Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]#[C:31][CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:13])[C:14]1[CH:15]=[C:16]([C:30]#[C:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20]
Reactant: CCN(c1cc(C#CC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN(c1cc(C#CC2CCNCC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)ethynyl)piperidine-1-carboxylate (250 mg, 0.413 mmol) in DCM (3 mL) was added 4M HCl in 1,4-dioxane (3 mL, 12.0 mmol) at 20° C. The mixture was stirred at 20° C. for 1 h. LCMS indicated that the reaction was completed. The reaction mixture was directly concentrated and the residue was dissolved in DCM and then neutralized with sat. NaHCO3/brine. The organic layer was dried (Na2SO4) and filtered. And the filtrate was concentrated. The residue was used for alkylation without further purification (209 mg, 100%). 1H-NMR (500 MHz, CD3OD) δ ppm 7.21 (brs, 1H), 7.07 (brs, 1H), 6.11 (s, 1H), 4.46 (s, 2H), 3.95-3.89 (m, 2H), 3.39-3.34 (m, 2H), 3.08 (q, J=7.0 Hz, 2H), 3.06-2.98 (m, 3H), 2.79-2.72 (m, 1H), 2.72-2.65 (m, 2H), 2.38 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 1.94-1.88 (m, 2H), 1.73-1.68 (m, 2H), 1.68-1.56 (m, 4H), 0.85 (t, J=7.0 Hz, 3H); MS (ESI) [M+H]+505.5.
Reaction SMILES: [I-:1].F[C:3]1[CH:12]=[CH:11][C:10]2[N+:9]3[CH:13]=[C:14]4[CH:23]=[CH:22][C:21]5[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=5[N:15]4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN1CCCC1=O>[I-:1].[N:25]1([C:3]2[CH:12]=[CH:11][C:10]3[N+:9]4[CH:13]=[C:14]5[CH:23]=[CH:22][C:21]6[CH:20]=[C:19]([N:25]7[CH2:29][CH2:28][CH2:27][CH2:26]7)[CH:18]=[CH:17][C:16]=6[N:15]5[C:8]=4[CH:7]=[CH:6][C:5]=3[CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Fc1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Reactant: C1CCNC1
Agent: [I-]
Solvent: CN1CCCC1=O
Product: c1cc2c(ccc3c[n+]4c5ccc(N6CCCC6)cc5ccc4n32)cc1N1CCCC1
Reaction time: 1 h

Procedure:
A mixture of 4.41 g. of 3,10-difluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 9.0 ml. of pyrrolidine and 130 ml. of N-methyl-2-pyrrolidinone is stirred and heated at 130°-160° C. for 4.5 hours, then cooled. The resulting precipitate is collected, washed with methanol and stirred with 100 ml. of 2% aqueous triethylamine hydroiodide for 1 hour. The resulting precipitate of 3,10-di-(1-pyrrolidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, washed with water and dried; m.p. 345° C. (dec.), after crystallization from dimethylformamide/-2-propanol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[C:17]([CH:18]=1)[O:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
Methyl 2-hydroxybenzoate (2.75 mL, 21.3 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (1.85 g, 10.6 mmol) were dissolved in acetonitrile (25.0 mL). The cesium carbonate (6.94 g, 21.3 mmol) was added and the reaction mixture was stirred at 80° C. for 24 hours. The mixture was cooled down to room temperature then poor into ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (10-30% ethyl acetate in hexanes) to afford title compound 419 (2.55 g, 78%). MS (m/z): 308.2 (M+H). 1H NMR (DMSO-d6) δ (ppm): 8.14 (d, J=8.8 Hz, 1H), 7.98 (dd, J=7.8, 1.6 Hz, 1H), 7.74 (ddd, J=8.1, 7.4, 1.8 Hz, 1H), 7.47 (td, J=7.6, 1.2 Hz, 1H), 7.39 (dd, J=8.8, 2.2 Hz, 1H), 7.36 (dd, J=8.3, 1.1 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H), 3.69 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[C:21](=O)[CH3:22])=[CH:15][CH:14]=1.C1(C)C=CC(S([NH:39][NH2:40])(=O)=O)=CC=1>C(O)(=O)C>[CH3:22][C:21]1[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:14][CH:15]=2)[NH:40][N:39]=1
