Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:2]=[CH2:3].[H-].[Na+].Cl[C:16]1[N:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1.O>C1COCC1>[CH2:1]([N:4]([CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:16]1[N:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCCCO
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCN(C)CCCCCCOc1ccc(C(C)=O)cn1
Temperature: 25 °C
Yield: 23.2 %

Procedure:
490 mg of 6-(allyl-methyl-amino)-hexan-1-ol (Ex. 42.B) in 5 ml of THF are treated over a period of 1.5 h. with 240 mg of NaH (55-60% dispersion in mineral oil) and with 410 mg of 1-(6-chloro-pyridin-3-yl)-ethanone (Ex. 42.D.a) in 4 ml of THF. The solution is stirred at RT, treated with water and filtered and the residue is washed with methylene chloride. The phases are separated and the inorganic phase is extracted with methylene chloride and then with ethyl acetate. The organic phases are concentrated, taken up in methylene chloride and extracted with 1M HCl. The acidic-aqueous phase is washed with methylene chloride, made basic with NaOH and extracted with methylene chloride. The organic phase is washed with NaHCO3 solution and saturated sodium chloride solution and dried. The crude product is purified on silica gel with methylene chloride:methanol (9:1). 177.8 mg of 1-[6-[6-(allyl-methyl-amino)-hexyloxy]-pyridin-3-yl]-ethanone are obtained as an oil. 176.4 mg of this are converted with 70 mg of fumaric acid into 1-[6-[6-(allyl-methyl-amino)-hexyloxy]pyridin-3-yl]-ethanone.fumarate (1:1), MS: m/e 291 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][CH3:26])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CO.[Pd].CCO>[CH2:25]([N:8]([C@@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH3:26]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CCCNC1
Reaction time: 4 h

Procedure:
A solution of (R)-benzyl 3-(tert-butoxycarbonyl(ethyl)amino)piperidine-1-carboxylate (5.00 g, 13.8 mmol) in a mixture of EtOH:MeOH (1:1, 50 mL) was added to a suspension of 10% palladium on activated carbon (1.47 g, 1.38 mmol) in EtOH (20 mL) under N2 atmosphere. The mixture was degassed under N2 (3 cycles) and back filled with H2 (3 cycles) using a H2 balloon. The mixture was then stirred under H2 atmosphere for 4 hours. The reaction mixture was then filtered through a pad of celite washing with 5% MeOH/EtOAc (3×30 mL). The filtrate collected was concentrated in vacuo to provide the crude (R)-tert-butyl ethyl(piperidin-3-yl)carbamate. LCMS (APCI+) m/z 229 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1)C.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+].Cl>CO>[C:4]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH2:21])[CH3:12])=[CH:7][CH:6]=1)([OH:3])=[O:14]
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC(N)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 g of 4-acetylbenzoic acid ethyl ester and 40 g of ammonium acetate are dissolved in 210 ml of absolute methanol, and 3.63 g of sodium cyanoborohydride are added. The reaction solution is stirred for 24 hours at room temperature, cooled to 4° and adjusted to a pH of 1 by the addition of concentrated hydrochloric acid. The methanol is removed under reduced pressure and the suspension that remains is filtered. The aqueous filtrate is washed with diethyl ether, adjusted to a pH of 10 at 4° by the addition of solid sodium hydroxide and extracted with diethyl ether. Drying is carried out over sodium sulfate and is followed by concentration to dryness by evaporation under reduced pressure, and the oil that remains is distilled under reduced pressure to give 1-(4-carboxyphenyl)ethylamine having a boiling point of 130°-140° (6×10-2 mbar).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[C:22]1([CH3:30])[CH:27]=[CH:26][CH:25]=[C:24]([Mg]Br)[CH:23]=1.O1CCCC1>C(OCC)C>[NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])=[CH:10][C:3]=1[C:4]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH3:30])[CH:23]=1)=[O:5]
Reactant: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1N
Reactant: Cc1cccc([Mg]Br)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)c2cc(O[Si](C)(C)C(C)(C)C)ccc2N)c1
Temperature: 0 °C

