Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1>>[Cl:8][C:7]1[C:2]([N:17]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:12])[CH2:18]2)=[N:3][CH:4]=[C:5]([CH2:9][O:10][CH3:11])[CH:6]=1
Reactant: COCc1cnc(Cl)c(Cl)c1
Reactant: C[C@@H]1CNCCN1
Product: COCc1cnc(N2CCN[C@H](C)C2)c(Cl)c1

Procedure:
A mixture of 2,3-dichloro-5-methoxymethyl-pyridine from step (a) above (370 mg, 1.93 mmol) and (R)-(−)-2-methyl-piperazine (231 mg, 2.3 mmol, Aldrich) reacted under the condition of Example 3a to give the title compound. MS (ESI, pos. ion) m/z: 256 (M+1).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1.CI>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:13][C:14]([O:16][CH3:1])=[O:15])=[CH:17][CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C=Cc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 94283.6 %

Procedure:
Anhydrous potassium carbonate (20.7 g, 0.15 mmole) was added to a solution of 4-bromocinnamic acid (22.7 g, 0.1 mmole) in dry N,N-dimethylformamide (150 ml) and the mixture was stirred for 30 minutes. Methyl iodide (21.3 g, 9.4 ml, 0.15 mmole) was then added and the total mixture stirred for a further 24 hours at room temperature before the solvent was evaporated in vacuo. Water was added to the residue and the product extracted into ether. The ethereal extracts were washed with saturated aqueous sodium bicarbonate solution, the brine and dried (MgSO4). Evaporation afforded 22.73 g (94%) of the ester as a white solid of mp (methanol) 82°-86° C. (lit mp 80° C., Dictionary of Organic Compounds), υmax (mull), 1718, 1640, 1595, 1495 cm-1. δ(CDCl3) 3.80 (3H, s, ester CH3), 6.37 (1H, d, J 13 Hz, =CHCO2), 7.42 (4H, m, arom), 7.62 (1H, d, J 13 Hz, ArCH=).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N)C.[CH2:18]([N:25]1CCC[CH:27](NCC)[CH2:26]1)[C:19]1C=CC=CC=1.C(=O)C>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:25]([CH2:26][CH3:27])[CH2:18][CH3:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: CCNC1CCCN(Cc2ccccc2)C1
Agent: CC=O
Agent: CCN
Product: CCN(CC)C1CCCN(Cc2ccccc2)C1

Procedure:
By the procedure of Example 1, hydrogenating 1-benzyl-3-piperidone and ethylamine, then treating the resulting 1-benzyl-3-ethylaminopiperidine with acetaldehyde and hydrogenating to give 1-benzyl-3-diethylaminopiperidine, and removing the benzyl group by hydrogenating with palladium on carbon in methanol gives 3-diethylaminopiperidine.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].[N:7]1([CH2:12][C:13](=O)[CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:11]=[CH:10][N:9]=[CH:8]1.[OH2:26]>O1CCCC1>[N:7]1([CH2:12][C:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:16][CH2:17][CH2:18][CH2:19][CH2:5][C:2]([OH:26])=[O:4])[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: O
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(COCC(=O)Cn2ccnc2)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(COCC(=CCCCCC(=O)O)Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred suspension containing 5-(carboxypentyl) triphenylphosphonium bromide (22 g, 0.048 mol) in dry tetrahydrofuran (100 ml) at 0° C. under a nitrogen atmosphere was treated with potassium t-butoxide (11.2 g, 0.10 mol) and stirred for 2 hours at room temperature. The resulting orange mixture was cooled to 0° C. and treated with a solution of 1-(1H-imidazol-1-yl)-3-[(4-methoxyphenyl)methoxy]-2-propanone (as prepared in Example 1c, 6.4 g, 0.025 mol) in dry tetrahydrofuran (25 ml). The reaction mixture was stirred at room temperature for 4 hours after which time the solvent was evaporated off under reduced pressure to yield a residue which was treated with water (200 ml) and extracted with ethyl acetate (4×150 ml). The aqueous solution was acidified to pH 1 using 12M hydrochloric acid washed with ethyl acetate (3×100 ml), basified to pH 5.5 using sodium bicarbonate and extracted with ethyl acetate (4×150 ml). The extracts were combined, washed with water then brine, dried over sodium sulfate and the solvent was evaporated off under reduced pressure to yield a crude product. The crude product was purified by column chromatography (silica gel, 5% ethanol in chloroform) to yield an isomeric mixture of E- and Z-8-(1-H-imidazol-1-yl)-7-[[(4-methoxyphenyl)methoxy]methyl]-6-octenoic acid as a pale yellow oil having the following structural characteristics:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11](S([O-])(=O)=O)=[C:12]([OH:18])[C:13]=3[OH:17])[C:7](=[O:8])[C:5]=2[CH:6]=1.[Na+].[Na+].[Cl-].C=O>>[CH:1]1[CH:6]=[C:5]2[C:7]([C:9]3[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([OH:17])[C:14]=3[C:15](=[O:16])[C:4]2=[CH:3][CH:2]=1)=[O:8]
Reactant: O=C1c2ccccc2C(=O)c2c1cc(S(=O)(=O)[O-])c(O)c2O
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)c2c1ccc(O)c2O
Reaction time: 0.08 h

