Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:12]Br>C(Cl)(Cl)Cl.CC(O)=O>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([OH:8])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-methyl-2-nitro-phenol (20 g, 0.13 mol) in CHCl3 (20 mL) was added a solution of Br2 (6.4 mL) in HOAc (15 mL) dropwise at 0° C. and the mixture was stirred at 0° C. for 3 h. Ice was added and the mixture was extracted with CHCl3. After drying over Na2SO4, CHCl3 was removed to give 4-bromo-3-methyl-2-nitro-phenol (30 g) which was used without further purification.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[OH-].[Na+].[CH2:11]([O:13][C:14](Cl)=[O:15])[CH3:12].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH2:11]([O:13][C:14]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:15])[CH3:12]
Reactant: Nc1ccc(O)cc1
Reactant: CCOC(=O)Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)Nc1ccc(O)cc1

Procedure:
p-aminophenol 33.36 g (0.3 mole) and 12 g NaOH were dissolved in 120 ml water and cooled to ice salt bath temperature. To the stirring solution, 24 ml ethylchloroformate were slowly added. A white precipitate was found. One gram sodium dithionite was added and mixed. The solid was filtered by suction and washed with cold water (50 ml). Recrystallization from hot water gave a crystalline powder, 48.3 g (89%), MP 120°-123°.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.O.Cl>CN(C)C=O.C([O-])([O-])=O.[K+].[K+]>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([OH:10])=[O:9])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1S
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CSc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Thiosalicylic acid 15.419 g(0.1 M) was dissolved in 150 mL of dimethylformamide (DMF) and 41.463 g(0.3M) of K2CO3, was added to the mixture with stirring. To the above solution, 4-methoxybenzyl chloride 15.661 g(0.1M) was added and the mixture was refluxed for 10 hours. The solution then was cooled to room temperature and 150 mL of water was added and the mixture was acidified with 3M HCl. The precipitated material was collected by gravity filtration and washed with acetone to give 27.364 g(99.7%) of white powder with a melting point of 225-227° C. and the following specifications:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][CH:6]([NH2:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:5][CH:6]([NH:13][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCC(C)N
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCC(C)NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of acetyl chloride (7.11 mL, 100 mmol) was added dropwise to an ice water-cooled solution of 1-methylheptyl amine (8.30 g, 64 mmol) and triethylamine (20.91 mL, 150 mmol) in TF (100 mL). The resulting mixture was stirred at RT for 1 h, then was diluted with ethyl acetate and washed twice with 10% HCl, twice with sat aq NaHCO3, and then twice with brine. The organic solution was dried (MgSO4), and concentrated to afford 8.13 g N-(1-methylhept-1-yl)acetamide, a 73% yield.
Reaction SMILES: [CH3:1]C1C=C(O)C=CC=1O.CC1C(C)=C(C=CC=1O)O.[CH3:20][C:21]1[C:22]([OH:30])=[C:23]([CH3:29])[C:24]([CH3:28])=[C:25]([CH:27]=1)[OH:26]>[O-2].[O-2].[Mn+4].CO>[CH3:20][C:21]1[C:22]([OH:30])=[C:23]([CH3:29])[C:24]([CH3:28])=[C:25]([OH:26])[C:27]=1[CH3:1]
Reactant: Cc1cc(O)ccc1O
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: [Mn+4]
Agent: Cc1c(O)ccc(O)c1C
Agent: [O-2]
Solvent: CO
Product: Cc1c(C)c(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into an autoclave (inner volume: 9 ml, made of SUS 316, equipped with a manometer) were charged 0.111 g of methylhydroquinone, 3.463 g of methanol and 4.6 mg of manganese dioxide (manufactured by High Purity Chemicals Co.). The reaction was started by elevating the temperature up to 350° C. with sand bath. The pressure during the reaction was 16 MPa. After 2 hours, the autoclave was quickly cooled and the reaction solution was taken out from the autoclave when the temperature was cooled back to the room temperature. The measurement according to the process described above revealed that the conversion of methylhydroquinone was 45% by mole, the selectivity of dimethylhydroquinone was 64% by mole, the selectivity of trimethylhydroquinone was 17% by mole and no tetramethylhydroquinone was produced. As byproducts, methyl ethers of dimethylquinone and trimethylquinone, represented by the formulae shown above, were formed with a selectivity of 6% and 2%, respectively.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:11](O)(=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14](O)=[O:15].O1CCOCC1.C(OCC)C>O>[C:11]1(=[O:21])[N:1]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)[C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: Nc1n[nH]c2ccccc12
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccccc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
5.0 g of the same 3-aminoindazole as Example 1 and 6.68 g of phthalic acid were added to 50 ml of dioxane, and the mixture was stirred for 5 hours at 120° C. The mixture was condensed under reduced pressure, 30 ml of diethyl ether was added and the mixture was stirred under cooling with ice and water for 30 minutes to separate crystals. The crystals were obtained by filtration and dried under reduced pressure to give 8.6 g of 3-phthalimidoindazole in a yield of 87%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>Cl[Pd](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>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=1>C1COCC1.C(OCC)(=O)C.O>[OH:55][C:52]1[CH:53]=[CH:54][C:49]([NH:48][C:21](=[O:23])[C:20]2[CH:19]=[CH:18][C:17]([C:16]#[C:15][Se:14][C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:1])([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)=[CH:25][CH:24]=2)=[CH:50][CH:51]=1
Reactant: CC1(C)CCC(C)(C)c2cc([Se]C#Cc3ccc(C(=O)O)cc3)ccc21
Reactant: Nc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc([Se]C#Cc3ccc(C(=O)Nc4ccc(O)cc4)cc3)ccc21
Yield: 63.2 %

