Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([OH:13])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.Cl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:8][C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:13])[C:6]=2[CH:7]=1
Reactant: O=C(O)c1ccccc1Nc1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2ccccc2[nH]c2ccc(F)cc12
Temperature: 115 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
N-(4-Fluorophenyl)anthranilic acid (0.70 gm; 3 mmol) and phosphorous oxychloride (3 ml) were stirred together and heated to 115° C. for 3.5 hours, then allowed to cool. The reaction mixture was placed on ice and small pieces of ice added, a vigorous reaction occurred with the evolution of hydrogen chloride. When the reaction had subsided, water (15 ml) was added and the mixture was boiled for 2 hours. On cooling, a solid precipitated out. This was filtered off and washed with water until the filtrate was colourless. The precipitate was further washed with cold methanol then diethyl ether and dried under vacuum to give 383 mg (59%) of 2-fluoroacridone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=2)[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32](OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C1(CNC)CCCCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH3:32])[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Fc1ccc(CNc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: CNCC1CCCCC1
Product: CN(CC1CCCCC1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 26 %

Procedure:
Prepared as described for 5,6-bis(benzyloxy)-N-[(4-fluorophenyl)methyl]pyridazin-3-amine (Intermediate 45) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-cyclohexyl-N-methylmethanamine in 26% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28]OS(C)(=O)=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C.C(Cl)(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][N:6]2[C:7]3[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(CCCOS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cccc2c1ccn2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 55.2 %

Procedure:
To a stirred solution of 4-methyl-1H-indole (1.0 g, 7.62 mmol) in DMF (20 mL), cooled at 0° C., was added NaH (60% in mineral oil; 0.40 mg, 9.91 mmol). After 45 min at 0° C., a solution of 4-(3-methanesulfonyloxy-propyl)-piperidine-1-carboxylic acid tert-butyl ester (2.44 g, 7.62 mmol) in DMF (10 mL) was added dropwise. The mixture was warmed to rt and stirred for 18 h. The mixture was diluted with CHCl3 (100 mL) and washed with water (100 mL). The organic layer was dried and concentrated to obtain the crude residue which was purified by FCC (EtOAc/hexanes) to give 1.50 g (55%) of a colorless oil. 1H NMR (CD3OD): 7.17 (d, J=8.2, 1H), 7.13-7.09 (m, 1H), 7.07 (d, J=3.2, 1H), 6.90 (d, J=6.9, 1H), 6.49 (d, J=3.2, 1H), 4.09 (t, J=7.1, 1H), 2.68-2.57 (m, 2H), 2.55 (s, 3H), 1.90-1.79 (m, 2H), 1.64-1.55 (m, 2H), 1.44 (s, 9H), 1.40-1.21 (m, 3H), 1.13-0.98 (m, 1H).
Reaction SMILES: F[C:2](F)(F)[C:3](OC(=O)C(F)(F)F)=[O:4].C(O)(=O)C.P(=O)(O)(O)O.[Br:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([C:34]([O:36][CH3:37])=[O:35])[N:28]2[CH3:33]>C(#N)C>[C:3]([C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[CH:32][C:24]=2[Br:23])[N:28]([CH3:33])[C:27]=1[C:34]([O:36][CH3:37])=[O:35])(=[O:4])[CH3:2]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc2c(Br)cccc2n1C
Agent: O=P(O)(O)O
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)c1c(C(C)=O)c2c(Br)cccc2n1C
Reaction time: 0.17 h

