Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][Al](C)C.[CH2:5]([C:7]1[NH:8][C:9]([CH2:18][CH3:19])=[CH:10][C:11](=[O:17])[C:12]=1[C:13](OC)=[O:14])[CH3:6].CO>ClCCl>[CH2:5]([C:7]1[NH:8][C:9]([CH2:18][CH3:19])=[CH:10][C:11](=[O:17])[C:12]=1[C:13]([NH2:1])=[O:14])[CH3:6]
Reactant: C[Al](C)N
Reactant: CCc1cc(=O)c(C(=O)OC)c(CC)[nH]1
Solvent: ClCCl
Solvent: CO
Product: CCc1cc(=O)c(C(N)=O)c(CC)[nH]1
Reaction time: 20 h

Procedure:
A 1.3M solution of aminodimethyl aluminium in dichloromethane (obtained as described in Tetrahedron Letters, 1979, 4907) (7.8 ml) was added to a solution of methyl 2,6-diethyl-1,4-dihydro-4-oxopyridine-3-carboxylate (1.05 g in dichloromethane (50 ml) and the solution was left to stand for 20 hours. Methanol (5 ml) was added and the mixture was stirred for 1 hour. The precipitated solid was removed by filtration through a bed of diatomaceous earth. The filtrate was concentrated and the residue purified by flash chromatography, eluting with methanol/dichloromethane (1:9 v/v), to give 2,6-diethyl-1,4-dihydro-4-oxopyridine-3-carboxamide (0.5 g), m.p. 254° C.; NMR (d6 -DMSO): 1.15-1.25(m,6H), 2.5(q,2H), 3.0(q,2H), 6.1(s,1H), 7.0(br s, 1H), 9.6(br s, 1H), 11.3(br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:30](=[O:32])=[O:31]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:30]([OH:32])=[O:31])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)cc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)c(C(=O)O)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-5-fluoro-1,2-benzisoxazole (0.30 g) in tetrahydrofuran (20 ml) was added lithium diisopropylamide (1.4 ml, 1.5M cyclohexane solution) dropwise at -70° C. under nitrogen atmosphere, and the reaction mixture was stirred at the same temperature for 15 minutes. Gaseous carbon dioxide was introduced for 10 minutes and the temperature was allowed to rise to 0° C. The reaction mixture was poured into ice water (40 ml) and washed with diethylether (40 ml each) twice. The aqueous layer was separated, and after the pH was adjusted to 4 with potassium dihydrogen phosphate, it was then extracted with ethyl acetate (each with 40 ml) twice. The combined extracts were dried over anhydrous magnesium sulphate, filtered and the solvent was evaporated under reduced pressure to give the title compound (0.31 g, 90% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C@:2]12[C@@H:22]([Cl:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17]O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:37])[CH:4]=[CH:5][C:6](=[O:36])[CH:7]=1.[Cl-:38].[Li+]>CN(C)C=O.O>[Cl:1][C@:2]12[C@@H:22]([Cl:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][Cl:38])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:37])[CH:4]=[CH:5][C:6](=[O:36])[CH:7]=1
Reactant: [Cl-]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCC(=O)c4ccccc4)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](Cl)[C@@]12Cl
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCC(=O)c4ccccc4)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](Cl)[C@@]12Cl

Procedure:
A solution of 9,11β-dichloro-17,21-dihydroxy-16α-(2-oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione, 21-methanesulfonate (1 mmole) in 20 ml of dimethylformamide is heated at 80°C for 3 hours with 1 g of lithium chloride, cooled, diluted with water and filtered to give the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([NH2:39])[C:18]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([NH:39][C:1](=[O:3])[CH3:2])[C:18]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CC1CCN(CCOc2ccc(C#Cc3ncc(-c4ccc(Cl)cc4)cc3N)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2ccc(Cl)cc2)cnc1C#Cc1ccc(OCCN2CCC(C)CC2)cc1

Procedure:
125 μL (1.345 mmol) of acetic anhydride was added at RT to a solution of 100 mg (0.224 mmol) of 5-(4-chlorophenyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridin-3-ylamine (Example 19.1d) and 62 μL (0.448 mmol) of triethylamine in 5 mL of DCM and the mixture was refluxed for 72 hours. The reaction mixture was diluted with DCM, and the organic phase was washed with saturated aqueous sodium bicarbonate solution, water, and 12% aqueous HCl, dried over magnesium sulfate, and evaporated down in vacuo. The residue was triturated with DIPE, and the precipitate was filtered off and dried in vacuo. The crude product was purified by HPLC-MS (Zorbax Stable Bond C18, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). Yield: 23 mg (21% of theoretical); C29H30ClN3O2 (M=488.020); calc.: molpeak (M+H)+: 488/490 (Cl); found: molpeak (M+H)+: 488/490 (Cl); HPLC-MS: 5.01 minutes (method B).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33]C(C1N(C)C(C(S(C2C=CC=CC=2)(=O)=O)N)=CC(=O)C=1OCC1C=CC=CC=1)=O>>[CH3:32][NH:33][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])(=[O:19])=[O:20])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:31]
Reactant: Cn1c(CNS(=O)(=O)c2ccccc2Cl)cc(=O)c(OCc2ccccc2)c1C(=O)O
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2Cl)n1C
Yield: 58.24 %

