Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:9][CH:8]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Br:20][C:18]1[CH:17]=[CH:16][C:15]([Cl:21])=[C:14]([CH:19]=1)[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][OH:4])=[CH:8][CH:9]=1
Reactant: CC(=O)OCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Yield: 76 %

Procedure:
4-(5-bromo-2-chlorobenzyl)phenethyl acetate (intermediate BG) (400 mg, 1.09 mmol) and potassium carbonate (481 mg, 3.48 mmol) were stirred at room temperature in a mixture of 3 mL methyl alcohol and 0.5 mL water for 3 h. Solvents were evaporated and the residue taken up in 25 mL ether was washed with water (5 mL) and brine (20 mL), dried (Na2SO4), filtered and evaporated. Purification on silica gel using an ISCO column with 15:1 hexane:EtOAc gave intermediate BH (271 mg, yield 76%). 1H NMR (300 MHz, CDCl3): δ 7.27-7.07 (m, 7H), 4.02 (s, 2H), 3.84 (m, 2H), 2.86 (m, 3H); LC-ESI-MS (m/z): 325 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:25])[CH2:18][CH2:19][CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:26]([O:28]C)=[O:27].[I-].[Li+].Cl>N1C=CC=CC=1.O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:25])[CH2:18][CH2:19][CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:26]([OH:28])=[O:27]
Reactant: COC(=O)c1cnc2c3cc(NC(=O)CCC4CCCC4)ccc3ncn2c1=O
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(CCC1CCCC1)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
A mixture of methyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (5.72 g) and anhydrous lithium iodide (14.3 g) in dry pyridine (59 ml) was stirred at 120° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give crystalline residue, which was suspended in water (100 ml). The suspension was adjusted to pH 1.7 with conc. hydrochloric acid to yield yellow crystals, which were separated by filtration, washed with water and dried. Recrystallization from N,N-dimethylformamide gave crystalline 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (4.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.CCOCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1cc(Cl)ccc1C=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc(Cl)ccc1C=Nc1ccccc1
Yield: 32.7 %

Procedure:
A mixture of 4-chloro-2-methylbenzaldehyde (3.5 g, 22.6 mmol) and aniline (2.11 g, 22.6 mmol) in toluene (40 ml) was heated at reflux in a Dean-Stark apparatus for 1 hour. The mixture was cooled and evaporated in vacuo to leave an oily residue. The residue was redissolved in ether, washed with 5% sodium bicarbonate solution. The organic phase was separated, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford an oily residue which was purified by distillation via a Kugelrohr apparatus (oven temperature 160° C., 0.5 mm) to provide the title compound (4.0 g, 7.4 mmol, 77%) as a viscous oil; pmr(CDCl3) δ 2.5 (3H, s), 6.3~7.5 (7H, m), 7.95 (H, d), 8.6 (H, s).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C1(C)C=CC=CC=1.Cl[Sn](Cl)(Cl)Cl.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>[OH-].[Na+]>[C:29]([C:5]1[CH:6]=[C:2]([CH3:1])[N:3]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[C:4]=1[CH3:7])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOc1ccc(-n2c(C)ccc2C)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOc1ccc(-n2c(C)cc(C(=O)c3ccccc3)c2C)cc1
Temperature: 25 °C

