Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH:9]1C(O)=O)([O:3][C:4](C)(C)[CH3:5])=[O:2].Cl.C(OC(=O)[C@H](CS)N)C.C(N(CC)CC)C.BrC(Br)C>C1COCC1>[CH2:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][S:11][CH2:12][CH2:13]1)=[O:2])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCSCC1C(=O)O
Agent: CC(Br)Br
Agent: CCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCSCC1
Reaction time: 1 h
Yield: 87 %

Procedure:
4-Boc-thiomorpholine-3-carboxylic acid can also be substituted for the compound of formula (XXIV) in Reaction Scheme 7 and can be prepared in the following manner: To THF was added cysteine ethyl ester hydrochloride (1.15 g, 6.18 mmol), triethylamine (4.17 mL, 30 mmol) and dibromoethane (2.51 mL, 6.2 mmol). After stirring for 1 hour and refluxing for 16 hours, the solids were removed by filtration. The solvent was removed in vacuo and the residue was chromatographed on silica to give thiomorpholinecarboxylic acid ethyl ester (0.94 g, 87%). The ester (15.3 g, 95 mmol) was dissolved in dioxane/water (1/1) and di-t-butyldicarbonate (24 g, 110 mmol) and LiOH were added. After stirring for 3 hours, the solvent was removed in vacuo and the pH was adjusted to 3 with KHSO3 and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4), and the solvent was removed in vacuo to give 17.4 g (78%) 4-Boc-thiomorpholine-3-carboxylic acid: 1H NMR (CDCl3) δ 1.45 (m, 9), 2.45 (m, 1), 2.71 (m, 1). 2.93 (m, 1), 3.10 (m. 1), 3.29 (m, 1), 4.11 (m, 1), 4.19 (m, 1), 5.20 (m, 1).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](O)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1.CN(C=O)C>[N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([Cl:21])=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
To a suspension of 2-morpholin-4-yl-5-nitro-benzoic acid (4.0 g, 16 mmol) in toluene were added 2 drops of DMF and thionylchloride (5.7 ml, 79.3 mmol). The mixture was heated to 80° C. for 50 minutes. The solvent was removed in vacuo, and the resulting solid was stirred in ether, filtered and dried to provide the title compound (4.0 g, 93%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([NH:8][C:9](=[O:14])[C:10]2([CH3:13])[O:12][CH2:11]2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2].[NH3:21]>CO>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([NH:8][C:9](=[O:14])[C:10]([OH:12])([CH3:13])[CH2:11][NH2:21])=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2]
Reactant: N
Reactant: CC1(C(=O)Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CO1
Solvent: CO
Product: CC(O)(CN)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: -70 °C
Reaction time: 14 h
Yield: 58 %

Procedure:
A pressure reactor was charged with 4-nitro-3-trifluoromethyl-N-[2,3-epoxy-2-methyl propionyl]aniline, BP-33, (10.0 g, 34.46 mmol) and methanol (100 mL). After cooling to −70° C., ammonia in excess was condensed into the reactor which was sealed and stirred 14 hours. Following evaporation, the crude solid was washed with cold CH2Cl2 (5 mL). Filtration and drying gave 6.1 g BP-34 (58% yield).
Reaction SMILES: O.C(O)(=O)C.[S:6]([N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19][C:18](=[O:27])[CH2:17]1)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[C-:28]#[N:29].[Na+]>C(O)C>[OH:27][C:18]1([C:28]#[N:29])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:16]([S:6]([C:9]2[CH:10]=[CH:11][C:12]([CH3:13])=[CH:14][CH:15]=2)(=[O:7])=[O:8])[CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)N2CC(=O)CCc3ccccc32)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N2CC(O)(C#N)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 64.5 %

