Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([N:27]1[CH:31]=[C-]O[C:28]1=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:20]([N:27]1[CH2:31][CH:11]2[CH:12]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C:10]2=[O:13])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1o[c-]cn1Cc1ccccc1
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Solvent: Cc1ccccc1
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Yield: 16.4 %

Procedure:
A solution of 4,4-diphenyl-2-cyclohexen-1-one (25 g) and 3-benzyl-5-oxazolidone (2.5 g) in dry toluene (100 cc) is heated to reflux for 2 hours 30 minutes. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 4.5 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (80:20 by volume) and collecting 50-cc fractions. Fractions 13 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-benzyl-7,7-diphenylperhydro-4-isoindolone (0.9 g) in the form of white crystals, m.p. 132° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[CH:13]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1.N1C=CC=CC=1>C(OCC)C>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[CH:13]=[CH:16][C:17]([OH:19])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cnccc1-c1ccccc1
Reactant: O=C(O)CC(=O)O
Solvent: CCOCC
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cnccc1-c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
A mixture of 4.3 g of 4-phenyl-3-pyridinecarbaldehyde [cf. Heterocycles, 14, 813 (1980)], 2.5 g of malonic acid, 0.5 ml of piperidine, and 6 ml of pyridine is stirred at 100° C. for 2 hours. After cooling, 50 ml of diethyl ether is added, and the resulting precipitate is collected. The obtained solid is washed with water and dried to give 3.4 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2=[O:15].[Si](OC)(OC)(OC)OC.[F-].[K+].[N+:27]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)([O-:29])=[O:28]>CN(C)C=O.CCOCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:13])([CH3:14])[C:7](=[CH:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=1)[C:6]2=[O:15]
Reactant: COc1ccc2c(c1)C(=O)CC(C)(C)O2
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CO[Si](OC)(OC)OC
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc2c(c1)C(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)(C)O2
Temperature: 80 °C
Yield: 59.8 %

Procedure:
A mixture of 7.0 g (0.034 mole) of the product of Example 109, 2.5 mL (2.6 g, 0.017 mole) tetramethyl orthosilicate, 1.9 g (0.034 mole) potassium fluoride and 5.1 g (0.034 mole) 3-nitrobenzaldehyde in 10 mL dimethylformamide was heated to 80° C. for 4 hours. The mixture was diluted with ether and washed successively with 1N HCl, 5% NaHCO3, water and brine and then dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel eluting with 20% ethyl acetate in hexanes yielded an oil. Recrystallization from ether/hexanes afforded 6.9 g (60%) of the title product as a solid. Mp 103°-105° C. Analysis calculated for C15H17NO5 : C, 67.25; H, 5.05; N, 4.13. Found: C, 67.22; H, 4.87; N, 4.11.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28]O)=[CH:23][C:22]=3[F:30])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)[NH:54]C(=O)C2=CC=CC=C12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][NH2:54])=[CH:23][C:22]=3[F:30])[CH2:19][CH2:20]2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CO)cc3F)CC2)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CN)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 10-1 (30 mg, 0.07 mmol), triphenylphosphine (19 mg), phthalimide (11 mg) and DEAD (12 μL) in THF (1 mL) was stirred at room temperature for 3 days. The mixture was concentrated under a stream of nitrogen and combined with DCM (0.2 mL), ethanol (0.5 mL) and hydrazine (50 μL). The mixture was stirred at room temperature for 20 h, filtered and concentrated under a stream of nitrogen. The crude mixture was taken up with methanol and purified by preparative HPLC to afford 16a as a brown oil: LC-MS 408.2 (MH+-17).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22]([NH:24][NH2:25])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:14]([O:21][C:22]([NH:24][NH:25][C:10](=[O:12])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:13])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CC(=O)NNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 88 %

