Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[C:5](Cl)(=[O:9])[C:6](Cl)=O.[C:11]([O:15][C:16](=[O:36])[C@:17]1([CH2:32][CH2:33]CO)[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:11]([O:15][C:16](=[O:36])[C@:17]1([CH2:32][CH2:33][CH2:6][CH:5]=[O:9])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)[C@]1(CCCO)CCCN1C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@]1(CCCC=O)CCCN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 3.2 %

Procedure:
Dry DMSO (9.90 mL, 139 mmol) was added dropwise over 5 min to a stirred cooled (−78° C.) solution of distilled oxalyl chloride (6.3 imL, 73.1 mmol) in CH2Cl2 (150 mL). After 20 min, a solution of the alcohol 5 (26.6 g, 73.1 mmol) in CH2Cl2 (50 mL) was added over 3 h. The resultant slurry was stirred for 30 min at −78° C. and then dry diisopropylethylamine (32.0 mL, 183 mmol) was injected dropwise over 3 h. Stirring was continued at −78° C. for 30 min, the cold bath removed, and after a further 30 min, H2O (100 mL) was added. The mixture was stirred for a further 10 min and the aqueous layer was extracted with CH2Cl2 (2×400 mL). The combined organic layers were washed with 10% v/v aqueous HCl (2×100 mL), saturated aqueous NaHCO3 (2×100 mL), and brine (1×100 mL), dried over MgSO4, and evaporated in vacuo. The residue (26.0 g, 98.5%) could be used without further purification or purified (1 g) by flash chromatograghy (SiO2; 2/8 EtOAc/hexane, Rƒ 0.32) to give 6 (880 mg, 88%) as a clear oil: IR (CH2Cl2 cast) 3032 (w), 2975 (m), 2880 (m), 1719 (s), 1698 (s) cm1; 1H NMR (200 MHz, CDCl3) δ 9.52 & 9.61 (t, 1H, J=2.0 Hz, CHO), 7.18-7.36 (m, 5H, Ar—H, 5.12 & 5.18 (d, 1H, J=10.0 Hz, 1×OCH2), 4.93 & 4.99 (d, 1H, J=11.5 Hz, 1×OCH2:), 3.51-3.78 (m, 1H, 1×δ-CH2), 3.32-3.48 (rn, 1H, 1×δ-CH2), 2.32-2.64 (m, 2H), 1.70-2.32 (m, 6H), 1.30 & 1.32 (s, 9H, C(CH3)3); 13C NMR (50 MHz, CDCl3) δ 202.05 & 201.20, 172.61 & 172.46, 154.47 & 154.44, 136.90 & 136.89, 128.27 & 128.21, 128.08 & 127.93, 127.69 & 127.60, 81.16 & 80.99, 68.11 & 67.38, 66.96 & 66.41, 49.00 & 48.08, 39.02 & 38.63, 37.14 & 35.96, 27.42, 27.02 & 26.75, 22.82 & 22.15.
Reaction SMILES: [H-].[Na+].C[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20]C)([CH3:13])[CH3:12].CCOCC>CN(C)C=O>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])([CH3:13])[CH3:12]
Reactant: COc1ccccc1C(C)(C)c1ccccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(c1ccccc1O)c1ccccc1O
Reaction time: 1 h
Yield: 42.4 %