Procedure:
Alizarin red S (Wako Pure Chemical Industries Co., Ltd.) was adjusted to have 0.9% NaCl (pH 4.2). The cells were dyed with the stain for 5 minutes, then, fixed with 4% paraformaldehyde, and observed with a microscope.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:11][C:10]=1[Cl:22])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH2:8][C:9]1[C:10]([Cl:22])=[CH:11][C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:13]([CH:15]=[CH2:16])[CH:14]=1
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)c(Cl)cc1NS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cc(CN)c(Cl)cc1NS(C)(=O)=O
Reaction time: 12 h
Yield: 129.7 %

Procedure:
To a dried 25 ml round bottom flask was added (2-chloro-4-methanesulfonylamino-5-vinyl-benzyl)-carbamic acid t-butyl ester (103.9 mg, 0.29 mmol) and diluted with methylenechloride. To the solution were added 5-6 drops of CF3COOH and stirred for 12 hours. After confirming the completion of the reaction with TLC, the resulting solution was concentrated under reduced pressure using toluene to yield a brownish syrup (98.1 mg, 130.74%).
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[CH2:19](I)[CH3:20]>>[CH3:1][N:2]([CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([N:5]([CH2:19][CH3:20])[C:6]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[O:8][N:7]=1)=[O:4]
Reactant: CCCCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: CCI
Product: CCCCN(C)C(=O)N(CC)c1cc(C(C)(C)C)on1