Procedure:
6.95 g of 2-(tert-butoxycarbonyl-methyl-amino)-acetic acid, 6.1 g of hydrazine carboxylic acid benzyl ester, 6.18 g of 1-hydroxybenzotriazole monohydrate and 19.2 mL of N,N-diisopropylethylamine were dissolved in 120 mL of N,N-dimethylformamide, and 10.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under stirring at room temperature. After stirring at room temperature for 17 hours, the reaction solution was added with water and extracted with ethyl acetate, and the resultant organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, followed by purification by silica gel column chromatography (hexane:ethyl acetate=1:1), to obtain 10.9 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:20][O:21][CH3:22].[Cl-].[Na+].O.[C:26]([O:29][CH2:30]C)(=O)C>CN(C)C=O>[CH3:20][O:21][CH2:22][O:16][C:13]1[CH:14]=[CH:15][C:10]([S:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:26][O:29][CH3:30])=[CH:7][CH:6]=2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(SSc2ccc(O)cc2)cc1
Reactant: CCOC(C)=O
Reactant: COCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(SSc2ccc(OCOC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-hydroxyphenyldisulfide (650 mg, 2.60 mmol) in 10 mL of anhydrous N,N-dimethylformamide at 10° C. was added sodium hydride (230 mg, 5.75 mmol, 60% dispersion in mineral oil). After stirring for 15 minutes, chloromethylmethyl ether (0.44 mL, 5.75 mmol) was added via syringe. The reaction was warmed to ambient temperature and stirred for 0.5 hours. The mixture was distributed between brine/ethyl acetate (20 mL each). The layers were separated and the aqueous phase extracted with ethyl acetate (2×20 mL). The organic was dried (sodium sulfate) and concentrated to a yellow oil (993 mg, 100%). An analytical sample of 4-(methoxymethyloxy)-phenyldisulfide was prepared by chromatography (silicon dioxide, 4% ethyl acetate/hexanes). 1H NMR (DMSO-d6) d 7.40 (d, J=6.9 Hz, 4H), 7.00 (d, J=6.9 Hz, 4H), 5.15 (s, 4H), 3.32 (s, 6H). FD mass spec: 338. Anal. Calcd. for C16H18O4S2 : C, 56.78; H, 5.36. Found: C, 57.08; H, 5.44.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[C:19]1([C:25]2[N:26]=[C:27]3[N:32]=[C:31]([NH2:33])[CH:30]=[CH:29][N:28]3[CH:34]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:35]([O:37][C:38]([C:40]1[C:44]([C:45](O)=[O:46])=[CH:43][N:42]([CH3:48])[N:41]=1)=[O:39])[CH3:36].C(C(N(C(C)C)C(C)C)C)C>C(OCC)(=O)C>[CH2:35]([O:37][C:38]([C:40]1[C:44]([C:45](=[O:46])[NH:33][C:31]2[CH:30]=[CH:29][N:28]3[CH:34]=[C:25]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:26]=[C:27]3[N:32]=2)=[CH:43][N:42]([CH3:48])[N:41]=1)=[O:39])[CH3:36]
Reactant: CCOC(=O)c1nn(C)cc1C(=O)O
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: CCC(C)N(C(C)C)C(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C)cc1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
At 0° C., propylphosphonic acid anhydride (1-propanephosphonic acid cyclic anhydride, 50% in ethyl acetate, 7.4 ml, 2.5 eq.) was added slowly to a solution of 2-phenylimidazo[1,2-a]pyrimidin-7-amine (example 1, step 1, 1.27 g, 6 mmol), 1-methyl-1H-pyrazole-3,4-dicarboxylic acid 3-ethyl ester (1.00 g, 5 mmol), and ethyldiisopropylethylamine (2.0 ml, 15 mmol) in ethyl acetate (20 ml). The mixture was stirred for 30 min at 0° C., and subsequently at RT for 48 h. The mixture was taken up in ethyl acetate, and washed with water. The combined water layers were adjusted to pH=9 (NaOH), and extracted with dichloromethane. All organic layers were combined, dried (Na2SO4), and evaporated. The title compound (580 mg, 29%) was obtained from the residue by column chromatography (silica gel, heptane:ethyl acetate=100:0-80:20). (1-Methyl-1H-pyrazole-3,4-dicarboxylic acid 3-ethyl ester was obtained by the method of Pérez et al., Spanish patent appl. ES 493459.)
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.[C:12](OC(C)(C)C)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>C1(C)C=CC=CC=1>[C:12]([O:10][C@H:3]1[C@H:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][C@@H:1]([CH3:11])[CH2:2]1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 23 °C
Yield: 114.5 %

