Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21](OC)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.Cl>C1COCC1>[OH:22][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([C:8](=[C:25]2[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]([CH3:32])([CH3:31])[CH2:30]2)[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccccc1-c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccccc3CO)cc2)CC(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of methyl 4′-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-2-biphenylcarboxylate (248) (0.102 g, 0.23 mmol) in THF (8 mL) at 0° C. was added lithium aluminum hydride (1 M in THF, 0.56 mL, 0.56 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 h. EtOAc (5 mL) was added, and stirring continued for 10 minutes. The mixture was then acidified to pH=2 with an aqueous solution of 1 N HCl, extracted with EtOAc (2×50 mL). The combined organic extract washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as light yellow oil. The crude product was purified by flash chromatography over SiO2 eluted with a gradient from hexanes to 40% EtOAc in hexanes to give 83 mg (87%) of the title compound (250) as a white solid. mp 171-172° C. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (s, 6H), 0.90 (s, 6H), 1.25(s, 2H), 1.91 (s, 2H), 1.92 (s, 2H), 4.36 (d, J=5.1 Hz, 2H), 5.10 (t, J=5.3 Hz, 1H), 6.67 (d, J=8.2 Hz, 2H), 6.96 (d, J=8.2 Hz, 2H), 7.12-7.23 (m, 3H), 7.24-7.36 (m, 4H), 7.53 (d, J=7.5 Hz, 1H), 9.27 (s, 1H). LCMS (ESI): m/z 425 (M−H)−.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14].Cl>O.COC1C=CC(O)=CC=1>[C:12]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)N[C@@H](CC(=O)O)C(=O)O
Reaction time: 3 h
Yield: 59.6 %

Procedure:
L-Aspartic acid (67 g, 0.5 mol) is dissolved in 48 g (1 mol) of sodium hydroxide in 300 ml of water and the solution is cooled down in an ice-bath. p-Methoxyphenol (50 mg) is used as an inhibitor. To the above reaction mixture, is added 58 g (0.5 mol) of methacryloyl chloride (freshly distilled) and 20 g (0.5 mol) of sodium hydroxide in 80 ml of water simultaneously at a rate to keep the reaction temperature below 5° C. The reaction is allowed to reach room temperature and stirred for another three hours. The reaction mixture is acidified to pH 3.0 with 3N HCl and extracted with ethyl acetate. The combined organic layer is washed with saturated sodium chloride solution and dried over magnesium sulfate. The dried organic layer is evaporated to dryness and crystallized from ethylacetate to yield 60 g (56%) of product. Melting point (93°-96° C.). NMR (D2O), 5.6 gamma (d, 1H, =CH2), 5.4 gamma (d, 1H, =CH 2), 2.9 gamma (d, 2H, CH2), 1.8 gamma (s, 3H, CH3).
Reaction SMILES: [Cl-].[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>>[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH:16][CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1
Reactant: [NH3+]CCOc1ccc2ccccc2c1F
Reactant: O=Cc1cccs1
Agent: [Cl-]
Product: Fc1c(OCCNCc2cccs2)ccc2ccccc12
Yield: 82 %

Procedure:
Prepared from 2-[(1-fluoronaphthalen-2-yl)oxy]ethanaminium chloride and thiophen-2-carbaldehyde in 82% yield as a white oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([S:22]([N:1]([S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])[C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Solvent: c1ccncc1
Product: CCOC(=O)c1c(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)sc2ccccc12
Temperature: 80 °C
Yield: 46.3 %

Procedure:
A mixture of ethyl 2-aminobenzo(b)thiophene-3-carboxylate (0.165 g) and benzenesulphonyl chloride (0.53 g) in pyridine (7 ml) was stirred and heated at 80° C. for 5 hours. Further benzenesulphonyl chloride (0.53 g) was added and the mixture was stirred and heated at 80° C. for 24 hours. The mixture was concentrated and the residue was partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and pentane (5-10%) to give ethyl 2-[bis-(benzenesulphonyl)amino]benzo[b]thiophene-3-carboxylate (0.173 g) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:13])=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[CH:5]=1>CO.Cl.[Pd]>[CH2:3]([C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)[CH:2]([CH3:13])[CH3:1]
Reactant: CC(C)=Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)Cc1cccc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.4 %

