Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:9][C:10]1[C:14](=[CH2:15])[CH:13]=[CH:12][CH:11]=1.B(F)(F)F.CCOCC.O>C(Cl)Cl>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([CH2:15][C:14]2[C:10](=[CH2:9])[CH:11]=[CH:12][CH:13]=2)=[CH:3][CH:2]=1
Reactant: C=C1C=CC=C1CO
Reactant: Oc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: C=C1C=CC=C1Cc1ccc(O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 174.5 %

Procedure:
Phenol (40 mg, 0.4 mmol) was added to a solution of hydroxymethyl-fulvene (70 mg, 0.28 mmol) in dry CH2Cl2 (25 mL). The mixture was cooled to -78° C. and boron triflouride etherate (0.3 mL, 2.7 mmol) was added dropwise.. The reaction was stirred at that temperature for 1 hour and water was added to quench the reaction. The organic layer was washed with H2O, NaHCO3 and brine, and dried over MgSO4. Chromatography on silica gel with hexane-ethyl acetate yielded 90 mg (98%) of red crystals (m.p. 143°-144° C). 1H NMR δ0.59-1.43 (m, 4 H), 1.36 (s, 3 H), 1.76 (s, 3 H), 2.07 (s, 3 H), 3.95 (s, 1 H), 3.97 (d, J=7.2 Hz, 2 H), 4.83 (s, 1 H), 6.74 (d, J=8.4 Hz, 2 H), 6.91 (d, J=8.4 Hz, 2 H), 7.22 (s, 1 H). MS m/Z 322 (M+), 294 (M+-2 CH2), 279 (M+-2 CH2 -CH3), 251 (M+-2 CH2 -CH3CO), 215, 107 UV 228 nm (12×104, with inflections at 243 and 262 nm), 325 (7.1×103), 410 nm (2.6×103). The compound has the structure: ##STR16##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH2:20])=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:20][CH2:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2)n1
Yield: 94.3 %