Procedure:
33 ml of trifluoroacetic anhydride are added to a solution of 13.2 ml of acetic acid, of 1.6 ml of phosphoric acid and of 170 ml of acetonitrile, stirring is carried out for 10 min at room temperature and a solution of 20.6 g (77 mmol) of methyl 4-bromo-1-methyl-1H-indole-2-carboxylate in 120 ml of acetonitrile is added. The mixture is stirred for 4 h at room temperature and is poured onto water and extracted with ether. The organic phase is dried over sodium sulphate, the solvent is evaporated under reduced pressure and the residue is taken up in a mixture of cyclohexane and of dichloromethane. The precipitate is collected by filtration, washed with ether and dried under reduced pressure. 18.8 g (61 mmol) of product are obtained. The mother liquors are concentrated and the residue is purified by chromatography on a column of silica gel. 3.2 g (10 mmol) of additional product are isolated.
Reaction SMILES: CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4:17].[CH2:18]([C:20]([CH2:25][OH:26])([CH2:23][OH:24])[CH2:21][CH3:22])[OH:19].[CH2:27]([OH:45])[CH2:28][CH2:29][CH2:30]CCCCCCCCCCCCCC.C(O)CCC>>[CH2:18]([C:20]([CH2:25][OH:26])([CH2:23][OH:24])[CH2:21][CH3:22])[OH:19].[CH2:27]([OH:45])[CH2:28][CH2:29][CH3:30].[Ti:17]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: [Ti+4]
Agent: CC(C)[O-]
Agent: CCC(CO)(CO)CO
Solvent: CCCCO
Product: [Ti]

Procedure:
A liquid mixture of 28.4 g (0.1 mole) of tetraisopropyl titanate, 4.5 g (0.033 mole) of trimethylolpropane, 0.1 g (0.0004 mole) of stearyl alcohol and an excess amount, i.e., 100 g (1.37 moles) of butanol was heated under reflux to dissolve the solid substance completely. The resultant isopropyl alcohol and butanol were then distilled off to obtain trimethylolpropane-butyl alcohol-titanate (polyol titanate). The polyol titanate was then cooled by ice, followed by an addition of butanol which contained 1.8002 g (0.10 mole) of water. After heating the resultant mixture to form a uniform solution, butanol was removed by distillation. Under cooling, butanol with 0.9005 g (0.05 mole) of water incorporated therein was added again. The resultant mixture was heated to effect polymerization and crosslinking. Butanol was then removed thoroughly under reduced pressure. After heating the residue again at 100° C. for 30 minutes in water-containing butanol, the product was dried under reduced pressure to obtain 12.2 g of a solid substance. This solid substance had such properties that it showed water repellency when water was added thereto but its surface was wet immediately when an alcohol was added thereto.
Reaction SMILES: [N:1]1([C:7](=[O:15])[CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[C@@H:36]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[N:35]([C:44](Cl)=[O:45])[C:34]([C:47]3[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][C:48]=3[O:55][CH2:56][CH3:57])=[N:33]2)=[CH:28][CH:27]=1.Cl>C(Cl)Cl.O>[ClH:25].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C@H:32]2[C@@H:36]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)[N:35]([C:44]([N:12]3[CH2:11][CH2:10][N:9]([CH2:8][C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:15])[CH2:14][CH2:13]3)=[O:45])[C:34]([C:47]3[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][C:48]=3[O:55][CH2:56][CH3:57])=[N:33]2)=[CH:30][CH:31]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1cc(C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOc1cc(C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 191 %

Procedure:
A solution of morpholin-4-yl-2-piperazin-1-yl-ethanone (17 mg, 0.081 mmol, Oakwood Products) and diisopropylethylamine (10 mg, 0.077 mmol) in 0.5 mL of methylene chloride was added to a solution of (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (35 mg, 0.070 mmol, example 29) in 0.5 mL of methylene in a 4-mL vial. The vial was then capped and shaken for 1 h at room temperature. The reaction mixture was diluted with 1 mL of methylene chloride and 1 mL of water. The vial was agitated and centrifuged. The organic layer was transferred to a 4-mL vial and concentrated in vacuo. The crude was dissolved in 0.5 mL of acetonitrile, and then 0.6 mL of water and 0.492 mL of 0.5 M hydrochloric acid (2.46 mmol) were added to the sample. The sample was frozen with liquid nitrogen and lyophilized to give 4-{(4S,5R)-4,5-bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-benzonitrile hydrochloride (47.6 mg, 91% yield). LC-MS: 675.3 [(M+H)+].
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](F)=[O:16])=[C:13]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:12]=1.C(O)(=O)C>CN(C)C=O>[NH2:8][C:7]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:13]2[C:14]([C:15](=[O:16])[C:6]=1[C:5]([NH:4][CH3:3])=[O:9])=[CH:18][CH:19]=[C:11]([Cl:10])[N:12]=2
Reactant: CNC(=O)CC#N
Reactant: O=C(F)c1ccc(Cl)nc1NCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CNC(=O)c1c(N)n(Cc2ccccn2)c2nc(Cl)ccc2c1=O
Reaction time: 1 h
Yield: 234.8 %