Reactant: CC(=O)C(=Cc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CC(=O)O
Product: Cc1n[nH]c(-c2ccc(OCc3ccc4ccccc4n3)cc2)c1-c1ccncc1

Procedure:
A mixture of 4-(4-((quinolin-2-yl)methoxy)phenyl)-3-(pyridin-4-yl)but-3-en-2-one (1.00 g, 2.60 mmol) and p-toluensulfonylhydrazine (484 mg, 2.6 mmol) in acetic acid (14 mL) was heated at reflux for 10 h. Additional p-toluenesulfonylhydrazine (242 mg, 0.5 mmol) was added and the mixture heated at reflux 2 h. The mixture was concentrated, the residue dissolved in dichloromethane and the resulting solution washed with water (2×25 mL), dried and concentrated. The residue was chromatographed on silica eluted with 1%, 2%, and 3% methanol in dichloromethane containing 0.5% concentrated ammonium hydroxide giving a solid which was triturated with ether and dried. Yield 293 mg, 29%. 1H NMR (CDCl3, 400 mHz) δ 8.51 (m, 2H), 8.18 (d, 1H, J=8.7 Hz), 8.06 (d, 1H, J=7.9 Hz), 7.81 (d, 1H, J=8.3 Hz), 7.72 (m, 1H), 7.64 (d, 1H, J=8.3 Hz), 7.54 (m, 1H), 7.24 (m, 2H), 7.13 (m, 2H), 6.96 (m, 2H), 5.36 (s, 2H), 2.33 (s, 3H). HPLC-MS (system 1) 4.65 min, m/e 393 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:17]([CH:18]=[CH:19][C:20](=[O:27])[CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH2:15][C:10]21OCC[O:11]2.Cl>>[CH3:26][CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[C:20](=[O:27])[CH:19]=[CH:18][CH:17]1[CH2:16][CH2:15][C:10](=[O:11])[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: CCCCC(C)C(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Agent: Cl
Product: CCCCC(C)C(=O)C=CC1CCC(=O)C1CCCCCCCO
Temperature: 60 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A mixture of 6-(7-hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane (1.0 g.) and hydrochloric acid (25 ml; 1 N) was stirred at 60° C. for 2 hours, cooled to ambient temperature and extracted with diethyl ether. The ether extract was washed with 2 N aqueous sodium carbonate solution and water respectively, then dried over magnesium sulphate. Removal of the solvent under reduced pressure gave a crude product (0.7 g.) which was purified by preparative thin layer chromatography on silica gel, using a mixture of diethyl ether, ethyl acetate and hexane (2:1:1 v/v) as eluant, to give 7-[2-(4-methyl-3-oxooct-1-enyl)-5-oxocyclopentyl]heptanol (0.38 g.), νmax (liquid film) 3450 cm-1, 1730 cm-1, 1690 cm-1, 1660 cm-1, 1380 cm-1, 995 cm-1 ; λmax. (ethanol) 230 nm (ε=13,600); Elemental analysis: Found: C, 74.9; H 11.0%; C21H36O3 requires C, 74.95; H, 10.8%; N.M.R. (approximately 10% solution in deuterochloroform): Triplets at 3.57 δ (J=6 cycles/sec.) and 0.88 δ, doublet of doublets at 6.81 δ (J=15.5 cycles/sec. and J=7 cycles/sec.), doublets at 6.20 δ (J=15.5 cycles/sec.) and 1.11 δ (J=7 cycles/sec.), broad singlet 2.0 δ.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>C(Cl)(Cl)Cl>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:5][NH:4][C:3]([NH:2][CH3:1])=[S:6])=[O:11]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CNC(=S)NN
Solvent: ClC(Cl)Cl