Procedure:
30 ml of water, 40 ml of acetic acid and 20 g of 1,2,4,5-tetrahydro-N-tosyl-[3H]-1-benzazepine-3-one [J. Chem. So., Vol. C (1970), p.2192] were successively added to 300 ml of ethanol and then 20 g of sodium cyanide were added thereto over 2 minutes. The mixture was stirred for 4 hours at room temperature and was then concentrated to 100 ml under reduced pressure. The mixture was extracted with ether and the ether extracts were washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 21 g of raw product which was crystallized from a minimum of ether. The mixture was vacuum filtered to obtain 14 g of 3-hydroxy-1-(4-methylphenylsulfonyl)-1,2,4,5-tetrahydro-[3H]-1-benzazepine-3-carbonitrile in the form of colorless crystals melting at 128°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH2:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)[CH3:23].C(=O)([O-])[O-].[Na+].[Na+].[N:39]1[CH:44]=[CH:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=1>O.CN(C=O)C.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH2:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:41]3[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:23]
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: CCc1ccccc1B(O)O
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCc1ccccc1-c1c[nH]c2ncc(-c3cccnc3)cc12
Reaction time: 6 h
Yield: 61.7 %

Procedure:
To 5-bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (15 mg, 0.0314 mmol, prepared as described in method 1), 2-ethylphenyl boronic acid (5.2 mg, 0.034-mmol), and dichlorobis (triphenylphosphino)palladium (II) (1.3 mg, 0.0002 mmol) in a Smith process vial was added 0.5 ml of a 1:1 mixture of acetonitrile and a 2 M solution of sodium carbonate in water. The reaction mixture was stirred for 6 h, then 3-pyridyl boronic acid pinacol ester (8.4 mg, 0.041 mmol) and dichlorobis (triphenylphosphino)palladium (II) (1.3 mg, 0.0002 mmol) were added and the reaction was run in a Personal Chemistry® microwave reactor at 150° C. for 900 s. The mixture was diluted with DMF (2 mL), filtered on a silica plug, and solvent was evaporated. Purification by reverse phase chromatography using a gradient of H2O and acetonitrile (with 0.1% formic acid as a modifier) afforded 3-(2-ethyl-phenyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine as a solid (5.8 mg, 61% yield). 1H NMR (500 MHz. DMSO-d6) δ 1.05 (t, J=7.5 Hz, 3H), 2.66 (q, J=7.5 Hz, 2H), 7.27 (t, J=7.0 Hz, 1H), 7.31 (t, J=7.0 Hz, 1H), 7.38 (d, J=7.5 Hz, 2H), 7.45 (dd, J=5.5, 8.5 Hz, 1H), 7.60 (s, 1H), 7.98 (d, J=2.0 Hz, 1H), 8.10 (dd, J=1.5, 8.0 Hz, 1H), 8.54 (d, J=5.0 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.90 (s, 1H), 12.0 (s, 1H). MS: m/z 300 (M+H+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:18][C:17]2[NH:16][CH:15]=[C:14]([CH3:19])[C:13]=2[C:12](=[O:20])[CH2:11]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:18][C:17]2[N:16]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:15]=[C:14]([CH3:19])[C:13]=2[C:12](=[O:20])[CH2:11]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
To a suspension of 60% sodium hydride (0.18 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydroindol-4-one (1.0 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added methanesulfonylchloride (0.53 g) in dimethylformamide (3 ml), and the mixture was stirred at the same temperature for 9 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The mixture was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane), and the resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 6-(2-chlorophenyl)-1-methanesulfonyl-3-methyl-4,5,6,7-tetrahydroindol-4-one (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.CN(C)C1C=CC=CC=1.[C:22](Cl)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CO>[C:22]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C)c([N+](=O)[O-])c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(C)cc(C)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-amino-4,6-dimethyl-3-nitropyridine (14.91 g) and N,N-dimethylaniline (80 ml) was heated at 70° C. To the solution was added dropwise acetyl chloride at 70° C. and the mixture was stirred at 70° C. for 2.5 hours. To the reaction mixture was added ethyl acetate(500 ml). The organic layer was separated. and washed with water three times and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was dissolved in hot isopropyl ether (200 ml), and cooled to ambient temperature. After the mixture was cooled in an ice bath for an hour, the resulting solid collected by filtration, was washed with cold isopropyl ether, purified by flash column chromatography on silica gel eluted by a mixture of ethyl acetate and n-hexane (1:9 then 2:1) to yield a brown oil and the oil was dissolved methanol(40 ml). To the solution was added saturated sodium bicarbonate (10 ml), and stirred at room temperature for 70 minutes. The mixture was diluted with ethy acetate, organic layer was separated, and the aqueous layer was extracted with ethy acetate. The combined ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentated in vacuo. To the residue was added diisopropyl ether (50 ml). After cooling, the solid was collected by filtration and washed diisopropyl ether to give 2-acetylamino-4,6-dimethyl-3-nitropyridine(5.56 g) as colorless powder.
Reaction SMILES: IC.[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N:11]([CH3:15])[C:12]([NH2:14])=S)=[CH:6][C:5]=1[CH3:16].CO[CH:19](OC)[CH2:20][NH2:21]>CC(C)=O.C(O)C(C)C>[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N:11]([C:12]2[NH:21][CH:20]=[CH:19][N:14]=2)[CH3:15])=[CH:6][C:5]=1[CH3:16]
Reactant: Cc1cc(N(C)C(N)=S)cc(C)c1Br
Reactant: COC(CN)OC
Solvent: CC(C)CO
Solvent: CC(C)=O
Solvent: CI
Product: Cc1cc(N(C)c2ncc[nH]2)cc(C)c1Br
Yield: 28.3 %