Procedure:
To a solution of 1-(2-methyl-l-propenyl)-3-nitrobenzene (4.57 g) in a mixture of methanol (50 ml) and 6N hydrochloric acid (14 ml) was added 10% palladium on activated carbon (1 g), and the mixture was stirred under hydrogen atmosphere (3 atm) at 25° C. for 3 hours. The catalyst was filtered off, and the filtrate was evaporated. The residue was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. Evaporation of the solvent gave 3-isobutylphenylamine (3.98 g) as a brown oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]1(O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.S(=O)(=O)(O)O>>[CH:10]1([O:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OCCc1ccccc1
Reactant: OC1CCCCC1
Agent: O=S(=O)(O)O
Product: c1ccc(CCOC2CCCCC2)cc1
Temperature: 115 °C
Reaction time: 3 h

Procedure:
Into a 2 liter reaction vessel equipped with stirrer, thermometer, heating mantle and overhead condenser with azeotrope takeoff apparatus is placed 488 grams of betaphenylethyl alcohol; 440 grams of cyclohexanol and 100 grams of concentrated sulfuric acid. The reaction mass is then heated to a temperature of 115° C. and maintained at a temperature in the range of 104°-127° C. at reflux while azeotropically removing 80 ml water, for a period of 3 hours. At the end of the 3 hour period, a sample is analyzed by means of GLC analysis (conditions: 180° C. isothermal using an SE-30 packed column). FIG. 1A is the GLC profile of the reaction product at this point.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][C:11](=[O:19])[N:12]2[CH2:15][CH2:16][CH2:17]Br)=[C:8]([NH2:20])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH3:27][C:28]1[CH:40]=[CH:39][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:30][CH:29]=1>CN(C=O)C>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][C:11](=[O:19])[N:12]2[CH2:15][CH2:16][CH2:17][N:36]2[CH2:37][CH2:38][N:33]([CH2:32][C:31]3[CH:39]=[CH:40][C:28]([CH3:27])=[CH:29][CH:30]=3)[CH2:34][CH2:35]2)=[C:8]([NH2:20])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(CN2CCNCC2)cc1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCBr)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN3CCN(Cc4ccc(C)cc4)CC3)c2n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 20.2 %

Procedure:
The compound (180 mg) obtained in Step (ii), potassium carbonate (140 mg) and 4-methylbenzylpiperazine (130 mg) were added to DMF (5 mL), and the mixture was stirred at 70° C. for 3 hours. The insoluble materials were collected by filtration, and the residue was purified by silica gel column chromatography (CHCl3:MeOH:28% NH3 aq.=100:3:2) to give the title compound (48 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH3:23])([O-:22])=[O:21]>>[CH2:11]([N:10]([C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[CH:23][N+:20]([O-:22])=[O:21])=[CH:3][C:2]=1[CH3:1])[CH2:13][CH3:14])[CH3:12]
Reactant: C[N+](=O)[O-]
Reactant: CCN(CC)c1ccc(C=O)cc1C
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCN(CC)c1ccc(C=C[N+](=O)[O-])cc1C
Temperature: 100 °C
Yield: 45 %

