Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]([CH3:21])[CH3:20].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:18]([O:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:2][CH:3]([CH3:7])[CH3:4])=[CH:7][C:3]=1[C:4]([O:6][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:5])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CBr
Reactant: O=C(O)c1cc(O)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)COC(=O)c1cc(OCC(C)C)ccc1OCC(C)C
Temperature: 110 °C
Reaction time: 6 h

Procedure:
In 200 ml of N,N-dimethylformamide are suspended 10 g of 2,5-dihydroxybenzoic acid, 148 g of potassium carbonate and 106 ml of isobutyl bromide. The mixture is stirred at 110° C. for 6 hours. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) to obtain 18 g of isobutyl 2,5-diisobutoxybenzoate as a light yellow oily product.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.C([C:27]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=1[C:34]([C:36]1C=CC(O)=CC=1CC1C=CC=CC=1)=[O:35])C1C=CC=CC=1>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:33][C:31]2[CH:32]=[CH:27][C:28]([C:34](=[O:35])[CH2:36][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:29][CH:30]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Reactant: O=C(c1ccc(O)cc1Cc1ccccc1)c1ccc(O)cc1Cc1ccccc1
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=O)Cc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and benzyl-4-hydroxyphenylketone in a manner analogous to that described for Example 5, Step B. MS(ES) for C27H24O5 [M−H]−: 427.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[OH:31])/[C:8]([NH:10][C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([OH:27])=[O:26])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:38](=[O:50])([O:46][CH:47](I)[CH3:48])[O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.Cl>CN(C)C(=O)C.C(OCC)(=O)C.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[OH:31])/[C:8]([NH:10][C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O:27][CH2:48][CH2:47][O:46][C:38]([O:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:50])=[O:26])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(I)OC(=O)OC1CCCCC1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cn[nH]c4)CS[C@H]23)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)OCCOC(=O)OC4CCCCC4)=C(SCc4cn[nH]c4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.9 %

Procedure:
To a solution of 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid (300 mg) in N,N-dimethylacetamide (6 ml) was added potassium carbonate (81.8 mg) under ice-cooling. After stirring at room temperature for 30 minutes, cyclohexyl 1-iodoethyl carbonate (371.47 mg) was added thereto under ice-cooling. The mixture was stirred at the same temperature for 30 minutes, poured into a mixture of water and ethyl acetate and adjusted to pH 5 with 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated to give (cyclohexyloxycarbonyloxy)ethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (15.8 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][CH:8]([CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1)[C:9](OCC)=[O:10].Cl.C(OCC)(=O)C>C1COCC1>[F:7][CH:8]([CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:22][CH2:23][CH:24]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:26]2)[CH2:17][CH2:16]1)[CH2:9][OH:10]
Reactant: CCCC1CCC(C2CCC(CC(F)C(=O)OCC)CC2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(CC(F)CO)CC2)CC1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 0.3 g of lithium aluminum hydride and 10 ml of THF were added and the resultant mixture was cooled to −10° C. Thereto, 1.4 g of ethyl 2-fluoro-3-(4′-propyl-[1,1′-bi(cyclohexane)]-4-yl)propanoate (e-5) dissolved in 10 ml of THF was added dropwise in a temperature range of −10° C. to 0° C. Then, the resultant mixture was heated to 25° C., and stirred for 1 hour. Subsequently, 100 ml of 1 N HCl aqueous solution and 100 ml of ethyl acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was isolated, and washed with water, and then the resultant solution was dried over anhydrous magnesium sulfate. The resultant solution was concentrated under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=5:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 1.2 g of 2-fluoro-3-(4′-propyl-[1,1′-bi(cyclohexane)]-4-yl)propan-1-ol (e-6) was obtained. A yield based on compound (e-5) was 92.8%.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][N:8]1[C:13](=O)[NH:12][C:11]([CH2:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17].P(Cl)(Cl)([Cl:21])=O>ClCCCl>[Cl:21][C:13]1[N:8]([CH3:7])[S:9](=[O:18])(=[O:17])[N:10]=[C:11]([CH2:15][CH3:16])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC1=NS(=O)(=O)N(C)C(=O)N1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCC1=NS(=O)(=O)N(C)C(Cl)=N1

