Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.Cl.[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH3:29])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:28]([CH3:29])[C:2]2[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=2)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1nnc(Cl)s1
Reactant: CNC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1nnc(C(F)(F)F)s1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A mixture of 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole (0.70 g, 3.72 mmol) (prepared by a procedure similar to that described in DE 82/3218482), 4-methylamino-piperidine-1-carboxylic acid benzyl ester hydrochloride (1.06 g, 3.72 mmol) and diisopropylethylamine (1.60 ml, 9.30 mmol) in acetonitrile (10 ml) was stirred at 120° C. for 30 min., under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by short open column chromatography (silica gel; 0-0.5% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo to yield D1 (0.91 g, 62%) as a solid. C17H19F3N4O2S requires 400. Found 401 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:49][N:50]([CH3:60])[C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[CH:54]([OH:56])[CH3:55]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:56][CH:54]([C:53]2[CH:57]=[CH:58][CH:59]=[C:51]([N:50]([CH3:49])[CH3:60])[CH:52]=2)[CH3:55])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(O)c1cccc(N(C)C)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4cccc(N(C)C)c4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 38.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-dimethylamino-α-methylbenzyl alcohol (66 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (51 mg, yield 36%).
Reaction SMILES: C(C1C=CC=CC=1C([NH:8][CH:9]1[C:40](=[O:41])[N:11]2[C:12]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:13]([CH2:16][S:17][C:18]3[S:19][C:20]([CH3:23])=[N:21][N:22]=3)[CH2:14][S:15][C@H:10]12)=O)(O)=O.ClC(OCC)=O.CNN>CCN(CC)CC.O1CCCC1>[NH2:8][CH:9]1[C:40](=[O:41])[N:11]2[C:12]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:13]([CH2:16][S:17][C:18]3[S:19][C:20]([CH3:23])=[N:21][N:22]=3)[CH2:14][S:15][C@H:10]12
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)c4ccccc4C(=O)O)[C@H]3SC2)s1
Agent: CCOC(=O)Cl
Agent: CNN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)s1
Reaction time: 0.33 h

Procedure:
A solution of benzhydryl 7-(2-carboxybenzamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (2 mmol.) in 30 ml. of dry tetrahydrofuran is cooled in an ice-salt bath, and 0.28 ml. (2 mmol.) of triethylamine and 0.20 ml. (2. mmol.) of ethyl chloroformate are added. After cooling and stirring for 20 minutes, 0.106 ml. (2 mmol.) of N-methylhydrazine in 5 ml. of tetrahydrofuran is added. Stirring is continued for about 10 minutes. The Et3N. HCl salt is filtered, and the filtrate is evaporated to dryness. The residue is taken up in about 15 ml. of chloroform, and the mixture is allowed to stand at room temperature for about one hour during which time methylphthalhydrazide (m,p, 243°-245° C.) precipitates. Filtration and evaporation in vacuo of the filtrate gives crude benzhydryl 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6]CC)=O.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:11]([O:10][C:3](=[O:9])[C:4](=[O:6])[CH2:28][C:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:22][CH:23]=1)=[O:29])[CH3:12]
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 147 %