Procedure:
A solution was prepared by dissolving 30 grams (0.16 mol) of 3-methyl-4-(N,N-diethylamino)benzaldehyde in 150 ml of nitromethane, and added with 5 grams of ammonium acetate. The mixture was heated at 100° C. for 5 hours under agitation. The reaction solution was then cooled on a dry ice-acetone bath until crystallization had been completed. The separated solid (crystal) was filtered off and dried in vacuum. The obtained product was recrystallized from acetonitrile for two times. An amount of 17 grams of red crystals was obtained. The yield was 45%.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[OH:19])[C:12]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH3:29])[CH2:24][CH2:23]3)=[O:21])=[CH:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:31][CH2:32][F:33]>CN(C)C=O>[CH:3]1([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH2:31][CH2:32][F:33])[C:12]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH2:27]3)=[O:21])=[CH:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCN1CCN(C(=O)c2cn(CC3CCCCC3)c3c(O)cccc23)CC1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCN(C(=O)c2cn(CC3CCCCC3)c3c(OCCF)cccc23)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 65 mg, 1.62 mmol) was added portionwise with stirring under a stream of nitrogen to a solution of 4-{[1-(cyclohexylmethyl)-7-hydroxy-1H-indole-3-yl]carbonyl}-1-ethylpiperazine (200 mg, 0.54 mmol) in dimethylformamide (5 ml). After 30 minutes, 1-bromo-2-fluoroethane (49 μl, 0.65 mmol) was added. The mixture was heated to 60° C. with stirring for 48 hours. The reaction was quenched with 2-propanol (10 ml) and then concentrated. The resulting brown gum was partitioned between dichloromethane (50 ml) and 5% sodium hydrogen carbonate solution (50 ml). The organic layer was washed with water (50 ml), dried over sodium sulfate and concentrated. The crude intermediate was purified by flash chromatography using 95% dichloromethane, 5% methanol as eluent to afford the title compound (54 mg, 0.1 mmol). 1H NMR (400 MHz, CD3OD) δH 1.05 (2H, m), 1.19 (3H, m), 1.39 (3H, t, J 7.5), 1.56 (2H, m), 1.69 (3H, m), 1.92 (1H, m), 2.48 (2H, q, J 7.0), 2.53 (4H, m), 3.75 (4H, t, J 5.0), 4.26 (2H, d, J 7.5), 4.32 (1H, m), 4.39 (1H, m), 4.75 (1H, m), 4.87 (1H, m), 6.73 (1H, d, J 8.0), 7.06 (1H, t, J 8.0), 7.26 (1H, d, J 8.0), 7.44 (1H, s); EIMS: m/z=416.2 [M+H]+.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:5]([NH:7]N)=[O:6])[CH2:3][OH:4].N(OCCC(C)C)=O.C(N(CC)CC)C.N[C@H:35]([C:40]([NH:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38]>CN(C)C=O>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:5]([NH:7][C@H:35]([C:40]([NH:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:6])[CH2:3][OH:4]
Reactant: NNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CNC(=O)[C@@H](N)CC(C)C
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
2.48 Grams of Z-Ser-NHNH2 was dissolved in 20 ml of dimethylformamide and 4.89 ml of N-hydrochloric acid/dioxane, after cooled the reaction mixture to -15° C., then 1.31 ml of isoamyl nitrite was added thereto and stirred for 5 minutes. Then 4.11 ml of triethylamine was added to the reaction mixture to neutralize the mixture. This reaction mixture was added into 10 ml of a dimethylformamide solution containing the above-mentioned H-Leu-Gly-OC2H5 and 1.24 ml of triethylamine and stirred at 4° C. for 20 hours. After removal of dimethylformamide by distillation, the residue thus obtained was extracted with ethyl acetate, and the extract was washed with 1N-citric acid and a saturated aqueous solution of sodium chloride in this order, then the extract was dried with anhydrous magnesium sulfate. After removal of ethyl acetate, reprecipitated from ethyl acetate to obtain 2.64 g of Z-Ser-Leu-Gly-OC2H5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)(=[O:27])=[O:26].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:19]([O:18][C:16](=[O:17])[NH:15][C:9]1[CH:10]=[CH:11][C:12]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[S:25]([CH3:24])(=[O:27])=[O:26])=[CH:13][C:8]=1[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1NC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A mixture of (5-bromo-2-tert-butoxycarbonylamino-phenyl)-carbamic acid tert-butyl ester (Example 1, Step A, 8.81 g, 0.0385 mol), 2-methylsulfonylphenylboronic acid (10.00 g, 0.0500 mol), Pd(dppf)Cl2.CH2Cl2 (4.71 g, 0.0578 mmol), and Na2CO3 (24.46 g, 0.116 mol) in 1,2-dimethoxyethane (200 mL) and water (50 mL) was heated 80° C. for 12 hours under inert atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica, EtOAc: hexanes, 1:2) to afford the title compound as a yellow oil (15.30 g, 86%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O-]CC.[Na+].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:17]>C(O)C.C(O)C.C1(C)C=CC=CC=1>[C:3]([CH:2]([CH2:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1ccc(Cl)cc1Cl)C(C)=O
Reaction time: 0.25 h