Procedure:
1.12 g (28.06 mmol) of sodium hydride at 60% in mineral oil are added, fractionwise, to a solution, cooled to 0-5° C., of 1.31 g (13.36 mmol) of N-methylcyanoacetamide (prepared according to 1.3) in 20 ml of anhydrous dimethylformamide. Stirring is continued at this temperature for ten minutes and then a solution of 3.55 g (4.93 mmol) of 6-chloro-2-[(pyridin-2-ylmethyl)amino]nicotinoyl fluoride in 20 ml of dimethylformamide is added. The medium is stirred overnight at ambient temperature and then 0.561 g (14.03 mmol) of sodium hydride at 60% is added fractionwise. Stirring is continued at this temperature for 1 hour minutes, and then the reaction mixture is poured onto ice and the subsequent mixture is acidified to pH 5-6 with an aqueous solution of acetic acid at 10%. The precipitate is isolated by filtration and, after drying in an oven, 3.98 g of the expected product are obtained in the form of a beige solid. MH+=344. Yield=87%.
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:18][C:15]([C:19]([OH:21])=[O:20])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=O)C1C=CC=CC=1.CO.Cl.[H][H]>[Pd].CO.C(OCC)(=O)C>[NH2:11][C:12]12[CH2:18][C:15]([C:19]([OH:21])=[O:20])([CH2:14][CH2:13]1)[CH2:16][CH2:17]2
Reactant: O=C(NC12CCC(C(=O)O)(CC1)C2)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NC12CCC(C(=O)O)(CC1)C2
Yield: 99.9 %

Procedure:
A 2-L Parr bottle was charged with 4-(benzyloxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylic acid (105 g, 363 mmol), methanol (500 mL), 0.8 N hydrochloric acid (500 mL), and 10% palladium on carbon (38.6 g, 18.15 mmol, 50% wet with water). The reaction mixture was reacted on a Parr shaker under 30 gpsi hydrogen for 10 h when TLC analysis (10% methanol/ethyl acetate) indicated a complete reaction. The catalyst was removed by filtration through a short plug of celite and the plug was washed thoroughly with water (4×100 mL). The filtrate was concentrated to provide 4-aminobicyclo[2.2.1]heptane-1-carboxylic acid (56.3 g, 100%) as a wet white solid which was used in the next step without any further purification; MS (ESI) m/z 156.2 [M+1]+
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:4][CH2:3]1.[CH:23](=O)[CH2:24][CH2:25][CH2:26][CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][C:2]1([CH3:22])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:17]2)=[CH:4][CH2:3]1
Reactant: CCCCC=O
Reactant: COc1ccc(C2=CCC(C)(C)CC2)c(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCN1CCN(c2cc(OC)ccc2C2=CCC(C)(C)CC2)CC1
Reaction time: 3 h
Yield: 102.4 %

Procedure:
To a solution of 1-[2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenyl]piperazine (90 mg, 0.29 mmol) prepared in Example (1e) in tetrahydrofuran (10 mL) were added valeraldehyde (31 mg, 0.36 mmol), sodium triacetoxyborohydride (95 mg, 0.59 mmol) and acetic acid (35 mg, 0.59 mmol) in that order, and the mixture was stirred for 3 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off and then the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 110 mg of 1-[2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenyl]-4-pentylpiperazine as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH2:15][CH2:14][CH2:13][CH:12]=3)[S:10][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1>[Pd].CN(C=O)C.CO>[NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[S:10][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1
Reactant: NC(=O)c1cnc(N)c2cc(C3=CCCC3)sc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1cnc(N)c2cc(C3CCCC3)sc12
Reaction time: 20 h
Yield: 30.9 %