Procedure:
3-Benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-03) (210.0 mg, 58.24%) was synthesized as a brown solid from 3-benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-03) (350.0 mg, 0.758 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyoxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-01).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1.CC(=CC)C.Cl([O-])=[O:18].[Na+].P(O)(O)([O-])=O.[Na+]>O.O1CCOCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([OH:18])=[O:11])=[CH:2]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c[nH]c2ncccc12
Temperature: 20 °C
Reaction time: 15 h
Yield: 86.4 %

Procedure:
2.3 g (15.7 mmol) of 1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde and 23 cm3 (217 mmol) of 2-methyl-2-butene were added to 120 cm3 of dioxane at a temperature of 20° C. and then a solution of 2.7 g (30 mmol) of sodium chlorite and 9.2 g (66.7 mmol) of monosodium phosphate in 100 cm3 of water was added. After stirring at a temperature in the region of 20° C. for 15 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was taken up in 50 cm3 of water, filtered off, rinsed with 3 times 30 cm3 of water and then dried under a hood for 16 h. 2.2 g of 1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid were thus obtained in the form of a white powder. Mass spectrum: EI: m/z=162 M+ base peak.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].N1C=CC=CC=1.[F:12][C:13]([F:18])([F:17])[C:14](Cl)=[O:15]>C(Cl)Cl>[CH2:1]([O:3][CH:4]=[CH:5][C:14](=[O:15])[C:13]([F:18])([F:17])[F:12])[CH3:2]
Reactant: C=COCC
Reactant: O=C(Cl)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC=CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In 150 ml of methylene chloride, 21 ml (0.22 mol) of ethyl vinyl ether and 26.1 g (0.33 mol) of pyridine were dissolved, and 43.8 g (0.33 mol) of trifluoroacetyl chloride was blown into this solution over a period of 30 minutes at room temperature. The mixture was further stirred at room temperature for 2.5 hours. Then, the reaction solution was extracted by an addition of 100 ml of methylene chloride and 100 ml of ice water.
Reaction SMILES: CN(C)S(C1C=[C:10]2[C:11]([O:13][C:14](=[O:16])[NH:15][C:9]2=[CH:8]C=1)=O)(=O)=O.COC([N:23]1CCN[CH2:25][CH2:24]1)=O.C(=O)=O>O1CCOCC1>[CH2:11]([O:13][C:14]([N:15]1[CH2:9][CH2:8][NH:23][CH2:24][CH2:25]1)=[O:16])[CH3:10]
Reactant: CN(C)S(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: COC(=O)N1CCNCC1
Agent: O=C=O
Solvent: C1COCCO1
Product: CCOC(=O)N1CCNCC1

Procedure:
13.5 g of 5-(dimethylsulphamoyl)-isatoic acid anhydride and 70 ml of absolute dioxane are gently warmed. As soon as the reaction mixture has reached 40°C, a solution of 8.3 g of N-methoxycarbonylpiperazine is added dropwise and the mixture is then heated further, an evolution of carbon dioxide setting in at about 70°C. The mixture is heated under reflux for a further hour and allowed to cool somewhat, insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The colourless crystals which are precipitated are filtered off with suction and recrystallised from 350 ml of methanol. 13.1 g of 1-[5-dimethylsulphamoyl)-anthraniloyl]-4-ethoxycarbonyl-piperazine, melting point 202°-204°C, are thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:8](O)=[O:9]>>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:8]=[O:9])=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: O=CO
Product: O=CNc1ccncc1

