Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Li]CCCC.[Br:14][C:15]1[CH:28]=[CH:27][C:18](/[CH:19]=[N:20]/[S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])=[CH:17][CH:16]=1>C1COCC1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C@H:19]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)[NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])=[CH:27][CH:28]=1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ccc(Br)cc1
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The solution of 1-bromo-4-fluorobenzene (66.7 g, 0.38 mol) in THF (400 mL) was cooled to −78° C. Then n-BuLi (140 mL, 0.38 mol) was dropwise added at −78° C. and maintained at this temperature for about 1 h. (S,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide, 19-a, (70 g, 0.19 mol) in anhydrous THF (100 ml) was also dropwise added at −78° C. The mixture was stirred at −78° C. for 1 h, warmed to rt for 2 h, and then quenched by NH4Cl aq. The organic phase was dried and purified by column chromatography (PE:EA=10:1) afford the product 19-b as a light yellow solid, recrystallized by PE:EA=20:1 to give the white solid, (26 g, 35%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.C(N(CC)CC)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH:45]=O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH:45]=[C:21]([Br:24])[Br:20])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Temperature: 20 °C
Yield: 75.1 %

Procedure:
A solution of 160.86 g (613.3 mmol) of triphenylphosphine in 600 ml CH2Cl2 was treated with 101.7 g (306.6 mmol) of tetrabromomethane (the reaction heated up to 32° C.) and after 50 min at 20° C., 97.8 ml (705.3 mmol) of triethylamine was added (the reaction heated up to 35° C. and the color became dark violet). After cooling (0° C.), 32.7 g (153.4 mmol) of 4-Formyl-piperidine-1-carboxylic acid tert-butyl ester in 380 ml CH2Cl2 were added slowly (20 min). The solution was stirred over night at RT, evaporated and filtered through silica gel (deactivated with hexane/Et3N; with hexane and then hexane/ether 4:1 to 1:1) to give 42.54 g (75%) of 4-(2,2-dibromo-vinyl)-piperidine-1-carboxylic acid tert-butyl ester, mp: 82.3-83.9° C., MS: 368 (MH+, 2Br).
Reaction SMILES: [C:1](O[CH2:7][CH:8]1[O:10][CH2:9]1)(=O)[C:2](C)=[CH2:3].C[O:12]C1C=[CH:17][C:16]([OH:19])=[CH:15]C=1.[OH:20][CH:21]([CH3:31])[CH2:22][NH:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([OH:30])[CH3:29]>CO>[CH3:29][CH:28]([OH:30])[CH2:27][N:26]([CH2:9][CH:8]([OH:10])[CH3:7])[CH2:25][CH2:24][N:23]([CH2:17][CH:16]([OH:19])[CH3:15])[CH2:22][CH:21]([OH:20])[CH3:31].[CH3:1][C:2]([CH3:3])=[CH:29][C:28]([O-:30])=[O:12]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: COc1ccc(O)cc1
Reactant: CC(O)CNCCNCC(C)O
Solvent: CO
Product: CC(C)=CC(=O)[O-]
Product: CC(O)CN(CCN(CC(C)O)CC(C)O)CC(C)O
Temperature: 30 °C
Yield: 48 %