Procedure:
Iodomethane (260 mg, 9.15 mmol) was added to a solution of 1-(4-bromo-3,5-dimethyl-phenyl)-1-methyl-thiourea (500 mg, 1.83 mmol) in acetone (10 ml) with stirring in a nitrogen stream, and the mixture was heated with stirring at 50° C. for two hours. The reaction solution was concentrated under reduced pressure, and a mixture of the resulting residue and aminoacetaldehyde dimethylacetal (250 mg, 2.38 mmol) in iso-BuOH (8.3 ml) was then heated under reflux for four hours. The reaction mixture was concentrated under reduced pressure. Concentrated hydrochloric acid (3 ml) was then added to the resulting residue, and the mixture was heated with stirring at 90° C. for 30 minutes. The reaction mixture was cooled and then adjusted to pH 10 with a 2 N aqueous sodium hydroxide solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-methanol) to give (4-bromo-3,5-dimethyl-phenyl)-(1H-imidazol-2-yl)-methyl-amine (145 mg, 28%).
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:9](C)[C:10](OC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][Mg]I.CC[O:27][CH2:28][CH3:29]>>[CH2:15]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([CH3:10])[C:28]([CH3:29])([OH:27])[CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[Mg]I
Reactant: COC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCOCC
Product: C[C@H](N(Cc1ccccc1)Cc1ccccc1)C(C)(C)O
Temperature: 0 °C

Procedure:
(S)-Methyl 2-(dibenzylamino)propanoate (15.76 g, 55.6 mmol) was dissolved in Et2O (400 mL) and then cooled to ca. 0° C. Methylmagnesium iodide (27.7 mL, 3 M) was added next. The mixture turned heterogeneous white with addition of the latter. The mixture was allowed to warm to ambient temperature. LCMS the next day (17 h) indicated conversion to the desired product. The reaction was slowly quenched with sat. aqueous NH4Cl and then diluted with water and EtOAc. The layers were separated and the aqueous portion was further extracted with EtOAc. The combined organic portions were dried over Na2SO4, filtered and concentrated to a pale yellow oil. LCMS after thorough drying showed the desired product. This material was used directly for the next step: MS (ESI) m/z 284 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[C:14]#[CH:15])[C:7](=[O:18])[C:6]([C:19]([O:21]CC)=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[C:14]#[CH:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Yield: 60.7 %