Procedure:
The reaction is effected as in Example 171 by using 1-methyl-1-butyl-3-(5-t-butyl-3-isoxazolyl)urea and ethyl iodide to give 1-methyl-1-butyl-3-ethyl-3-(5-t-butyl-3-isoxazolyl)urea as an oil boiling at 130° to 135° C (bath temperature)/0.25 mm Hg.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH2:1]([N:13]([CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[S:28]([CH3:27])(=[O:30])=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNCc1cccnc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCCCCCCCN(Cc1cccnc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 4.1 g. portion of 3-dodecylaminomethylpyridine was dissolved in 15 ml. of dichloromethane, and 2.7 g. of potassium carbonate and 1.6 ml. of methanesulfonyl chloride were added. The mixture was stirred for 3 days at ambient temperature, and was then diluted with dichloromethane and extracted with water. The organic layer was dried and evaporated to an oil, which was dissolved in dichloromethane and chromatographed over silica gel, eluting with dichloromethane. The product-containing fractions were combined and evaporated to obtain 3.5 g. of oil which crystallized on standing, and was triturated with cold petroleum ether and diethyl ether. The solids were dried to obtain 3.2 g. of the desired product, m.p. 43°-44°.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7]([OH:10])=[N:8][O:9][C:5]=2[CH:4]=1.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1.O>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[N:8]([C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:9][C:5]=2[CH:4]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1noc2cc(CCl)ccc12
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1c2ccc(CCl)cc2on1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
In 50 mL of methylene chloride, 5.00 g of 6-(chloromethyl)-1,2-benzisoxazol-3-ol, 7.59 g of triphenylmethyl chloride and 2.20 mL of pyridine were suspended and stirred for 5 hours at room temperature. To the reaction mixture, 15 mL of water and 15 mL of methylene chloride were added, and the result was stirred for 5 minutes under reflux and heating. After cooling the reaction mixture, 2.50 g of silica gel was added. After insoluble matter was filtered off, the cake was washed with 10 mL of methylene chloride. The filtrate and the washing solution were combined and, after adding 8 mL of methylene chloride and 15 mL of water, 45 mL of solvent was distilled off under atmospheric pressure. To the reaction mixture, 35 mL of acetone was added and 33 mL of solvent was distilled off under atmospheric pressure. After adding 20 mL of water, solids were filtered and 11.3 g of 6-(chloromethyl)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-one was obtained in the form of a pale yellowish-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]=1[O:26]C)[CH:8]=[CH:7]2.B(Br)(Br)Br.C(Cl)Cl>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([C:18]([CH3:19])([CH3:20])[CH3:21])[CH:15]=[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]=1[OH:26])[CH:8]=[CH:7]2
Reactant: COc1c(-c2ccc3cccc(Br)c3n2)cc(C(C)(C)C)cc1C(C)(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(-c2ccc3cccc(Br)c3n2)c(O)c(C(C)(C)C)c1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A mixture of 8-bromo-2-(3,5-di-tert-butyl-2-methoxyphenyl)quinoline (4.89 g, 11.5 mmol), BBr3 (1.63 mL, 18 mmol), and CH2Cl2 (50 mL) is stirred for 4 h at 20° C. The reaction mixture is then diluted with cold water (100 mL). The organic phase is separated, washed with water and brine, and then concentrated. The residue is recrystallized from hexane/benzene. Yield: 3.3 g (70%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].Br[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:16][CH:17]=2)[CH:9]=1)=[O:4]
Reactant: Brc1ncccn1
Reactant: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Product: COC(=O)c1cc(COc2ccc(-c3ncccn3)cc2)c(C)o1

Procedure:
Compound (136) was prepared from compound (119) and 2-bromo-pyrimidine by adapting the procedure of Example 30(a). LC/MS System A; Rt=3.43 mins, m/z (ES+)=325 (M+H for C18H16N2O4).
Reaction SMILES: [C:1]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.NC[CH2:19][CH2:20][C:21]([OH:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>O>[C:7]1(=[O:16])[N:6]([CH2:1][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: NCCCC(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCN1C(=O)c2ccccc2C1=O
Yield: 63 %

Procedure:
N-Carboethoxyphthalimide (10.96 g) was added on one portion to a vigorously stirred solution of 4-aminobutanoic acid (5.16 g) and sodium carbonate (5.35 g) in water (150 ml) at RT. The mixture was stirred until essentially all the solid material had dissolved (30 min), then it was filtered. The filtrate was acidified to pH1 with 6N aqueous hydrochloric acid (ca. 22 ml) and the white precipitate was collected by filtration and washed thoroughly with water (150 ml). The solid was dried in air, then in vacuo to give the title compound as a colourless solid (7.35 g).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([CH:19]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35](O)=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH2:20][CH2:21][CH2:22][CH3:23])[CH3:18]>>[CH2:17]([CH:19]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH2:20][CH2:21][CH2:22][CH3:23])[CH3:18]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CCCCC(CC)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Product: CCCCC(CC)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
1.11 g of compound 18 was obtained in a similar manner to those described in the Examples 1 and 2 using 2.18 g of ethyl 4-(2-aminophenoxy)butyrate and 1.47 g of 3-[1-(1-ethylpentyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1.CO>CN(C)C1C=CN=CC=1.ClCCl>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][N:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:3])[CH3:2])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccccc2)CC1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Acetyl chloride (0.71 mL, 0.79 g, 10.0 mmol) was added dropwise to a stirred, cooled (0° C.) solution of N-phenyl-1-t-butoxycarbonylpiperidine-4-methylamine (2.42 g, 8.3 mmol), pyridine (1.01 mL, 0.99 g, 12.5 mmol) and 4-dimethylaminopyridine (204 mg, 1.7 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 1 h. Methanol (5 mL) was added and the solvent was evaporated under reduced pressure. Aqueous sodium hydrogen carbonate (saturated, 50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×50 mL), aqueous sodium hydrogen carbonate (saturated, 50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (2.73 g, 99%), δH (250 MHz, CDCl3) 7.47-7.15 (5H, m), 4.06 (2H, br m), 3.62 (2H, br m), 2.64 (2H, br m), 1.85 (3H, s), 1.66 (3H, m), 1.44 (9H, s), and 1.20 (2H, m).
Reaction SMILES: P(=O)(O)(O)O.COC([C:10]1[C:19]2[C:13]([CH:14]=[CH:15][C:16]([CH:20]([CH3:22])[CH3:21])=[CH:17][CH:18]=2)=[CH:12][C:11]=1[CH3:23])=O.[OH-].[Na+]>>[CH3:23][C:11]1[CH:12]=[C:13]2[C:19](=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:14]2)[CH:10]=1
Reactant: COC(=O)c1c(C)cc2ccc(C(C)C)ccc1-2
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2ccc(C(C)C)ccc-2c1
Temperature: 100 °C
Yield: 74.7 %