Procedure:
To a solution of 3.26 ml of ethyl acetoacetate in ethanol (20 ml) is added dropwise 0.5 ml of a sodium ethoxide solution (21% in EtOH) at 0° C. The mixture is stirred for 15 minutes and 5.82 g de 2-bromo-1-(2,4-dichlorophenyl)ethanone predissolved in 30 ml of an ethanol/toluene mixture (2/1; v/v) is then added. The mixture is stirred for 4 hours at RT and then concentrated to dryness. The residue is purified by chromatography on silica gel to give 3.8 g of liquid corresponding to the expected product.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:14]1[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[CH:13]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccccc1F
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccccc2F)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 2-fluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.94 (td, J=19.93, 6.60 Hz, 6H), 1.58 (dt, J=13.39, 6.63 Hz, 1H), 1.78 (ddd, J=13.69, 7.21, 6.97 Hz, 1H), 2.01-2.11 (m, 1H), 3.80 (t, J=7.83 Hz, 1H), 7.16-7.27 (m, 2H), 7.29-7.40 (m, 1H), 7.47 (td, J=7.70, 1.71 Hz, 1H), 7.52-7.61 (m, 2H), 7.66-7.76 (m, 5H); Calcd for C25H22F4O2 (M+Na) 453.16, Found 453.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][C:24]2=[O:29])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(O)C.C([BH3-])#N.[Na+]>C(OCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=3)[CH2:25][C:24]2=[O:29])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: N#Cc1ccc(CC=O)cc1
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)C(=O)C2)cc1
Reaction time: 0.25 h

Procedure:
The crude 4-(2-Oxoethyl)benzonitrile (100 mg, 0.69 mmol) was treated with 1-[2-(4-nitrophenyl)ethyl]piperazin-2-one (197 mg, 0.69 mmol) and titanium(IV) isopropoxide (2.0 mL). After stirring the mixture for 15 minutes, ethanol and sodium cyanoborohydride was added into the reaction. The mixture was allowed to stir for 4 hours. The reaction was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated to give the crude residue. The desired product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 378 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][C@@H:15]([CH3:19])[CH2:14]1)=[N:7]2.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][N:16]([S:35]([CH3:34])(=[O:37])=[O:36])[C@@H:15]([CH3:19])[CH2:14]1)=[N:7]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(N2CCN[C@@H](C)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(S(C)(=O)=O)[C@@H](C)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure M using (S)-5,7-difluoro-3-methyl-2-(3-methylpiperazin-1-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine (50 mg, 0.11 mmol) and methylsulfonyl chloride to give (S)-5,7-difluoro-3-methyl-2-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 7.95 (1H, d, J=2.5 Hz), 7.66 (1H, d, J=2.3 Hz), 7.30 (1H, ddd, J=9.9, 2.5, 1.3 Hz), 6.92 (1H, d, J=13.3 Hz), 6.83 (1H, ddd, J=13.9, 8.7, 2.6 Hz), 6.60 (1H, t, J=2.3 Hz), 4.15-4.28 (1H, m), 3.86 (4H, dd, J=5.7, 4.1 Hz), 3.65-3.80 (2H, m), 3.58 (1H, dt, J=12.9, 1.9 Hz), 3.51 (1H, td, J=12.3, 2.9 Hz), 3.22 (1H, dd, J=12.9, 3.5 Hz), 3.13-3.19 (4H, m), 3.06 (1H, td, J=12.3, 3.2 Hz), 2.93 (3H, s), 2.09 (3H, s), 1.41 (3H, d, J=6.8 Hz). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:10])([CH3:9])[C:7](=[O:11])[NH:6][C:5]1=[O:12].CO.C(N(CC)C(C)C)(C)C.[Br:24][C:25]1[C:26]([C:32]2[S:33][C:34]([Cl:38])=[CH:35][C:36]=2[Br:37])=[N:27][C:28](Cl)=[N:29][CH:30]=1>CC(O)C>[Br:24][C:25]1[C:26]([C:32]2[S:33][C:34]([Cl:38])=[CH:35][C:36]=2[Br:37])=[N:27][C:28]([NH:1][CH2:2][CH2:3][N:4]2[C:8]([CH3:9])([CH3:10])[C:7](=[O:11])[NH:6][C:5]2=[O:12])=[N:29][CH:30]=1
Reactant: Clc1ncc(Br)c(-c2sc(Cl)cc2Br)n1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2sc(Cl)cc2Br)n1
Temperature: 170 °C