Procedure:
Glycidyl methacrylate (4.8g, 34 mmol) and 4-methoxyphenol (0.13 g) were added to a solution of N,N'-bis-(2-hydroxypropyl)ethylenediamine (IV-a) (3.0 g, 17 mmol) in 80 mL of methanol at 0° C. The mixture was brought to room temperature and maintained for eight days, followed by heating for 24 hours at 30° C. A quantitative yield of a viscous, slightly brown liquid was obtained after removal of the solvent. The product was further purified by dissolving the liquid in water followed by the addition of sodium chloride to saturation. The oil layer was separated, dissol ved in CH2Cl2 and dried over magnesium sulfate. Filtration and removal of solvent yielded Quadrol dimethylacrylate (VII-a) [yield 48 percent: IR(neet):3350(broad OH); 1700 (C=O); 1620(C=C); NMR (CDCl3): δ6.1(s,2H); 5.6(s,2H); 3.8(broad m,8H); 2.6(broad m,12); 2.0(s,6H); 1.1(d,6H)].
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[CH3:20][O:21][CH2:22]C(Cl)=O.[CH2:26]([N:28]1[C:40]2[CH:39]=[CH:38][C:37]([NH2:41])=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:27]>>[CH2:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[CH2:22][O:21][CH3:20])[C@H:9]([C:17]([NH:41][C:37]2[CH:38]=[CH:39][C:40]3[N:28]([CH2:26][CH3:27])[C:29]4[C:34]([C:35]=3[CH:36]=2)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:19])[CH2:10]1)[CH3:16]
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COCC(=O)Cl
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)COC)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, methoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 88% purity by LC/MS. MS(ESI+): m/z=437.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:19])[NH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O.Cl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:19])[N:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CI
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)ccc(NC(=O)OCc2ccccc2)c1=O
Reaction time: 0.75 h
Yield: 55.5 %

Procedure:
The compound of Example 13 (1.80 g, 7.0 mmole) was added to a stirred suspension of sodium hydride (0.33 g, 8.4 mmole) in dry dimethylformamide (50 mL). After 45 minutes, ethyl iodoacetate (1.43 g, 6.7 mmole) was added, and the mixture was stirred overnight, diluted with 10% hydrochloric acid (300 mL) and extracted with ethyl acetate (3×150 mL). The organic layer was washed with brine (twice), dried and evaporated. The resulting yellow, waxy solid was chromatographed, eluting with 3% ethyl acetate in dichloromethane, to give the title compound (1.28 g, 53% yield). Rf =0.52 (silica gel, 5:95 methanol:dichloromethane). Fast atom bombardment mass spectrometry confirmed the theoretical molecular weight of 344.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[Cl:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][N:29]=[C:30]=[O:31]>ClCCl>[C:28]1([NH:29][C:30]([N:12]2[CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[Cl:27])=[CH:16][CH:15]=3)[CH2:8][CH:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:31])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCNC(c4ccccc4)C3)cc2)c1
Reactant: CN=C=O
Solvent: ClCCl
Product: Cc1ccc(Cl)c(-c2ccc(CN3CCN(C(=O)Nc4ccccc4)C(c4ccccc4)C3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
55 mg of 3-phenyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine were dissolved in dichloromethane, 2 equiv. methylisocyanate were added. The reaction was shaken at room temperature overnight. The reaction was concentrated in vacuo. The residue was diluted with DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as free base. Addition of 1 equiv. of 1M HCl in dioxane and concentratation in vacuo afforded the title compound as hydrochloride salt. Yield 33%, ES MS m/z 496.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([OH:5])[CH3:4].[F:6][C:7]([F:26])([F:25])[C:8]1[CH:24]=[CH:23][C:11]2[S:12][C:13]3[CH:20]=[CH:19][CH:18]=C(C#N)[C:14]=3[CH2:15][CH2:16][C:10]=2[CH:9]=1.[OH-].[Na+]>O.CCOCC>[F:6][C:7]([F:26])([F:25])[C:8]1[CH:24]=[CH:23][C:11]2[S:12][C:13]3[CH:20]=[CH:19][CH:18]=[C:4]([C:3]([OH:1])=[O:5])[C:14]=3[CH2:15][CH2:16][C:10]=2[CH:9]=1
Reactant: [OH-]
Reactant: CCO
Reactant: N#Cc1cccc2c1CCc1cc(C(F)(F)F)ccc1S2
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1cccc2c1CCc1cc(C(F)(F)F)ccc1S2