Procedure:
To a solution of 1-(4-hydroxy-phenyl)-ethanone (10 g, 0.0735 mole) in DMF (50 mL) was added K2CO3 (20.2 g, 0.147 mole) at ambient temperature. Benzyl bromide (13.83 g, 0.0808 mole) was then added and the resulting mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then quenched with iced water. The resulting precipitate was isolated by filtration and dried to afford 16.2 g (98%) of 1-(4-benzyloxy-phenyl)-ethanone. LCMS: 227.1 (M+1)+, 98.38%. A mixture of THF (130 mL) and NaH (60% w/w dispersion in oil) (5.28 g, 0.132 mole) was cooled to 0° C. with stirring for 5 minutes. Diethyl oxalate (12.87 g, 0.0886 mole) was added and the mixture was heated to reflux for 15 minutes. after cooling to ambient temperature 1-(4-benzyloxy-phenyl)-ethanone (10 g, 0.0442 mole) in THF (50 mL) was added dropwise over a period of 45 minutes. The resulting mixture was heated to 70° C. for 1 hour. The reaction mixture was then quenched with cold aqueous NH4Cl solution. The resulting precipitate was isolated by filtration and dried to afford 21.2 g of 4-(4-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester. LCMS: 327.12 (M+1)+, 36.5%. A solution of 4-(4-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (10 g, 0.03064 mole), acetic acid (20 mL) and hydrazine hydrate (1.685 g, 0.0337 mole) was heated to reflux for 8 hours. The reaction mixture was then poured into iced water and basified with saturated aqueous NaHCO3 solution. The product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 6.3 g (64%) of 5-(4-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 323.13 (M+1)+, 95.10%.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([CH3:16])([S:7]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)(=[O:9])=[O:8])[CH3:6])C.[OH-].[Na+]>O1CCOCC1.O>[CH3:16][C:5]([S:7]([CH:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)(=[O:8])=[O:9])([CH3:6])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)S(=O)(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 82.6 %

Procedure:
To a solution of 166 g (0.63 mol) of 2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid ethyl ester in THF/water (4/1, 1.66 L) are added 50.5 g (1.26 mol) of NaOH pellets in portions over 20 min. The reaction is stirred at room temperature for 2.5 d. The organic solvent is removed under reduced pressure and the aqueous residue is diluted with water (2 L) and washed with DCM (2 L). The aqueous layer is acidified to pH 1-2 with concentrated HCl and then extracted with DCM (3×2 L). The acidic aqueous is further saturated with NaCl and extracted again with DCM (6×2 L). The combined organic extracts are concentrated under reduced pressure to give 123 g of 2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid as a white solid. Yield: 83%, ES-MS: m/z 235 [M−H]; 1H-NMR (500 MHz, CHLOROFORM-d) δ ppm 1.71 (6 H, s), 1.94-2.12 (4 H, m), 3.47 (2 H, td, J=11.41, 2.98 Hz), 3.73-3.86 (1 H, m), 4.07-4.15 (2 H, m), 6.82 (1 H, br. s.)
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH:16]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]1.[NH3:24]>CO>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[O:14][CH2:15][CH:16]2[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]2)=[C:2]([NH2:24])[N:10]=1
Reactant: CC1(C)OCC(COn2cnc3c(Cl)nc(NC=O)nc32)CO1
Reactant: N
Solvent: CO
Product: CC1(C)OCC(COn2cnc3c(N)nc(N)nc32)CO1
Temperature: 110 °C
Yield: 63 %

Procedure:
A mixture of 6-Chloro-9-(2,2-dimethyl-1,3-dioxan-5-ylmethoxy)-2-formamidopurine (630 mg, 1.84 mmol), ammonia (10 ml) and methanol (15 ml) was heated at 110° C. for 7.5 hours in an autoclave and then allowed to cool over 16 hours. The mixture was evaporated to dryness and the residue chromatographed on silica (eluted with chloroform-ethanol, 20:1), affording the title compound (340 mg, 63%). 1R: υmax (KBr) 3409, 3321, 3158, 1669, 1640, 1589, 1488, 1457, 1409 cm-1. H NMR: δH [(CD3)2SO] 1.32(3H,s,CH3), 1.35(3H,s,CH3), 2.00(1H,m,CH3), 3.77(2H,dd, J=11.8, 6.1 Hz, 2×H(ax)), 3.98(2H,dd, J=11.8, 4.1 Hz, 2×H(eq)), 4.32(2H,d, J=7.1 Hz, CH2ON), 5.91(2H,br.s, D2O exchangeable, 6-NH2), 6.78(2H.br,s,D2O exchangeable, 2-NH2), 7.96(1H,s,H-8). Found: C, 48.34; H, 6.18; N, 28.21%; M+ 294.1437. C12H18N6O3 0.2H2O requires: C, 48.37; H, 6.24; N, 28.21%; M+ 294.1440.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[CH:3]=1.CN(C=O)C.I[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[CH:18][CH:17]=1.O>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[CH:18][CH:17]=2)[CH:3]=1
Reactant: FC(F)Oc1ccc(I)cc1
Reactant: C#Cc1cccc(Br)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(C#Cc2cccc(Br)c2)cc1
Reaction time: 4 h