Product: CNC(=S)NNC(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred room temperature suspension of 4-methylthiosemicarbazide (7.9 g, 7.5×10-2 mole) and CHCl3 (190 ml), 2-fluorobenzoyl chloride (9.4 ml, 7.9×10-2 mole) was added dropwise. After stirring overnight at room temperature, the precipitate was collected by filtration and the product was washed with two portions of Et2O. Drying by suction gave a colorless powder which was used without further purification in the subsequent cyclization step.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[N+:9]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH:14]=[CH:15][CH2:16][OH:17])([O-:11])=[O:10].N1C=CN=C1>CN(C=O)C>[Si:5]([O:17][CH:16]=[CH:15][CH2:14][C:13]1[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=1[N+:9]([O-:11])=[O:10])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: O=[N+]([O-])c1ccccc1C=CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC=CCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Tert-butyldimethylchlorosilane (5.10 g, 33.8 mmol) was added to a solution of 2-nitrocinnamyl alcohol (5.05 g, 28.2 mmol) and imidazole (2.88 g, 42.3 mmol) in DMF (100 ml). After stirring at room temperature for 18 hours the reaction mixture was partitioned between water (200 ml) and ethyl acetate (200 ml). The organic layer was separated washed with brine (2×m 100 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by flash chromatography on silica gel with ethyl acetate-hexane (1:3) as eluant. (7.82 g, 95%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[N:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([NH2:24])(=[O:23])=[O:22])[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:6]=2[CH2:5][CH2:4][N:3]1[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]2=[O:37])=[CH:27][CH:26]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:8]1[C:7]2[C:2](=[O:1])[N:3]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]4=[O:37])=[CH:27][CH:26]=3)[CH2:4][CH2:5][C:6]=2[C:10]([C:11]([F:12])([F:14])[F:13])=[N:9]1)(=[O:22])=[O:23])(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1ccccc1-n1nc(C(F)(F)F)c2c1C(=O)N(c1ccc(-n3ccccc3=O)cc1)CC2
Product: CC(=O)NS(=O)(=O)c1ccccc1-n1nc(C(F)(F)F)c2c1C(=O)N(c1ccc(-n3ccccc3=O)cc1)CC2

Procedure:
The sulfonamide of Example 121 was acetylated with acetic anhydride to afford the title compound. MS (ES+): 572.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=[O:8])[CH2:5][C@@H:4]([CH3:9])[C:3]1=[O:10].[CH3:12][C:13]([CH3:18])([CH2:16]O)[CH2:14][OH:15].C1C=CC=CC=1>O>[CH3:12][C:13]1([CH3:18])[CH2:14][O:15][C:6]2([CH2:5][C@@H:4]([CH3:9])[C:3](=[O:10])[C:2]([CH3:1])([CH3:11])[CH2:7]2)[O:8][CH2:16]1
Reactant: CC(C)(CO)CO
Reactant: C[C@@H]1CC(=O)CC(C)(C)C1=O
Solvent: c1ccccc1
Solvent: O
Product: C[C@@H]1CC2(CC(C)(C)C1=O)OCC(C)(C)CO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
A mixture of (-)-(6R)-2,2,6-trimethyl-1,4-cyclohexandione (924 mg, 6.0 mmol), 2,2-dimethyl-1,3-propandiol (791 mg, 7.6 mmol), pyridinium p-tosylate (34 mg, 0.13 mmol), and benzene (15 mL) was heated to reflux under a Dean-Stark water separator for 4 h. The reaction mixture was allowed to cool to room temperature before it was washed with H2O, and dried over anhydrous Na2SO4. Evaporation of solvent gave a pale yellow oil (1.43 g) as the crude product, which was distilled using the Kugel-rohr apparatus (80°-100° C., 0.03 mm Hg) to give pure ketal as a colorless oil (1.31 g, 91%), [a]D -87.7° C. (c 1.10, CH3OH); ir: 1710 cm-1; 1H nmr d: 0.85 (s, 3H, CH3), 0.91 (d, J=6.6 Hz, 3H, CHCH3), 0.97 (s, 6H, 2 CH3), 1.16 (s, 3H, CH3), 1.56 (dd, J=13.5, 13.5 Hz, H-11ax), 1.58 (d, J=14.2 Hz, H-7ax), 2.38 (ddd, J=13.5, 5.3, 3.8 Hz, 1H, H-11eq), 2.47 (dd, J=14.2, 3.8 Hz, 1H, H-7eq), 2.85 (m, 1H, CHCH3), 3.41 and 3.48 (2dd, J=11.4, 1.6 Hz, 2H, 2 equatorial H at C2 and C4), 3.53 and 3.61 (2d, J=11.4 Hz, 2H, 2 axial H at C2 and C4); ms m/e: 240 (M+, 0.58), 141 (27), 155 (98), 83 (27), 69 (100).