Procedure:
70 ml of phosphoric acid was added to 3.93 g (16.2 mmol) of 1-methoxycarbonyl-2-methyl-6-isopropylazulene, and the mixture was heated at 100° C. for one hour. The resultant reaction solution was added to 300 ml of an aqueous solution containing 30 g of sodium hydroxide and extracted with hexane. An organic phase of the extract was dried with magnesium sulfate, and the solvent remaining therein was removed under a reduced pressure. The obtained crude product was filtered through silica gel. Further, the solvent contained in the filtered solid component was removed, thereby obtaining 2.23 g of 2-methyl-6-isopropylazulene (yield: 75%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.[Na].C(OCC)(=[O:31])C.[Cl-].[Na+]>CO.O>[CH3:1][S:2]([C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1)=[O:31]
Reactant: CCCCCC(O)C=CC1C=C(SC)C(=O)C1=CCCCCCC(=O)OC
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: CCCCCC(O)C=CC1C=C(S(C)=O)C(=O)C1=CCCCCCC(=O)OC
Reaction time: 18 h
Yield: 42 %

Procedure:
To a solution of 21.9 mg of 2-methylthio-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone obtained in Example 544 in methanol (3 ml) was added a solution of sodium metaperiodide (118.7 mg) in water (0.5 ml), and the mixture was stirred for 18 hours. To the reaction mixture were added ethyl acetate and saturated aqueous sodium chloride, and the product was extracted into the organic layer. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered, followed by concentration. The concentrate was subjected to silica gel chromatography to give 9.6 mg (yield 42%) of 2-methylsulfinyl-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH2:11])[CH3:10])[CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH:11][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])[CH3:10])[CH:6]=[N:7][CH:8]=1
Reactant: CCS(=O)(=O)Cl
Reactant: C[C@@H](N)c1cncc(Br)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N[C@H](C)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
To a 100-mL flask are added (1R)-1-(5-bromo(3-pyridyl))ethylamine HCl salt (0.5 g, 2.105 mmol), DCM (5 mL), and triethylamine (1.2 mL, 8.52 mmol). The mixture is cooled to 0° C. Ethanesulfonyl chloride (0.24 mL, 2.526 mmol, dissolved in 3 mL of DCM) is added dropwise. The mixture is stirred at 0° C. for 15 min. The ice/water bath is removed and the mixture is stirred at room temperature for 25 min. The mixture is diluted with EtOAc (50 mL), washed with water (3×5 mL), and brine, dried over sodium sulfate, filtered, and concentrated. The resulting crude product is purified by normal phase chromatography using 0-5% MeOH in DCM as the gradient to afford ethanesulfonic acid [(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-amide (482.5 mg, 78% yield).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:35]([NH:34][C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[O:36])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccc(N=C=O)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: COc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