Procedure:
To a solution of 2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (EXAMPLE 1) (1.0 g, 4.7 mmol) and toluene (15 mL) at 0° C. was added dropwise SnCl4 (4.7 mL, 4.7 mmol, 1.0M solution in CH2Cl2) and benzoyl chloride (0.54 mL, 4.7 mmol). The mixture was warmed to rt and heated at 50° C. overnight. After cooling to rt, the mixture was diluted with 1N NaOH (50 mL), extracted with EtOAc (2×50 mL), the combined extracts washed with brine (50 mL), dried MgSO4), filtered, concentrated in vacuo, and purified by flash chromatography on silica gel (0-25% EtOAc/hexanes) to give 3-benzoyl-2,5-dimethyl-1-(4ethoxyphenyl)pyrrole as a tan solid: 1H NMR (CDCl3, 500 MHz) δ 7.84-7.82 (m, 2H), 7.52-7.43 (m, 3H), 7.14-7.12 (m, 2H), 7.01-6.98 (m, 2H), 6.18 (s, 1H), 4.10 (q, 2H), 2.33 (s, 3H), 1.98 (s, 3H), 1.47 (t, 3H). MS (ESI) 320 (M+H)+.
Reaction SMILES: [Mg].BrCCBr.[C:6]([C:10]1[CH:11]=[C:12]2[C:16](=[C:17](Br)[CH:18]=1)[CH2:15][C:14]([CH3:20])=[CH:13]2)([CH3:9])([CH3:8])[CH3:7].[Cl:21][Si:22](Cl)([CH3:24])[CH3:23]>C1COCC1>[C:6]([C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([Si:22]([Cl:21])([CH3:24])[CH3:23])[CH:18]=1)[CH2:15][C:14]([CH3:20])=[CH:13]2)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC1=Cc2cc(C(C)(C)C)cc(Br)c2C1
Reactant: C[Si](C)(Cl)Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC1=Cc2cc(C(C)(C)C)cc([Si](C)(C)Cl)c2C1
Reaction time: 0.5 h

Procedure:
To 6.68 g (0.278 mol) of magnesium turnings in 200 mL of dry THF 5.26 g (0.028 mol) of 1,2-dibromoethane was added dropwise for 30 minutes. This mixture was stirred for additional 30 minutes, and then a solution of 66.3 g (0.250 mol) of 5-tert-butyl-2-methyl-7-bromo-1H-indene in 900 mL of THF was added dropwise by vigorous stirring in such rate that the mixture is refluxed. Then, this mixture was additionally refluxed for 30 minutes. Further on, to a solution of 113 g (0.875 mol) of dichlorodimethylsilane in 100 mL of THF the above-obtained solution of the Grignard reagent was added dropwise by vigorous stirring at room temperature using a water bath to cool the reaction mixture. The resulting mixture was additionally stirred for 12 hours at ambient temperature, evaporated to dryness, and then 200 mL of dry ether was added. The obtained suspension was stirred for 20 minutes at room temperature and then filtered through glass frit (G3). The precipitate was additionally washed by 2×100 mL of ether. The combined filtrate was evaporated to dryness, and the residue was rectificated in vacuum, b.p. 147° C.-155° C./1 mm Hg. Yield 50.1 g (72%) of the title product. 1H NMR (CD2Cl2): δ 7.46 (s, 1H, 6-H), 7.43 (s, 1H, 4-H), 6.55 (s, 1H, 3-H), 3.47 (s, 2H, 1,1′-H), 2.22 (s, 3H, 2-Me), 1.41 (s, 9H, tBu), 0.82 (s, 6H, SiMe2). Anal. Calc. for C16H23ClSi: C, 68.91; H, 8.31%. Found: C, 69.13; H, 8.58%.
Reaction SMILES: [C:1]1(C=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13](O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[C:9]1([C:14](=[CH2:13])[C:15]([OH:17])=[O:16])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C(C(=O)O)c1cccc2ccccc12
Temperature: 25 °C

Procedure:
1-Naphthyl acrylic acid was prepared by reaction of 1-naphthaldehyde and malonic acid. 1-Naphthaldehyde (46.8 g.), malonic acid (60.0 g.), pyridine (120 ml.), and piperidine (3 ml.) were charged into a 500 ml. round bottom flask and refluxed on a water bath for 4 hours. The reaction solution was cooled to room temperature and poured onto a mixture of 175 ml. concentrated hydrochloric acid and 300 g. of crushed ice. A white precipitate formed and the slurry was stirred until all the ice had melted. The precipitate was separated from the slurry by filtration and washed with one portion of 10% hydrochloric acid (75 ml.) and two portions of deionized water (each 75 ml.). The 1-naphthyl acrylic acid precipitate was fully dewatered by continued application of suction on the filter, and then vacuum dried at 40°C. for 24 hours.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=O)[CH2:18]Br)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]2[C:9]3=[C:10]4[C:5]([C:6](=[O:11])[CH2:7][CH2:8]3)=[CH:4][CH:3]=[CH:2][N:1]4[CH:18]=2)=[CH:15][CH:14]=1
Reactant: O=C1CCCc2ncccc21
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C1CCc2c(-c3ccc(Cl)cc3)cn3cccc1c23
Temperature: 25 °C