Reaction SMILES: [F:1][C:2]([F:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](OCC)=[O:4].[NH3:15]>CCO>[F:1][C:2]([F:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([NH2:15])=[O:4]
Reactant: CCOC(=O)C(F)(F)c1ccccc1
Reactant: N
Solvent: CCO
Product: NC(=O)C(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 91 %

Procedure:
A solution of the title compound of Step (A) (6.00 g; 30 mmol) in 50 ml of EtOH was saturated with anhydrous NH3. An exothermic reaction was observed. After stirring the reaction mixture 60 hr at room temperature, the volatiles were removed in vacuo and the solid residue was taken up in a minimal amount of hot ethyl acetate. A small amount of insoluble material was filtered off and hexane was added to the filtrate until slightly turbid. After cooling to room temperature and standing several hr, the crystals were filtered and dried to afford 4.68 g (91%) of the title compound of this step as a colorless crystalline solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:16])[C:5]=2[N:6]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[O:16]=[C:7]1[C:5]2[N:6]=[C:2]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:3][C:4]=2[C:14](=[O:15])[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: Nc1ccccc1
Reactant: O=C1c2ccccc2C(=O)c2sc(Cl)nc21
Solvent: CCO
Product: O=C1c2ccccc2C(=O)c2sc(Nc3ccccc3)nc21
Yield: 80 %

Procedure:
To a solution of 200 mg (0.8 mmol) of 2-chloro-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]thiazole in 100 mL of ethanol, 730 μL (8 mmol) of aniline are added at 80° C. The reaction mixture is heated to reflux for 3.5 h; the red precipitate obtained is filtered after cooling, then purified on a cake (support: silica 6-35 μm; eluant: dichloromethane/heptane, 20/80 to 100/0, then dichloromethane/ethyl acetate, 99.5/0.5 to 0/100). The clean fractions are combined, then filtered through micropores; the solvent is evaporated at reduced pressure to produce 196 mg of 4,9-dihydro-4,9-dioxo-2-phenylamino-naphtho[2,3-d]thiazole in the form of red crystals.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:9](O)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][O:3]1.O=P(Cl)(Cl)[Cl:14]>C(#N)C>[Cl:14][C:9]1[C:10]2[CH:2]([CH3:1])[O:3][CH2:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC1OCc2ncnc(O)c21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1OCc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a suspension of 5-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (1.2 g, 7.9 mmol) in acetonitrile (50 mL) was added via syringe POCl3 (3.6 g, 23.7 mmol) and the mixture heated to reflux for 3 hours. The mixture was allowed to cool to room temperature and then concentrated. The residue was diluted with EtOAc and quenched by pouring into saturated NaHCO3. The organic layer was separated and the aqueous layer extracted with EtOAc (3×100 mL). The combined organic layers were dried (MgSO4) and concentrated to give 4-chloro-5-methyl-5,7-dihydrofuro[3,4-d]pyrimidine (1.3 g, 96%) as a light brown oil which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 8.89 (s, 1H), 5.46 (q, J=6.4 Hz, 1H), 5.15 (dd, J=14.4, 2.8 Hz, 1H), 5.02 (dd, J=14.4, 2.8 Hz, 1H), 1.62 (d, J=6.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:19])[C:7](=[O:18])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:17])[CH2:14][O:15][CH3:16])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:26])=[CH:23][C:22]=1[O:37][CH3:38].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO>[CH3:38][O:37][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][C:21]=1[NH:20][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[N:6]([CH3:19])[C:7](=[O:18])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:17])[CH2:14][O:15][CH3:16])[C:25]([NH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)=[O:26]
Reactant: COCC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)CC(C)O
Solvent: O
Product: COCC(C)N1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)nc21
Temperature: 100 °C

Procedure:
10-chloro-2-(1-methoxypropan-2-yl)-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 112 60 mg, 0.21 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 56 mg, 0.21 mmol), and p-toluenesulphonic acid monohydrate (100 mg, 0.53 mmol) were combined in 4-Methyl-2-pentanol (2 mL) and heated at 100° C. for 16 hrs. The reaction mixture was cooled to room temperature and dissolved in Methanol. The resultant solution was added to a 5 g SCX-3 column pre wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) and crude product eluted with 2M ammonia in MeOH and solvents evaporated. The resultant residue was dissolved in DCM and purified on silica eluting with a gradient of 5-15% MeOH/DCM. Product containing fractions were combined and evaporated to a yellow gum which was purified by base modified reverse phase HPLC to give the title compound as a beige solid. (35 mg, 32%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:9]=1[CH2:10]Cl>>[Cl:7][C:8]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:9]=1[CH2:10][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)c(Cl)c1