TEA (0.28 g, 2.8 mmol) was added to a mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) and 4-methoxyphenylisocyanate (0.21 g, 1.4 mmol) in acetonitrile (30 mL) at 0° C. The mixture was stirred at ambient temperature for 2 h and then 10% aqueous HCl solution (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-methoxy-phenyl)-urea as a white solid (0.48 g, 84% yield); mp 255-257° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 6.39 (99.34%); 1H NMR (DMSO-d6) δ 1.93-2.06 (m, 1H, CHH), 2.29-2.47 (m, 1H, CHH), 2.54-2.66 (m, 1H, CHH), 2.83-2.99 (m, 1H, CHH), 3.69 (s, 3H, CH3), 4.30 (d, 1H, CHH), 4.36-4.50 (m, 3H, CH2 and CHH), 5.11 (dd, 1H, CH), 6.65 (t, 1H, NH), 6.81 (d, J=8.9 Hz, 2H, Ar), 7.31 (d, 2H, Ar), 7.44 (d, 1H, Ar), 7.51 (s, 1H, Ar), 7.69 (d, 1H, Ar), 8.44 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 8.60, 22.49, 31.20, 42.79, 45.69, 47.10, 51.56, 55.12, 113.86, 119.50, 121.85, 122.91, 126.88, 130.25, 133.50, 142.36, 145.03, 153.98, 155.45, 167.96, 170.99, 172.86; LCMS: MH=423; Anal. Calcd for C22H22N4O5+0.1H2O: C, 62.55; H, 5.25; N, 13.26. Found: C, 62.12; H, 5.36; N, 13.21.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[CH:4][C:3]=1[F:10].[N+]([C:14]1[CH:19]=CC=C[CH:15]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[Br:1][C:2]1[C:7]([F:8])=[C:6]2[C:5](=[CH:4][C:3]=1[F:10])[N:9]=[CH:19][CH:14]=[CH:15]2
Reactant: Nc1cc(F)c(Br)c(F)c1
Reactant: O=[N+]([O-])c1ccccc1
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: Fc1cc2ncccc2c(F)c1Br

Procedure:
A mixture of 4-bromo-3,5-difluoro-phenylamine (6.0 g, 28.8 mmole), ferrous sulfate (1.82 g), glycerol (8.6 mL), nitrobenzene (1.79 mL) and 5.0 ml of concentrated sulfuric acid (5 mL) was heated gently. After the first vigorous reaction, the mixture was heated to reflux for five hours. Nitrobenzene was removed by distillation in vacuo. The aqueous solution was acidified with glacial acetic acid, and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum/ethyl acetate=12/1) to return the title compound as a white solid (3.5 g, 49.8%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:6]1[CH:7]=[C:8]2[C:14](=[O:15])[N:13]([C:16]([CH:21]([CH3:23])[CH3:22])([CH3:20])[C:17]([NH2:19])=[O:18])[C:12](=O)[C:9]2=[N:10][CH:11]=1)[CH2:4][CH3:5].O>C1(C)C=CC=CC=1>[CH:21]([C:16]1([CH3:20])[N:13]2[C:14](=[O:15])[C:8]3[C:9](=[N:10][CH:11]=[C:6]([CH2:3][CH2:4][CH3:5])[CH:7]=3)[C:12]2=[N:19][C:17]1=[O:18])([CH3:23])[CH3:22]
Reactant: CCCc1cnc2c(c1)C(=O)N(C(C)(C(N)=O)C(C)C)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1cnc2c(c1)C(=O)N1C2=NC(=O)C1(C)C(C)C

Procedure:
With the simultaneous addition of 0.5 g of powdered sodium hydroxide, a solution of α-[3-n-propyl-6H-pyrrolo[3,4-b]pyridine-5,7-dione-6-yl]-α-isopropyl-α-methyl-acetamide (m.p.: 82° C.) in 100 ml of toluene is heated under reflux for 2 hours in a water separator. After the reaction solution has cooled, it is filtered through silica gel and the filtrate is washed with ethyl acetate and then concentrated by evaporation. The residue is recrystallised from ethyl acetate/petroleum ether, affording 13.1 g of the title compound which melts at 116° C.