Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH2:25][CH3:26])[CH2:21][CH2:20]2)[CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:9][C:10]1[CH:18]=[C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH2:25][CH3:26])[CH2:21][CH2:20]2)[CH:16]=[CH:15][C:11]=1[C:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: CC[C@H]1CC[C@H](c2ccc(C(=O)Cl)c(F)c2)CC1
Reactant: Oc1ccc(F)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC[C@H]1CC[C@H](c2ccc(C(=O)Oc3ccc(F)cc3)c(F)c2)CC1
Temperature: 60 °C

Procedure:
4-Fluorophenol (5.6 g, 0.05 mol) was dissolved in pyridine (10 ml), followed by adding to the solution, a solution of 2-fluoro-4-(trans-4-ethylcyclohexyl)benzoyl chloride (13.4 g, 0.05 mol) dissolved in toluene (50 ml), with stirring, thereafter heating the reaction mixture at 60° C. for 3 hours, adding water (100 ml) to the reaction material, washing the separated toluene layer with 6N HCl, then with 2N NaOH aqueous solution and further with water, thereafter drying it with anhydrous sodium sulfate, distilling off toluene and recrystallizing the residual solids from ethyl acetate to obtain the objective 4-fluorophenyl 2-fluoro-4-(trans-4-ethylcyclohexyl)benzoate (12.2 g, yield 65%). This compound exhibited following phase transition points:
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](C(OC)=O)=[CH:16][C:15]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[N:14]2)=[CH:9][CH:8]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH:17]=[CH:16][C:15]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[N:14]2)=[CH:11][CH:12]=1
Reactant: COC(=O)Nc1cc(C(=O)OC)n(-c2ccc(OC)cc2)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)Nc1ccn(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Yield: 191.9 %

Procedure:
To a solution of (2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)amine (0.90 g, 2.95 mmol) in 20 mL of methylene chloride at ambient temperature was added trimethylaluminum (8.85 mL of a 2.0 M solution in toluene, 17.68 mmol) dropwise. The resulting solution was allowed to stir until no more gas evolution was observed (~15 min). To this solution was added 1-[(4-methoxy)phenyl]-3-(methoxycarbonylamino) -5-(methoxycarbonyl)pyrazole (0.90 g, 2.95 mmol) in 10 mL of methylene chloride. The resulting solution was stirred at 40° C. for 16 h and then was cooled to ambient temperature and quenched by the addition of saturated aq NH4Cl. After diluting with ethyl acetate, the organic layer was washed with 10% aq HCl, saturated aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The solid residue was recrystallized from hexanes/ethyl acetate to afford 1.4 g (82%) of the title compound. LRMS (ES+): 577.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2OCCO2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[O:34]1[CH2:38][C:37](=[O:39])[NH:36][C:35]1=[O:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:38]2[O:34][C:35](=[O:40])[NH:36][C:37]2=[O:39])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: COc1cc(CCCCCCC2OCCO2)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=C1COC(=O)N1
Product: COc1cc(CCCCCCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 18, 2-[6-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]hexyl]-1,3-dioxolan was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[7-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]heptyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.109-111° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][N:20]=[C:21]=[O:22]>C1(C)C=CC=CC=1>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:10][C:21]([NH:20][CH3:19])=[O:22])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN=C=O
Reactant: NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 61.3 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (54 mg, 0,19 mmol) in toluene (5 mL) was treated with methyl isocyanate (0.03 mL, 0.47 mmol). The resulting solution was heated under reflux for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh 70/30 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea (40 mg, 63%) as a white solid: mp 124.8-127.5° C.; [α]23589=−21.2° (c=0.099, chloroform); EI-HRMS m/e calcd for C16H20Cl2N2O2 (M+) 342.0902, found 342.0902.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:26]([O:27][CH3:28])=[CH:25][C:6]2[NH:7][C:8]([S:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:9][C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:37])C=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:26]([O:27][CH3:28])=[CH:25][C:6]2[NH:7][C:8]([S:10]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:37])=[N:9][C:5]=2[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2ccccn2)c(Sc2nc3cc(OC)c(OC)cc3[nH]2)c1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccccn2)c(S(=O)c2nc3cc(OC)c(OC)cc3[nH]2)c1
Reaction time: 1 h

