Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl.[N:14]([O-])=O.[Na+].[C:18]([CH:21](C(=O)C)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:19]>C(O)C.N1C=CC=CC=1.O>[N:9]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][NH:14][CH:21]([C:18](=[O:20])[CH3:19])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:7][CH:6]=2)[N:12]=[N:11][CH:10]=1
Reactant: Nc1ccc(-n2ncnn2)cc1
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(NNc1ccc(-n2ncnn2)cc1)C(C)=O
Reaction time: 1 h

Procedure:
A solution of 1.06 gm. (6.58 mmoles) of 2-(4-aminophenyl)tetrazole in 20 ml. of ethanol and 1.18 ml. of concentrated hydrochloric acid and 10 ml. of water was cooled in an ice bath and treated dropwise with a solution of 500 mg. of sodium nitrite in 10 ml. of water. After the addition of an additional 10 ml. of water, the mixture was stirred for 25 minutes at room temperature. The mixture was then added to a solution of 1.35 gm. (7.2 mmoles) of ethyl 3-acetyl-4-oxopentanoate and 2.66 ml. of pyridine in 15 ml. of ethanol. A solid began to separate. After 1 hour, 10 ml. of 1 M hydrochloric acid was added to adjust the pH to 2-3. An additional 50 ml. of water was added and the solid was collected and washed thoroughly with water and dried. 1.74 g. was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C@H:8]2[C@@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](O)[CH:15]=3)[O:10][CH2:9]2)=[CH:5][CH:4]=1.[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28](CCl)[CH:27]=[CH:26]2>C(Cl)Cl>[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([C:14]1[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C@@H:8]([O:7][C:6]1[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C@H:17]3[OH:18])[CH:27]=[CH:26]2
Reactant: Fc1ccc2nc(CCl)ccc2c1
Reactant: COc1ccc(O[C@@H]2COc3ccc(O)cc3[C@@H]2O)cc1
Solvent: ClCCl
Product: COc1ccc(O[C@@H]2COc3ccc(-c4ccc5cc(F)ccc5n4)cc3[C@@H]2O)cc1

Procedure:
By the method of Example 13, using flash chromatography with 35:1 CH2Cl2 :isopropanol as eluant and recrystallization from CH2Cl2 for purification of the product, the title product of Example 20 (0.20 g, 0.69 mmol) and 6-fluoro-2-chloromethylquinoline were converted to present title product, 0.104 g (34%), m.p. 151°-153.5° C. MS calculated: 447.1486, found: 447.1494.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][C:7](=O)[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[Br:14]C1C=CC2CNC(=O)CCC=2C=1>O1CCCC1>[Br:14][C:12]1[CH:5]=[CH:6][C:7]2[NH:8][CH2:9][CH2:10][CH2:4][CH2:3][C:2]=2[CH:13]=1
Reactant: O=C1CCc2cc(Br)ccc2CN1
Reactant: O=C1Cc2ccc(Br)cc2CCN1
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CCCCN2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 1000-mL round-bottom flask was added the mixture of 7-bromo-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 7-bromo-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one (12.6 g, 52 4 mmol) and tetrahydrofuran (260 mL). The solution was cooled to 0° C. and borane-methylsulfide complex (12.4 mL, 210 mmol) was slowly added. The reaction mixture was stirred at 0° C. for 10 min, warmed to room temperature and stirred for 3 h, then heated at reflux for 4 h. Upon cooling to room temperature, the mixture was quenched with MeOH (50 mL) to remove excess borane. The solvent was then evaporated to give 7-bromo-2,3,4,5-tetrahydro-1H-benzoazepine and 7-bromo-2,3,4,5-tetrahydro-1H-benzoazepine as sticky oil. LCMS: (FA) ES+226 and 228.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:12][O:11]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1>CCO.O>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@@H:10]([OH:11])[CH2:12][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Yield: 39 %

Procedure:
A mixture of (R)-tert-butyl-dimethyl-(3-oxiranyl-propoxy)-silane (13 g, 60 mmol; prepared according to Org. Lett. (2005), 7, 3997) and 6-amino-4H-benzo[1,4]oxazin-3-one (9.9 g) in EtOH/H2O (9:1, 325 mL) was heated at reflux overnight. The volatiles were removed under reduced pressure and the residue purified by CC (Hept/EA 1:1) to give the desired intermediate as a brown oil (8.9 g, 39% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:10][C:11]([C:15]([O:17]CC)=O)=[C:12]([CH3:14])[N:13]=1.O.[NH2:21][NH2:22]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:10][C:11]([C:15]([NH:21][NH2:22])=[O:17])=[C:12]([CH3:14])[N:13]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2Cl)nc1C
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(Cl)cc2Cl)sc1C(=O)NN
Yield: 88.3 %