Procedure:
A solution of (-)-menthol (23.0 g, 147 mmol, 1 equiv) and t-butyl acetoacetate (20.0 mL, 121 mmol, 0.80 equiv) in toluene (50 mL) was heated at reflux for 12 h, then was cooled to 23° C. Volatiles were removed in vacuo and toluene (20 mL) and t-butyl acetoacetate (12.2 mL, 73.5 mmol, 0.50 equiv) were added to the residue. The resulting solution was heated at reflux for 12 h, then was cooled to 23° C. The cooled reaction mixture was concentrated in vacuo and the residue was purified by distillation under reduced pressure (bp 90° C., 30 mmHg) to afford (1R, 3R, 4S)-p-menth-3-yl acetoacetate (1) as a low-melting solid (33.3 g, 94%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1.[OH:29][CH2:30][CH2:31][NH2:32].O>C1COCC1>[OH:29][CH2:30][CH2:31][NH:32][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1
Reactant: NCCO
Reactant: N#Cc1c(Cl)nc(OCc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCO2
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(NCCO)nc(OCc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCO2

Procedure:
30 mg (0.08 mmol) of 2-chloro-4-(1,3-benzodioxol-5-yl)-6-benzyloxy-3,5-pyridinedicarbonitrile (example 4, step 1) and 14.1 mg (0.23 mmol) of 2-hydroxyethylamine are shaken together in 0.5 ml of THF for about 16 h. Water is added to the reaction solution and the product that crystallizes out is filtered off with suction and dried under reduced pressure. The crude product is purified by silica gel chromatography using the mobile phases dichloromethane and dichloromethane/methanol 50:1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.O=[CH:12][C:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[N:9]=[C:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)[CH:12]=[N:10]2
Reactant: COC(=O)c1ccc(C(=O)C=O)cc1
Reactant: COc1ccc(N)c(N)c1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2cnc3cc(OC)ccc3n2)cc1

Procedure:
To a solution of methyl 4-acetylbenzoate (1.00 g, 5.61 mmol) in DMSO (5 mL) was slowly added 40% HBr (1.5 mL) at 20° C. under stiffing. The mixture was stirred at 60° C. for 12 hours. The mixture was diluted with water (10 mL) and the resulting mixture was extracted with DCM (10 mL×3), washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give methyl 4-(2-oxoacetyl)benzoate (150 mg), which was taken forward without further purification. To a solution of 4-methoxybenzene-1,2-diamine (107 mg, 0.78 mmol) in 5 mL of acetic acid was added the crude methyl 4-(2-oxoacetyl)benzoate (150 mg). The mixture was refluxed for 2.5 hours. The solvent was removed in vacuo. The crude product was purified by prep-TLC (PE/EA:1/1) to separate the desired methyl 4-(6-methoxyquinoxalin-2-yl)benzoate (more polar) from the undesired methyl 4-(7-methoxyquinoxalin-2-yl)benzoate. The two structures were confirmed by HMBC spectra.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.S(=O)(=O)(O)[OH:30]>>[CH3:5][CH:6]([NH:4][C:1](=[O:30])[CH:2]=[CH2:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=S(=O)(O)O
Reactant: C=CCCCCCCCC
Reactant: C=CC#N
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC(=O)NC(C)CCCCCCCC