Procedure:
To a solution of 2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methylbenzamide (2.0 g, 6.4 mmol) in diethyl ether (50 ml) was added dropwise 1.0 M solution of m-tolylmagnesium bromide in tetrahydrofuran (30 ml, 30 mmol) under ice-cooling over 30 min. Ice water (250 g) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(3-methylphenyl)methanone as a mixture. To a solution of the obtained mixture (1.4 g) of (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(3-methylphenyl)methanone and 5-methyl-3-oxohexanenitrile (0.60 g, 4.7 mmol) in toluene (50 ml) was added methanesulfonic acid (0.38 g, 4.0 mmol), and the mixture was heated under reflux for 6 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), and the organic layer was washed with saturated brine (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained crude crystals were recrystallized from n-hexane-ethyl acetate to give 6-hydroxy-2-isobutyl-4-(3-methylphenyl)quinoline-3-carbonitrile (0.73 g, yield 36%) as pale-yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]2[NH:9][C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:31][Si:32]([CH3:39])([CH3:38])[CH2:33][CH2:34][O:35][CH2:36]Cl>CN(C)C=O>[C:1]([C:5]1[CH:24]=[CH:23][C:8]2[N:9]([CH2:36][O:35][CH2:34][CH2:33][Si:32]([CH3:39])([CH3:38])[CH3:31])[C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C1CC(Cc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC(Cc2nc3cc(C(C)(C)C)ccc3n2COCC[Si](C)(C)C)C1
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a solution of 3-[(5-tert-butyl-1H-1,3-benzodiazol-2-yl)methyl]-N-methoxy-N-methylcyclobutane-1-carboxamide (80%, 2.02 g, 4.91 mmol) in N,N-dimethylformamide (40 ml) under N2 was added potassium carbonate (1.36 g, 9.81 mmol) and the reaction was stirred for 1 h. 2-(Trimethylsilyl)ethoxymethyl chloride (1.31 ml, 7.36 mmol) was added slowly, and stirring maintained for 20 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was taken up in EtOAc (50 ml) and washed with water (3×50 ml), then brine (50 ml) before being dried (MgSO4) and concentrated. The crude material was purified by silica flash column chromatography, eluting with 50-100% EtOAc in heptane to afford the title compound (1.21 g, 54%) as a colourless gum: MS (ESI+) for C25H41N3O3Si m/z 461.0 [M+H]+; LC purity 97% (UV), 100% (ELS), (ret. time, 1.98 min); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.58-7.89 (m, 1H), 7.33 (s, 2H), 5.39-5.53 (m, 2H), 3.65 (s, 3H), 3.49-3.58 (m, 2H), 3.41 (br. s., 1H), 3.10-3.23 (m, 3H), 3.03 (s, 3H), 2.32-2.63 (m, 2H), 2.00-2.18 (m, 2H), 1.32-1.45 (m, 9H), 0.91 (td, J=8.1, 4.9 Hz, 2H), −0.13-0.07 (m, 9H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[CH2:36]([C:29]1[CH:30]=[C:31]([OH:35])[C:32]([F:34])=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]2[C:27]([C:19]([C:17]3[NH:16][C:13]4[CH2:14][CH2:15][N:10]([C:8]([C:5]5[CH:4]=[N:3][C:2]([N:38]6[CH2:43][CH2:42][O:41][CH2:40][CH2:39]6)=[CH:7][N:6]=5)=[O:9])[CH2:11][C:12]=4[N:18]=3)=[N:20][NH:21]2)=[CH:26][CH:25]=1)[CH3:37]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Reactant: C1COCCN1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5CCOCC5)cn3)C4)n[nH]c2c1
Yield: 48 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (100 mg, 154 μmol) and morpholine, (34 mg, 386 μmol) using the method of Example 32. The crude material was purified by HPLC Method F to afford (42 mg, 38%) of the title compound as off-white solid.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[CH3:11][O:12][C:13](=[O:34])[CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:34])[CH2:14][C:2]1[O:1][C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: O=C1Cc2ccccc2O1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc2ccccc2o1
Reaction time: 5 h

Procedure:
A solution of 2-coumaranone (5.0 g, 37 mmol) and methyl(triphenylphosphoranylideneacetate) (13.5 g, 40 mmol) in toluene (70 mL) was heated to reflux for 25 hours. More toluene was added (10 mL), and after a further 5 hours, more methyl(triphenylphosphoranylideneacetate) (0.5 g, 1.5 mmol). After another 19 hours, a further 1.0 g (3.0 mmol) was added, and after a further 21 hours, the solvent was removed in vacuo. Column chromatography (heptane:ethyl acetate 4:1) gave the product as a brown oil, 28 mmol, 75%.
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][CH:8]([Cl:13])[C:9]([F:12])([F:11])[F:10].[CH:14](=[O:19])[CH:15]=[C:16]([CH3:18])[CH3:17]>O1CCCC1>[Br:7][C:8]([Cl:13])([C:9]([F:12])([F:11])[F:10])[CH:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH3:17]
Reactant: FC(F)(F)C(Cl)Br
Reactant: CC(C)=CC=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CC(O)C(Cl)(Br)C(F)(F)F
Temperature: -60 °C
Yield: 73.8 %