Procedure:
The product of step (c) above (370 mg) was dissolved in ethyl acetate (90 ml) and cooled to -10°. To the stirred solution was added a solution of m-chloroperbenzoic acid (191 mg of 85%) in ethyl acetate (10 ml). After stirring for 1 hour the solution was washed with sodium bicarbonate solution, sodium metabisulphite solution, water and brine then dried and evaporated. The residue was flash chromatographed to afford the title compound as a buff solid, mp 208°-210°.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:15][NH2:16].C(OCC)(=O)C>O1CCCC1.C(N(CC)CC)C.ClC(OCC)=O>[CH3:15][NH:16][C:7](=[O:8])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([CH3:14])=[CH:4][C:5]=1[O:11][CH2:12][CH3:13]
Reactant: CN
Reactant: CCOc1cc(C)c(Br)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOc1cc(C)c(Br)cc1C(=O)NC
Reaction time: 1 h

Procedure:
After dissolving 5-bromo-2-ethoxy-4-methylbenzoic acid in tetrahydrofuran (80 ml), triethylamine (3.5 ml) and ethyl chloroformate (2.4 ml) were added while cooling on ice, the mixture was stirred for 1 hour, and then a 40% methylamine aqueous solution (3.5 ml) was added. The reaction mixture was stirred for 1 hour, ethyl acetate was added and the mixture was washed with brine, after which the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The crystals of the residue were washed with hexane and filtered to yield the title compound (5.08 g) as white crystals.
Reaction SMILES: [CH:1]1([CH:9]([OH:11])[CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH:1]1([C:9](=[O:11])[CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CC(O)C1C=CCCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)C1C=CCCCCC1
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 51.1 %

Procedure:
At 0° C., a solution of 1-cyclooct-2-enylethanol (1.4 g, 9 mmol) in dichloromethane (20 ml) was added to pyridiniumchlorochromate (2.35 g, 11 mmol) in dichloromethane (30 ml). The resulting mixture was stirred at 20° C. during 3.5 h and filtered through Celite®. The filtrate was concentrated and the crude product purified by flash chromatography (hexane/Et2O 6:1) to give 0.7 g of 1-cyclooct-2-enylethanone (55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([CH3:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.[CH3:18][C:19]([OH:23])([C:21]#[CH:22])[CH3:20]>C(#N)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]#[C:21][C:19]([OH:23])([CH3:20])[CH3:18])[C:5]([CH3:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1
Reactant: C#CC(C)(C)O
Reactant: Cc1c(I)cc(Cl)cc1NC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1c(C#CC(C)(C)O)cc(Cl)cc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 91.8 %

Procedure:
A solution of 1,1-dimethylethyl (5-chloro-3-iodo-2-methylphenyl)carbamate (610 mg, 1.7 mmol), 2-methyl-3-butyn-2-ol (245 μl, 2.5 mmol), and triphenylphosphine (30 mg, 0.12 mmol) in acetonitrile (2 mL) was deoxygenated for 20 minutes. The solution was cooled to 0° C., followed by the addition of copper(I)iodide (12 mg, 0.07 mmol), and palladium(II)dichloride (13 mg, 0.06 mmol). The mixture was stirred at reflux for 1.5 hours, then cooled to room temperature and concentrated in-vacuo. The resultant residue was partitioned between water and ethyl acetate. The aqueous portion was extracted twice with ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford a brown residue which was purified by column chromatography (silica gel, 20% ethyl acetate in hexanes). The product was collected to afford 504 mg, 1.56 mmol (94%) of 1,1-dimethylethyl [5-chloro-3-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-methylphenyl]carbamate as a yellow solid. 1H NMR (400 MHz, CDCl3): 7.36 (d, 1H), 7.06 (d, 1H), 2.26 (s, 3H), 1.63 (s, 6H), 1.41 (s, 9H); MS (EI) for C17H22ClNO3: 324 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH3:12]>C(O)C>[NH2:12]/[C:3](/[CH:2]([CH3:11])[CH3:1])=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: N
Solvent: CCO
Product: CCOC(=O)/C=C(/N)C(C)C
Reaction time: 16 h