Procedure:
110 parts of phosphorus pentachloride were added to a stirred mixture of 86 parts of 2-methyl-5-ethyl-2H-1,2,4,6-thiatriazine-3-one-1,1-dioxide, 100 parts of 1,2-dichloroethane and 112 parts of phosphorus oxychloride at room temperature. The reaction mixture was then stirred under reflux for 12 hours. After concentration, 94 parts (100% of theory) of 3-chloro-2-methyl-5-ethyl-2H-1,2,4,6-thiatriazine-1,1-dioxide of nD25 =1.5331 were obtained. (NMR (60 MHz, CDCl3): CH3 -N 3.7δ). The very pure product (nD25 =1.5337) boils at 123°-125° C./0.2 mbar (Compound No. 3).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])=[C:19]([Cl:30])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C)C=O>[Cl:30][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[C:7]([O:31][CH3:32])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCBr)c(OC)cc23)cc1Cl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCN4CCCCC4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (500 mg), potassium carbonate (857 mg), and 1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 451 mg (yield 71%) of N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea. N-(4-{[7-(3-Bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea (70 mg), potassium carbonate (54 mg), and piperidine (39 μl) were dissolved in N,N-dimethylformamide (2 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol (20/1) to give 35 mg (yield 50%) of the title compound.
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[O:1]=[C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:31]2[CH2:32][CH2:33][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:29][CH2:30]2)=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)CCC(=O)c1ccc(CCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC(=O)c1ccc(CCCCN2CCN(c3cccc(C)c3)CC2)cc1
Yield: 58.5 %

Procedure:
20 g of ethyl 4-oxo-4-[4-(4-chlorobutyl)phenyl]butyrate and 12 g of 1-(3-methylphenyl)piperazine are dissolved in a mixed solvent of 80 ml of dimethylformamide and 80 ml of toluene. To this solution, 14 g of potassium carbonate is added, and this is followed by reflux with heating for 18 hours under stirring the solution. After the completion of the reaction, the reaction liquid is concentrated under reduced pressure and extracted with ethyl acetate. After being washed with water, the extract is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting oily substance is purified by silica gel column chromatography, after which it is crystallized with isopropyl ether to give 17.2 g of ethyl 4-oxo-4-[4-(4-(4-(3-methylphenyl)piperazin-1-yl)butyl)phenyl ]butyrate having a melting point of 62° to 63° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH3:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:24][N:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19](=[O:21])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:23])([F:1])[F:22])=[N:4]2)=[CH:13][CH:14]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: CN(Cc1ccccc1)C(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid and N-methylbenzylamine using a similar procedure to that described for Example 13, but purified by flash column chromatography eluting from 0-66% ethyl acetate in hexane.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][C:22]=4[C:29]([F:32])([F:31])[F:30])[N:17]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:41])C=1>C(Cl)Cl>[O:41]1[CH2:28][CH:27]1[C:24]1[CH:25]=[CH:26][C:21]([C:18]2[N:17]=[C:16]([C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:11]=3[C:12]([F:13])([F:14])[F:15])[O:20][N:19]=2)=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:23]=1
Reactant: C=Cc1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)c(C(F)(F)F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: FC(F)(F)c1cc(C2CO2)ccc1-c1noc(-c2onc(-c3ccccc3)c2C(F)(F)F)n1
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a mixture of 5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-3-(2-(trifluoromethyl)-4-vinylphenyl)-1,2,4-oxadiazole (56 mg, 0.124 mmol) in DCM (5 mL) was added mCPBA (64.2 mg, 0.372 mmol). The reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethane and washed with 1N NaOH. The organic layer was dried with MgSO4, filtered, and concentrated to yield 50 mg of 3-(4-(oxiran-2-yl)-2-(trifluoromethyl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole. MS (m+1)=468. HPLC Peak RT=2.12 minutes (Analytical Method B).
Reaction SMILES: [OH:1][CH:2]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:3]([NH:5][CH:6]1[C:17](=[O:18])[N:8]2[C:9]([C:14]([O-:16])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]12)=[O:4].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[OH:1][CH:2]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:3]([NH:5][CH:6]1[C:17](=[O:18])[N:8]2[C:9]([C:14]([OH:16])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]12)=[O:4]
Reactant: CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(O)c3cccs3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3cccs3)[C@H]2SC1
Yield: 90.6 %

