C:13](O)=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]([OH:16])[CH2:12][C:13](=[O:14])[NH:19][N:20]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(C(=O)C(O)CC(=O)O)cc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1c(Cl)cc(C2=NNC(=O)CC2O)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
A mixture of 2.77 g of 4-(3,5-dichloro-4-methylphenyl)-3-hydroxy-4-oxobutyric acid (prepared as described in Preparation 1), 0.5 g of hydrazine hydrate (100%) and 20 ml of ethanol was stirred at room temperature for 6 hours. The resulting white powder was then collected by filtration, to give 1.77 g (yield 65%) of the desired Compound No. 7, melting at 253°-256° C.
Reaction SMILES: CC1[O:11][C:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3NCCC=2N=1.S(Cl)(Cl)=O.C([N:22]([CH2:25][CH3:26])CC)C.[CH2:27]([N:34]1[C:43]2[C:42]3[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=3[NH:40][CH2:39][CH2:38][C:37]=2[N:36]=[C:35]1[CH3:48])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH2:27]([N:34]1[C:43]2[C:42]3[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=3[N:40]([C:10]([C:9]3[CH:12]=[CH:13][C:26]([C:25]#[N:22])=[C:15]([CH3:14])[CH:8]=3)=[O:11])[CH2:39][CH2:38][C:37]=2[N:36]=[C:35]1[CH3:48])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1nc2c(n1Cc1ccccc1)-c1ccccc1NCC2
Reactant: CCN(CC)CC
Reactant: Cc1nc2c(o1)-c1ccccc1NCC2
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A mixture of 4-cyano-3-methyl-benzoic acid from Example E6 (557 mg, 3.4 mmol) and thionyl chloride (0.755 ml, 10.3 mmol) in toluene (100 ml) was heated at reflux for 2 h. After cooling to room temperature, solvents were re-moved in vacuo and azeotroped with toluene. The residue was redissolved in dichloromethane (100 ml) and triethylamine (0.962 ml, 6.9 mmol) then 1-benzyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene from Example E5a (1.0 g, 3.4 mmol) was added. The mixture was stirred at room temperature for 2 h, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% pet. ether then EtOAc) to yield the title compound (844 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][O:31][C:32](=[O:35])[CH2:33]Cl.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:33][C:32]([O:31][CH3:30])=[O:35])=[CH:4][C:3]=1[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: COC(=O)CCl
Reactant: Nc1ncc(-c2cccc(O)c2)cc1-c1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[6-amino-5-(1,3-benzothiazol-2-yl)pyridin-3-yl]phenol (80 mg, 0.20 mmol), potassium carbonate (100 mg, 0.700 mmol) and chloroacetic acid methyl ester (33 mg, 0.30 mmol) in DMF was left to stir at rt overnight. To the mixture was added EtOAc (10 mL), which was left to stir at rt for 10 min. Then, the mixture was washed with NaHCO3 aq. soln. (2×). The combined organic extracts were treated with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. Purification via silica gel chromatography (5% MeOH in DCM) afforded the title compound as a yellow solid. MS (ES+): m/z=392.02 (100) [MH+]. HPLC: tR=3.63 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([OH:14])=O)[C:6]=2[CH2:5][CH2:4]1)#[N:2].S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[C:1]([CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([Cl:17])=[O:14])[C:6]=2[CH2:5][CH2:4]1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#CC1CCc2c(C(=O)O)cccc21
Solvent: ClC(Cl)Cl
Product: N#CC1CCc2c(C(=O)Cl)cccc21
Reaction time: 15 h