Procedure:
5,6,7,8-Tetrahydroquinolin-5-one (35 g) was dissolved in 80 ml of toluene. To this solution was added 4-chlorophenacyl bromide (55.6 g) gradually and refluxed for 18 hours. The reaction mixture was cooled to room temperature, and depositing crystals were collected by filtration (78 g). These solids were dissolved in 700 ml of N,N-dimethylformamide. To this solution was added, molecular sieves 3A (30 g) and triethylamine (34 ml), then the reaction mixture was heated at 100° C. for 1 hour. The reaction mixture became dark brown. The dark brown solution that obtained after removing insoluble matter by filtration was concentrated under reduced pressure. To the residue was added 300 ml of water, and extracted with 200 ml of methylene chloride three times. This methylene chloride solution was washed with 100 ml of brine and dried over anhydrous sodium sulfate. The dark brown solution that obtained after removing drying agent by filtration was concentrated under reduced pressure, the resultant dark brown residue was purified by alumina column chromatography. The title compound was obtained as dark red crystals (29 g).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[CH:11][NH:12][CH:13]=[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6]1=[O:16])[CH:2]([CH3:4])[CH3:3].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:5]1[C:10]2=[CH:11][N:12]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:13]=[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6]1=[O:16])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c[nH]cc21
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc3c(=O)n(C)c(=O)n(CC(C)C)c3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (1.8 g, 8.3 mmol), 1-(chloromethyl)-4-methoxybenzene (1.3 mL, 9.9 mmol) and potassium carbonate (1.7 g, 12 mmol) in anhydrous DMF is stirred at room temperature overnight. The mixture is diluted with 100 mL of water, and then extracted with CH2Cl2 three times. The combined organic phase is washed with brine, and then dried with anhydrous Na2SO4. After filtration, the filtrate is concentrated under vacuum. The residue is purified by silica gel chromatography to give product as pale yellow solids. MS (ESI) m/z 342.2 [M+H]+.
Reaction SMILES: [CH3:1][O-].[Na+].[Na].[C:5]([C:9]1[O:13][N:12]=[C:11]([NH:14][C:15](=[O:18])[O:16][CH3:17])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>CO>[CH3:1][N:14]([C:11]1[CH:10]=[C:9]([C:5]([CH3:8])([CH3:6])[CH3:7])[O:13][N:12]=1)[C:15](=[O:18])[O:16][CH3:17]
Reactant: COC(=O)Nc1cc(C(C)(C)C)on1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)N(C)c1cc(C(C)(C)C)on1
Reaction time: 1 h

Procedure:
To the sodium methoxide obtained by mixing sodium (1.57 g) with anhydrous methanol (45 ml), methyl N-(5-t-butyl-3-isoxazolyl)carbamate (12.88 g) is added. The resultant mixture is stirred at room temperature for 10 minutes, and the methanol is evaporated under reduced pressure. The residue is mixed with anhydrous benzene (100 ml) and dimethyl sulfate (8.61 g). The resultant mixture is stirred for 1 hour and refluxed for 1 hour. After cooling, the precipitate is filtered off. The organic layer is washed with an aqueous saturated solution of sodium bicarbonate and water in order, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue is distilled to give methyl N-methyl-N-(5-t-butyl-3-isoxazolyl)carbamate (11.45 g) as a distillate boiling at 84.0° to 87.0° C./0.55 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](Cl)=[O:13])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.[NH2:20][NH2:21]>C(Cl)Cl>[Cl:1][C:2]1[C:11]([C:12]([NH:20][NH2:21])=[O:13])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)Cl)c1Cl
Reactant: NN
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)NN)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
At room temperature, 3.11 g (10 mmol) of methyl 2-chloro-3-chloroformyl-4-methylsulfonylbenzoate in 50 ml of methylene chloride were added dropwise to 1.0 g (20 mmol) of hydrazine hydrate in 30 ml of methylene chloride. The reaction mixture was stirred at room temperature for 1 hour and then washed with water, dried and concentrated. 1.2 g (39% of theory) of methyl 2-chloro-3-hydrazinocarbonyl-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11](Cl)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].O>CO>[CH2:14]([O:13][C:11]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cccc(C(=O)O)c1
Solvent: CO
Solvent: O
Product: O=C(Nc1cccc(C(=O)O)c1)OCc1ccccc1
Yield: 67 %