Procedure:
To a mixture of 1-bromo-3-ethynylbenzene (9.1 g, 50.26 mmol), TEA (22.38 g, 30.8 mL, 221.1 mmol), PdCl2(ACN)2 (1.41 g, 2.01 mmol) and DMF (60 mL) was added 4-iodo(difluoromethoxy)benzene (10.85 g, 40.21 mmol). The reaction mixture became warm after the addition was completed. The mixture was stirred for 4 h. Then it was poured into water and diluted with EtOAc. The aqueous layer was separated and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated onto 40 g Celite. Flash chromatography (SiO2, Hexanes) provided 12 g, 92%, of the title compound as a yellow oil that crystallized into a yellow solid upon standing.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.CCN(CC)CC.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: NC1CCCc2c(Br)cncc21
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NC1CCCc2c(Br)cncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of (rac)-4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-ylamine (intermediate A-2 [D]) (227 mg, 1 mmol) and Et3N (152 mg, 1.5 mmol) in DCM (5 mL) was added ethanesulfonyl chloride (193 mg, 1.5 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr before it was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and the organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product (302 mg, 95% yield). MS: 319.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:21](O)[CH2:22][OH:23].CC1C=CC(S(O)(=O)=O)=CC=1>CC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=3)[O:23][CH2:22][CH2:21][O:9]2)=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: COc1cc(C(=O)c2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(C2(c3ccc(Cl)cc3)OCCO2)ccc1[N+](=O)[O-]
Yield: 50.4 %

Procedure:
A mixture of (4-chlorophenyl)(3-methoxy-4-nitrophenyl)methanone (40.7 g), 1,2-ethanediol (31.2 ml) and 4-methylbenzene sulfonic acid (5.31 g) in methylbenzene (320 ml) was stirred and refluxed using a Dean-Stark apparatus. The mixture was washed with K2CO3 (10%) and extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 22.48 g (50.4%) of 2-(4-chlorophenyl)-2-(3-methoxy-4-nitrophenyl)-1,3-dioxolane (interm. 39).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7](Cl)([CH3:17])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])([CH3:4])([CH3:3])[CH3:2].CCCCC.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOCC>[C:1]([N:5]=[N:6][C:7]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:17])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: Br[Mg]c1ccccc1
Reactant: CCCCOC(=O)CCC(C)(Cl)N=NC(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CCCCOC(=O)CCC(C)(N=NC(C)(C)C)c1ccccc1
Yield: 66 %