Procedure:
To 1g of potassium hydroxide dissolved in 1ml of water and 4ml of ethanol was added 106mg of 2-trifluoromethyl-9-cyano-10,11-dihydrodibenzo[b,f]thiepin and the resulting mixture was refluxed for 24 hrs. After cooling, to this was added 4% sodium hydroxide solution and ether. After shaking, the aqueous layer was separated, acidified by adding conc. hydrochloric acid and extracted with chloroform. Extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 87 mg (77.3% of yield) of the desired product as colorless powder. This was recrystallized from the mixed solvent of benzene and n-hexane to afford 2-trifluoromethyl-10,11-dihydrodibenzo[b,f]thiepin-9-carboxylic acid having a melting point of 178.5° to 179.5° C as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH2:21].[CH3:22][N:23]([CH:25]=[O:26])C>>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:23]2[CH2:22][CH2:6][CH:5]([CH2:4][C:3]([O:10][CH2:11][CH3:12])=[O:21])[C:25]2=[O:26])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: O
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1F
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC1CCN(c2ccc(OCc3ccccc3)cc2[N+](=O)[O-])C1=O
Temperature: 0 °C

Procedure:
Ethyl 2-(2-oxopyn-olidin-3-yl)acetate (1.77 g, 10.34 mmol) was dissolved in DMF (20 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil, 0.414 g, 10.34 mmol) was added. After stirring for several min, the reaction was allowed to warm to room temperature and stirred for 10 min. 4-(Benzyloxy)-1-fluoro-2-nitrobenzene (2.56 g, 10.34 mmol) was added and the mixture was stirred at room temperature for 21 h. The reaction was poured into water and acidified to pH 5 with 1.0 M HCL. The aqueous mixture was extracted three times with EtOAc and the combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide the title compound (1.09 g). LCMS m/z=399.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (t, J=7.2 Hz, 3H), 1.97-2.01 (m, 1H), 2.46-2.59 (m, 2H), 2.95 (dd, J=12.9, 3.8 Hz, 1H), 2.96-3.06 (m, 1H), 3.69-3.76 (m, 1H), 3.79-3.88 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 5.13 (s, 2H), 6.90 (d, J=2.5 Hz, 1H), 6.94 (dd, J=9.0, 2.7 Hz, 1H), 7.37-7.42 (m, 5H), 8.04 (d, J=9.1 Hz, 1H).
Reaction SMILES: [BrH:1].[CH:2]([C:4]([CH3:6])=[O:5])=[CH2:3].[CH2:7]([OH:10])[CH2:8]O>>[Br:1][CH2:3][CH2:2][C:4]1([CH3:6])[O:10][CH2:7][CH2:8][O:5]1
Reactant: OCCO
Reactant: Br
Reactant: C=CC(C)=O
Product: CC1(CCBr)OCCO1
Temperature: 25 °C

Procedure:
To a cold HBr saturated solution of ethylene glycol (210 mL) was added dropwise 118 mL of methyl vinyl ketone. The solution was allowed to warm to RT and the reaction mixture was extracted four times with pentane. The pentane layers were combined, washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated on a rotary evaporator to yield a yellow oil which was vacuum distilled to 67 g of a clear oil, bp 55°-60° C., which was the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]([C@H:21]1[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]1)[C:8](=[O:20])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1.[H][H]>CO.[C].[Pd]>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]([C@H:21]1[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]1)[C:8](=[O:20])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1
Reactant: COc1cc(C=CC(=O)N(CCCCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N(CCCCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1O