Procedure:
Sodium hydride (2.60 g of 60 percent dispersion in oil) was placed in a 1 1 flask and extracted twice with pentane. To this was added first 250 ml of dimethylformamide and then, dropwise with stirring over 1 hour, 6.0 ml of ethanethiol in 40 ml of dimethylformamide. 2,2-Bis(2-methoxyphenyl)propane (8.0 g, 31 mmol) in 100 ml of dimethylformamide was then added and the mixture was heated at reflux with stirring for 24 hours and allowed to stand at ambient temperature for another approximately 18 hours. One 1 of ether was added and the resulting solution was extracted with water and twice with 4.0 N sodium hydroxide solution. The combined aqueous extracts were neutralized with concentrated hydrochloric acid to a pH of about 9-10. Ether (500 ml) was then added and, after shaking, the ether layer was separated, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain about 3 g of the title compound as a brown oil containing some dimethylformamide. The proton NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][CH:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>CN(C)C(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[N:3][CH:2]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccncn1
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: O=C(Nc1ccncn1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of pyrimidine-4-amine (1.00 g, 10.5 mmol) and pyridine (2.55 ml, 31.5 mmol) in N,N-dimethylacetamide (50 ml) was added 2,2,2-trichloroethyl chloroformate (2.55 ml, 31.5 mmol) with ice-cooling, and the mixture was stirred for 1 hour with ice-cooling. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate and the desired product (1.97 g, 69.4%) as a solid was collected by filtration.
Reaction SMILES: [C:1]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=O)[CH3:11])[CH2:3][CH:2]=1.C(N(CC)CC)C.Cl.[O:21]([NH2:23])[CH3:22]>CO>[CH3:22][O:21][N:23]=[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]1[CH2:3][CH:2]=1)[CH3:11]
Reactant: CC(=O)CCCCCCC1=CC1
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=C(C)CCCCCCC1=CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.4 %

Procedure:
To a solution of 0.15 g (0.9 mmol) of 8-cycloprop-1-enyl-octan-2-one in 10 mL of methanol cooled in an ice bath was added 0.30 g (3 mmol1) of triethylamine and 0.83 g of a 30-35% aqueous solution of methoxylamine hydrochloride (3 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 1.5 hours. Water and ether were added. The phases were separated and the aqueous phase was washed with ether. The combined ether phases were washed with dilute aqueous hydrochloride acid, water (2×), and brine, then dried over magnesium sulfate, filtered and stripped. Column chromatography gave 50 mg of 8-cycloprop-1-enyl-octan-2-one O-methyl oxime (Compound 47) as a 30% solution in ether. The ratio of oxime isomers was 3:1.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][C:19]=1[CH3:25])([O-:17])=[O:16]>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:11][CH:10]([O:12][C:21]2[CH:22]=[CH:23][C:18]([N+:15]([O-:17])=[O:16])=[C:19]([CH3:25])[CH:20]=2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
In a dry flask, N-Boc-3-hydroxy-azetidine (9.8 g, 57 mmol) was dissolved in 200 mL of dry THF. The solution was cooled with an ice-water bath and sodium hydride (2.0 g, 83.mmol) was added in several portions. The suspension was stirred for an additional 0.5 hours, then 7.9 g of 2-nitro-5-fluorotoluene (7.9 g, 51 mmol) in 100 mL of dry THF was added dropwise. The solution was stirred overnight at room temperature. The THF was removed under vacuum and the residue was partitioned between ethyl acetate and water (100 mL each). The organic layer was collected and the aqueous layer was subsequently extracted twice with ethyl acetate. The combined organic layers were washed with 1 N HCl, water, saturated sodium bicarbonate and brine (50 mL each). The organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by silica gel column (EtOAc/Hexanes 1:19→1:4 gradient) to give 12.0 g (43 mmol, 84% yield) of the title compound, which was used directly in the next step. MS: 309 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][OH:6].N1C=CC=CC=1.[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([O-:19])=[O:18].CCO>C1COCC1>[OH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)[CH:3]=1
Reactant: Cc1ccc(CO)cc1N
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1ccc(CO)cc1NC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a stirred, cooled (0° C.) mixture of 3-amino-4-methylbenzyl alcohol (10.0 g, 0.072 mol) and pyridine (5.8 g, 0.072 mol) in THF (100 ML) was added 3-nitrobenzoyl chloride (13.5 g, 0.072 mol). After 2 h, the mixture was concentrated, suspended in water and filtered to give a brown solid. Trituration with hot EtOH gave 18.8 g (90%) of product as a white solid, mp 198°-200° C.; 1H NMR (DMSO-d6) δ 2.20 (s, 3 H), 4.46 (s, 2 H), 7.12 (dd, J=7.8 Hz, 1.5 Hz, 1 H), 7.25 (dd, J=7.8, 1.5 Hz, 1 H), 7.82 (m, 1 H), 8.41 (m, 2 H), 8.78 (s, 1 H), 10.26 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:25])[CH2:12][CH2:13][NH:14]C(OCC1C=CC=CC=1)=O)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.O.[H][H]>CO.[Pd]>[CH3:9][C:2]([NH:10][C:11](=[O:25])[CH2:12][CH2:13][NH2:14])([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(NC(=O)CCNC(=O)OCc1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(NC(=O)CCN)c1ccccc1
Yield: 84.2 %