Procedure:
10.3 g of ethyl 1-cyclopropyl-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are refluxed for 4 hours in a mixture of 100 ml of glacial acetic acid, 8 ml of water and 3 ml of concentrated sulphuric acid. After cooling to room temperature, the solid is filtered off with suction, washed with water and dried. In this way, 5.7 g of 1-cyclopropyl-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (62% of theory) are obtained.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=O)[C:18]2=[O:25].FC1C=C2C(=CC=1)NC(=O)C2=O>>[CH3:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]1[C:19](=[N:11][C:5]3[C:6]([C:7]1=[O:8])=[CH:13][CH:2]=[CH:3][CH:4]=3)[C:18]2=[O:25]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: Cc1ccc2c(c1)C(=O)c1nc3ccccc3c(=O)n1-2
Yield: 36 %

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 5-methylisatin for 5-fluoroisatin gave the title compound in 36% yield: mp 282.8°-284.8° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.28-8.38 (m, 2H) 7.94 (d, 2H) 7.64-7.78 (m, 3H) 3.34 (s, 3H); MS (M+H)+ 263.
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.[C:7]1(O)[CH:12]=[CH:11]C=[CH:9][CH:8]=1>[F-].[K+]>[O:2]([CH2:3][CH2:4][OH:5])[C:1]1[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1OCCO1
Reactant: Oc1ccccc1
Agent: [F-]
Agent: [K+]
Product: OCCOc1ccccc1
Yield: 99.2 %

Procedure:
Ethylene carbonate (89.9 g, 1.02 mole), phenol (94.1 g, 1.0 mole) and potassium fluoride (1 g, 0.5 percent of total reactant weight) were placed in a 500 ml round-bottomed flask equipped with a condenser and gas bubbler. A magnetic stirrer provided agitation. The mixture was heated to 160° C.±2° C. in an oil bath. After 2.5 hours the reaction vessel was removed from the oil bath, cooled and the contents removed. Purification of the product by distillation gave 137 g of 2-phenoxyethanol (99 percent conversion based on phenol limiting reagent).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:25][CH3:26])[C:23]=2[OH:24])=[O:18])[C:5]([CH3:16])=[C:6]2[C:11]=1[S:10][CH:9]([CH3:12])[CH2:8][CH:7]2[O:13][CH2:14][CH3:15].C(O)(=[O:29])C.OO.[OH2:33]>>[F:1][C:2]1[CH:3]=[C:4]([C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:25][CH3:26])[C:23]=2[OH:24])=[O:18])[C:5]([CH3:16])=[C:6]2[C:11]=1[S:10](=[O:29])(=[O:33])[CH:9]([CH3:12])[CH2:8][CH:7]2[O:13][CH2:14][CH3:15]
Reactant: CC(=O)O
Reactant: CCOC1CC(C)Sc2c(F)cc(C(=O)c3cnn(CC)c3O)c(C)c21
Reactant: O
Agent: OO
Product: CCOC1CC(C)S(=O)(=O)c2c(F)cc(C(=O)c3cnn(CC)c3O)c(C)c21
Temperature: 100 °C

Procedure:
A 50-ml egg-plant type flask was charged with 4.8 g (0.013 mol) of 8-fluoro-4-ethoxy-2,5-dimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman (Compound 43), 20 ml of acetic acid and 4.5 g (0.04 mol) of a 30% hydrogen peroxide aqueous solution, and the mixture was heated at 100° C. for 1 hour. After allowed to cool, the reaction mixture was poured into 100 ml of water. The precipitated oil was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 4.6 g of 8-fluoro-4-ethoxy-2,5-dimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-thiochroman-1,1-dioxide (Compound 59) shown in Table 5.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.CN1CCOCC1.[CH3:15][O:16][C:17](Cl)=[O:18]>C(OCC)(=O)C>[CH3:15][O:16][C:17]([N:5]1[C:4](=[O:6])[CH:3]=[CH:2][C:1]1=[O:7])=[O:18]
Reactant: COC(=O)Cl
Reactant: O=C1C=CC(=O)N1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)N1C(=O)C=CC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Maleimide (2.00 g, 20.6 mmol) and N-methyl morpholine (2.08 g, 20.6 mmol) in ethyl acetate were cooled to 0° C. Dropwise addition of methylchloroformate (1.4 mL, 20.7 mmol) produced white precipitate. The solution was stirred for 1 hour at 0° C., after which the solids were removed by filtration. Concentration of the filtrate yielded a pink oil, which was purified by column chromatography (eluant 3:1 hexanes:ethyl acetate) to yield pale yellow crystals.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9](=[O:14])[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([CH3:15])=[C:4]([CH3:16])[CH:3]=1.C([O-])=O.[NH4+]>CO.[C].[Pd]>[CH3:16][C:4]1[CH:3]=[CH:2][C:7]2[NH:8][C:9](=[O:14])[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]=1[CH3:15]
Reactant: Cc1cc(Br)c2c(c1C)S(=O)(=O)NC(=O)N2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc2c(c1C)S(=O)(=O)NC(=O)N2
Temperature: 25 °C