Procedure:
Tetrahydrofuran (230 ml) and sodium t-butoxide (57.6 g; 40% w/v solution in dimethylformamide) was charged to a split-neck reaction flask, and cooled to -60° C. with stirring. 1-Bromo-1-chloro-2,2,2-trifluorethane (47.6 g) and senecialdehyde (20.9 g) were charged simultaneously over 25 minutes, then the mixture was stirred at -60° C. for a further 30 minutes. On completion of reaction, the mass was quenched by controlled addition of saturated ammonium chloride solution (120 ml). Hexane (500 ml) was added to the mixture, then the aqueous phase was separated and extracted with further hexane (2×500 ml). The combined organics were washed with brine (2×100 ml) and then water (3×20 ml). Drying (sodium sulphate) and concentration in vacuo then gave the product 5-bromo-5-chloro-4-hydroxy-2-methyl-6,6,6-trifluorohex-2-ene as a mobile yellow oil (50.1 g, 70% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18](=[O:19])[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[OH:20])[CH:5]=[CH:6][C:7]=1[Cl:8].O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18](=[O:19])[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[O:20][C:22](=[O:24])[CH3:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c2nccnc2c(O)c1-c1ccc(Cl)c(Cl)c1
Solvent: O
Product: CC(=O)Oc1c(-c2ccc(Cl)c(Cl)c2)c(=O)[nH]c2nccnc12
Reaction time: 16 h

Procedure:
Crude 7-(3,4-dichlorophenyl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (0.13 g) was heated in acetic anhydride (10 mL) for 3 hours and then allowed to cool and stored at ambient temperature for 16 hours. The reaction mixture was poured onto ice and water, stirred vigorously and extracted with ethyl acetate. The organic extract was washed with water and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:1) to give Compound B29 of Table B as a yellow solid (0.077 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=O)=[CH:5][NH:6]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:11])=[CH:5][NH:6]2
Reactant: O=Cc1c[nH]c2cccc(Br)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c[nH]c2cccc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a refluxing solution of 4-bromo-1H-indole-3-carbaldehyde (644 mg, 2.87 mmol) in dry THF (20 mL) was added LiAlH4 (218 mg, 5.75 mmol) in several small portions. Heating at reflux was continued for 1 h, the reaction cooled to RT and quenched with water (220 μL), 15% aq. NaOH (w/w, 220 μL), and water (650 μL). The resulting precipitate was filtered and the filtrate was concentrated under reduced pressure to dryness. To the residue was added aq. NaOH (10 mL) and the solution twice extracted with DCM (2×10 mL). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to afford 454 mg (75%) of 4-bromo-3-methyl-1H-indole (230) as light brown oil: MS (ESI) m/z=210.1 [M+1]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[CH3:12][C:13]([O:15][C:16]1[C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].O>N1C=CC=CC=1.C(OCC)(=O)C>[C:13]([O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:22]([NH:5][C:4]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:23])(=[O:14])[CH3:12]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: COc1ccc(OC)c(N)c1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(OC)c(NC(=O)c2ccccc2OC(C)=O)c1
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
2,5-Dimethoxyaniline (10.0 g, 65.3 mmol) was dissolved in pyridine (100 ml), and a solution of O-acetylsalicyloyl chloride (13.0 g, 65.3 mmol) in ethyl acetate (50 ml) was added thereto over 15 minutes under ice cooling. Thereafter, the mixture was stirred for 15 minutes at the same temperature as above. After adding water (10 ml) to the reaction mixture to stop the reaction, ethyl acetate (500 ml) was added and the reaction mixture was washed with 3 N hydrochloric acid (500 ml), water (500 ml), 2% sodium hydrogen carbonate solution (500 ml), and water (500 ml) in order. After drying it over Glauber's salt, the ethyl acetate layer was concentrated under reduced pressure and dried under vacuum to obtain the titled compound (19.8 g) as pale yellow syrup. The compound was used in the subsequent step without purification. The titled compound purified by preparative thin layer chromatography had the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO.O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:15]([S:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[C:3]([O:2][CH3:1])=[O:22])[C:8]([OH:10])=[O:9])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(SCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(=O)O)cc1SCc1ccccc1

Procedure:
50G of benzylmercapto terephthalic acid dimethyl ester is suspended in a solution of 750 ml of methanol to which is added 200 ml of a solution of 15 g of sodium carbonate monohydrate in 350 ml of water. The reaction mixture is refluxed for 30 minutes, cooled and diluted with 750 ml of water. The solid is filtered and resuspended in 375 ml of methanol and 100 ml of the above sodium carbonate solution, refluxed 30 minutes, cooled, 375 ml of water is added thereto, filtered and the damp cake resuspended in 187 ml of methanol. The remaining 50 ml of the sodium carbonate solution is then added and the reflux process repeated. The combined aqueous filtrates are acidified with 50 ml of conentrated hydrochloric acid yielding a precipitate which is filtered, washed with water and the damp cake is dissolved in ethyl acetate. The ethyl acetate solution is washed with water, dried over sodium sulfate and evaporated to yield 46 g of crude 3-benzylmercapto-4-carbomethoxy benzoic acid, which is used without further purification in part D.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N+:38]([O-:40])=[O:39]>CN(C=O)C>[N+:38]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1)([O-:40])=[O:39]
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccccc1CBr
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccccc2[N+](=O)[O-])c1
Reaction time: 14 h
Yield: 32.9 %

