Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].CC(C(O)=O)C1C=CC(CC2C(=O)CCC2)=CC=1>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)CCCCCCO
Agent: [Ti+4]
Agent: CC(C(=O)O)c1ccc(CC2CCCC2=O)cc1
Agent: CCCC[O-]
Product: CC(C)CCCCCCOC(=O)c1ccccc1

Procedure:
976 g of benzoic acid (8 mol), 1728 g of isononanol from OXENO Olefinchemie GmbH (12 mol), and 0.59 g of butyl titanate (0.06%, based on the amount of acid) are weighed into a four liter distillation flask on top of which a water separator and reflux condenser have been attached, and which has a sampling port and thermometer, and are heated to boiling under nitrogen. The water of reaction produced during the esterification process was removed sequentially. Once the acid value fell below 0.1 mg KOH/g (after about 3 hours), the mixture was first cooled below 60° C., and a 20 cm multifill column was placed on the apparatus. The pressure was then reduced to 2 mbar, and excess alcohol was first distilled off (about 120° C.). After removal of an intermediate fraction at up to 140° C. it was possible to distill over the isononyl benzoate within a range of 142 to 147° C. (at 2 mbar) measured at the head of the column. Purity >99.7% was determined by gas chromatography.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[NH:21][C:22](=[O:25])[CH2:23]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[CH3:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH3:13])[C:15]=1[NH:21][C:22](=[O:25])[CH2:23][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2,6-dimethylphenyl)-2-chloroacetamide (39 mg, 0.20 mmol, Aldrich) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 43.7 mg (90.9%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.08 (s, 6H), 2.65 (t, J=4 Hz, 4H), 3.18 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=5 Hz, 1H), 7.08 (s, 3H), 7.52 (t, J=5 Hz, 1H), 8.10 (d, J=5 Hz, 1H), 9.23 (s, 1H); MS (ESI/APCI+) m/e 325 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH2:14]Br>>[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH2:14][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Fc1ccc(CBr)c(F)c1
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2F)cc1
Yield: 86 %

Procedure:
Prepared in analogy to example 8 from 4-nitrophenol and 2,4-difluoro-benzylbromide. Colorless solid. Yield=86%. MS: m/e=265.1 (M+).
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=2)[CH2:4][O:3]1>CO>[CH2:15]([C:12]1[CH:11]=[CH:10][C:9]([NH:8][CH:5]([CH2:6][OH:7])[CH2:4][OH:3])=[CH:14][CH:13]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCc1ccc(NC2COC(C)(C)OC2)cc1
Solvent: CO
Product: CCCCCCCCc1ccc(NC(CO)CO)cc1
Reaction time: 1 h
Yield: 115.4 %

Procedure:
To a solution of the product of Step A (0.1 g; 0.31 mmol) in MeOH (1 ml) Me3SiCl (0.5 ml) was added at room temperature. After stirring for 1 h, the mixture was evaporated to dryness under reduced pressure to give a hydrochloride salt of the title compound (0.1 g; 100%) as a colourless solid. 1H-NMR (CDCl3) 10.66 (bs, 2H); 7.53 (d, 2H, J=7.98 Hz); 7.18 (d, 2H, J=7.98 Hz); 4.82 (broad s, 2H); 3.98 (broad m, 4H); 3.51 (broad m, 1H); 2.58 (t, 2H, J=7.68 Hz); 1.56 (m, 2H); 1.43 (s, 3H); 1.27 (m, 10H); 0.86 (t, 3H, J=6.96 Hz).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[N:16]3[C:17](=[O:30])[CH:18](P(=O)(OCC)OCC)[CH2:19][CH2:20][CH2:21][C@@H:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[N:41]1[CH:45]=[C:44]([CH3:46])[N:43]=[CH:42]1)[CH:36]=O.C(OCC)(=O)C>O1CCCC1.C(O)C.[Cl-].[Na+].O>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[N:16]3[C:17](=[O:30])/[C:18](=[CH:36]/[C:35]4[CH:38]=[CH:39][C:40]([N:41]5[CH:45]=[C:44]([CH3:46])[N:43]=[CH:42]5)=[C:33]([O:32][CH3:31])[CH:34]=4)/[CH2:19][CH2:20][CH2:21][C@H:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: CCOP(=O)(OCC)C1CCC[C@@H]2CCC[C@H](c3ccc(F)cc3)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCC[C@H]3CCC[C@@H](c4ccc(F)cc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 50.8 %