Procedure:
Following a procedure analogous to that of Example 1, treat acrylonitrile with 1-decene in the presence of phenothiazine and 83% sulfuric acid to obtain the title product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[Br:22][CH2:23]CCCCC(C)(C1C=CC=CC=1)CO.O1C=CCCC1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:22][CH2:23][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CC(CO)(CCCCCBr)c1ccccc1
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(CCCCCBr)(COC1CCCCO1)c1ccccc1
Yield: 76 %

Procedure:
According to the method described for the synthesis of 207d, 206h (51.0 g, 179 mmol) was reacted with 3,4-dihydro-2H-pyran (18.80 g, 223 mmol) and p-toluenesulfonic acid hydrate (1.21 g, 6.36 mmol). Filtration through aluminum oxide (370 g) and concentration in vacuo afforded 207h (48.75 g, 76%) as a yellowish oil. 1H NMR (CDCl3): δ 7.35-7.17 (m, 10 H), 4.53 (m, 1 H), 4.49 (m, 1 H), 3.82 (m, 2 H), 3.79 (m, 1 H), 3.68-3.60 (m, 2 H), 3.45-3.35 (m, 2 H), 3.32 (t, 4 H, J=6.9), 1.82-1.18 (m, 28 H), 1.35 (s, 6 H). 13C NMR (CDCl3): δ 146.12, 128.11, 126.66, 125.89, 99.18, 99.04, 76.46, 62.02, 61.83, 42.17, 42.07, 38.91, 38.73, 34.12, 32.80, 30.70, 29.04, 25.66, 23.33, 22.97, 22.89, 19.49, 19.39. HRMS (LSIMS, nba): Calcd for C19H30BrO2 (MH+): 369.1429, found: 369.1430.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=[O:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13]1[CH:18]=CC=CC=1.C1(C)C=CC(S(O)(=O)=[O:26])=CC=1>C(O)CO>[CH3:1][O:2][N:3]=[C:4]([C:10]1([O:26][CH2:13][CH2:18][O:12]1)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccccc1
Reactant: CCOC(=O)C(=NOC)C(C)=O
Solvent: OCCO
Product: CCOC(=O)C(=NOC)C1(C)OCCO1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a solution of ethyl 2-methoxyimino-3-oxobutyrate (syn isomer, 200 g) in ethylene glycol (179 g) were added dried benzene (3 l) and p-toluenesulfonic acid (6 g), and the mixture was heated for 20 hours under reflux while removing water azeotropically. The reaction mixture was cooled to ambient temperature, washed with water, a saturated aqueous solution of sodium bicarbonade, water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and then filtered. After the filtrate was evaporated, the residual oil was distilled under reduced pressure to give ethyl 2-methoxyimino-3,3-ethylenedioxybutyrate (syn isomer), bp 89.5°-91° C./0.6 mmHg, in 85.5% yield.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O:16]C(C)(C)C)=[O:15])=[O:8])(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl.O>[C:1]([O:4][CH2:5][C@H:6]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=[O:15])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of compound 2 (1 g, 2.30 mmol) in CH2Cl2 (5 mL) was added 20% TFA-DCM (10 mL) and stirred at RT for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×15 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield compound 3 (800 mg, 92%).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].C1(=O)NC(=O)CC1.[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([N:29]1[CH2:34][CH2:33][N:32]([C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[NH:1][C:2](=[O:3])[CH2:4][CH2:5]3)=[O:14])[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1CCc2cc(C(=O)O)ccc2N1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C1CCC(=O)N1
Solvent: O
Product: O=C1CCc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
127 Milligrams of succinimide 3,4-dihydrocarbostyril-6-carboxylate and 93 mg of benzylpiperazine were dissolved in 2 ml of dimethylformaide and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture and extracted with chloroform, the chloroform layer was washed with water and a saturated sodium chloride aqueous solution. After drying the chloroform layer with anhydrous sodium sulfate, chloroform was removed by distillation under a reduced pressure, then acetone was added to the thus obtained residue to crystallize the product. Recrystallize from ethanol to obtain 130 mg of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([Cl:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[S:23]([O:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)([C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=1)(=[O:25])=[O:24].[Cl:26][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC#Cc1ccc(-c2cccs2)s1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC#Cc2ccc(-c3cccs3)s2)cc1
Product: ClCCC#Cc1ccc(-c2cccs2)s1
Reaction time: 8 h