Procedure:
A solution of [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (0.15 g, 0.38 mmol), 1-Bromomethyl-2-nitro-benzene (0.10 g, 0.46 mmol) and CsCO3 (0.25 g, 0.76 mmol) in DMF (3 ml) was heated to 60° C. After 14 hr, the reaction was cooled, filtered and concentrated. The crude residue was purified by reverse phase HPLC to provide the desired compound (0.066 g, Yield=33%); MS (ESI) m/z 529;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=1.[CH:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].[F-].[K+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[C:8]([C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([CH:16]=[O:17])=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC(=O)c1cccc(Br)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCCC(=O)c1cccc(-c2ccc(C=O)cc2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To a solution of 1-bromo-3-heptanoyl benzene (0.30 g, 1.11 mmol, from Step A), 4-formylphenylboronic acid (0.25 g, 1.68 mmol) and potassium fluoride (0.20 g, 3.36 mmol) in tetrahydrofuran (2.5 mL) was added palladium(II) acetate (0.006 g, 0.025 mmol) and 2-(dicyclohexylphosphino)biphenyl (0.016 g, 0.050 mmol). After stirring for 3 h at 50° C., the reaction was placed onto silica gel and eluted with 10% ethyl acetate/hexanes to give 0.26 g (0.88 mmol, 80%) of product as a yellow oil: 1H NMR (500 MHz) δ 8.22 (t, J=1.7 Hz, 1H), 7.90-8.10 (m, 3H), 8.30 (d, J=8.0 Hz, 1H), 7.99 (d, J=8.3 Hz, 2H), 7.58 (t, J=7.8 Hz, 1H), 3.02 (t, J=7.4 Hz, 2H), 1.66-1.80 (m, 2H), 1.38-1.44 (m, 2H), 1.30-1.38 (m, 4H), 0.90 (t, J=7.0 Hz, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[C:16]1([C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=[CH:25][CH:26]=[O:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[OH:27][CH:26](/[CH:25]=[CH:24]/[CH:23]=[C:22]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH3:10])=[O:8]
Reactant: O=CC=CC=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/C=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
A 60% dispersion of sodium hydride (0.095 g of dispersion, 0.057 g of NaH, 2.4 mmol) was triturated with anhydrous THF (3×20 ml). The pure sodium hydride was then suspended in anhydrous THF (10 ml) and cooled to 0° C. Methyl acetoacetate (0.227 g, 1.95 mmol) was added dropwise. After stirring the resulting colorless solution for 10 minutes at 0° C., butyllithium in hexanes (0.96 ml, 2.5M, 2.4 mmol) was added dropwise via syringe. After stirring the reaction mixture for another 10 minutes at 0° C., a solution of 5,5-diphenyl-2,4-pentadienal (0.410 g, 1.75 mmol) in anhydrous tetrahydrofuran (10 ml) was added slowly via syringe. After completion of the addition, the reaction was stirred for 10 minutes at 0° C. The reaction mixture was then quenched by pouring it into saturated aqueous ammonium chloride. After stirring vigorously for 5 minutes, the phases were separated and the aqueous phase was extracted with ether (3×25 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (40 ml) and water (2×40 ml), dried over magnesium sulfate and concentrated in vacuo to give 0.610 g (98% yield) of methyl (E)-5-hydroxy-9,9-diphenyl-3-oxo-6,8-nonadienoate as a viscous liquid. Since this material was quite pure and unstable on silica gel, it was carried onto the next step without purification.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([C:25]2[CH:32]=[CH:31][C:28]([CH2:29][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=Cc1ccc(N2CCCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(N5CCCC5)cc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-pyrrolidin-1-ylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Phenomenex Luna C18 100A, 10 m silica, 21 mm diameter, 150 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-pyrrolidin-1-ylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[H][H]>[Pt].[Pt]=O.C(OC(=O)C)C.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: Brc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: O=[Pt]
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc2[nH]cc(C3CCNCC3)c2c1
Reaction time: 18 h
Yield: 75.5 %

Procedure:
To a solution of 13.61 gm (49 mmol) 5-bromo 3-[1,2,3,6-tetrahydro-4-pyridinyl]-1H-indole in 75 ml 2:1 tetrahydro-furan ethyl acetate were added 8.0 gm 3% sulfided platinum on carbon and 4.0 gm platinum oxide. The reaction mixture was hydrogenated with an initial hydrogen pressure of 60 p.s.i. at 40° C. for 18 hours and then at ambient temperature for 30 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give 10.33 gm (75.6%) of the title compound as a light yellow solid.