Procedure:
A solution of 4,6-dichloro-2-methoxypyrimidine [0.7 g, Intermediate (4)], 2-(4-chlorophenyl)-ethylamine (0.66 g) and sodium bicarbonate (0.88 g) in EtOH (25 ml) is heated at 80° C. for three hours, poured into water (400 mL) and the solid is filtered and air dried affording (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-chlorophenyl)-ethyl]amine [1.1 g, Intermediate (14)]. MS: 299 (M+H). 1H NMR (CD3)2SO]: δ 8 (d, 2H, J=3 Hz); 7.4 (2H, d, J=3 Hz); 6.05 (1H, s); 4 (3H, s): 3.6-3.7 (2H, m); 2.95 (2H, t).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[C:8]([OH:20])(=[O:19])[CH2:9][C:10]([CH2:15][C:16]([OH:18])=[O:17])([C:12]([OH:14])=[O:13])[OH:11]>[Cl-].OCC[N+](C)(C)C>[C:8]([O-:20])(=[O:19])[CH2:9][C:10]([CH2:15][C:16]([O-:18])=[O:17])([C:12]([O-:14])=[O:13])[OH:11].[OH:1][CH2:2][CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[OH:1][CH2:2][CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[OH:1][CH2:2][CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[N+](C)(C)CCO
Agent: [Cl-]
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
The preparation of the several recited choline salts is breifly recited here, though all can be obtained from commercial manufacturers. Choline ascorbate can be prepared from choline and ascorbic acid in methanol according to the procedure set out in U.S. Pat. No. 2,823,166. Choline bicarbonate can be prepared by passing carbon dioxide through a solution of choline until the pH reaction mixture is 9.0 or lower. The mixture is then concentrated and treated with carbon dioxide to pH of 8.5-8.9. Choline bicarbonate is finally isolated by vacuum evaporation of the solution. The preparation of choline chloride can be found in U.S. Pat. No. 2,623,901. Choline and citric acid are combined according to the procedure set out in U.S. Pat. No. 2,774,759 to give choline citrate (tricholinecitrate). Choline dihydrogen citrate, (2-hydroxyethyl)trimethylammonium citrate, is prepared according to the scheme set out in U.S. Pat. No. 2,870,198. The preparation of choline gluconate, the D-gluconic acid salt of choline is given in U.S. Pat. No. 2,691,617.
Reaction SMILES: [CH2:1]([N:3]([C:15]1[CH:26]=[C:25]2[C:27]3[CH:21]([CH2:22][CH2:23][CH2:24]2)[CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=1)[C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([N:3]([C:15]1[CH:26]=[C:25]2[C:27]3[CH:21]([CH2:22][CH2:23][CH2:24]2)[CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=1)[C:4]1[CH:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N(CC)c2cc3c4c(c2)CCCC4CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(c1ccc(C(=O)O)cc1)c1cc2c3c(c1)CCCC3CCC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A suspension of ethyl 4-[N-ethyl-(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]benzoate (0.036 g) in ethanol (5 ml) was added with 20% aqueous sodium hydroxide (1 ml), and the mixture was stirred overnight at 50° C. The reaction mixture was left to cool and then made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol to obtain the title compound (0.026 g, yield: 79%) as colorless needles (melting point: 284-285° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:6][C:5]([C@H:18]2[C@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[O:19]2)=[CH:4][C:3]=1[OH:57].[Br:58]Br.[Cl-].[NH4+]>CC(O)=O>[Br:58][C:4]1[C:5]([C@H:18]2[C@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[O:19]2)=[CH:6][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)=[C:2]([Cl:1])[C:3]=1[OH:57]
Reactant: BrBr
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cc(O)c2Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(O)c2Cl)cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a solution of compound 77 (2.36 g, 3.0 mmol) in AcOH (30 mL) were added TEA (0.6 mL, 4.51 mmol) and Br2 (0.18 mL, 3.61 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 15 min and at room temperature for 15 hours. To a mixture was added saturated ammonium chloride and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was carried on to the next step without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([NH:20][CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.CCN(CC)CC>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([N:20]([CH3:21])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccc(C(F)(F)F)cc1)C1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(3-chloro-phenyl)-pyrrolidin-3-yl]-methyl-amine (0.46 g, 1.59 mmol) in THF (15 ml) was added 1-bromomethyl-4-trifluoromethyl-benzene (0.44 g, 1.86 mmol) and Et3N (0.155 ml, 1.59 mmol). The reaction mixture was stirred overnight at RT and concentrated under vacuo. The product purified by flash chromatography (SiO2, EtOAc/Heptane 1:4) to afford 500 mg (71%) of the title compound as a colorless oil. ES-MS m/e: 459.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]=[C:12]2[CH:15]2[CH2:17][CH2:16]2)=[C:7]([O:18]C(=O)C)[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Cl>C1COCC1.CO.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]=[C:12]2[CH:15]2[CH2:16][CH2:17]2)=[C:7]([OH:18])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OC(C)=O)c2ccnc(C3CC3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(O)c2ccnc(C3CC3)c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-Acetoxy-1-cyclopropyl-isoquinoline-7-carboxylic acid methyl ester (12.7 g, 44.6 mmol) was dissolved in THF (90 ml)-MeOH (30 ml) and K2CO3 (3.69 g, 26.7 mmol) was added thereto. After stirring at room temperature for 20 h, the reaction mixture was diluted with EtOAc and diluted HCl aq. (26.7 mmol). The mixture was extracted with EtOAc and the organic layer was washed with brine, dried over MgSO4. The desiccant was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was triturated with EtOAc and hexane (1:2) and the insoluble solid was collected through filtration to obtain the intended compound as a colorless solid.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][O:8][C:9]1[C:14]([C:15](=[O:24])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:12]([C:25](=[O:34])[NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:11][N:10]=1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:17]([NH:16][C:15]([C:14]1[C:9]([O:8][CH2:7][C:6]([OH:35])=[O:5])=[N:10][CH:11]=[C:12]([C:25](=[O:34])[NH:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:13]=1)=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)COc1ncc(C(=O)NCc2ccccc2)cc1C(=O)NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(O)COc1ncc(C(=O)NCc2ccccc2)cc1C(=O)NCc1ccccc1
Yield: 67.5 %