Procedure:
Ethyl 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylate (250 mg) prepared in the Step 23-1-1 was dissolved in ethanol (10 ml), and hydrazine monohydrate (794 mg) was added thereto. The mixture was heated under reflux for 23 hours. After the mixture was allowed to cool, the precipitated crystal was separated by filtration, washed with water, and dried to give 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylic acid hydrazide (211 mg, 88%).
Reaction SMILES: C(N1CCO[C@H](CC2C=CC=C(CO)C=2)C1)(OC(C)(C)C)=O.[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][C:31]1=[O:36])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[F:37][CH:38]([F:48])[O:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42]Br>>[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=2[O:39][CH:38]([F:37])[F:48])[C:31]1=[O:36])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1COCCN1Cc1ccccc1
Reactant: FC(F)Oc1ccccc1CBr
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Product: O=C1C(Cc2ccccc2OC(F)F)OCCN1Cc1ccccc1

Procedure:
N-Benzyl-2-(2-difluoromethoxy-benzyl)-morpholin-3-one was prepared as described for example 70, intermediate (b), but using 4-benzylmorpholine-3-one and 2-difluoromethoxybenzyl bromide and was isolated as a pale yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[CH2:10]([O:17][C:18](=[O:24])[C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:4]([CH2:3][CH2:2][N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[C:18]([O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:24])([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CCBr
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Product: CCOC(=O)CCN1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 49.7 %

Procedure:
Using the same reactions described above, 7.23 g (0.03) of ethyl β-bromopropionate and 7.33 g (0.04 m) of proline benzyl ester hydrochloride gave N-(2-carbethoxy)ethyl-L-proline, benzyl ester (4.6 g, 50.2%). This compound (4.6 g, 0.015 m) was hydrogenated over palladium-on-carbon to give 2.96 g (78%) of N-(2-carbethoxy)ethyl-L-propline, hydrochloride, m.p. 169°-171°. This compound (2.42 g, 0.0096 m) was condensed with 2.25 g (0.0072 m) of L-alanyl-L-proline, benzyl ester hydrochloride in the dicyclohexylcarbodiimide procedure to give 0.8 g of N-(2-carbethoxy)ethyl-L-prolyl-L-alanyl-L-proline, benzyl ester. The pro-drug precursor was hydrolyzed with barium hydroxide in aqueous methanol to give 0.498 g (64%) of N-(2-carboxyethyl)-L-prolyl-L-alanyl-L-proline, m.p. 133°-136°.
Reaction SMILES: [F:1][C:2]1([F:42])[CH2:7][CH2:6][CH:5]([C:8]2[CH:41]=[CH:40][C:11]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[N:25]=[C:24]([N:26]4[C:30]([C:31]([F:34])([F:33])[F:32])=[C:29]([C:35]([O:37]CC)=[O:36])[CH:28]=[N:27]4)[CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-:43].[Li+].Cl.[O:46]1CCOCC1>>[C:30]([OH:46])([C:31]([F:34])([F:33])[F:32])=[O:43].[F:42][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[CH:41]=[CH:40][C:11]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[N:25]=[C:24]([N:26]4[C:30]([C:31]([F:33])([F:34])[F:32])=[C:29]([C:35]([OH:37])=[O:36])[CH:28]=[N:27]4)[CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: C1COCCO1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(C4CCC(F)(F)CC4)cc3)n2)c1C(F)(F)F
Agent: Cl
Agent: [Li+]
Product: O=C(O)C(F)(F)F
Product: O=C(O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(C4CCC(F)(F)CC4)cc3)n2)c1C(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title compound from Example 11 Step A (20.0 mg, 0.034 mmol) in 1,4-dioxane (1 mL) was added lithium hydroxide (0.500 mL, 2.0 M in water, 1.00 mmol), and the resulting mixture was stirred at 50° C. After 30 min, the reaction mixture was rendered acidic by addition of aqueous hydrochloric acid, then was diluted with 1,4-dioxane and passed through a 0.45 micron syringe filter. Purification by reverse phase HPLC (50 to 100% acetonitrile in water, each with 0.1% v/v TFA) provided the title compound: LCMS m/z 558.2 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 8.29 (s, 1H), 8.15-8.09 (m, 2H), 7.73 (dd, J=8.0, 1.5 Hz, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.35 (d, J=7.0 Hz, 2H), 7.27 (d, J=8.5 Hz, 1H), 7.23 (d, J=7.0 Hz, 2H), 7.09 (t, J=8.5 Hz, 1H), 5.20 (s, 2H), 2.71-2.66 (m, 1H), 2.11-2.07 (m, 2H), 2.00-1.83 (m, 4H), 1.67-1.60 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13]O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:19])=O>>[ClH:19].[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][Cl:19])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Reactant: O=S(Cl)Cl
Product: Cl
Product: N#Cc1ccc(Cn2cncc2CCl)cc1
Reaction time: 8 h