Procedure:
0.05 g of 10% palladium-carbon was added to a solution of 1 g of N-(4-dimethylaminobutyl)-N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 75) in 60 ml of methanol. Under normal-pressure hydrogen gas, the solution was reacted for 16 hours, while it was vigorously stirred. After reaction, the catalyst was filtered out, and the solvent was removed in vacuo from the filtrate, yielding 0.92 g of N-(4-dimethylaminobutyl)-N-(trans-4-methylcyclohexyl)-3-(4-hydroxy-3-methoxyphenyl)propionamide (a compound of the present invention) as a pale yellow oily oil, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:50][N:51]([CH3:56])[S:52](Cl)(=[O:54])=[O:53].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]1([NH:28][C:11]2[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][S:52](=[O:54])(=[O:53])[N:51]([CH3:56])[CH3:50])[CH2:3][CH2:4]3)[CH:10]=2)[CH2:40][CH2:39]1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 8B (30 mg, 0.055 mmol) in CH2Cl2 (1 mL) was added DIEA (0.0062 mL, 0.035 mmol) and dimethylsulfamoyl chloride (1.5 mg, 10.45 μmol). The reaction mixture was stirred at room temperature for 2 hrs, concentrated, re-dissolved in TFA (0.849 mL, 11.02 mmol) and heated at 70° C. for 1 hr. The reaction mixture was concentrated and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate the title compound, 8-(cyclopropylamino)-6-((trans-4-((dimethylsulfamoyl)amino)cyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)imidazo[1,2-b]pyridazine-3-carboxamide, as a white solid (13.0 mg, 44.4%). LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.61 (M+H=532.26). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.39 (1H, s), 8.71 (1H, d, J=2.52 Hz), 8.49 (1H, t, J=6.17 Hz), 8.43 (1H, d, J=5.29 Hz), 8.00 (1H, s), 7.61 (1H, s), 7.28 (1H, d, J=8.06 Hz), 6.92 (1H, d, J=8.31 Hz), 5.98 (1H, s), 3.78 (1H, br. s.), 3.00 (2H, br. s.), 2.58-2.73 (6H, m), 2.01 (2H, br. s.), 1.90 (2H, br. s.), 1.26 (4H, d, J=13.09 Hz), 0.68-0.85 (2H, m), 0.51-0.69 (2H, m).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.[CH3:13][N:14]([CH3:16])[CH3:15]>C1COCC1>[Br-:1].[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N+:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: BrCCCCCCCCCCBr
Reactant: CN(C)C
Solvent: C1CCOC1
Product: C[N+](C)(C)CCCCCCCCCCBr
Product: [Br-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1,10-Dibromodecane (20 grams, 66.7 mmoles) and THF (100 milliliters) were placed in a 500-mL, three-necked flask. The solution was cooled to 0° C. with an ice-water bath. Anhydrous trimethylamine (3 grams, 50.8 mmoles) was added to the mixture by slowly bubbling trimethylamine gas for about 15 minutes. Then the reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The solid material was filtered and washed with THF (5×30 milliliters). After drying in vacuo overnight, 12.5 grams (34.82 mmoles, 69% based on the amine used) of the product was obtained as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10]Cl)=[CH:3][CH:2]=1.[C:12]1([C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[K+]>C(#N)C>[C:12]1([C:18]2[CH2:23][CH2:22][N:21]([CH2:10][CH2:9][CH2:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCCCCc1ccncc1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: C1=C(c2ccccc2)CCN(CCCCc2ccncc2)C1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A mixture of 4-(4-pyridinyl)-1-butylchloride (Example A) (0.76 g, 4.47 mmol), 1,2,3,6-tetrahydro-4-phenylpyridine (0.796 g, 5.0 mmol), and potassium bicarbonate (1.0 g, 10 mmol) in 5 mL of acetonitrile are heated to reflux for 8 hours. The reaction is cooled to room temperature and the acetonitrile removed in vacuo. The residue is partitioned between 50 mL of water and 50 mL of chloroform. The aqueous layer is extracted again with 50 mL of chloroform and the combined organic extracts are dried over sodium sulfate and the solvent removed in vacuo. The resulting residue is chromatographed on silica gel (2% to 3% methanol, 0.1% ammonia, chloroform) to obtain 1.10 g of 4-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-butyl]pyridine as a white solid; mp 89°-90° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][NH:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[N:18]=2)[C:13](=[O:21])[C:12]([C:22]([OH:24])=[O:23])=[CH:11]1>C(O)C>[ClH:20].[CH3:8][NH:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[N:18]=2)[C:13](=[O:21])[C:12]([C:22]([OH:24])=[O:23])=[CH:11]1
Reactant: CN1CCNCC1
Reactant: CNn1cc(C(=O)O)c(=O)c2ccc(Cl)nc21
Solvent: CCO
Product: CNn1cc(C(=O)O)c(=O)c2ccc(N3CCN(C)CC3)nc21
Product: Cl
Yield: 87.8 %