Procedure:
Was prepared according to Example 2 from 4-aminopyridine and formic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:15]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:21][CH2:22][CH2:23][NH:24][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: NCCCc1ccccc1
Product: COc1cccc2cc(C(=O)NCCCc3ccccc3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and 3-phenylpropylamine to give N-(3-phenylpropyl)-7-methoxybenzofuran-2-carboxamide (Compound 239a). Successively, it was formylated to give N-(3-phenylpropyl)-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 239b), then compound 239b was reacted with cyclobutylamine to give compound 23.9 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2.C(O)(=O)C>O>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[C:4]([F:19])[CH:3]=1
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetrahydrophthalic anhydride (7.56 g) and acetic acid (50 g) was heated at 90° to 95° C. for 7 hours. The reaction mixture was cooled to room temperature, and water (75 g) was added thereto. The precipitated crystals were collected by filtration to give the compound (I) (15.7 g).
Reaction SMILES: [C:1]1([CH:7]([CH2:12][C:13]([OH:15])=[O:14])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CCCCCC>[C:1]1([CH:7]2[CH2:8][C:9](=[O:11])[O:15][C:13](=[O:14])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(CC(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C1CC(c2ccccc2)CC(=O)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
3-Phenylglutaric acid (100 g) in CH2Cl2 (800 mL) was treated with dicyclohexylcarbodiimide (104 g) in CH2Cl2 (400 mL) over 30 minutes. The resulting mixture was stirred at ambient temperature for 48 hours. The reaction mixture was then diluted with hexane (800 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue crystallized from ethyl acetate/hexane to afford the title compound (53 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]3=[O:31])[C@H:26]([OH:37])[C@@H:25]2[OH:38])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:50]([CH2:52][CH2:53][O:54][CH2:55]Cl)#[N:51].C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]3=[O:31])[C@H:26]([O:37][CH2:55][O:54][CH2:53][CH2:52][C:50]#[N:51])[C@@H:25]2[OH:38])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[CH:39]=[CH:40][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: N#CCCOCCl
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 31.3 %

Procedure:
5′-O-(4,4′-Dimethoxytrityl)uridine (546 mg, 1 mmol) was dissolved in 4 mL of 1,2-dichloroethane, and 452 mg of diisopropylethylamine (3.5 mmol) was added thereto, and 365 mg of dibutylstannyl dichloride (1.2 mmol) was further added thereto. The reaction was performed at room temperature for 1 hour. Subsequently, the reaction was performed at 80° C., and 155.4 mg of chloromethyl 2-cyanoethyl ether (1.3 mmol) was added dropwise, and the reaction solution was stirred for 30 minutes. After the reaction completed, the reaction solution was added into an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride, and the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by 30 g of silica gel column chromatography to obtain 5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl)uridine (197 mg, yield 34%).
Reaction SMILES: C(O)C.[NH:4](C(OCC1C=CC=CC=1)=O)[C@H:5]([C:25]([O:27]CC1C=CC=CC=1)=[O:26])[CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:15]([O:17]CC1C=CC=CC=1)=[O:16])[CH2:12][CH2:13][CH3:14])=[O:9].[H][H]>[Pd].O>[NH2:4][C@H:5]([C:25]([OH:27])=[O:26])[CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:15]([OH:17])=[O:16])[CH2:12][CH2:13][CH3:14])=[O:9]
Reactant: [H][H]
Reactant: CCC[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a mixed solution of ethanol (150 mL) and water (30 mL), Z-Glu(Nva-OBzl)-OBzl (4.05 g) and 5% palladium on carbon (5% palladium/carbon, 0.70 g) was added, and a catalytic reducing reaction was carried out at 50° C. overnight (14 hours) in a hydrogen gas atmosphere. Water (50 mL) was added to the reaction system in small portions during the reaction. The palladium/carbon was removed from the reaction system through filtration and the resulting filtrate was concentrated under reduced pressure. The residue was recrystallized from a small amount of water and ethanol to thus give γ-Glu-Nva (1.50 g) as white crystals. Furthermore, the crystals were dissolved in water (100 mL) followed by the lyophilization of the solution to give γ-Glu-Nva (1.27 g, 5.16 mM) as white powder. The characteristic values thereof are given below:
Reaction SMILES: O[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH2:32])[CH3:28].Cl>O.C(O)C>[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH:32][C:5]1[C:6]2[C:7](=[O:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([NH:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[CH:3][CH:4]=1)[CH3:28]
Reactant: CCN(CC)CCN
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC)CCNc1ccc(NCCN(CC)CC)c2c1C(=O)c1ccccc1C2=O
Temperature: 90 °C
Yield: 7.6 %