Procedure:
m-Aminobenzoic acid (2.94 g, 21 mmol) was suspended in 50 ml of methanol and treated with carbobenzoxy chloride (3.0 ml, 21 mmol). The mixture was sonicated for 10 min and water was added resulting in the crystallization of the product, 3-(benzyloxycarbonylamino)benzoic acid, (mp 218-219° C.), obtained in 67% yield. C, H, and N analysis: calc. 66.41% C, 4.83% H, 5.16% N; found 66.30% C, 4.82% H, 5.20% N.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:21][OH:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([O:22][CH2:21][C:11]1[N:10]([CH2:9][C:8]2[CH:23]=[CH:24][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)[C:18]2[C:13]([CH:12]=1)=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)cc(CO)n2Cc1ccc(C(C)(C)C)cc1
Product: COc1ccc2c(c1)cc(COC(C)=O)n2Cc1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared from [1-(4-tert-butylbenzyl)-5-methoxy-1H-indol-2-yl]methanol and acetyl chloride in substantially the same manner, as described in step 4 of Example 1. The product was obtained as a white solid. Mass spectrum (ESI, [M+H]+) m/z 366. 1H NMR (400 MHz, DMSO-d6) δ 7.30 (s, 1H), 7.28 (d, 2H, J=8.10 Hz), 7.07 (d, 1H, J=2.45 Hz), 7.86 (d, 2H, J=8.24 Hz), 7.76 (dd, 1H, J=8.86 and 2.29 Hz), 6.54 (s, 1H), 5.36 (s, 2H), 5.18 (s, 2H), 3.74 (s, 3H), 1.77 (s, 3H), and 1.20 ppm (s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].CS([C:18]1[N:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1)(=O)=O.O>CN(C)C=O>[F:25][C:24]([F:27])([F:26])[C:21]1[CH:20]=[N:19][C:18]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[N:23][CH:22]=1
Reactant: CS(=O)(=O)c1ncc(C(F)(F)F)cn1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OC1CCN(c2ncc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-hydroxypiperidine (6.18 g, 61 mmol), and potassium carbonate (11.0 g, 80 mmol) in N,N dimethylformamide (150 mL) was added 2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (12.3 g, 54 mmol) and stirred at room temperature for 18 h. To the reaction mixture was added 300 mL of water and the heterogeneous mixture was stirred for an additional 10 minutes. The white solid was filtered and washed with water to afford the desired product.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:23]=[CH:22][C:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:24][O:25][CH2:26][CH2:27]Br.O>CN(C)C=O>[C:3]([O:7][C:8]([N:10]([C:11]1[CH:12]=[CH:13][C:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=1)[CH2:27][CH2:26][O:25][CH3:24])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: COCCBr
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(N(CCOC)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 165 mg) in N,N-dimethylformamide (1 ml) was added dropwise a solution of ethyl 4-(tert-butoxycarbonyl-amino)cinnamate (1.00 g) in N,N-dimethylformamide (5 ml) in ice water bath under nitrogen and stirred for 1 hour under same condition. To the mixture was added 2-bromoethyl methyl ether (602 mg) and stirred for 1 hour at same condition and at ambient temperature for 20 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting to a mixture of n-hexane and ethyl acetate (4:1) to give ethyl 4-[N-tert-butoxycarbonyl-N-(2-methoxyethyl)amino]cinnamate (935 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[N:36]1([CH2:42][C:43]([N:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:44])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:39]3[CH2:38][CH2:37][N:36]([CH2:42][C:43]([N:45]4[CH2:46][CH2:47][CH2:48][CH2:49]4)=[O:44])[CH2:41][CH2:40]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:33])[CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(=O)N3CCCC3)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Aldrich) to give the title compound. LC-MS: 692.3 [(M+H)+]
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[N:27](C(OC(C)(C)C)=O)[N:26]=[C:25]([CH2:35][CH2:36][C:37]2[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH3:46])[CH:38]=2)[CH:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:21]=[CH:20][C:14]([C:15]([NH:22][C:23]4[CH:24]=[C:25]([CH2:35][CH2:36][C:37]5[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH3:46])[CH:38]=5)[NH:26][N:27]=4)=[O:16])=[CH:13][CH:12]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCN(C3CCC3)CC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C5CCC5)CC4)cc3)n[nH]2)cc(OC)c1
Yield: 6.1 %