Procedure:
A solution of 250 mg (0.63 mmol) of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid obtained in Example 5, 169 mg (1.25 mmol) of 1-hydroxybenzotriazole, 240 mg (1.25 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 82 mg (0.75 mmol) of 4-aminophenol in 20 ml of THF is stirred at room temperature for 15 h. Water and ethyl acetate are then added. After stirring and separation of the phases by settling, the aqueous phase is extracted with ethyl acetate. The organic phases are then combined and washed with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified on a column of silica (ethyl acetate 20/heptane 80). 200 mg (65%) of a white solid are obtained. m.p.=202° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])O)O)O.C(OS(C1C=CC=CC=1)(=O)=O)CCCCCCCCCCC.[Na].C1(C)C=CC=CC=1.[ClH:43]>O>[Cl:43][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Cl
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CCl)o1
Reaction time: 7 h

Procedure:
Five grams of a commercially available D-glucose and 97.6 mg of sodium laurylbenzenesulfonate were added to the same three-necked flask. Then, 5 ml of water and 30 ml of toluene were added thereto and the mixture was stirred. Thereafter, a molar excess of hydrogen chloride was passed through the mixture at room temperature for about 25 minutes. Stirring was continued at 50° C. for a further 7 hours. The reaction solution was diluted with a little water and filtered through Celite while being washed with toluene. The upper toluene layer was neutralized, dried and concentrated to obtain about 1.4 g of 5-chloromethylfurfural.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18](=O)[CH3:19])[CH:15]=[CH:16][CH:17]=1.[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22].C(Cl)Cl>C(O)(=O)C.O>[C:21]([C:23](=[C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=1)[CH3:19])[C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22]
Reactant: COc1cccc(C(C)=O)c1
Reactant: CCOC(=O)CC#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C#N)=C(C)c1cccc(OC)c1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
Hexamethyldisilazane (17.45 mL, 83 mmol) was added dropwise to acetic acid (38.1 mL, 666 mmol) (caution exothermic, maintain below 70° C.) stirred under an atmosphere of nitrogen. The resulting mixture was added to a solution of 1-[3-(methyloxy)phenyl]ethanone (9.14 mL, 66.6 mmol) and ethyl cyanoacetate (11.75 mL, 110 mmol) in acetic acid (16 mL), which was then stirred at 70° C. for 18 h. The mixture was then allowed to cool to RT and DCM (350 mL) and water (125 mL) were added. The organic layer was then separated and washed with additional water (125 mL) and dried with anhydrous MgSO4, filtered and evaporated to dryness. The residue was purified on silica, eluting with a gradient of 0-30% ethyl acetate in isohexane and further purified on silica, eluting with a gradient of 0-25% ethyl acetate in isohexane, to afford the title compound (14.1 g). LCMS (A) m/z: 246 [M+1]+, Rt 1.28 min (basic).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[N:7]#[N:8].[CH3:9][C:10]([CH3:35])([O:12][C:13]([NH:15][C@H:16]([C:32]([OH:34])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:14])[CH3:11].CO.CI>C(OCC)(=O)C>[N:7]#[N:8].[CH3:11][C:10]([CH3:35])([O:12][C:13]([NH:15][C@H:16]([C:32]([O:34][CH3:1])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:14])[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: N#N
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CI
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