Procedure:
1.5 g of palladium-on-carbon were suspended in a solution of 4.51 g of N-(α,α-dimethylbenzyl)-3-(benzyloxycarbonylamino)propionamide (prepared as described in Preparation 2) in 110 ml of an 8:2:1 by volume mixture in methanol, acetic acid and water, and then hydrogen was passed through the solution for 4 hours at room temperature under normal atmospheric pressure. Undissolved materials were filtered off, the pH was adjusted to a value of 10 by the addition of a 10% w/v aqueous solution of sodium hydroxide, and then the mixture was extracted with 150 ml of ethyl acetate. The solution was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure to give 2.3 g of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O>C(#N)C>[NH2:11][C:9]([CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:10]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: NC(=O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CC(N)=O
Temperature: 80 °C

Procedure:
2-Hydroxyphenyl acetamide (1.2 g, 7.93 mmol) was dissolved in acetonitrile (10 mL), and potassium carbonate (5.5 g, 39.6 mmol) was added to the solution. Subsequently, to the mixture, tert-butyl 2-bromoisobutyrate (8.9 g, 39.6 mmol) was added, followed by stirring at 80° C. After completion of reaction, water was added to the mixture. The resultant mixture was extracted with ethyl acetate, followed by washing the organic layer with water. The mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=40/1), whereby the target compound was obtained (1.4 g, 4.87 mmol, 61%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N+:3]=1[O-:12].CC#N.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:19].C([O-])(O)=O.[Na+]>CO>[OH:12][N:3]1[C:2](=[O:19])[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4]1
Reactant: COC(=O)c1ccc(Cl)[n+]([O-])c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1ccc(=O)n(O)c1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
To a 250 mL round bottom flask containing 2-chloro-5-(methoxycarbonyl)pyridine 1-oxide (2.45 g, 13.06 mmol) was added MeCN (10 mL). The resulting mixture was stirred at 23° C. for 5 min. At this time, trifluoroacetic anhydride (20 mL) was added and the reaction was stirred 1 h. Solid NaHCO3 (25 g) was added to the flask followed by MeOH (100 mL). The solid was filtered away and the filtrate was concentrated and subjected to silica gel chromatography (80 g ISCO column, 0-5% MeOH in CHCl3) to give methyl 1-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.N1C=CN=[CH:12]1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].Cl>CN(C)C=O>[C:19]([Si:16]([CH3:18])([CH3:17])[O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:12])=[CH:3][CH:4]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: c1c[nH]cn1
Reactant: OCCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 120.6 %