Procedure:
A solution of 0.25 g (0.53 mmol) (3,5-Bis-benzylcarbamoyl-pyridin-2-yloxy)-acetic acid tert-butyl ester in 10 ml 50% trifluoroacetic acid in CHCl3 was stirred for 3 hours at room temperature. The reaction mixture was then concentrated at reduced pressure to obtain a solid. The solid was slurried in ethyl acetate, filtered, washed with ethyl acetate, and then dried at 55° C. at reduced pressure overnight. 0.15 g (68% yield) of the title compound. MS: m/z (APCI, AP+) 420 [M−]+. CHN Analysis: Calcd: C, 65.86; H, 5.05; N, 10.02. Found: C, 65.73; H, 5.08; N, 9.86.
Reaction SMILES: [C:1]([C:5]1[C:6]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2].[H-].[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.CCOC(C)=O.CO>CN(C=O)C>[N:22]1([C:15]2[CH:16]=[CH:17][C:12]([C:11]([C:6]3[C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:10][CH:9]=[CH:8][N:7]=3)=[O:19])=[CH:13][CH:14]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1cccnc1C(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cccnc1C(=O)c1ccc(-n2ccnc2)cc1
Temperature: 120 °C

Procedure:
A solution of 3-carbomethoxy-2-(4-fluorobenzoyl)pyridine (2.38 g, 9.18 mmol) in 7 ml of DMF is added dropwise to a mixture of NaH (0.25 g, 10.56 mmol) and imidazole (0.63 g, 9.18 mmol) in 25 mL of DMF. The mixture is heated at 120° C. for 20 hours, then allowed to cool, quenched with H2O and extracted with CH2Cl2 (4×50 mL). The combined organic layers are dried (Na2SO4) and evaporated to produce an oil. Chromatography on silica gel (using EtOAc-MeOH, 9.5:0.5 as the eluent) gives 2-[4-(1H-imidazol-1-yl)benzoyl]3-carbomethoxypyridine. M.P. 171°-173.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.C1C=CC=CC=1.CCCCCC.[O:20]=[C:21]1[CH:30]2[C:25]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=3)([CH2:26][C:27](=[O:38])[CH:28](C(OC(C)(C)C)=O)[CH2:29]2)[CH2:24][CH2:23][N:22]1[CH3:47]>CO.C1C=CC=CC=1>[O:20]=[C:21]1[C@H:30]2[C@@:25]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=3)([CH2:26][C:27](=[O:38])[CH2:28][CH2:29]2)[CH2:24][CH2:23][N:22]1[CH3:47]
Reactant: COc1cccc(C23CCN(C)C(=O)C2CC(C(=O)OC(C)(C)C)C(=O)C3)c1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Solvent: CO
Product: COc1cccc([C@]23CCN(C)C(=O)[C@@H]2CCC(=O)C3)c1

Procedure:
In a process of preparing 4a-aryldecahydroisoquinolines the steps consisting essentially of the conversion of nipecotates to substituted methylenepiperidone and carboxylic ring formation according to the following reaction system: ##STR10## wherein 4-carboxymethyl-4-(3'-methoxyphenyl)-1-methyl-3-methylene-2-piperidone (29) is converted to an imidazolide (31) by the action of carbonyldiimidazole in CHCl3 /THF and subsequently with the magnesium enolate of tert-butyl hydrogen malonate to produce tert-butyl 4-[4'-[4'-(3"-methoxy-phenyl)-1'-methyl-3'-methylene-2'-oxopiperidyl]]-3-oxobutyrate (32) and this material 32 is cyclized by an alkali metal methanolate dissolved in methanol to tert-butyl 1,6-dioxo-4a-(3'-methoxyphenyl)-2-methyl-decahydroisoquinoline-7-carboxylate (33) and subsequently 33 is treated with trifluoroacetic acid in benzene and subsequent recovery by recrystallization from a benzene-hexane mixture to produce trans 1,6-dioxo-4a-(3'-methoxyphenyl)-2-methyl-decahydroisoquinoline (9).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=O)[CH3:13])=[CH:7][CH:6]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH3:13])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(OCCF)cc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNc1ccc(OCCF)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.2 %