Procedure:
A 10% (w/v) solution of 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione in MeOH (4.3 mL, 2.5 mmol) was added to a 10 mL microwave vessel. The MeOH was evaporated with a stream of N2, to leave an oily solid which was dissolved in 0.58 mL (3.3 mmol) of N,N-diisopropylethylamine and 5 mL of iPrOH, to which was added 0.65 g (1.7 mmol) of 5-bromo-4-(3-bromo-5-chlorothiophen-2-yl)-2-chloropyrimidine. The reaction mixture was heated in a microwave to 170° C. for 20 min then concentrated in vacuo and purified by flash chromatography eluting with a linear gradient of 60% EtOAc in hexane to neat EtOAc to deliver the title compound. MS (M+H)+ 524.
Reaction SMILES: [OH:1][C:2]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([OH:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[OH:1][C:2]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4cc(C=O)c(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4cc(C=O)c(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reaction time: 0.08 h
Yield: 62 %

Procedure:
To a solution of 3,17β-dihydroxyestra-1,3,5(10)-triene-2-carboxaldehyde (57, 0.300 g, 1.0 mmol) in acetone (20 mL) was added Jones reagent (0.5 mL) at 0° C. The reaction mixture was stirred for 5 min, and quenched with 2-propanol, and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (MgSO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:THF (4:1→3:1, v/v) to afford 0.185 g of 60 (62% yield) mp: 154-157° C.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][C:12]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:13][CH:14]=3)[C:9](=[O:25])[C:8]=2[CH:7]=1.[C:27](=O)([O-])[O-].[Na+].[Na+].CN(N=O)C(=O)OCC>CO.CCOCC.Cl>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][O:19][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[C:8](=[CH:7][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:26])[CH3:1])=[CH:18][CH:17]=3)[C:9]([OH:25])=[CH:27][C:10]=2[CH:11]=1
Reactant: CN(C)CCOc1ccc2c(c1)C(=O)c1cc(OCCN(C)C)ccc1-2
Reactant: O=C([O-])[O-]
Agent: CCOC(=O)N(C)N=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CN(C)CCOc1ccc2c(c1)cc(O)c1cc(OCCN(C)C)ccc12
Reaction time: 24 h

Procedure:
A solution of 8.1 g (0.023 mole) of 2,7-bis[2-(dimethylamino)ethoxy]fluoren-9-one in 50 ml of methanol and 25 ml of ether is stirred and treated with 0.5 gram of finely powdered sodium carbonate. To this mixture is added 75 g (0.06 mole) of ethyl N-methyl-N-nitrosocarbamate in 20 ml of methanol over a period of 2 hours. The temperature of this reaction mixture is kept below 30° C. for a period of 24 hours. The reaction mixture is then freed of most of the volatile materials in vacuo, dissolved in an aqueous solution of hydrochloric acid, and extracted several times with diethyl ether. The resulting aqueous solution is made strongly alkaline with an aqueous sodium hydroxide solution and extracted with ether. The remaining aqueous solution is neutralized to an approximate pH of 10 using a 10% hydrochloric acid solution and extracted with ether. Evaporation of the combined ether extracts in vacuo and recrystallization from a methanol-water mixture yields the desired 2,7-bis[2-(dimethylamino)ethoxy]- 9-phenanthrol.