Procedure:
3 g of 1-methylpiperazine are added dropwise to a suspension of 2.53 g of 1-methylamino-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid in 30 ml of ethanol, with stirring, the acid dissolving in a slightly exothermic reaction. The mixture is heated at the boiling point for 1 hour, the ethanol is distilled off and the reactin product is dissolved in 1N sodium hydroxide solution. The filtered solution is brought to pH 6 with 10% strength hydrochloric acid. The precipitate is filtered off in the cold, washed with a little cold water and ethanol and dried in vacuo at 80° C. 3.1 g of 1-methylamino-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride of decomposition point 328° C. are obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[C:20](Cl)=[O:21])([O-:16])=[O:15].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:20](=[O:21])[C:19]1[CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=1
Reactant: OCCCCCCCCCCCBr
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCCCCCCCCCCCBr)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 89.5 %

Procedure:
11.4 g (45.4 mmol) 11-bromo-1-undecanol, 11.0 g (47.7 mmol) 3,5-dinitrobenzoyl chloride and 54 mg 4-dimethylaminopyridine were dissolved in 94 ml dichloromethane. The solution was subsequently cooled to 0° C. and then 18.3 ml is (227 mmol) pyridine was added dropwise, in the course of 25 minutes. After 4.5 hours at 0° C. the reaction mixture was partitioned between dichloromethane and water. The organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 200 g silica gel using toluene yielded 18.1 g (90%) 3,5-dinitrobenzoic acid 11-bromoundecyl ester as yellow powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([CH3:36])=[CH:30]2.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([CH3:36])=[CH:30]2)#[N:13]
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2cc(Oc3ccnc4cc(OCCCN5CCS(=O)(=O)CC5)c(C#N)cc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.5 %

Procedure:
A suspension of 4-chloro-6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (100 mg, 0.26 mmol), (prepared as described for the starting material in Example 1), 5-hydroxy-2-methylindole (46 mg, 0.32 mmol) and cesium carbonate (129 mg, 0.39 mmol) in DMF (1 ml) was stirred for 10 minutes at ambient temperature followed by 1.5 hours at 70° C. After cooling, water (5 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methanol/methylene chloride/ethyl acetate (5/45/50) to give 6cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(2-methylindol-5-yloxy)quinoline (30 mg, 23%).
Reaction SMILES: Cl.[NH2:2][OH:3].O.[OH-].[Na+].[NH2:7][C:8]1[CH:13]=[C:12]([C:14](=O)[CH3:15])[CH:11]=[CH:10][N:9]=1>CO>[NH2:7][C:8]1[CH:13]=[C:12]([C:14](=[N:2][OH:3])[CH3:15])[CH:11]=[CH:10][N:9]=1
Reactant: CC(=O)c1ccnc(N)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NO)c1ccnc(N)c1
Temperature: 0 °C

Procedure:
To a solution of 3.1 g. (45 mmoles) of hydroxylamine hydrochloride in 10 ml. of water was added 22.5 ml. of 2 N sodium hyroxide solution. To this solution was added 3.6 g. (26 mmoles) of 1-(2-amino-4-pyridyl)-1-ethanone and the mixture heated to the boiling point for 5 minutes. Methanol was added slowly until the mixture became homogeneous. Heating was continued until a precipitate began to form. The mixture was cooled to 0° C., and the resulting precipitate was filtered, washed with water and dried in vacuo. Recrystallization from ethyl acetate afforded 3.6 g. (92%) of the desired oxime, m.p. 215°-217° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[CH:13]1([CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[Cl-:1].[CH:13]1([CH2:19][N+:20]2[CH:24]=[CH:23][N:22]([CH2:11][CH2:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:21]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: c1cn(CC2CCCCC2)cn1
Reactant: ClCCCCc1ccc(Cl)cc1
Product: Clc1ccc(CCCCn2cc[n+](CC3CCCCC3)c2)cc1
Product: [Cl-]
Temperature: 130 °C

Procedure:
Add 6.55 g (0.03 mole) of 1-chloro-4-(4-chlorobutyl)benzene to 4.81 g (0.293 mole) of 1-cyclohexylmethyl-1H-imidazole and heat at 130° C. for 18 hours.