Procedure:
A solution of 3.0 grams (0.015 mole) of 4-acetamidophenyl 2-fluoroethyl ether in 15 ml of dry tetrahydrofuran was added dropwise to a stirred solution of 15 ml of a 3.4 M solution of sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al®) in toluene and 50 ml of dry tetrahydrofuran. The reaction mixture was stirred at room temperature for approximately 18 hours. The mixture was quenched with 1 ml of water and was filtered. The filtrate was evaporated under reduced pressure leaving a dark liquid which solidified upon standing. This solid was dissolved in ethyl acetate to which a small amount of water was added. A small amount of precipitate formed from which the organic solution was decanted. The organic solution was evaporated under reduced pressure leaving a dark liquid residue. This residue was purified by column chromatography on silica gel followed by distillation under reduced pressure to yield 1.6 grams of 4-(ethylamino)phenyl 2-fluoroethyl ether as a solid.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH:13]([CH2:15][NH:16][C:17]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][N:25]=3)[CH:20]=[C:19]([Cl:27])[N:18]=2)[CH2:12][N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:27][C:19]1[N:18]=[C:17]([NH:16][CH2:15][CH:13]2[CH2:14][CH:9]([OH:8])[CH2:10][N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:12]2)[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC(CNc2nc(Cl)cc3nccnc23)CC(O[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)CC(CNc2nc(Cl)cc3nccnc23)C1

Procedure:
A solution of tert-butyl 3-(tert-butyldimethylsilyloxy)-5-(7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)piperidine-1-carboxylate from step E in THF (16 mL) was treated with TBAF (5.17 g, 16.4 mmol) at room temperature for 2 hours, then diluted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to give the title compound. MS (m/z): 394 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.Cl[CH2:12][CH2:13][CH2:14][C:15]#[N:16].C([Mg]Br)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:12][CH2:13][CH2:14][C:15]#[N:16]
Reactant: N#CCCCCl
Reactant: Brc1cccc2cc[nH]c12
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: N#CCCCc1c[nH]c2c(Br)cccc12

Procedure:
To an anhydrous toluene (12 mL) solution of 7-bromoindole (1.0 g) and 4-chlorobutyronitrile (0.26 g), ethylmagnesium bromide (3.0M diethyl ether solution; 1.7 mL) was added dropwise under ice cooling and the mixture was heated to reflux for 4.5 hours. To the reaction mixture, an aqueous saturated ammonium chloride solution was added under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed in turn with water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10→70:30) to obtain the titled compound having the following physical properties (0.40 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH2:16]>C(O)C>[CH3:15][NH:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCO
Product: CNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a suspension of 2.0 g of 4-chloro-3-nitroquinoline in 20 ml of dry ethanol is added 15 ml of 30% methylamine in ethanol. The mixture is stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is triturated with excess water. The resulting crystals are collected by filtration and washed repeatedly with water. The crystals are dried over phosphorus pentoxide in vacuo to afford 1.82 g (93%) of 4-methylamino-3-nitroquinoline.
Reaction SMILES: [C:1]([NH:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[NH:3])[NH2:2].[CH3:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17](=O)[CH2:18]Br>C(O)C>[NH2:3][C:1]1[N:4]([N:5]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:18]=[C:17]([C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[O:14][CH3:13])[N:2]=1
Reactant: N=C(N)NN=Cc1ccccc1
Reactant: COc1ccccc1C(=O)CBr
Solvent: CCO
Product: COc1ccccc1-c1cn(N=Cc2ccccc2)c(N)n1