Procedure:
Lithium hydroxide monohydrate (68 mg) was added to a mixed solution of diethyl [(4R*,10aS*)-4-(4-fluorophenyl)-6-oxodecahydropyrido[1,2-a]azepin-7-yl]phosphonate (213 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (116 mg) in tetrahydrofuran (6 mL) and ethanol (1.5 mL), and the reaction solution was stirred at room temperature for 25 hours. Ethyl acetate and brine were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 125 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:13]1[C:22](=[O:41])[C@@H:23]([NH:27][C:28](=[O:40])[C@@H:29]([N:31](C)[C:32](=O)OC(C)(C)C)[CH3:30])[CH:24]([CH3:26])[CH3:25])=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:13]1[C:22](=[O:41])[C@@H:23]([NH:27][C:28](=[O:40])[C@@H:29]([NH:31][CH3:32])[CH3:30])[CH:24]([CH3:26])[CH3:25])=[O:11]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1Cc2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (S)-1-((S)-1-((S)-3-(2,6-difluorophenylcarbamoyl)-3,4-dihydro isoquinolin-2 (1H)-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (138 mg, 241 μmol, Eq: 1.00) in DCM (2 mL) was added TFA (2.96 g, 2 mL, 26.0 mmol, Eq: 108) and the resulting solution stirred at RT for 1 h. The mixture was concentrated in vacuo, saturated NaHCO3 was added to the residue and the resulting mixture extracted with DCM. The combined extracts were dried over Na2SO4 and concentrated in vacuo. The residue was treated with ether/hexanes to give (S)-2-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (2,6-difluoro-phenyl)-amide as a white solid which was used without purification (70 mg), m/z=473 (M+H).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][N:10]=[CH:9][CH:8]=1>C(O)C.[OH-].[Na+]>[C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cnccc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1-c1ccncc1C(=O)O
Yield: 93.8 %

Procedure:
A solution of 1.13 g (5.0 mmol) methyl 4-o-tolyl-nicotinoate in 15 ml ethanol and 12 ml 2 N sodium hydroxide solution was heated to reflux for 1 h. The pH was adjusted to 5 and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried (sodium sulfate) and evaporated to give 1 g (94%) of the title compound as off white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:19])([F:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:20])[C:15]([F:19])([F:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:25])[CH3:22]
Reactant: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: ClC(C1C(CC2CC2)=C(C(OC)=O)C(C(F)F)=NC=1C(F)(F)F)=O.[CH:25]1([CH2:28][C:29]2[C:34]([C:35]#[N:36])=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=[C:31]([CH:41]([F:43])[F:42])[C:30]=2[C:44]([O:46][CH3:47])=[O:45])[CH2:27][CH2:26]1.C(NCC)C.[SH2:53]>CN(C=O)C>[NH2:36][C:35](=[S:53])[C:34]1[C:29]([CH2:28][CH:25]2[CH2:27][CH2:26]2)=[C:30]([C:44]([O:46][CH3:47])=[O:45])[C:31]([CH:41]([F:43])[F:42])=[N:32][C:33]=1[C:37]([F:40])([F:38])[F:39]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C#N)c1CC1CC1
Reactant: S
Agent: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)Cl)c1CC1CC1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(N)=S)c1CC1CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Methyl 5-chlorocarbonyl-4-(cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (example B3 of U.S. Pat. No. 5,156,670) was converted to methyl 4-(cyclopropylmethyl)-5-cyano-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridine-carboxylate by the procedure similar to example 88 and 92 of U.S. Pat. No. 4,692,184. A solution of 20 g (60 mmol) of this cyano compound and 0.62 g (6 mmol) of diethylamine in 60 ml of DMF was heated to 50° C. Hydrogen sulfide gas was introduced into this solution. When absorption of hydrogen sulfide was complete the reaction mixture was stirred at 50° C. for 1 h and poured into water and extracted with ether. The ether extract was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was kugelrohr distilled to give 17.7 g (80% yield) of yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([S:5]([NH2:8])(=[O:7])=[O:6])[CH3:4].[CH3:9][C:10]1([CH3:35])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20](O)=[O:21])[CH:17]=2)[NH:12][CH:11]1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:24]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:9][C:10]1([CH3:35])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]([NH:8][S:5]([CH2:3][CH3:4])(=[O:7])=[O:6])=[O:21])[CH:17]=2)[NH:12][CH:11]1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:24]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCOCC2)c1
Reactant: CCS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a suspension of 60% sodium hydride (745 mg, 18.6 mmol) in N,N-dimethylformamide (2.5 mL) was added ethanesulfonamide (2.3 g, 19 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (690 mg, 1.9 mmol) and 1,1′-carbonyldiimidazole (650 mg, 3.8 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of ethanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded ethanesulfonic acid [3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (347 mg, 40%) as a white solid: LC/MS m/e calcd for C24H31N3O4S (M+H)+: 458.61, observed: 458.0.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[C:5]([O:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:6]([N+:17]([O-])=O)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1>CO.O.[Fe]>[Cl:3][C:4]1[C:5]([O:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[NH2:17]
Reactant: O=[N+]([O-])c1ccc(Oc2cccnc2)c(Cl)c1Oc1cccnc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(Oc2cccnc2)c(Cl)c1Oc1cccnc1