Procedure:
A mixture of 5 g (0.021 mol) of 1,4-dihydroxyanthracene-9,10-dione and 2 g (0.014 mol) of sodium dithionite in 20 ml water is stirred whilst heating under nitrogen at 90° C. until the mixture turns from orange to brown indicating the presence of 2,3-dihydro(leuco)-1,4-dihydroxyanthracene-9,10-dione. To this reaction mixture is added dropwise 20 g (0.17 mol) of 2-(diethylamino)-ethylamine over a 30 minute period. The mixture is heated at 50°-55° C. for 2 hours and 20 ml of ethanol are added. The solution is then aerated and 200 ml of 2M hydrochloric acid are added. The acidic mixture is washed with 3×200 ml of diethylether followed by 3×200 ml of chloroform. The aqueous phase is made alkaline by the addition of sodium hydroxide solution and extracted with 3×200 ml chloroform. The mixture is evaporated in vacuo to a 5 ml volume and subjected to flash chromatography using a column of 70-230 mesh (60 A) silica gel (SiO2) and an eluting solvent of chloroform followed by chloroform:methanol (1:1 v/v). The blue black material removed from the column in chloroform/methanol is evaporated in vacuo to yield 0.7 g of the title compound, m.p. 107.5°-108.5° C.; λmax λmax (deionised water) (E/cm/M) 256 nm (50950), 584 nm (18650).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:16]([S:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]O)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH2:16]([S:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][O:1][C:2]3[CH:15]=[CH:14][C:5]4[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=4[CH:3]=3)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:17]
Reactant: CCSCCOc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCSCCOc1cc(C)c(-c2cccc(COc3ccc4c(c3)OC[C@H]4CC(=O)OC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.250 g, 1.20 mmol), {4′-[2-(ethylthio)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methanol (0.380 g, 1.20 mmol) and tributylphosphine (0.388 g, 1.92 mmol) in toluene (20 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.484 g, 1.92 mmol) was added, and the mixture was stirred at room temperature for 1 hr under nitrogen atmosphere. Hexane (10 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60) to give the title compound (0.363 g, yield 60%) as a pale-yellow oil.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:26](OCC)=[O:27]>C1COCC1.CCCCCC>[C:15]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:26]=[O:27])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC=O
Reactant: Cn1nnnc1C=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nnnc1C(C=O)=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
A solution of 2,2-diphenyl-1-(1-methyl-1H-tetrazol-5-yl)ethene (3.75 g; 14.29 mmole) in dry THF (40 mL) was cooled to -78° C. and treated with n-butyllithium (6.3 mL of a 2.5M soln. in hexane; 15.75 mmole) and the resulting mixture stirred at -78° C. for 30 minutes. Ethyl formate (1.5 mL; 18.58 mmole) was added and the mixture stirred at -78° C. for 2 hours. The reaction was quenched with 2N HCl and the solvent removed by evaporation. The residue was extracted with EtOAc (3×30 mL) and the combined organic layers were dried (MgSO4) and evaporated. The residue was purified by chromatography using 25-35% EtOAc-hexane as eluent to afford starting material (1.35 g; 36%) and the desired title compound (1.65 g; 39%); m.p.=185°-186° C. (crystallized EtOAc-hexane). MS (EI): m/e=290 for M+
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27].Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]1[C:8](=[O:10])[C:7]2[C:2](=[N:3][C:4]([S:13][CH3:14])=[N:5][CH:6]=2)[NH:1][C:26]1=[O:27]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1cnc(SC)nc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ncc2c(=O)n(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
To a solution of 1.0 g of ethyl 4-amino-2-(methylsulfanyl)pyrimidine-5-carboxylate in 15 mL of N,N-dimethylformamide, 315 mg of sodium hydride was added, and the resulting mixture was stirred at room temperature for 5 minutes. To the reaction mixture, 970 mg of 2,6-dichlorophenyl isocyanate was added, and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture, ethyl acetate and a 1 N aqueous hydrochloric acid solution were added and the organic layer was separated. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The precipitated solid was solidified with methanol and collected by filtration, whereby 1.43 g of the title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:19][CH3:20])=[CH:8][C:9]([N+:16]([O-])=O)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]>CCOC(C)=O.[Pd]>[NH2:16][C:9]1[CH:8]=[C:7]([O:19][CH3:20])[C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(OCCCCl)c(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCCCCl)c(OC)cc1N
Yield: 99.5 %

Procedure:
Methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate (6.70 g, 22.1 mmol) in EtOAc (100 mL) was reacted with H2 in the presence of 10% palladium on carbon in the manner described in Example 16A Step 3 to give methyl 2-amino-5-(3-chloropropoxy)-4-methoxybenzoate (6.0 g, 22.0 mmol, 99%). 1H NMR (300 MHz, DMSO-d6) δ 7.18 (s, 1H), 6.49 (br s, 2H), 6.37 (s, 1H), 3.93 (t, 2H), 3.82-3.71 (m, 8H), 2.14-2.06 (m, 2H); LC-MS (ESI) m/z 274 (M+H)+.