Procedure:
5-Bromo-7,8-dimethyl-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione (5.27 g, 17.3 mmol) was suspended in methanol (60 mL), and then ammonium formate (5.45 g, 86.5 mmol, 5 eq) was added and nitrogen substitution was performed. Next, 10% palladium-carbon powder (1.84 g, 1.73 mmol, 10 mol %) was added and the mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was cooled on ice and the precipitated crystals were filtered out and dried to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][C:5]=1[CH2:21][CH2:22][OH:23])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([O:23][CH2:22][CH2:21][C:5]2[CH:6]=[C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])[CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(Cc1ccc(OCC)c(CCO)c1)OC(C)C
Reactant: O=C=Nc1cccc(Cl)c1
Product: CCOc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1cccc(Cl)c1

Procedure:
Using ethyl 3-[4-ethoxy-3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 3-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[N+:6](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:8])=[O:7].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH2:3]([C@@H:2]([C@H:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][N+:6]([O-:8])=[O:7])[CH:1]=[O:5])[CH3:4]
Reactant: CCCC=O
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC[C@H](C=O)[C@@H](C[N+](=O)[O-])c1ccccc1

Procedure:
The title compound was prepared from butyraldehyde and (E)-(2-nitrovinyl)-benzene according to the general procedure. The enantiomeric ratio was determined by HPLC with an OD-H column at 220 nm (2-propanol:hexane=5:95), 1.0 mL/min; major enantiomer tmajor=40.61 min, minor enantiomer tminor=51.74 min. The diastereomeric excess was determined by 1H NMR. [α]D20=−99.5 (c=1.1, CHCl3).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][NH:27]2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][N:27]2[C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Reactant: Clc1ccc2c(c1)NCC2
Product: O=[N+]([O-])c1ccc(-c2cc3c(N4CCc5ccc(Cl)cc54)ncnc3[nH]2)cc1

Procedure:
This product is prepared in a manner analogous to that described in Example 6 from 4-chloro-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 6-chloro-2,3-dihydroindole (1.1 equivalents).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])=[CH:19][CH:18]=1)([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:6][O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:41])=[O:24])=[CH:19][CH:18]=1)([CH2:6][O:7][C:8](=[O:10])[CH3:9])[CH2:11][O:12][C:13](=[O:15])[CH3:14])(=[O:3])[CH3:2]
Reactant: CCCCCCCCS(=O)c1ccc(CC(COC(C)=O)(COC(C)=O)NC(C)=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCS(=O)(=O)c1ccc(CC(COC(C)=O)(COC(C)=O)NC(C)=O)cc1
Reaction time: 2.5 h
Yield: 47.5 %

Procedure:
To a solution (10 ml) of 2-acetamido-1,3-diacetoxy-2-(4-octylsulfinylbenzyl)propane (330 mg) in chloroform was added m-chloroperbenzoic acid (244 mg) under ice-cooling. The mixture was stirred for 2.5 hours and then at room temperature for 1.5 hours. Calcium hydroxide (0.1 g) was added to the reaction mixture and the mixture was stirred at room temperature for 45 minutes. The insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give 162 mg of the subject compound.