Cesium carbonate (2.14 g., 6.55 mmole) is added to a mixture of N2 -[(1,1-dimethylethoxy)carbonyl]-N6 -[(phenylmethoxy)carbonyl]-L-lysine (5.0 g., 13.10 mmole) and 20% aqueous methanol (30 ml.). The solution becomes homogeneous after 5 minutes, the methanol is stripped, and the residual water is removed azetropically with acetonitrile (twice). The resulting oil is taken up in dry methylene chloride (10 ml.) and treated with methyl iodide (1.6 ml., 2.0 eq.) at 25° in an argon atmosphere. After 4 hours the reaction mixture is taken up in ethyl acetate and washed successively with water, saturated sodium bicarbonate and brine, dried (MgSO4), and evaporated. The residue (4.7 g.) is chromatographed on silica (160 g.) eluting with hexane/ethyl acetate (3:1) to give 4.0 g. of N2 -[(1,1-dimethylethoxy)carbonyl]-N6 -[(phenylmethoxy)carbonyl]-L-lysine, methyl ester as an oil after evaporation. TLC (hexane/ethyl acetate; 2:1) major spot at Rf =0.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([O:31][C:32]([O:34][CH3:35])=[O:33])=[CH:26][C:24]=1[NH2:25]>C(O)(C)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:25][C:24]3[CH:26]=[C:27]([O:31][C:32]([O:34][CH3:35])=[O:33])[C:28]([CH3:30])=[CH:29][C:23]=3[F:22])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: COC(=O)Oc1cc(N)c(F)cc1C
Solvent: CC(C)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c(F)cc1C
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of 7-benzyloxy4-chloro-6-methoxyquinazoline (800 mg, 2.6 mmol), (prepared as described for the starting material in Example 4 but with an aqueous work up), and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (570 mg, 2.89 mmol) in isopropanol (20 ml) was refluxed for 2 hours. After cooling to ambient temperature, the solid was filtered, washed with isopropanol and dried under vacuum to give 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy4-methylanilino)-6-methoxyquinazoline (1.0 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:19]=[C:13]2[C:14](=[O:18])[NH:15][CH2:16][CH:17]=[C:12]2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]#[CH:28]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:28][C:27]#[CH:26])[CH:6]=[CH:5][C:4]=1[C:10]1[N:19]=[C:13]2[C:14](=[O:18])[NH:15][CH2:16][CH:17]=[C:12]2[N:11]=1
Reactant: COc1cc(O)ccc1C1=NC2=CCNC(=O)C2=N1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCOc1ccc(C2=NC3=CCNC(=O)C3=N2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1 g of 2-(2-methoxy-4-hydroxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-one was suspended in 30 1.41 g of potassium carbonate were added, and the mixture was stirred at room temperature. After 15 minutes and again after one hour, 0.9 ml of propargyl bromide was added, and the mixture was then stirred for another 1.25 hours. The solvent was substantially evaporated in vacuo, and the residue was stirred with methylene chloride. After the precipitate had been filtered off and washed with water, the product contained in the organic phase was purified on a silica gel column (eluant: methylene chloride/ethanol 1:0 to 1:0.03). The product crystallized with half a mol of ethanol. Yield: 0.07 g (7% of theory). Melting point: 178°-180° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:11][C:9](=O)[CH2:8][CH2:7]1.S(Cl)([Cl:14])=O.[CH3:16][OH:17]>[Cl-].[Zn+2].[Cl-]>[CH3:16][O:17][C:9](=[O:11])[CH2:8][CH2:7][CH:6]([Cl:14])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCC1CCC(=O)O1
Reactant: O=S(Cl)Cl
Reactant: CO
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCCCC(Cl)CCC(=O)OC
Reaction time: 24 h

Procedure:
To a solution of γ-nonalactone (0.32 ml, 2 mmol) in thionyl chloride (164 μl, 2.25 mmol), zinc chloride (12 mg, 0.088 mmol) is added at room temperature and the mixture is stirred for 24 h. Excess methanol is added and the reaction mixture is stirred for 10 min and then concentrated under reduced pressure to give 4-chloro-nonanoic acid methyl ester used as such.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:20])(=[O:19])[N:11]([CH2:13][C:14]([O:16][CH2:17]C)=[O:15])[CH3:12])=O.C[O-].[Na+]>>[C:14]([C:13]1[N:11]([CH3:12])[S:10](=[O:20])(=[O:19])[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]=1[OH:2])([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CN(C)S(=O)(=O)c1ccsc1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C1=C(O)c2sccc2S(=O)(=O)N1C
Reaction time: 0.25 h