Procedure:
A mixture of 1-(4-cyanobenzyl)-5-hydroxymethylimidazole (10.8 g, 50.70 mmol) and thionyl chloride (70 mL, 960 mmol) was stirred at room temp. overnight under a calcium chloride drying tube. The resultant mixture was concentrated under vacuum, and residual thionyl chloride removed by co-evaporation with toluene. The residue was recrystallized from boiling methanol. After cooling to room temp., the white solid precipitated was obtained by filtration, and residual solvent removed under vacuum overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][C:12](=O)[CH2:13]2)[CH2:8][C:7]1=[O:16].[H][H].[NH3:25]>CO.[Pd]>[NH2:25][CH:12]1[CH2:13][CH:14]2[CH:9]([CH2:8][C:7](=[O:16])[N:6]2[CH2:5][C:4]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: COc1ccc(CN2C(=O)CC3CCC(=O)CC32)c(OC)c1
Reactant: N
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CN2C(=O)CC3CCC(N)CC32)c(OC)c1
Yield: 61 %

Procedure:
To a solution of 1-(2,4-Dimethoxy-benzyl)-hexahydro-indole-2,6-dione (47 mg, 0.15 mmol) in 7.0 M of ammonia in methanol (10 mL) was added palladium (10 wt % on activated carbon, 26 mg). The reaction mixture was stirred at room temperature under 1 atm of hydrogen gas for 20 hours. The reaction mixture was then filtered through celite and evaporated in vacuo. Purification by column chromatography on silica gel (gradient: 0 to 5% methanol in dichloromethane containing 2% triethylamine) yielded 28.7 mg (61%) of 6-Amino-1-(2,4-dimethoxy-benzyl)-octahydro-indol-2-one. LCMS (Method E, ESI): RT=0.94 min, m+H=305.2; 1H NMR (400 MHz, CD3OD) δ: 7.11 (d, J=8.3, 1H), 6.52 (d, J=1.7, 1H), 6.50-6.44 (m, 1H), 4.73 (d, J=15.1, 1H), 4.13 (d, J=15.1, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.64 (d, J=3.2, 1H), 2.56-2.52 (m, 1H), 2.49 (dd, J=16.5, 6.9, 1H), 2.25 (d, J=14.5, 1H), 2.19 (td, J=11.4, 5.7, 1H), 2.01 (d, J=16.2, 1H), 1.83-1.69 (m, 2H), 1.25 (s, 2H), 1.14 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[Mn]([O-])(=O)(=O)=[O:17].[K+]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O1CCCC1>[Br:1][C:2]1[C:3](=[O:17])[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=1)[CH:5]=2
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1C(Br)=CC=C2C1=Cc1cc(Br)ccc12
Temperature: 177.5 °C
Yield: 86 %

Procedure:
2,7-Dibromofluorene (20.00 g, 61.72 mmol), potassium permanganate (31.61 g, 200.0 mmol) and copper(II) sulphate pentahydrate (49.94 g, 200.0 mmol) were ground together to afford a fine powder. The powder was heated at 175-180° C. for 6 h. After cooling to room temperature, tetrahydrofuran (1 L) was added and the mixture was sonicated for 30 minutes before being filtered through celite. The solvent was removed under reduced pressure to afford a crude product, which was triturated with hot methanol (300 mL) and filtered before being dried under reduced pressure to afford 2,7-dibromofluorenone (1) (17.94 g, 86%) as a yellow solid, purity 100% (GC): 1H and 13C NMR spectra as expected; M+=338 (t).
Reaction SMILES: F[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH2:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:11])[C:7]=1[N+:8]([O-:10])=[O:9].[NH2:19][C:20]([NH2:22])=[O:21].O>CN(C)C=O>[NH:19]([C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH2:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:11])[C:7]=1[N+:8]([O-:10])=[O:9])[C:20]([NH2:22])=[O:21]
Reactant: Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(F)c1[N+](=O)[O-]
Reactant: NC(N)=O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(N)c1[N+](=O)[O-]
Yield: 92.4 %