Procedure:
To a clean, dry, 500 ml, 4-neck round bottom flask equipped with a mechanical stirrer, thermometer, condenser with drying tube and under a nitrogen atmosphere was added a solution of 70 grams (0.253 moles) of n-butyl 4-t-butylazo-4-chlorovalerate (prepared as in Example XX) in 200 ml. of pentane and the solution cooled to 5° C. With rapid stirring 86.6 ml. (0.26 moles) of a 3 molar solution of phenylmagnesium bromide in ether was added from a dropping funnel over 1/2 hour holding the reaction temperature at 10°-15° C with an ice bath. After the addition was complete, the reaction was stirred for an additional 45 minutes at 15° C. Ice chips were then added to the stirred reaction until the excess phenylmagnesium bromide was destroyed. The reaction mixture was then stirred into 200 ml. of 5% HCl until the magnesium salts dissolved. The pentane layer was separated, washed with 5% HCl, water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated to leave 53 grams (66% yield) of product.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][NH2:19])=[CH:4][CH:3]=1.[CH2:22]([N:30]=[C:31]=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][NH:19][C:31]([NH:30][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:32])=[CH:4][CH:3]=1
Reactant: O=C=NCCc1ccccc1
Reactant: NCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: O=C(NCCc1ccccc1)NCCN1Cc2ccccc2CC1Cc1ccc(F)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 2-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 210-a) as a starting material, and using phenethyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[C:5]([CH3:11])[C:4]=1[OH:12].[OH:13]O>CCOCC.O.C(O)(=O)C>[CH3:11][C:5]1[C:4](=[O:12])[C:3]([CH3:2])=[C:8]([CH3:9])[C:7](=[O:13])[C:6]=1[CH3:10]
Reactant: OO
Reactant: Cc1cc(C)c(C)c(O)c1C
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)C(C)=C(C)C1=O
Yield: 55 %

Procedure:
To 30 mg of the catalyst prepared in the same manner as in Example 19, 100 mg of water was added and stirred, and then 5 ml of an acetic acid solution containing 1% of hydrochloric acid was added. While cooling the mixture with water, 500 mg of 2,3,5,6-tetramethylphenol and 1 g of a 31% hydrogen peroxide aqueous solution were added, and the mixture was stirred for 2.5 hours. After the completion of the reaction, the mixture was diluted with ether, and the catalyst was filtered and washed successively with a NaHCO3 aqueous solution and a saturated sodium chloride aqueous solution. The filtrate was dried over MgSO4 and then concentrated, and the residue was purified by silica gel chromatography by eluting it with a solvent mixture of hexane-dichloromethane (1:1), whereby 300 mg (55% yield) of tetramethylbenzoquinone was obtained.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:36]([N:38]1[CH2:47][CH2:46][CH2:45][C@H:39]1[C:40]([NH:42][CH2:43][CH3:44])=[O:41])=[O:37])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:35])[NH:24][S:25]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:55](C(OC(C)(C)C)=O)[C@H:56]([C:72]([OH:74])=O)[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:60][CH:59]=1.CS(O)(=O)=O.[C:87](=[O:90])([O-])[O-:88].[Na+].[Na+]>ClCCl>[NH:55]([C:87]([O:88][C:4]([CH3:6])([CH3:5])[CH3:3])=[O:90])[C@H:56]([C:72]([NH:1][C@@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:36]([N:38]1[CH2:47][CH2:46][CH2:45][C@H:39]1[C:40]([NH:42][CH2:43][CH3:44])=[O:41])=[O:37])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:35])[NH:24][S:25]([C:28]1[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=1)(=[O:27])=[O:26])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:74])[CH2:57][C:58]1[CH:59]=[CH:60][C:61]([O:64][CH2:65][C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)=[CH:62][CH:63]=1
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Boc-Tyr(Bn)-D-Leu-Leu-Arg(Ts)-Pro-NHEt was prepared from Boc-D-Leu-Leu-Arg(Ts)-Pro-NHEt obtained in Example 2 and Boc-Tyr(Bn) by the same procedure as Example 2. To a solution composed of this compound (0.46 g) and dichloromethane (5 ml), methanesulfonic acid (0.42 g) was added at room temperature, and the resulting mixture was stirred at room temperature for 1 hour, thereby the Boc group was removed (reaction conversion ratio: 99.9%). After the reaction, 5% aqueous sodium carbonate solution (5 ml) was added thereto, and the resulting mixture was stirred for 15 minutes, and then, the aqueous layer was separated off. After Boc-Ser (Bn) (0.19 g) and HOBt monohydrate (0.12 g) were added to the obtained dichloromethane solution of Tyr(Bn)-D-Leu-Leu-Arg(Ts)-Pro-NHEt, the reaction solution was cooled with ice. Then, EDC hydrochloride (0.15 g) was added thereto, and the resulting mixture was stirred for 1 hour. Subsequently, the temperature of the mixture was raised to room temperature and the mixture was stirred for 15 hours, thereby a condensation reaction was carried out (reaction conversion ratio: 99.9%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][C:23]([O:25]C)=[O:24])([CH2:18][CH2:19]3)[O:16][CH2:15]4)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[C:27](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:28].[CH:43]1([C:47]([NH:49][NH2:50])=O)[CH2:46][CH2:45][CH2:44]1>ClCCl>[CH:43]1([C:47]2[S:28][C:27]([NH:1][C:2]3[N:7]=[CH:6][C:5]([C:8]4[CH:9]=[CH:10][C:11]([C:14]56[CH2:21][CH2:20][C:17]([CH2:22][C:23]([OH:25])=[O:24])([CH2:18][CH2:19]5)[O:16][CH2:15]6)=[CH:12][CH:13]=4)=[CH:4][N:3]=3)=[N:50][N:49]=2)[CH2:46][CH2:45][CH2:44]1
Reactant: COC(=O)CC12CCC(c3ccc(-c4cnc(N)nc4)cc3)(CC1)CO2
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: NNC(=O)C1CCC1
Solvent: ClCCl
Product: O=C(O)CC12CCC(c3ccc(-c4cnc(Nc5nnc(C6CCC6)s5)nc4)cc3)(CC1)CO2
Temperature: 50 °C
Yield: 83 %