Procedure:
To 6.0 g. of 1-cyanoindan-4-carboxylic acid are added 20 ml. of chloroform and 80 ml. of thionyl chloride and the mixture is allowed to stand at room temperature for 15 hours. The excess thionyl chloride and chloroform are distilled off under reduced pressure. To 1-cyanoindan-4-carbonyl chloride, which is thus obtained as the distillation residue, is added 100 ml. of chlorobenzene, followed by stirring under cooling with ice. Then, 6.0 g. of anhydrous aluminum chloride powder is added and the temperature is gradually increased to about 80° C., at which temperature the reaction mixture is stirred for 2.5 hours. After cooling, ice-hydrochloric acid is added, followed by extraction with ether. The extract is washed with water and dried. Then, the solvent is distilled off under reduced pressure and the residue obtained is purified by column chromatography on silica gel (700 g. silica gel; eluant; chloroform). The described procedure gives 4-(p-chlorobenzoyl)indan-1-carbonitrile as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O.CCOC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[C:11]([F:13])([F:12])[F:10])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)cn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cn1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
To a solution of 5-chloropicolinaldehyde (0.505 g, 3.57 mmol) in THF (7 mL) at 0° C. were added (trifluoromethyl)trimethylsilane (0.685 mL, 4.63 mmol) and tetra-N-butylammonium fluoride (1 M in THF, 0.036 mL, 0.036 mmol). The reaction mixture was stirred at 0° C. for 15 min and diluted with water (10 mL) and additional tetra-N-butylammonium fluoride (1 M in THF, 2.0 mL, 2.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was diluted with EtOAc, the organic phase was separated and washed with water, brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (5% to 20% EtOAc in heptane) to give the title compound (0.643 g, 3.04 mmol, 85% yield) as a yellow oil. MS m/z=211.9 [M+H]+. Calculated for C7H5ClF3NO 211.0.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]([CH3:23])[CH3:22])[C:13]3=[O:24])=[N:10][C:6]=2[CH:5]=1.[CH:32]1(N)C[CH2:33]1>>[CH:1]1([NH:2][CH2:3][C:4]2[CH:31]=[CH:30][C:7]3[N:8]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:9]([CH2:11][N:12]4[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=5[N:14]([CH:21]([CH3:23])[CH3:22])[C:13]4=[O:24])=[N:10][C:6]=3[CH:5]=2)[CH2:33][CH2:32]1
Reactant: CNCc1ccc2c(c1)nc(Cn1c(=O)n(C(C)C)c3ccccc31)n2CCC(C)C
Reactant: NC1CC1
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CNC3CC3)ccc21

Procedure:
1-[5-Cyclopropylaminomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one was prepared by the same procedure as 1-[5-methylaminomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one, except using cyclopropylamine.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][C:11]=4[N:10]3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][NH:20][CH3:21].[CH2:22]=O>O.C(#N)C>[CH3:19][N:20]([CH3:22])[CH2:21][C:18]1[N:10]2[C:11]3[CH2:17][CH2:16][O:15][C:12]=3[CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC
Reactant: c1ccc(-c2cn3c4c(ccc3n2)OCC4)cc1
Reactant: C=O
Solvent: CC#N
Solvent: O
Product: CN(C)Cc1c(-c2ccccc2)nc2ccc3c(n12)CCO3
Temperature: 70 °C
Reaction time: 4 h
Yield: 45.8 %

Procedure:
7-Phenyl-1,2-dihydrofuro[2,3-e]imidazo[1,2-a]pyridine (40 mg, 0.169 mol) was dissolved in a mixed solvent of water (400 μL) and acetonitrile (1 mL), 50% aqueous dimethylamine (15.1 mg) solution and 36% aqueous formalin (14.2 mg) solution were added, and the mixture was stirred at 70° C. for 4 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) to give the title compound (45 mg, 95%).
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:40])=[C:12]([NH:14][C:15]([C:17]2[N:18]=[CH:19][NH:20][C:21]=2[C:22]([NH:24][C:25]2[NH:29][C:28]3[CH:30]=[C:31]([N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[CH:32]=[CH:33][C:27]=3[N:26]=2)=[O:23])=[O:16])[CH:13]=1.[Na]>CN(C=O)C>[C:1]([OH:6])(=[O:16])[CH3:2].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:40])=[C:12]([NH:14][C:15]([C:17]2[N:18]=[CH:19][NH:20][C:21]=2[C:22]([NH:24][C:25]2[NH:26][C:27]3[CH:33]=[CH:32][C:31]([N:34]4[CH2:35][CH2:36][N:37]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:38][CH2:39]4)=[CH:30][C:28]=3[N:29]=2)=[O:23])=[O:16])[CH:13]=1
Reactant: CCCCC=O
Reactant: Cc1ccc(Br)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccc(N3CCNCC3)cc2[nH]1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)O
Product: CCCCCN1CCN(c2ccc3[nH]c(NC(=O)c4[nH]cnc4C(=O)Nc4cc(Br)ccc4C)nc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round-bottom flask was charged with pentanal (0.177 g, 2.0 mmol) and N4-(5-bromo-2-methylphenyl)-N5-(6-(piperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-imidazole-4,5-dicarboxamide (0.104 g 0.2 mmol), anhydrous DMF (5 mL) and sodium triacetoxybrohydride (0.212 g, 1.0 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and subsequently purified by preparative reverse phase HPLC (ammonium acetate/acetonitrile) to give N4-(5-bromo-2-methylphenyl)-N5-[5-(4-pentylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-imidazole-4,5-dicarboxamide acetate. 1H-NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.99 (d, 1H), 7.39 (dd, 1H), 7.29-7.3 (m, 2H), 6.87 (dd, 1H), 3.07 (t, 4H), 2.31 (t, 7H), 1.91 (s, 2H), 1.43-1.50 (m, 2H), 1.23-1.34 (m, 4H), 0.90 (t, 3H), MS (EI): 594.8 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:3]=1.[NH2:22][NH2:23].[C:24]1([CH3:32])[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.C(O)(=O)C>O1CCOCC1.C(Cl)Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[C:4]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH:3]=[C:2]2[NH:22][N:23]=[CH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH3:32])[CH:25]=1
Reactant: COc1cc2nc(N3CCOCC3)cc(Cl)c2cc1OC
Reactant: NN
Reactant: Cc1cccc(C=O)c1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc2nc(N3CCOCC3)cc(NN=Cc3cccc(C)c3)c2cc1OC
Temperature: 90 °C
Yield: 36.9 %