Procedure:
A solution of 5-fluoro-1,3-diamino-2,4,6trinitrobenzene (1.57 g, 6 mmol) and urea (1.80 g, 30 mmol) in 30 ml of dry dimethylformamide (DMF) was heated for 1 hour at 90° C. A yellow precipitate formed after about 5 minutes. The mixture was cooled, poured into 150 ml of cold H2O and the solid filtered. Trituration of the solid with warm DMF-H2O (1:1, 100 ml), filtration and drying gave 5-ureido-1,3-diamino-2,4,6-trinitrobenzene (1.67 g, 92.3%): mp 350° C. dec; IR (KBr) 1730 cm-1 (C=O); mass spectrum (CI, CH4) m/z 259 (M+1-HNCO, 100).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]1=2.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.O.[CH3:26][N:27]([CH:29]=[O:30])C>>[OH:16][NH:3][C:9](=[O:10])[CH2:8][CH:7]1[C:29](=[O:30])[NH:27][C:26]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[CH2:5][CH2:6]1.[CH2:15]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:3]2[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]3[CH:11]=[CH:12][CH:13]=[CH:14][C:4]2=3)=[CH:19][CH:18]=1)[CH3:26]
Reactant: CN(C)C=O
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CCCc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOc1ccc(CN2C(=O)CCCc3ccccc32)cc1
Product: O=C(CC1CCc2ccccc2NC1=O)NO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
NaH (60% in mineral oil) (1.86 mmol) is added to a solution a 1,3,4,5-tetrahydro-benzo[b]azepin-2-one (1.55 mmol) in 5 mL of DMF at 0° C., After stirring at 0° C. for 15 minutes, the mixture is allowed to warm up to room temperature. p-Methoxybenzyl chloride (1.94 mmol) is added to the mixture. After stirring at room temperature for 16 hours, the mixture is poured into 50 mL of water and extracted with EtOAc (3×25 mL). The organic layer are combined, washed with brine and dried over MgSO4. After removing the solvent under reduced pressure, the residue is purified by flash column chromatography (silica gel) to provide the desired product 1-(4-ethoxy-benzyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as white solid. Yield: 90%. MS: (ES+): 282.1 [M+1].
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[F:33][C:34]([F:43])([F:42])[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38].NC1C=C(O)C(C)=CC=1>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17]([NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[C:35]([C:34]([F:33])([F:42])[F:43])[CH:36]=3)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Cc1ccc(N)cc1O
Solvent: CO
Product: COc1ccc(Sc2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
The product from Example 14B was reacted with 3-(trifluoromethyl)aniline according to the procedure from Example 14C substituting 3-(trifluoromethyl)aniline for 5-amino-o-cresol to provide the title compound as an off white solid after trituration of the reaction product from methanol (73 mg, 77%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 10.54 (s, 1 H), 8.93 (d, J=8.46 Hz, 1 H), 8.67 (s, 1 H), 8.22 (s, 1 H), 8.04 (d, J=8.09 Hz, 1 H), 7.99 (s, 1 H), 7.85 (d, J=7.72 Hz, 1 H), 7.74 (d, J=8.46 Hz, 1 H), 7.59 (t, J=8.09 Hz, 1 H), 7.45 (d, J=8.46 Hz, 1 H), 7.41 (d, J=8.82 Hz, 2 H), 6.92-7.11 (m, 4 H), 3.77 (s, 3 H), 3.20-3.31 (m, 1 H), 1.35 (d, J=6.62 Hz, 6 H); MS (ESI+) m/z 590.3 (M+H)+, (ESI−) m/z 588.1 (M−H)−.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:13]([O:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)=[O:17])[CH3:14]>C(Cl)Cl>[CH2:13]([O:15][C:16]([C:18]1[NH:19][CH:20]=[C:21]([C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[CH:22]=1)=[O:17])[CH3:14]
Reactant: O=C(Cl)C1CCCC1
Reactant: CCOC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)C2CCCC2)c[nH]1
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
A mixture of cyclopentanecarbonyl chloride and aluminum chloride in dry DCM were stirred in an inert atmosphere at 0-5° C. for 15 minutes. To this, a solution of 1H-pyrrole-2-carboxylic acid ethyl ester in dry DCM was added drop wise under stirring at 0-5° C., stirred further at room temperature for 4 hrs. After completion of reaction, the reaction mixture was poured into ice water and extracted with DCM, DCM layer was washed with 1N NaOH followed by water and brine. The organic layer was dried over anhydrous sodium sulfate and was evaporated to get 4-Cyclopentanecarbonyl-1-H-pyrrole-2-carboxylic acid ethyl ester (A1-I).
Reaction SMILES: O=[C:2]([CH3:14])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[CH3:14][CH:2]([NH2:21])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: [BH3-]C#N
Reactant: CC(=O)CCn1cnc2ccccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)CCn1cnc2ccccc21