Procedure:
To a reaction vial containing methyl 2-(4-(4-(2-aminopyrimidin-5-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (40 mg, 0.11 mmol) was added dichloromethane (1 ml) at room temperature. 1,1′-thiocarbonyldipyridin-2(1H)-one (29 mg, 0.12 mmol) was added and the resulting mixture was heated to 50° C. for overnight. The mixture was cool down to room temperature and cyclobutanecarbohydrazide (19 mg, 0.17 mmol) was then added and stirred at room temperature for another hour. The content was then concentrated to dryness and the resulting residue was taken up in MeOH to form a nice slurry. The slurry was filtered and washed with small amount of MeOH to afford the title compound as off-white solid after drying (48 mg, 83% yield). LC/MS, ESI-MS(+): 510.4, RT: 1.26 (Condition E)
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=2)[C:5](=[O:18])[C:4]([C:19]2[N:23]([CH3:24])[N:22]=[N:21][N:20]=2)=[CH:3]1.ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[OH2:18].[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]3([O-:33])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=2)[C:5](=[O:18])[C:4]([C:19]2[N:23]([CH3:24])[N:22]=[N:21][N:20]=2)=[CH:3]1
Reactant: Cn1nnnc1-c1cn(C)c2cc(N3CCCCC3)ccc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1nnnc1-c1cn(C)c2cc([N+]3([O-])CCCCC3)ccc2c1=O
Product: O
Reaction time: 52 h

Procedure:
To a stirred solution of the 4-quinolone of Example 30 (1.44 g) in dichloromethane (100 ml) was added a solution of 3-chloroperbenzoic acid (85%, 0.86 g) in dichloromethane (20 ml) and the mixture was stirred for 52 hours. A solution of 3-chloroperbenzoic acid (85%, 0.27 g) in dichloromethane (10 ml) was added and the mixture was stirred for 20 hours. Saturated aqueous sodium bicarbonate (40 ml) was added and the mixture was stirred for 45 minutes. The mixture was evaporated to dryness and the residue was extracted with dichloromethane (75 ml) for 1.5 hours using a Soxhlet apparatus. The extract was evaporated and the residue was crystallised from industrial methylated spirit:diethyl ether 4:1 to give 1-[1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-oxo-1,4-dihydroquinolin-7-yl]piperidine 1-oxide monohydrate, m.p. 163°-166°.