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 4.29.a. from 4 mL (40 mmol) of piperidine and 2 g (9.71 mmol) of 2-chloro-4-nitrobenzylchloride. Yield: 2.39 g (97% of theory); C12H15ClN2O2 (M=254.71); calc.: molecular ion peak (M+H)+: 255/257 (Cl); found: molecular ion peak (M+H)+: 255/257 (Cl); Rf value: 0.32 (silica gel, petroleum ether/ethyl acetate (6:1)).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=O)#[N:10]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][CH2:20][C:11]=2[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CC1CCc2ccccc2C1=O
Reactant: Nc1ccc(F)cc1
Product: N#CC1=C(Nc2ccc(F)cc2)c2ccccc2CC1
Temperature: 150 °C

Procedure:
4-Fluoro-aniline (Aldrich Chemicals) (1.11 g, 10 mmol) and 2-cyano-3 ,4-dihydro-1 (2H) -naphthalenone (synthesised according to the method of Johnson. W. S. and Shelberg W. E. J. Amer. Chem. Soc., (1945), 67 p.1745.) (91.71 g 10 mmol) were heated together at 150° C. for 1 hour. After cooling, chromatography on silica with chloroform as the eluent followed by Kugelrohr distillation (175° C., 0.2 mmHg) gave the product as pale brown crystals.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)([O-:3])=[O:2].[CH3:11][Al](C)C>CCCCCC>[N+:1]([CH2:4][CH:5]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH3:11])([O-:3])=[O:2]
Reactant: C[Al](C)C
Reactant: O=[N+]([O-])C=Cc1ccsc1
Solvent: CCCCCC
Product: CC(C[N+](=O)[O-])c1ccsc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
When R2 was H, the 3-(2-nitroethenyl)thiophene (1 eq) was suspended in hexane, cooled to 5° C. in an ice bath under nitrogen and slowly treated with 2N trimethylaluminum in hexane (2.6 eq). After 30 min, the solution was quenched with 3N HCl, diluted with ether and filtered. The organic layer was dried (Na2SO4) and condensed under reduced pressure to afford the crude product. This material was purified by flash silica gel column chromatography using 70% hexane in CH2Cl2. The product was obtained as a colorless oil (80%); MH+ at m/z 172.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[OH:20].C(OCC)C>ClCCl>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: Cc1ccccc1C(O)c1ccncc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccccc1C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
Pyridinium chlorochromate (9.29 g, 43.1 mmol) was dissolved in dichloromethane (50 ml) and a solution of 2-methylphenyl-(4-pyridyl)methanol (5.72 g, 28.7 mmol) in dichloromethane (30 ml) was added. The reaction mixture became dark immediately, and was stirred for 2 h at room temperature. Diethyl ether (350 ml) was added, and the reaction mixture was filtered through "hyflo" and evaporated to a dark oil (11.26 g). Flash chromatography on silica gel (Merck Art 9385) eluting with heptane/tetrahydrofuran (4:1) provided the title compound (2.74 g, 48%) as an oil. T.l.c. rf=0.45 (SiO2, ethyl acetate).
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].O.NN.[OH-].[K+]>C(O)C.C(O)COCCO>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([C@H:9]2[CH2:10][CH2:11][C@H:6](/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]2)=[CH:17][CH:16]=1)[CH3:19]
Reactant: CCC/C=C/[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: OCCOCCO
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(CC)cc2)CC1
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A solution of 1.35 g of p-[trans-4-(trans-1-pentenyl)cyclohexyl]acetophenone in 16 ml of ethanol and 16 ml of diethylene glycol was treated with 0.486 ml of hydrazine hydrate while gassing with argon and then heated to reflux (bath temperature 110° C.) while stirring for 1.5 hours. The mixture was subsequently treated with 550 mg of solid potassium hydroxide, the bath temperature was increased to 210° C. and the ethanol was distilled off. After 2.5 hours at 210° C., the reaction was interrupted and the mixture was partitioned three times in water/petroleum ether. The organic extracts were washed twice with water, dried over magnesium sulphate and evaporated. Chromatographic separation of the residue (1.23 g) on silica gel with hexane as the eluent gave 1.16 g (91%) of 4-ethyl-1-[trans-4-(trans-1-pentenyl)cyclohexyl]benzene as a colourless oil; m.p. (C--I) -3.1° C.