Procedure:
Ethyl 4-methyl-3-oxopentanoate (2.0 g, 13 mmol) was treated with 2M ammonia in ethanol (20 mL), heated to 80 C. in a sealed tube for 16 hours and concentrated to dryness to provide the title compound.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][N:23]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26](=O)[C:24]2=[O:25])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34].[CH3:35][O:36][NH2:37].Cl>CO>[ClH:34].[ClH:34].[CH:1]([N:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][N:23]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26](=[N:37][O:36][CH3:35])[C:24]2=[O:25])[CH2:18][CH2:19]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON
Reactant: O=C1C(=O)N(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Agent: Cl
Solvent: CO
Product: CON=C1C(=O)N(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Yield: 121.2 %

Procedure:
A mixture of 1-[3-(4-benzhydryl-1-piperazinyl)propyl]isatin (1.81 g) and O-methylhydroxylamine hydrochloride (420 mg) in methanol (36 ml) was stirred for an hour at ambient temperature. After addition of 29% ethanolic hydrogen chloride (2 ml), the reaction mixture was evaporated to dryness. The residue was triturated with ethanol and then recrystallized from 90% ethanol to give pale yellow crystals of 1-[3-(4-benzhydryl-1-piperazinyl)propyl]-3-methoxyimino-2-indolinone dihydrochloride (1.65 g), mp. 191° to 196° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:51][CH:52]([CH3:61])[CH:53]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[OH:54]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:54][CH:53]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:52]([CH3:61])[CH3:51])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CC(C)C(O)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC(c4ccccc4)C(C)C)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 47 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (124 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-methyl-1-phenyl-1-propanol (61 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (58 mg, yield 44%).
Reaction SMILES: B(F)(F)F.C([N:12]1[C:21](=[O:22])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:15]2[S:16][CH:17]=[CH:18][CH2:19][N:14]2[C:13]1=[O:29])C1C=CC=CC=1.CO>C1(C)C=CC=CC=1>[C:23]1([C:20]2[C:21](=[O:22])[NH:12][C:13](=[O:29])[N:14]3[CH2:19][CH:18]=[CH:17][S:16][C:15]=23)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=c1c(-c2ccccc2)c2n(c(=O)n1Cc1ccccc1)CC=CS2
Agent: FB(F)F
Solvent: CO
Solvent: Cc1ccccc1
Product: O=c1[nH]c(=O)n2c(c1-c1ccccc1)SC=CC2
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
Boron trifluoride (0.7 ml) was added to a solution of 7-benzyl-9-phenyl-4H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (1 g) in toluene (25 ml) and the mixture was refluxed for 15 hours. Methanol (7.5 ml) was added to the reaction solution at room temperature and the solution was stirred for 30 minutes. The reaction solution was concentrated to dryness, and acetone was added to the resulting residue to obtain the presipitate by filtration. The resulting crude crystals were washed and recrystallized from DMF-water to give yellow needles (0.13 g, 18%).
Reaction SMILES: ClC1C(Cl)=C2C(CCC2=O)=CC=1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][C:23]([OH:25])=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]2[C:15]=1[CH2:21][CH2:22][C:23]2=[O:25]
Reactant: O=C(O)CCc1cccc(Cl)c1Cl
Agent: O=C1CCc2ccc(Cl)c(Cl)c21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1CCc2c1ccc(Cl)c2Cl

Procedure:
The 4,5-dichloro-1-indanone is prepared as in Example 15 for the preparation of 6,7-dichloro-1-indanone but star6ing with 26 g of 3-(2,3-dichlorophenyl)propionic acid, 138 ml of thionyl chloride, 550 ml of anhydrous dichloromethane and 20.5 g of aluminium chloride. After recrystallization from 100 ml of boiling ethanol, 12.67 g of 4,5-dichloro-1-indanone are thus obtained which melt at 78° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8]C)=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: C1COCCN1
Reactant: COCC(=O)CC(=O)OC
Product: COCC(=O)CC(=O)N1CCOCC1
Reaction time: 3 h