Procedure:
Diphenylmethyl (6R,7R,2'R and S)-7-(2' -hydroxy-2'-[thien-2-yl]-acetamido)-3-methylceph-3-em-4-carboxylate (543mg, 1.05mmole) was dissolved in anisole (4ml) and stirred with trifluoroacetic acid (4 ml) at +20 to +25° for 7 mins. The anisole and trifluoroacetic acid were evaporated and the residue partitioned between 3%-aqueous sodium bicarbonate solution (ca 50ml) and ethyl acetate (ca 50ml). The aqueous layer was washed with ethyl acetate (3×ca 50ml), layered with ethyl acetate and adjusted to pH 2.5. The ethyl layer was combined with the ethyl acetate backwash of the aqueous layer, dried, and evaporated to give (6R,7R,2'R and S)-7-(2' -hydroxy-2'-[thien-2-yl]-acetamido)-3-methylceph-3-em-4-carboxylic acid as a foam (337mg, 91%). This foam was dissolved in acetone (3ml) and stirred with a solution of sodium 2-ethylhexanoate (186mg, 1.05 mmole) in acetone (2ml) and ether (2ml). The precipitated material was filtered off, washed with ether, and dried to give the title compound containing 2mole-equivalents of water (i.r., microanalysis and 1/6 mole-equivalents of ether (n.m.r., microanalysis) as a pale-brown solid (183mg, 0.486 mmole, 46.4%); λmax (pH6-buffer) 237.5nm, inflexion at 255nm (ε12,640 and 9,250 respectively); νmax (nujol) 3380 (NH,H2O), 1760 (azetidin-2-one), 1680 and 1528 (CONH), and 1600 cm-1 (CO2 -); τ (Me2SO-D6) 1.48 and 1.63 (total 1H, 2d,J9Hz,NH), 2.54 to 3.10 (3H, m, thiophene protons), 4.46 (ca 1H, m, C7 -H), 4.60 and 4.62 (total ca 1H, 2S, CHOH), 5.00 (1H,d,J4.5Hz, C7 -H), 6.49 and 6.87 (2H, ABq, J18Hz, C2 -H2), 8.01 (3H,s, C3 -CH3). A signal at τ 8.89 revealed the presence of 1/6 mole-equivalent of diethyl ether. (Found: C,41.1, 41.4; H,3.6, 3.8;N,6.6, 7.0; S,14.5. C14H13N2NaO5S2. 1/6 C2H5OC2H5. 2H2O (424.7) requires C,41.5; H,4.4; N,6.5; S,15.1%).
Reaction SMILES: C([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1
Reactant: CCc1ccc(Cc2ccc(NC(C)=O)[nH]c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(Cc2ccc(N)[nH]c2=O)cc1
Yield: 8.1 %

Procedure:
To a solution of 6-(N-acetylamino)-3-(4-ethylbenzyl)-1H-pyridin-2-one (0.19 g) in methanol (1 mL) was added 2 mol/L aqueous sodium hydroxide solution (0.35 mL), and the mixture was added for 22 hours at 80° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloro-methane/methanol=6/1) to give 6-amino-3-(4-ethylbenzyl)-1H-pyridin-2-one (0.013 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]=[C:14]([Cl:16])[CH3:15])=[CH:7][N:6]=1)=[O:4].Cl>>[Cl:16][C:14]([CH3:15])=[CH:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCC=C(C)Cl)cn1
Agent: Cl
Product: CC(Cl)=CCOc1ccc(C(=O)O)nc1

Procedure:
A mixture of 3.0 g of 5-(3-chloro-2-butenyloxy)-2-pyridinecarboxylic acid methyl ester and 30 ml of 6 N-hydrochloric acid is heated on a steam bath for one hour. After that, the solution is cooled and the pH is adjusted to 5-6. Then the solution is evaporated and the residue extracted with ethanol. The ethanol extract is evaporated to yield 5-(3-chloro-2-butenyloxy)-2-pyridinecarboxylic acid melting at 96°-98°.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N[C@@H:17](C(O)=O)CC1C2C(=CC=CC=2)NC=1>>[CH2:17]1[C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH2:3][C@@H:2]([C:13]([OH:15])=[O:14])[NH:1]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1