Procedure:
To a solution of compound C (33 mg, 0.1 mmol) in 3 mL of dioxane was added an excess amount of hydrazine (0.02 mL, 0.65 mmol). The resulting mixture was heated at 90° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with methylene chloride, followed by washing with brine twice. The organic phase was dried and concentrated. The left residue was dried in vacuo, and then dissolved in 5 mL of methanol. To the above solution was added m-tolualdehyde (0.01 mL, 0.11 mmol) and a catalytic amount of acetic acid. After the reaction mixture was heated at 50° C. for 30 min, the mixture was cooled to room temperature. A small amount of precipitate was observed and collected to give 15 mg of the final product, N-(6,7-Dimethoxy-2-morpholin-4-yl-quinolin-4-yl)-N′-(3-methyl-benzylidene)-hydrazine (compound 7).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][N:11]1[C:15]([CH:16]=[O:17])=[CH:14][N:13]=[CH:12]1.C(=O)C1C=CC=NC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:16]([C:15]2[N:11]([CH3:10])[CH:12]=[N:13][CH:14]=2)[OH:17])=[CH:4][CH:3]=1
Reactant: Cn1cncc1C=O
Reactant: Fc1ccc([Mg]Br)cc1
Agent: O=Cc1cccnc1
Product: Cn1cncc1C(O)c1ccc(F)cc1

Procedure:
The title compound was prepared analogously to the method in Intermediate 27: step a using (4-fluorophenyl)magnesium bromide and 1-methyl-1H-imidazole-5-carbaldehyde in place of (3,4-dimethoxyphenyl)magnesium bromide and nicotinaldehyde, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:20]=[C:15]2[CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CN)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc2c(c1)c(-c1cc3nc(CNC(=O)c4ccccc4)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 77.8 %

Procedure:
(6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (0.095 g, 0.28 mmol, Example #20, Step G) in THF (5 mL) was treated with pyridine (0.026 ml, 0.33 mmol) and benzoyl chloride (0.033 ml, 0.28 mmol). The mixture was stirred for about 20 min at about 60° C. and cooled to ambient temperature, diluted with aqueous Na2CO3 (15 mL), and extracted with EtOAc (20 mL). The organic solution was dried over anhydrous MgSO4, filtered, and concentrated to give N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)benzamide (0.118 g, 100%): LC/MS (Table 2, Method d) Rt=1.64 min; MS m/z: 542 (M+H)+.
Reaction SMILES: Cl.[Cl:2]C1C=CC2OC=C(CCC[N:13]3[CH2:18][CH2:17][N:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)C=2C=1.S(O[CH2:40][CH2:41][C:42]1[C:43]2[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:44]=2[O:45][CH:46]=1)(C1C=CC(C)=CC=1)(=O)=O.COC1C(N2CCNCC2)=NC=CC=1>>[ClH:2].[Cl:51][C:49]1[CH:48]=[CH:47][C:44]2[O:45][CH:46]=[C:42]([CH2:41][CH2:40][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:17][CH2:18]3)[C:43]=2[CH:50]=1
Reactant: COc1cccnc1N1CCN(CCCc2coc3ccc(Cl)cc23)CC1
Reactant: Cc1ccc(S(=O)(=O)OCCc2coc3ccc(Cl)cc23)cc1
Agent: COc1cccnc1N1CCNCC1
Agent: Cl
Product: COc1cccnc1N1CCN(CCc2coc3ccc(Cl)cc23)CC1

Procedure:
The title compound was prepared (0.55 g, 63%, mp 217°-220° C.) in a manner analogous to the preparation of 1-[3-(5-chlorobenzo[b]furan-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)piperazine (Example 25) by the reaction of 5-chloro-3-benzo[b]furanethanol tosylate with 1-(3-methoxy-2-pyridinyl)piperazine.