Procedure:
0.346 mol (50.5 g) of methyl 4-methoxy-acetoacetate and 0.363 mol (31.6 g) of morpholine was stirred for 20 h at 110° C. in a Dean-Stark apparatus. There were further added 0.069 mol (6.02 g) of morpholine and stirred further 3 hours. Subsequently, the excess starting materials were distilled off on a rotary evaporator. 67.3 g of crude product was chromatographed over 600 g silica gel with ethyl acetate/ethanol 9/1. There were 36.9 g of the title compound.
Reaction SMILES: [F:1][C:2](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C.CO.[H][H]>C1C=CC=CC=1>[F:1][C:2](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][OH:4]
Reactant: [H][H]
Reactant: CCOC(=O)C(F)=Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: c1ccccc1
Product: OCC(F)=Cc1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of the above ester (1.80 g, 9.27 mmol) in 50 ml benzene is added dripwise at RT a 1.78 M solution of diisobutyl aluminum hydride; stir 20 minutes. Add 3 ml more diisobutyl aluminum hydride. Reaction is worked up by adding MeOH until hydrogen evolution ceases, then extracting in ether/dilute HCl solution. The aqueous layer is extracted 2X with ether. The ether layers are washed with dil. HCl, water and brine, dried (Na2SO4) and evaporated under vacuum to yield 2-fluoro-3-phenyl-2-propen-1-ol.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:12]3[CH:13]=[CH:14][C:15]([F:20])=[CH:16][C:17]=3[C:18](=O)[C:10]=2[CH:9]=[C:8]2[C:3]=1C(C)=CC(C)(C)[NH:7]2.CCCCCC.CC[O:32]C(C)=O>>[NH2:7][C:8]1[C:9](=[O:32])[C:10]2[C:11](=[C:2]([F:1])[CH:3]=1)[C:12]1[C:17](=[CH:16][C:15]([F:20])=[CH:14][CH:13]=1)[CH:18]=2
Reactant: CC1=CC(C)(C)Nc2cc3c(c(F)c21)-c1ccc(F)cc1C3=O
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: NC1=CC(F)=C2C(=Cc3cc(F)ccc32)C1=O

Procedure:
5,8-Difluoro-1,2-dihydro-2,2,4-trimethyl-10-oxoindeno[1,2-g]quinoline (structure 19 of Scheme VI, where R2, R5 =F, R3-4, R6 =H, X=C=O): This compound was prepared according to General Method 3 (EXAMPLE 16) from Compound 132 (1.0 g, 4.6 mmol) to afford 5,8-difluoro-1,2-dihydro-2,2,4-trimethyl-10-oxoindeno[1,2-g]quinoline (structure 19 of Scheme VI, where R2, R5 =F, R3-4, R6 =H). Data for 5,8-difluoro-1,2-dihydro-2,2,4-trimethyl-10-oxoindeno[1,2-g]quinoline: Rf =0.49 (silca gel, hexane/EtOAc, 3:1), 1H NMR (400 MHz, acetone-d6) 7.50 (dd, J=8.1, 4.6, 1 H), 7.27 (m, 2 H), 6.73 (s, 1 H), 6.03 (br s, 1 H), 5.47 (s, 1 H), 2.16 (dd, J=7.1, 1.5, 3 H), 1.29 (s, 6 H).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][NH:6][N:7]([CH3:17])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].C(N(CC)CC)C>C(Cl)(Cl)Cl.ClCCl>[CH3:5][N:6]1[C:1](=[S:2])[N:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8](=[O:9])[N:7]1[CH3:17]
Reactant: S=C(Cl)Cl
Reactant: CNN(C)C(=O)Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)n(-c2ccccc2)c(=S)n1C