Procedure:
A mixture of 7.0 grams of 1-(3-oxobutyl)-1H-benzimidazole, 28.7 grams of ammonium acetate and 1.6 grams of sodium cyanoborohydride in 100 ml. of methanol was stirred at room temperature for about 24 hours. The mixture was then acidified with about 40 ml. of concentrated hydrochloric acid and the solvent was evaporated. The residue was dissolved in 150 ml. of water and the aqueous solution was extracted first with ether and then it was made alkaline (pH greater than 10) with solid potassium hydroxide. The alkaline solution was extracted with several portions of methylene chloride and the organic extracts were combined, washed with water and dried over magnesium sulfate and the methylene chloride was evaporated. The residue was chromatographed on a silica gel column packed in acetonitrile and eluted with acetonitrile and acetonitrile containing increasing percentages of methanol. The fractions containing the desired product, as determined by thin-layer chromatography, were combined and the solvent evaporated to give α-methyl-1H-benzimidazole-1-propanamine as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:64]=[CH:63][C:38]([CH:39]=[CH:40][CH2:41][N:42]2[C:47](=[O:48])[C:46](COS(C)(=O)=O)=[CH:45][C:44]([C:55]3[CH:60]=[CH:59][C:58]([F:61])=[C:57]([CH3:62])[CH:56]=3)=[N:43]2)=[CH:37][CH:36]=1.N1(C(OC(C)(C)C)=O)CCNC[CH2:66]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:46]2[C:47](=[O:48])[N:42]([CH2:41][CH:40]=[CH:39][C:38]3[CH:37]=[CH:36][C:35]([Cl:34])=[CH:64][CH:63]=3)[N:43]=[C:44]([C:55]3[CH:60]=[CH:59][C:58]([F:61])=[C:57]([CH3:62])[CH:56]=3)[C:45]=2[CH3:66])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)ccc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Product: Cc1cc(-c2nn(CC=Cc3ccc(Cl)cc3)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)ccc1F
Yield: 87.9 %

Procedure:
Following the procedure of Example 1 (10), 2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 87.9%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:4]=1[C:5]#[N:6].[I:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>>[I:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][O:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:3]([F:2])[C:4]=3[C:5]#[N:6])[CH2:14][CH2:15]2)=[O:25])=[CH:22][CH:21]=1
Reactant: N#Cc1c(F)cccc1OCC1CCNCC1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: N#Cc1c(F)cccc1OCC1CCN(C(=O)c2ccc(I)cc2)CC1
Yield: 84 %

Procedure:
A mixture of 2-fluoro-6-(piperidin-4-ylmethoxy)-benzonitrile hydrochloride (200 mg; 0.7 mmol) (Example 123, Step 3) was stirred at room temperature with 4-iodobenzoyl chloride (187 mg; 0.7 mmol) and triethylamine (0.3 mL; 2.1 mmol) for 16 hours. Reaction was cooled and quenched with dilute HCl and mixture extracted with ethyl acetate (2×20 mL). Combined organics washed with water, saturated sodium bicarbonate, brine and dried over Na2SO4. Crude material was purified by chromatography using 0.5-1% methanol/DCM gradient to afford 2-[1-(4-iodo-benzoyl)-piperidin-4-ylmethoxy]-6-fluoro-benzonitrile as a white solid. (273 mg; 84% yield).
Reaction SMILES: Cl[CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: Clc1ccc(CCC(Cl)Cn2ccnc2)cc1
Reactant: COc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1SC(CCc1ccc(Cl)cc1)Cn1ccnc1

Procedure:
1-[2-Chloro-4-(4-chlorophenyl)-n-butyl]imidazole (prepared from 2.0 g of alcohol as in Preparation D) was treated with 2-methoxythiophenol (1.68 g) and anhydrous potassium carbonate (1.60 g) in acetone using the procedure of Example 1 to afford 1-[2-(2-methoxyphenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole which was converted to its nitrate salt and recrystallized from ethyl acetate to give 3.10 g of microcrystals, mp 105°-106.5° C.