Procedure:
A suspension of 4-amino-2-cyclopent-1-enyl-thieno[3,2-c]pyridine-7-carboxylic acid amide 34 (prepared in example 6 above) (0.056 g, 0.155 mmol) and 10% palladium on carbon (5 mol %) in DMF (1 mL) was stirred under H2 (1 atm) for 20 h. The suspension was diluted with MeOH (10 mL) and filtered. Solvent was removed in vacuo. To the crude solid of 35 was added concentrated H2SO4 (0.25 mL). The purple solution was stirred for 1 h followed by the addition of ice (2 g). The precipitate was filtered then purified by silica gel column chromatography (eluent: 10% MeOH, 1% NH4OH in CH2Cl2) and converted to the HCl salt to afford 12.5 mg of 36. 1H NMR (400 MHz, d6-DMSO) δ 8.76 (s, 2H), 8.45 (s, 1H), 8.29 (s, 1H), 7.75 (m, 3H), 3.37 (m, 1H), 2.14 (m, 2H), 1.72 (m, 6H).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[OH-].[K+].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>CO>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[C:3]2[C:4](=[O:10])[CH:5]3[CH2:8][CH2:9][N:2]2[CH2:7][CH2:6]3)[CH:14]=1
Reactant: O=Cc1cccnc1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2cccnc2)N2CCC1CC2
Reaction time: 12 h
Yield: 89.2 %

Procedure:
3-Quinuclidinone hydrochloride (8.25 kg, 51.0 mol) and methanol (49.5 L) were added to a 100 L glass reaction flask, under an nitrogen atmosphere, equipped with a mechanical stirrer, temperature probe, and condenser. Potassium hydroxide (5.55 kg, 99.0 mol) was added via a powder funnel over an approximately 30 min period, resulting in a rise in reaction temperature from 50° C. to 56° C. Over an approximately 2 h period, 3-pyridinecarboxaldehyde (4.80 kg, 44.9 mol) was added to the reaction mixture. The resulting mixture was stirred at 20° C.±5° C. for a minimum of 12 h, as the reaction was monitored by thin layer chromatography (TLC). Upon completion of the reaction, the reaction mixture was filtered through a sintered glass funnel and the filter cake was washed with methanol (74.2 L). The filtrate was concentrated, transferred to a reaction flask, and water (66.0 L) was added. The suspension was stirred for a minimum of 30 min, filtered, and the filter cake was washed with water (90.0 L) until the pH of the rinse was 7-9. The solid was dried under vacuum at 50° C.±5° C. for a minimum of 12 h to give 8.58 kg (89.3%) of 2-((3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one.
Reaction SMILES: [C:1]1([N:7]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:8]([O:10][CH2:11][CH2:12][C:13]2[C:22]3[C:17](=[C:18]([O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH:14]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].OO.C(OCC)(=[O:53])C>O1CCCC1.O>[C:41]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O:10][CH2:11][CH2:12][C@@H:13]2[C:22]3[C:17](=[C:18]([O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@H:14]2[OH:53])=[O:9])[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC=C2CCOC(=O)N(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cccc2c1CC[C@@H](O)[C@@H]2CCOC(=O)N(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-[2-(N,N-diphenylcarbamoyloxy)ethyl]-5-t-butyldiphenylsilyloxy-3,4-dihydronaphthalene (2.0 g) in THF (tetrahydrofuran) (20 ml) was added BH3 (4.8 ml, 1M solution in THF) at 0° C. under N2. After being stirred for 12 hours at the room temperature, 2N--NaOH solution (1.5 ml) and H2O2 (1.0 ml, 35% solution) were added to the solution and stirred for 4 hours. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N--HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (trans)-1-[2-(N,N-diphenylcarbamoyloxy)ethyl]-2-hydroxy-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.1 g).
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH3:12])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][CH:10]([CH2:11][CH3:12])[C:2](=[O:1])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: BrBr
Reactant: CCCCOC(=O)C(=O)CCC
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)C(=O)C(Br)CC
Yield: 98.9 %

Procedure:
The same operation as in Example (106a) was performed using butyl 2-oxopentanoate (described in Cuvigny; C. R. Hebd. Seances Acad. Sci.; 240; 1955; 206, 12 g, 69.8 mmol), bromine (3.33 mL, 65 mmol) and chloroform (80 mL), to obtain 16.15 g of the title compound as a colorless liquid (99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:27]1[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][N:28]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:36][O:35][C:33]([C:30]1[CH:31]=[CH:32][C:27]([O:25][CH2:24][C@@H:9]2[CH2:10][C@H:11]([O:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)[CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:28][CH:29]=1)=[O:34]
Reactant: COC(=O)c1ccc(O)nc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)OC(C)(C)C)nc1
Yield: 25.2 %