Procedure:
To N,N-dimethylformamide (6 mL) solution of 2-(4-bromophenyl)ethanol (552 mg), imidazole (248 mg) and tert-butyldimethylsilyl chloride (453 mg) were added. The reaction solution was stirred at room temperature for 3 hours. To the reaction solution, 1N-hydrochloric acid (10 mL) was added. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0→97:3) to obtain the title compound (829 mg) having the following physical properties.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:34])[N:14]([CH3:35])[CH:13]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[OH:33][CH2:32][CH2:31][N:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:16]3[C:15](=[O:34])[N:14]([CH3:35])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:36]5[CH2:48][CH2:47][N:39]6[C:40]7[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=7[CH:46]=[C:38]6[C:37]5=[O:49])[C:6]=4[CH2:5][OH:4])[CH:17]=3)=[N:20][CH:21]=2)[CH2:26][CH2:27]1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(CCO)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(CCO)CC3)cn2)c1=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
A mixture of 123d (187 mg, 0.28 mmol) and LiOH (235 mg, 5.6 mmol) in iPrOH/THF (1:1, 3.5 mL) and H2O (0.5 mL) was stirred at 35° C. for 0.5 h. It was then evaporated in vacuo and the residue was extracted with EtOAc (5 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 123 (40 mg, 31%) as a yellow solid. MS: [M+H]+ 625.4. 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J=2.5, 1H), 8.49 (d, J=5.0, 1H), 7.92 (d, J=2.5, 1H), 7.82 (d, J=2.0, 1H), 7.78 (s, 1H), 7.36 (d, J=5.5, 1H), 7.27-7.25 (m, 1H), 6.89 (s, 1H), 6.81 (d, J=9.5, 1H), 5.04-5.02 (m, 1H), 4.62 (d, J=10, 1H), 4.50-4.47 (m, 1H), 4.34-4.29 (m, 1H), 4.12-4.09 (m, 2H), 3.89-3.85 (m, 1H), 3.71-3.67 (m, 5H), 3.15-3.12 (m, 4H), 2.74-2.54 (m, 10H), 1.92-1.87 (m, 2H), 1.79-1.78 (m, 3H)
Reaction SMILES: C([C:8](CC1C=CC=CC=1)([C:20]([N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C@H:23]1[C:28]([NH:30][C@H:31]([C:37]([O-:39])=[O:38])[CH2:32][CH2:33][C:34]([O-:36])=[O:35])=[O:29])=[O:21])[NH:9]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.[ClH:47]>[Pd].O.O1CCCC1.CO>[ClH:47].[NH2:9][CH2:8][C:20]([N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C@H:23]1[C:28]([NH:30][C@H:31]([C:37]([OH:39])=[O:38])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:29])=[O:21]
Reactant: O=C([O-])CC[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)C(Cc1ccccc1)(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NCC(=O)N1C(=O)CC[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of protected tripeptide 7 (0.45 g, 0.80 mmol), conc. hydrochloric acid (38%, 0.13 cm3) and 10% palladium on activated carbon (0.08 g, 0.08 mmol) in 20% water/tetrahydrofuran (60 cm3) was stirred under an atmosphere of hydrogen at room temperature for 4 h. The solution was filtered through a Celite™ pad, washed with 20% water/tetrahydrofuran (2×30 cm3) and the filtrate evaporated to dryness to form GPyroE.HCl (0.19 g, 74%) as solid. GPyroE.HCl was shown to be exclusively the trans conformer by 1H and 13C NMR analysis5: mp 42-44° C.; [α]D −57.3 (c 0.09 in MeOH); OH (400 MHz; D2O) 2.07-2.14 (1H, m, Gluβ-HAHB), 2.20-2.25 (1H, m, Gluβ-HAHB), 2.30-2.34 (1H, m, Pyroβ-HAHB), 2.60-2.65 (3H, m, Pyro-HAHB and Gluγ-H2), 2.74-2.89 (2H, m, Pyroγ-H2), 4.48-4.59 (3H, Glyα-H2 and Gluα-H) and 4.93-4.95 (1H, m, Pyroα-H); δC (75 MHz, D2O) 22.5 (CH2, Pyroβ-C), 26.4 (CH2, Gluβ-C), 30.5 (CH2, Gluγ-C), 31.8 (CH2, Pyroγ-C), 44.3 (CH2, Glyα-C), 52.7 (CH, Gluα-C), 59.3 (CH, Pyroα-C), 168.5 (quat., Gly-CO), 173.6 (quat., Pyro-CO), 175.2 (quat., Pyro-CO), 177.6 (quat., Glu-CO) and 178.9 (quat., Glu-CO); m/z (FAB+) 316.1138 (MH+.C12H18N3O7 requires 316.1145).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:50])([CH3:49])[CH2:15][O:16][C@@H:17]1[CH2:20][C@H:19]([N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]3[N:46]=[CH:47][N:48]=[C:22]23)[CH2:18]1>C(OCC)(=O)C>[OH:13][C:14]([CH3:49])([CH3:50])[CH2:15][O:16][C@@H:17]1[CH2:18][C@H:19]([N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]4[NH:3][C:4](=[O:7])[O:5][N:42]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]3[N:46]=[CH:47][N:48]=[C:22]23)[CH2:20]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@@H](OCC(C)(C)O)C2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2C[C@@H](OCC(C)(C)O)C2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.31 g), sodium hydrogen carbonate (0.51 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({4-[cis-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.15 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.059 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.069 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].O=[C:20]([CH2:27][CH2:28][CH3:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:20]([CH2:27][CH2:28][CH3:29])=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1Cl
Product: CCCC(=CC(=O)OCC)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-4-fluoro-5-ureidobenzoate and ethyl 3-oxo-caproate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-propylvinyl]ureido}-benzoate,
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].N[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].ClC1C=CC=CC=1Cl>ClCCl>[F:1][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: F[B-](F)(F)F
Reactant: Nc1c([N+](=O)[O-])ccc2ccccc12
Agent: N#[O+]
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2ccccc2c1F
Reaction time: 0.5 h