Procedure:
A solution of 41.7 g (0.257 mol) of benzaldehyde guanylhydrazone (see Thiele, A., Liebigs Annalen der Chemie 270, 35) and 30.12 g of 2-methoxyphenacyl bromide (Aldrich, Buchs, Switzerland; 98%, Cat. no. 10,085-4) in 130 ml of ethanol is boiled under reflux for one hour. After cooling, the product that has crystallised out is filtered off with suction and recrystallized from ethanol. In that manner there is obtained the title compound, m.p. 166°-167° C., 1H-NMR (DMSO): δ=8.61 (s, 1H); 8.0 (m, 3H); 7.88 (s, 1H); 7.5 (m, 3H); 7.19 (m, 1H); 7.03 (d, 1H); 6.96 (t, 1H); 6.16 (s, 2H); 3.94 (s, 3H).
Reaction SMILES: C1CC=CCC=1.[CH3:7][N:8]1[C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][C:15]2=[O:30])=[N:11][CH:10]=[N:9]1>[Pd].C(O)C>[CH3:7][N:8]1[C:12]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]2=[O:30])=[N:11][CH:10]=[N:9]1
Reactant: Cn1ncnc1CN1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Cn1ncnc1CN1CCNCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
A slurry of palladium on carbon (10%, 1.7 g) and 1,4-cyclohexadiene (4.1 g, 51 mmol) in ethanol (10 mL) was added to a solution of phenylmethyl 4-[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]-3-oxo-1-piperazinecarboxylate (Description 140, 1.7 g, 5.2 mmol) in ethanol (40 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through Celite™ and the solvent was evaporated under reduced pressure, The residue was recrystallized from propan-2-ol to give the title compound (500 mg, 49%). m/z (ES+) 196 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH2:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([CH3:3])[CH3:2].C([Li])CCC.[CH3:18][Si:19](Cl)([CH3:36])[CH:20]1[C:28]2[C:23](=[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH3:35].[Cl-].[NH4+]>[Cu]C#N.CCCCCC.C(OCC)C>[CH3:18][Si:19]([CH3:36])([CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:4]1[CH:1]([CH3:3])[CH3:2])[CH:20]1[C:28]2[C:23](=[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH3:35]
Reactant: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)Cl
Reactant: CC(C)C1=Cc2ccccc2C1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)C1C(C(C)C)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.3 %

Procedure:
In a 200-ml two-necked flask were charged 4.5 g (28.5 mmol) of 2-i-propylindene, 70.2 mg (0.78 mmol) of copper (I) cyanide, and 150 ml of diethyl ether. To the mixture was added at -78° C. 19.6 ml of 1.6 M hexane solution of n-butyllithium and the mixture was stirred at room temperature for 2 hours. Subsequently, 6.57 g (23.6 mmol) of dimethyl(2-methyl-4-phenylindenyl)silyl chloride was added at -78° C. and the mixture was stirred at room temperature for 12 hours. After addition of aqueous ammonium chloride solution to the reaction mixture, the organic layer was washed with saturated saline and dried over sodium sulfate. The sodium sulfate was removed by filtration and the organic solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel, development solvent: n-hexane: methylene chloride=9:1) to obtain 8.3 g (19.9 mmol, yield: 70%) of a pale yellow oil. The product was confirmed to be a mixture of two isomers by 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2O)=[O:10])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:20]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]=[CH:12][C:11]=1[C:9](=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cnc2c(c1O)CCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1)c1cnc2c(c1Cl)CCCC2

Procedure:
A mixture of 1.0 g of 3-(N-p-chlorophenylcarbamoyl)-4-hydroxy-5,6,7,8-tetrahydroquinoline (Example 17a) and 25 mL of phosphorous oxychloride is heated at 80° for 3 hours to obtain a clear solution, and evaporated to dryness. The residue is treated with 400 mL of a 1:1 mixture of ice cold 2N aqueous sodium hydroxide and dichloromethane. The organic phase is separated, dried and evaporated to yield the 4-chloro-3-(N-p-chlorophenylcarbamoyl)-5,6,7,8-tetrahydroquinoline. The mixture of 0.6 g thereof, 1.0 g of O-methylhydroxylamine hydrochloride and 1.65 g of diisopropylethylamine is heated to 100° in a small pressure vessel for 18 hours. The cooled mixture is then triturated with water, dissolved in tetrahydrofuran, dried and evaporated to yield the 4-(O-methylhydroxylamino)-3-(N-p-chlorophenylcarbamoyl)-5,6,7,8-tetrahydroquinoline.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+]>CO>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25]([O:30][CH3:29])=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cn1

Procedure:
Experimental conditions analogous to those described for Example 141, from 38 mg (0.084 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-3-(6-chloro-pyridine-3-carbonyl)-1H-quinolin-4-one, 90 mg (1.67 mmol) of sodium methoxide and 1 mL dry methanol. Yield: 19 mg of a white powder. LC-MSD, m/z for C22H16BrN3O3 [M+H]+=450.0, 452.0; HPLC retention time: 2.3 min.