Procedure:
8.48 g of 5-(4-hydroxy-1-butynyl)-2,2'-bithiophene was dissolved in 100 ml of pyridine. 16 g of p-tosyl chloride was added in under nitrogen gas atmosphere. After stirred overnight, the pyridine was evaporated under reduced pressure. The reside was extracted with ethyl acetate (100 ml) twice, filtered, washed with water (100 ml) twice, HCl solution twice (5%, 100 ml) and water (100 ml) twice again. The organic layer dried over anhydrous magnesium sulfate was filtered and the solvent thereof was evaporated. The residual solid was further purified by rapid silica gel column chromatography. From the eluate of ethyl acetate/n-hexane (1/6). 6.25 g of 5-(4-tosyloxy-1-butynyl)-2,2'-bithiophene and 1.48 g of 5-(4-chloro-1-butynyl)-2,2'-bithiophene were respectively obtained and the yield thereof was 44% and 16%.
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O-:18])=[O:17].F[B-](F)(F)F.[C:27]1(=[O:41])[N:31](OC(N(C)C)=[N+](C)C)[C:30](=[O:40])[CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][N:31]1[C:27](=[O:41])[CH2:28][CH2:29][C:30]1=[O:40])=[O:17]
Reactant: COC(=O)CCCCCCCCCCCCCCC(=O)[O-]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 20 h
Yield: 96.8 %

Procedure:
Mono-methyl hexadecandioate (275 mg, 0.91 mmol) was dissolved in THF (3 ml) and treated with succinimidyl tetramethyluroniumtetrafluoroborate (331 mg, 1.1 mmol) and N,N-diisopropylethylamine (188 μL, 1.1 mmol), and the mixture was stirred for 20 hours. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate and washed with 0.1 M HCl (twice) and water. The organic phase was dried over MgSO4, filtered and evaporated in vacuo to give 350 mg (96%) of methyl succinimidyl hexadecandioate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][CH:11]=[N:12][OH:13].[Cl:14]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]([Cl:14])=[N:12][OH:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=CCCc1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)CCc1c(Cl)cccc1Cl
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A solution of 3-(2,6-dichlorophenyl)propanal oxime (1.05 g, 4.82 mmol) in dimethylformamide (3.8 mL) was stirred as N-chlorosuccinimide (0.64 g, 4.82 mmol) was added. The resulting solution was allowed to stir for one hour. The solution was poured into water and extracted with ether. The organic layer was washed with brine, dried with magnesium sulfate, filtered and concentrated to yield the title compound (1.05 g, 86%). 1H NMR (DMSO-d6): 11.67 (s, 1H), 7.45 (d, J=8 Hz, 2H), 7.28 (t, J=8 Hz, 1H), 3.17-3.13 (m, 2H), 2.68-2.64 (m, 2H).
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:6]=1.C(N(CC)CC)C.O.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>CN(C)C=O>[CH2:10]([O:9][C:7]([C:4]1[O:3][C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:6][CH:5]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1ccc(Br)o1
Reactant: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)o1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of the compound obtained in Example 29 (1) (0.5 g) in N,N-dimethylformamide (5 ml), trimethylsilylacetylene (0.65 ml), bistriphenylphosphine palladium dichloride (0.16 g), cuprous iodide (0.04 g) and triethylamine (0.64 ml) were added successively and the mixture was stirred in a sealed tube at 100° C. for 2 hours. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 0.3782 g of the desired product as a brown oil.