Procedure:
A solution of 4.26 g (0.037 mol) thiophosgene in about 10 ml chloroform was added dropwise to a solution of 6.7 g (0.037 mol) 1,2-dimethyl-4-phenylsemicarbazide and 7.47 g (0.074 mol) triethylamine in 200 ml chloroform. A slightly exothermic reaction ensued. One hour after the addition was completed, the reaction mixture was heated under reflux for about 16 hours, cooled and evaporated under reduced pressure to give an oil residue. The residue was dissolved in dichloromethane, washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a red viscous oil. The oil was chromatographed on 200 g of silica gel using dichloromethane as eluant. The major product (4 g) from the chromatography was a semisolid, which on trituration with ether gave the desired product as a light tan solid, m.p. 118°-122° C. Infrared spectrum of the product showed strong carbonyl absorption at 5.8 micron. The product is tabulated in Table I as Compound No. 1.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH2:24][OH:25])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:31][C:32](=[O:42])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37](O)[CH:36]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[CH2:24][O:25][C:39]1[CH:40]=[C:35]([CH2:34][CH2:33][C:32]([OH:42])=[O:31])[CH:36]=[CH:37][CH:38]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:27])[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1cccc(O)c1
Reactant: OCc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)CCc1cccc(OCc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from [3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenyl]-methanol and 3-(3-hydroxy-phenyl)-propionic acid methyl ester according to the procedure of Example 69. MS (ESI) m/z 542.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][CH3:14])=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=2.[C:16]([OH:20])(=O)[CH2:17][OH:18].Cl.[OH-].[Na+]>>[OH2:18].[ClH:1].[CH3:14][N:13]1[C:12]2[C:11]3[CH:10]=[C:9]([CH3:15])[CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:2]=[C:17]1[CH2:16][OH:20]
Reactant: CNc1c(N)cnc2ccc(C)cc12
Reactant: O=C(O)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2ncc3nc(CO)n(C)c3c2c1
Product: O

Procedure:
A mixture of 4.5 g (0.020 mole) of 3-amino-6-methyl-4-(methylamino)quinoline hydrochloride (from Example 32), 3.8 g (0.050 mole) of glycolic acid and 75 ml of 4 N hydrochloric acid was heated at its reflux temperature for two hours. The solution was cooled, and 50% aqueous sodium hydroxide was then added to make the solution slightly basic. The precipitate was separated by filtration and washed with water. The solid was redissolved in dilute hydrochloric acid and reprecipitated with ammonium hydroxide to provide 1,8-dimethyl-2-hydroxymethyl-1H-imidazo[4,5-c]quinoline hydrochloride hydrate. Analysis: Calculated for C13H13N3O.HCl.H2O: %C, 55.4; %H, 5.7; %N, 14.9; Found: %C, 55.2; %H, 5.6; %N, 15.5.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH:17]2[CH:13]([C:14](=[O:18])[NH:15][CH2:16]2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C(C)=C(N2C[C@@H]3[C@H](O)CC[C@@H]3C2=O)C=CC=1C#N.[H-].[Na+].Br[CH2:42][C:43]1[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[C:45]([Cl:51])[C:44]=1[CH3:52]>C1COCC1.CN(C=O)C>[C:1]([O:9][CH:10]1[CH:17]2[CH:13]([C:14](=[O:18])[N:15]([CH2:42][C:43]3[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[C:45]([Cl:51])[C:44]=3[CH3:52])[CH2:16]2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([O:9][CH:10]1[CH:17]2[CH:16]([N:15]([CH2:42][C:43]3[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[C:45]([Cl:51])[C:44]=3[CH3:52])[C:14](=[O:18])[CH2:13]2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC1CCC2C(=O)NCC12)c1ccccc1
Reactant: Cc1c(CBr)ccc(C#N)c1Cl
Agent: Cc1c(N2C[C@@H]3[C@H](O)CC[C@@H]3C2=O)ccc(C#N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(CN2C(=O)CC3C(OC(=O)c4ccccc4)CCC32)ccc(C#N)c1Cl
Product: Cc1c(CN2CC3C(OC(=O)c4ccccc4)CCC3C2=O)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution containing mixtures of compound 1I and 1J (170 mg, 0.69 mmol, different batch than previous lot in example 1) in anhydrous THF (4 mL) and anhydrous DMF (4 mL) was added sodium hydride (27.7 mg, 0.69 mmol) at 0° C., and stirred at 0° C. for 45 min. Compound 7C (169 mg, 0.69 mmol) was added at 0° C., the ice-water bath was removed, and the stirring was continued between 0° C. to RT for 2 hr before it was quenched with saturated NH4Cl solution. The mixture was diluted with EtOAc, organic layer was separated, washed with water, dried over MgSO4, and concentrated. Purification by silica gel chromatography (30-100% EtOAc in hexanes) provide the title compound 7D (90 mg) and 7E (151 mg). Compound 7D: (ES) m/z 409 [M+H]+. Compound 7E: (ES) m/z 409 [M+H]+.