Procedure:
963 mg of ammonium chloride and 503 mg of iron powder were added to a suspension of 1.2 g of 3-chloro-2,4-bis(pyridin-3-yloxy)-nitrobenzene in 15 ml of methanol and 7.5 ml of water, and the reaction liquid was heated under reflux for 3 hours. The reaction liquid was filtered, and the solvent was evaporated away under reduced pressure. The residue was diluted with ethyl acetate, washed with water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified with silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1 to ethyl acetate) to obtain the entitled compound as a pale yellow oily substance.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([C:23]1[C:24](C)=[C:25](C)[C:26]2[C:30]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[C:29](O[SiH3])[O:28][C:27]=2[CH:39]=1)(C)(C)C.C1C[O:45]CC1>>[N:33]1[CH:34]=[CH:35][CH:36]=[C:31]([C:30]2[C:26]3[CH:25]=[CH:24][C:23]([OH:45])=[CH:39][C:27]=3[O:28][CH:29]=2)[CH:32]=1
Reactant: Cc1c(C(C)(C)C)cc2oc(O[SiH3])c(-c3cccnc3)c2c1C
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Oc1ccc2c(-c3cccnc3)coc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
1M tetrabutylammonium fluoride solution in THF (16 ml, 16.00 mmol) was added to a THF (150 ml) solution of 3-(6-t-butyldimethyl silyloxybenzo[b]furan-3-yl)pyridine (5.2 g, 15.88 mmol) obtained above, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting concentrate was charged to short path silica gel column chromatography (chloroform:ethyl acetate=1:1-1:2). A white powder of 3-(3- pyridyl)benzo[b]furan-6-ol (2.7g, 79%) was then obtained by crystallization using ether-hexane.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)=[O:13].[CH3:23][CH:24]([CH3:40])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:29]=1)=[O:26]>>[CH3:23][CH:24]([CH3:40])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[O:13])[CH2:36][CH2:35]2)[CH:29]=1)=[O:26]
Reactant: O=C(CCCCCl)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 5-chloro-1-(3-nitrophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 452.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]([CH3:37])=[C:19]([CH3:36])[C:20]4[O:24][C:23]([CH3:26])([CH3:25])[C:22]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(O)[C:21]=4[C:34]=3[CH3:35])[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:18]([CH3:37])=[C:19]([CH3:36])[C:20]4[O:24][C:23]([CH3:26])([CH3:25])[CH:22]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:21]=4[C:34]=3[CH3:35])[CH2:15][CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccccc3)C(C)(C)O4)CC2)cc1OC
Solvent: CCO
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(c3ccccc3)C(C)(C)O4)CC2)cc1OC
Yield: 65 %

Procedure:
Using 5-(4-(3,4-dimethoxyphenyl)piperidino)-2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-3-ol obtained in Example 80, the title compound was synthesized in the same manner as in Example 46. Yield 65%. mp. 118–120° C. (ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[NH:4][C:5]1[NH:24][C:8]2=[CH:9][C:10]3[C:11]([CH3:23])([CH3:22])[C:12](=[O:21])[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:14]=3[CH:15]=[C:7]2[N:6]=1.[CH2:26](O)[CH:27]=C>>[CH2:1]([O:2][C:3](=[O:25])[NH:4][C:5]1[NH:24][C:8]2=[CH:9][C:10]3[C:11]([CH3:23])([CH3:22])[C:12](=[O:21])[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:14]=3[CH:15]=[C:7]2[N:6]=1)[CH:26]=[CH2:27]
Reactant: C=CCO
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)OC)nc3cc21
Product: C=CCOC(=O)Nc1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3CCCCC
Temperature: 120 °C

Procedure:
A suspension of (7,7-dimethyl-6-oxo-5-pentyl-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-carbamic acid methyl ester (150 mg) in allyl alcohol (2 ml) is heated in a microwave apparatus at 120° C. for 20 min. The mixture is evaporated to give the desired compound (161 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 91.1 %