Procedure:
To a well stirred slurry of nitrosonium tetrafluoroborate (Aldrich) (10 % molar excess, (cf. David J. Milner, Synthetic Communications (1992) 22 (1), 73-82.)) in dichloromethane at 0° C. is added 1-amino-2-nitronaphthalene. After 30 minutes, ortho-dichlorobenzene is added and the dichloromethane is distilled off, and the dichlorobenzene is heated at 50°-200 ° C. to decompose the diazonium tetrafluoroborate. Removal of solvent and purification of the product by chromatography or crystallization yields 1-fluoro-2-nitronaphthalene.
Reaction SMILES: Cl.CN(C)C(N)=N.[Na].C(=O)([O-:11])N.Cl[C:14]1[N:19]=[C:18](Cl)[N:17]=[C:16]([N:21]([CH3:23])[CH3:22])[N:15]=1.[CH2:24]([OH:26])[CH3:25]>>[CH3:22][N:21]([CH3:23])[C:16]1[N:17]=[C:18]([O:26][CH2:24][CH3:25])[NH:19][C:14](=[O:11])[N:15]=1
Reactant: CN(C)c1nc(Cl)nc(Cl)n1
Reactant: CCO
Reactant: NC(=O)[O-]
Agent: CN(C)C(=N)N
Agent: Cl
Agent: [Na]
Product: CCOc1nc(N(C)C)nc(=O)[nH]1

Procedure:
N,N-Dimethylguanidine hydrochloride (3.23g; 0.026 mol.) was added to a solution of sodium (0.61 g; 0.026 mol.) in anhydrous ethanol (50 ml.) and the mixture was heated under reflux for 30 minutes. The carbamate prepared in (a) above (5.0 g., 0.026 mol.) was then added and the mixture heated under reflux for 22 hours. The ethanol was removed, water (75 ml.) added, and the pH of the solution adjusted to 6 to 7 with acetic acid. The product was collected, washed with water, and recrystallised from ethanol to give 4-dimethylamino-6-ethoxy-1,3,5-triazin-2-one.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4]1.C(OC=C)(=O)C>C(OC(C)C)(C)C>[OH:1][CH2:2][C@@H:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(CO)c3ccccc32)cc1
Solvent: C=COC(C)=O
Solvent: CC(C)OC(C)C
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H](CO)c3ccccc32)cc1
Reaction time: 1.5 h

Procedure:
5-Hydroxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (9.94 g) is dissolved in diisopropyl ether (150 ml), and thereto are added with stirring vinyl acetate (7.75 g) and Lipase QL (8%) (0.80 g) at -2° C. The mixture is stirred at -2° C. to 1° C. for 1.5 hour. The Lipase QL is removed by filtration on celite, and the filtrate is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=3:1→1:1) to give (5S)-5-hydroxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (hereinafter, referred to as Compound C) (4.54 g) and (5R)-5-acetyloxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (hereinafter, referred to as Compound D) (5.63 g).