Procedure:
4-(4-cyclobutylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide was prepared as for Example 94, but starting from ethyl 4-(4-cyclobutylpiperazin-1-yl)benzoate (202 mg, 0.7 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (292 mg, 0.84 mmol) and 1M NaHMDS (1.23 ml, 1.23 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 39-59% gradient of acetonitrile in water containing 1% 0.880 ammonia. The clean fractions were combined and evaporated to afford the title compound (21 mg, 6%); 1H NMR (399.9 MHz, DMSO-d6) δ 1.61-1.71 (2H, m), 1.81-1.86 (2H, m), 1.99-2.02 (2H, m), 2.38 (4H, t), 2.75 (1H, s), 2.85-2.87 (4H, m), 3.26-3.27 (4H, m), 3.72 (6H, d), 6.33 (1H, t), 6.42-6.43 (2H, m), 6.45 (1H, s), 6.95 (2H, d), 7.90 (2H, d), 10.29 (1H, s), 12.07 (1H, s). MS=m/z 490 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13]([CH3:20])=[CH:14][CH:15]=[N:16]3)=[CH:11][C:10]=2[C:21](O)=[O:22])=[C:4]([F:24])[CH:3]=1.[CH:25]1([CH2:28][O:29][NH2:30])[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][O:29][NH:30][C:21]([C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([F:19])[C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:24])[N:16]=[CH:15][CH:14]=[C:13]3[CH3:20])=[O:22])[CH2:27][CH2:26]1
Reactant: NOCC1CC1
Reactant: Cc1ccnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)O)cc12
Product: Cc1ccnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NOCC3CC3)cc12

Procedure:
The title compound is prepared from 7-(4-bromo-2-fluorophenylamino)-8-fluoro-4-methyl-quinoline-6-carboxylic acid in the same manner described in step J for Example 1 using O-cyclopropylmethyl-hydroxylamine in place of O-(2-vinyloxy-ethyl)-hydroxylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[CH:16]=[CH:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.[C:25]([C:27]1[C:28](=[C:35]([C:38]#[N:39])[C:36]#[N:37])[O:29][C:30]([CH3:34])([CH3:33])[C:31]=1[CH3:32])#[N:26].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[C:25]([C:27]1[C:28](=[C:35]([C:36]#[N:37])[C:38]#[N:39])[O:29][C:30]([CH3:33])([CH3:34])[C:31]=1[CH:32]=[CH:23][C:21]1[S:22][C:18]([CH:17]=[CH:16][C:4]2[CH:5]=[C:6]3[C:15]4[N:10]([CH2:9][CH2:8][CH2:7]3)[CH2:11][CH2:12][CH2:13][C:14]=4[C:3]=2[O:2][CH3:1])=[CH:19][CH:20]=1)#[N:26]
Reactant: COc1c(C=Cc2ccc(C=O)s2)cc2c3c1CCCN3CCC2
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1c(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)cc2c3c1CCCN3CCC2
Temperature: 25 °C
Reaction time: 42 h
Yield: 61.3 %

Procedure:
In 5 ml of ethanol and 1.5 ml of tetrahydrofuran were dissolved 158 mg (0.47 mmol) of 5-[2-(8-methoxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-yl)vinyl]thiophene-2-carboaldehyde and 102 mg (0.51 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 36 mg of ammonium acetate, and the mixture was stirred at room temperature for 42 hours. The crystal was filtrated and washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 150 mg of a black powdered crystal (yield: 62.0%; mp: 201-204° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH3:15])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCNCC1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of EXAMPLE 175B (650mg) in dichloromethane (6 mL) was added trifluoroacetic acid (6 mL) at 0° C. The reaction mixture was stirred at 0° C. for 50 minutes and concentrated. The concentrate was dissolved in dichloromethane, washed with aqueous NaHCO3 and the organic layer was dried over Na2SO4, and concentrated.