Procedure:
To a solution of 3-(4-bromo-phenyl)-1-(6-methoxy-pyridin-3-yl)-3-o-tolyl-propan-1-one (384 mg) in 1,4-dioxane (16 ml) was added concentrated aqueous HCl (17 ml). The mixture was stirred for 1.5 h at 100° C. After cooling to room temperature, the mixture was poured into ice and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, dichloromethane/methanol 1:0 to 9:1) to give the title compound (338 mg) as a colorless foam, MS (ESI−): m/z=393.8 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:10]3[CH:19]=[C:20]([S:23][CH3:24])[CH:21]=[CH:22][C:9]=3[S:8][C:7]=2[CH:25]=1.Cl[CH2:27][C:28]#[C:29][CH2:30][OH:31]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([N:13]3[CH2:14][CH2:15][N:16]([CH2:27][C:28]#[C:29][CH2:30][OH:31])[CH2:17][CH2:18]3)[C:10]3[CH:19]=[C:20]([S:23][CH3:24])[CH:21]=[CH:22][C:9]=3[S:8][C:7]=2[CH:25]=1
Reactant: OCC#CCCl
Reactant: COc1ccc2c(c1)Sc1ccc(SC)cc1C(N1CCNCC1)C2
Product: COc1ccc2c(c1)Sc1ccc(SC)cc1C(N1CCN(CC#CCO)CC1)C2

Procedure:
In a manner analogous to that described in Example 5, from 1-[10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin-10-yl]-piperazine and 4-chloro-2-butyn-1-ol there is obtained 4-{4-[10,11-dihydro-3-methoxy-8-methylthio-dibenzo-[b,f]thiepin-10-yl]-1-piperazinyl}-2-butyn-1-ol, the dihydrochloride of which melts at 208°-210° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]#[N:21])=[CH:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]#[N:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1=CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: N#Cc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12

Procedure:
A mixture of 0.89 g (3 mmoles) 6-benzenesulfonyl-3,4-dihydro-naphthalene-1-carbonitrile and 0.68 g (3 mmoles) DDQ in 15 mL dioxane was heated under reflux for 18 hours. Another 0.25 g (0.12 mmole) DDQ was added and the reaction mixture was heated under reflux for another 20 hours. The mixture was filtered and the collected solids were washed with diethyl ether. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and washed with 5% sodium hydroxide and half-saturated aqueous sodium chloride. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to column chromatography over silica gel 230-400 mesh eluting with chloroform:hexane:ethyl acetate (50:49:1), then with 50:48:2 and finally with 50:46:4. The title compound was obtained as a white solid, 0.266 gram (30%). NMR (CDCl3) ppm δ: 8.67 (d, 1H, J=1.8 Hz), 8.34 (d, 1H, J=8.8 Hz), 8.24 (d, 1H, J=8.41 Hz), 8.04 (m, 4H), 7.69 (dd, 1H, J=4.25 Hz, J=11.5 Hz), 7.56 (m 3H).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Cl-].[Li+].C([O-])(=O)C.[K+].[CH3:22][CH:23]([OH:27])[C:24]#[C:25][CH3:26]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[C:25]([CH3:26])=[C:24]([CH:23]([OH:27])[CH3:22])[N:9]([CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[C:3]=2[N:4]=1
Reactant: CC#CC(C)O
Reactant: Clc1ncc(Br)c(NC2CCCC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1c(C(C)O)n(C2CCCC2)c2nc(Cl)ncc12
Temperature: 120 °C
Yield: 14.8 %

Procedure:
To a solution of (5-Bromo-2-chloro-pyrimidin-4-yl)cyclopentylamine (1 g, 3.616 mmol) is added lithium chloride (153.7 mg, 3.616 mmol) and potassium acetate (887.12 mg, 9.03 mmol) in DMF (50 mL). The solution is degassed and back-filled with N2. Palladium(II) acetate (40.6 mg, 0.18 mmol) is added and the solution is degassed and back-filled with nitrogen three times. 3-pentyn-2-ol (1.0 mL, 10.8 mmol) is added and the reaction solution is heated at 120° C. for 5 hours. LC-MS analysis indicated the absence of starting material and the formation of a pair of regio-isomeric products. After cooling to room temperature, the mixture is filtered through Celite, diluted with water, and extracted with ethyl acetate EtOAc three times. The organic layers are combined, washed with brine and dried over anhydrous sodium sulfate. The solvent is evaporated and the crude material is purified using silica gel chromatography (30% ethyl acetate/70% hexanes to give 1-(2-Chloro-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-ethanol as a pale powder (150 mg, 14.8%). [M+H]+=280.07.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24](=[O:29])N(OC)C)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][C:6]=2[CH:7]=1)=[O:29])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Reactant: Brc1ccc2occc2c1
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2cc(Br)ccc2o1

Procedure:
The title compound (0.96 g) was prepared from 5-bromo-benzofuran (3.6 g, prepared according to procedures similar to those described in Synth. Commun., 257, (1989)) and (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine, D1 (4.9 g) according to a procedure similar to that for Description 2.