Procedure:
When L-tryptophan is substituted for D-tryptophan in Example 1E, (3S)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid is obtained.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[K+].Cl.[F:36][C:37]([F:49])([F:48])[C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[CH2:44][NH:43][CH2:42][CH2:41]2.Br[C:51]1[CH:56]=[C:55]([CH3:57])[C:54]([NH:58][C:59](=[O:65])[CH2:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[C:53]([CH3:66])[CH:52]=1>C1(C)C=CC=CC=1>[CH3:57][C:55]1[CH:56]=[C:51]([N:43]2[CH2:42][CH2:41][C:40]3[C:45](=[CH:46][CH:47]=[C:38]([C:37]([F:36])([F:48])[F:49])[CH:39]=3)[CH2:44]2)[CH:52]=[C:53]([CH3:66])[C:54]=1[NH:58][C:59](=[O:65])[CH2:60][C:61]([CH3:63])([CH3:62])[CH3:64]
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(C(F)(F)F)ccc3C2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (800 mg, 2.0 mmol) were added to dry toluene (150 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (4.75 mg, 42.3 mmol), 6-Trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt (4.82 g, 20.3 mmol) and N-(4-Bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butyramide (5 g, 16.8 mmol) were then added and the reaction mixture was stirred at 80° C. over night. The reaction mixture was then cooled to room temperature and recrystallized from toluene to afford the title compound as a solid. (5.55 g, 79%).
Reaction SMILES: [N+:1]([C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH:12]=[C:11]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=3)[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.C(O)C.[H][H]>[Pd].C1COCC1>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]2[CH:12]=[C:11]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[CH:30][CH:31]=3)[CH:10]=[C:9]([O:8][C:7]3[CH:35]=[CH:36][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH:14]=2)=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Oc3ccc([N+](=O)[O-])cc3)cc(Oc3ccc([N+](=O)[O-])cc3)c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Oc2cc(Oc3ccc(N)cc3)cc(Oc3ccc(N)cc3)c2)cc1
Yield: 100 %

Procedure:
To a 300-mL, 4-necked flask were added 2.46 g (5.03 mmol) of 1,3,5-tri(4-nitrophenoxy)benzene and 5% Pd/C (149 mg), and the inside was replaced with argon. Ethanol (50 mL) and THF (50 mL) were added thereto, and then the flask was equipped with a hydrogen balloon, and the mixture was stirred in a normal-pressure hydrogen atmosphere at room temperature for 3 days. The catalyst was separated by filtration and then the solvent was removed away in vacuo, whereby a desired product was obtained (Quantity: 2.01 g, 5.03 mmol, Yield: 100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=O.[F:27][C:28]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:29][NH2:30]>>[F:27][C:28]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:29][NH:30][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:2]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nn1C
Reactant: NCC(F)(F)C(F)(F)F
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)NCC(F)(F)C(F)(F)F
Yield: 26 %

Procedure:
As described for example 100f, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.27 mmol) was converted, using 2,2,3,3,3-pentafluoropropylamine instead of isopropylamine, to the title compound (35 mg, 26%) which was obtained as a white solid. MS: m/e=495.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)=[C:22]([OH:31])[CH:21]=2)[CH2:15][CH2:14]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:34][CH2:35][N:36]([CH3:38])[CH3:37].O>CN(C)C=O>[CH3:3][N:4]([CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)=[C:22]([O:31][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:21]=2)[CH2:15][CH2:14]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CCCl
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2ccc(-n3cncn3)c(O)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1cc(C(=O)N2CCC(N(C)CCc3ccccc3)CC2)ccc1-n1cncn1
Reaction time: 1 h
Yield: 42.5 %

Procedure:
120 mg of sodium hydride was added, under ice-cooling, to a solution of 1.0 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[3-hydroxy-4-(1,2,4-triazol-1-yl)benzoyl]piperidine in 10 ml of dimethylformamide. The mixture was stirred for 1 hour. Thereto was dropwise added 320 mg of (2-chloroethyl)dimethylamine. The mixture was stirred at room temperature for 2 hours and then at 50° C. for 2 hours. The reaction mixture was poured into 50 ml of water. The mixture was extracted with three 50-ml portions of ethyl acetate. The extract was washed with 50 ml of a saturated aqueous sodium chloride solution, dried with magnesium sulfate, and subjected to distillation to remove the solvent. The residue was purified by a silica gel column chromatography (eluant: dichloromethane/methanol=10/1 to dichloromethane/methanol/ammonia water=100/10/1). The product was recrystallized from ethyl acetate-n-hexane to obtain 500 mg of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[3-(2-dimethylaminoethoxy)-4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.