Procedure:
13.2 G. of 3-(N-carbethoxymethyl-N-methyl-sulfamoyl)-thiophene-2-carboxylic acid methyl ester are suspended in 42 ml. of a 1-N methanolic sodium methylate solution in the cold and under a nitrogen stream. After stirring for 15 minutes, a clear solution results. The solution is heated to reflux for 20 minutes, then cooled, neutralized and evaporated in vacuo. The residue is taken up in methylene chloride, shaken once each time with water and a sodium bicarbonate solution, dried and evaporated. The residue is brought to crystallization with methanol. There is obtained 3-carbomethoxy-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine1,1-dioxide of melting point 193°-195° C.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[OH:16][C:15](=[C:4]([C:3]#[N:7])[C:5]#[N:6])[CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(C#N)=C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To 60% NaH/mineral oil dispersion (3.2 g, 79.5 mmol) in THF (100 ml) at room temperature under argon was added dropwise malononitrile (5.0 ml, 79.5 mmol) in THF (20 ml) over 30 minutes. The reaction mixture was stirred at room temperature for 30 minutes, then phenylacetyl chloride (10.5 ml, 79.5 mmol) in THF (10 ml) was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 1.5 hours, the solvent was removed in vacuo, and the residue was partitioned between ether and 2N H2SO4. The ether layer was separated, washed with water, dried over anhydrous MgSO4, filtered through a silica gel plug and the solvent was removed in vacuo to afford 13.8 g (94%) of (1-hydroxy-2-phenylethylidene)malononitrile as an amber oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=O)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:13][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a mixture of (3,4-dinitro-phenyl)-morpholin-4-yl-methanone (1 mol. eq.) in dry tetrahydrofuran (THF) (25 vol.), at 0-5° C., was added NaBH4 (2 mol. eq.) followed drop-wise by BF3.Et2O (1.01 mol. eq.) so as to maintain the temperature at 0-5° C. The mixture was then stirred at ambient temperature for 3 hours and then quenched through addition of methanol. The mixture was then reduced in vacuo, partitioned between ethyl acetate and saturated aqueous NaHCO3. The mixture was stirred rapidly for 30 minutes before separating the layers. The organic layer was washed successively with water and brine before being reduced in vacuo. The product was crystallised from methanol to give 4-(3,4-dinitro-benzyl)-morpholine (85%). (LC/MS (basic method): Rt 2.80, [M+H]+ 268).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[O:20][CH3:21])=[CH:3][C:2]=1[Cl:1]
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture of 3,4-dichlorophenol (38 g, 233.13 mmol, 1.00 equiv), 1-fluoro-2-methoxy-4-nitrobenzene (40 g, 233.75 mmol, 1.00 equiv) and potassium carbonate (64 g, 463.77 mmol, 1.99 equiv) in N,N-dimethylformamide (250 mL) was stirred overnight at 60° C. The resulting solution was diluted with 1000 mL of water, extracted with 3×200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 60 g (82%) of 1,2-dichloro-4-(2-methoxy-4-nitrophenoxy)benzene as a brown solid.
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][C:6]([OH:14])([CH2:7]3)[CH2:5]1)[CH2:11]2)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH2:19](N(CC)CC)C.CO>CN(C=O)C>[CH3:19][O:2][C:1]([C:4]12[CH2:11][CH:10]3[CH2:9][CH:8]([CH2:7][C:6]([OH:14])([CH2:12]3)[CH2:5]1)[CH2:13]2)=[O:3]
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C12CC3CC(CC(O)(C3)C1)C2
Reaction time: 2 h
Yield: 95 %

Procedure:
10 mmol of the 1-carboxy-3-adamantanol produced by the method of Preparation Example 5 under a nitrogen atmosphere was dissolved in 10 ml of DMF, and 15 mmol of thionyl chloride was dropped into the solution for 30 minutes. The temperature was elevated so that the solution starts its reflux at the end of dropping. After two hours of reflux, the reactant mixture was cooled, added 20 mmol of triethylamine, the temperature of the mixture was maintained at 10° C. or below, and 11 mmol of methanol was added dropwise for 30 minutes and stirred for 2 hours. And, at the result, the 1-carboxy-3-adamantanol was converted into a 1-methoxycarbonyl-3-adamantanol (yield: 95%) with a conversion of 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:11]1([CH2:20][NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(NCn1nnc2ccccc21)c1ccc(Cl)cc1

Procedure:
4-Chlorobenzamide, paraformaldehyede, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 18B to provide the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13].Cl.O>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:12](=[O:13])[NH:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NNC(=O)c1cccc(I)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2cccc(I)c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
3-Iodobenzohydrazide (1.00 g, 3.82 mmol) obtained in Step 1 of Example 52 was dissolved in THF (19 mL), and the mixture was stirred at room temperature for 1 hour after adding 1,1′-carbonyldiimidazole (681 mg, 4.18 mmol). The mixture was stirred after adding 6 mol/L hydrochloric acid (20 mL) and water (20 mL), and the precipitated solid was filtered off and dried to give 5-(3-iodophenyl)-1,3,4-oxadiazol-2(3H)-one (779 mg, 71%).