Procedure:
To a stirred mixture of (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylmethanol (484 mg, 1.41 mmol), methyl 2-hydroxy-5-pyridinecarboxylate (216 mg, 1.41 mmol) and PPh3 (370 mg, 1.41 mmol) in THF (15 ml) was added DIAD (0.28 ml, 1.41 mmol) at room temperature under an atmosphere of nitrogen. The mixture was stirred over night. After removal of the solvent, the resulting residue was chromatographed on silica gel [50 g, n-hexane/EtOAc(2/1)], to give methyl-2-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxypyridine-5-carboxylate (170 mg, 25%) as a colorless oil. 1H-NMR (CDCl3) δ 1.47 (s, 9H), 2.37 (m, 1H), 2.46 (d, J=14.2 Hz, 1H), 3.71–4.00 (m, 2H), 3.89 (s, 3H), 4.30–4.56 (m, 2H), 4.74 (dd, J=9.8, 4.6 Hz, 1H), 5.06 (br, 1H), 6.70 (d, J=8.8 Hz, 2H), 7.05–7.09 (m, 21H), 7.33 (t, J=6.9 Hz, 1H), 7.42 (t, J=6.9 Hz, 1H), 7.67–7.75 (m, 3H), 8.09 (d, J=8.8 Hz, 1H), 8.77 (d, J=2.2 Hz, 1H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5](Br)[CH:4]=1.Cl.[CH3:17]C1C=C(C)C=CC=1NN>>[ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5]([CH3:17])[CH:4]=1
Reactant: Cc1ccc(NN)c(C)c1
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Agent: Cl
Product: Cc1cc(C)c2[nH]cc(CCN)c2c1

Procedure:
5,7-Dimethyltryptamine hydrochloride was prepared (2.86 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2,4-dimethylphenylhydrazine hydrochloride (15.0 g) as starting material.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>C1COCC1>[CH2:17]([O:16][C:14](=[O:15])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11][C:12]([C:29]1[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[C:31]([O:32][CH3:33])[CH:30]=1)=[O:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Reactant: COc1ccc([Mg]Br)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CCC(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1OC
Reaction time: 2 h

Procedure:
A solution of (2S)5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (8.20 g, 0.026 mol, 1.0 equivalent) in anhydrous THF was cooled to 0° C. in an ice bath under N2. A chilled 0.5M solution of 3,4-dimethoxyphenylmagnesium bromide in THF (52.lmL, 0.026 mol, 1.0 equivalent) was slowly added. The reaction mixture was allowed to stir for two hours. The reaction was quenched upon addition of saturated NH4Cl solution (10 ml). The mixture was partitioned between ethyl acetate and brine. The organic extract was washed with brine (3×100 ml). The ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting crude blue oil was filtered through a layer of silica. The filtrate was concentrated in vacuo to afford 2-tert-butoxycarbonylamino-5-(3,4-dimethoxy-phenyl)-5-oxo-pentanoic acid benzyl ester (10.46 g, 0.023 mol, 88%yield). Analysis H1 NMR (400MHz, CDCl3): 7.5–7.3 (6H, m), 7.0–6.7 (2H, m), 5.2 (2H, m), 4.0–3.8 (6H, m), 3.0 (1H, m), 2.6–1.9 (4H, m), 1.4 (9H, s). MS (LC-MS): Calculated for C25H31NO7 457.21. Found 458.19 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([CH2:53][OH:54])[CH:49]=[C:50]([NH2:52])[CH:51]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1>>[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:51]=[C:50]([NH:52][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]6[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=6)[CH2:21][CH2:22]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH:49]=[C:48]([CH2:53][OH:54])[CH:47]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(Cl)cc(Cl)c3)CC2)cc1C(=O)O
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(Cl)cc(Cl)c3)CC2)cc1C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 71.2 %

Procedure:
The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3,5-dichlorophenyl)-piperazine-1-carbonyl]-amino}-6-methoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound.