Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:15][C:6]2=[N:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2].CN([CH:19]=[O:20])C.S(Cl)(Cl)=O.[CH:25]1C=CC=C[CH:26]=1>>[CH2:1]([C:3]1[S:15][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:25][CH2:26][O:20][CH3:19])=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(O)c(C(=O)O)cnc2s1
Reactant: CN(C)C=O
Reactant: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCc1cc2c(O)c(C(=O)OCCOC)cnc2s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
A mixture of 2-ethyl-4-hydroxythieno[2,3-b]pyridine-5-carboxylic acid (380 mg, 1.7 mmol) and DMF (0.13 ml, 1.7 mmol) in benzene (5 ml) was heated to 60° C. and to the reaction mixture was added thionyl chloride (0.15 ml, 2.1 mmol). The mixture was stirred at 60° C. for 3 hours and then allowed to cool with an ice bath. The precipitated product was collected by filtration and washed with benzene. The resulting precipitate (223 mg) was dissolved in a mixture of 2-methoxyethanol (0.3 ml) and CH2Cl2 (5 ml) and then triethyamine (0.7 ml) were added to the solution. The mixture was stirred for 30 minutes and poured into chloroform. The resulting mixture was washed with 1N hydrochloric acid, dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by flash column chromatography on silica gel. The column was eluted with ethyl acetate/hexane/chloroform (1:1:1) and then chloroform/methanol (9:1) to give 200 mg (41%) of the title compound as colorless powders.
Reaction SMILES: [N-]=C=S.C(Cl)Cl.Cl[CH:8](Cl)[CH3:9].[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][OH:18]>>[O:18]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:9][CH2:8][CH2:17]1
Reactant: c1ccccc1
Reactant: CO
Reactant: CC(Cl)Cl
Agent: [N-]=C=S
Solvent: ClCCl
Product: c1ccc2c(c1)CCCO2

Procedure:
Thus, a known alcohol of general formula (V-1) is reacted with an organic sulfonyl chloride in the presence of pyridine in the conventional manner to give a sulfonic acid ester of general formula (VI-1) and this sulfonic acid ester is then reacted with potassium phthalimide to give an N-substituted phthalimide of general formula (VII), which is further treated with hydrazine to give an amine of general formula (VIII). This amine of general formula (VIII) is reacted with 0.9 to 1.1 molar equivalents of an isothiocyanate in an inert solvent such as methylene chloride, dichloroethane, benzene, methanol, etc. at a temperature of room temperature to reflux temperature to give a 3,4-dihydrobenzopyran derivative of general formula (I-1b). And the amine of general formula (VIII) is reacted with 0.9 to 1.2 molar equivalents of methylisothiourea in an inert solvent such as methanol, ethanol, etc. at a temperature of room temperature to reflux temperature to give a 3,4-dihydrobenzopyran derivative of general formula (I-1c). The separation and purification of 3,4-dihydrobenzopyran derivative (I-1b) or 3,4-dihydrobenzopyran derivative (I-1c) from the reaction mixture can be carried out in the conventional manner.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH2:23])=[O:22].Cl.Cl[CH2:30][CH2:31][N:32]([CH3:34])[CH3:33].C(=O)([O-])[O-:36].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:33][N:32]([CH3:34])[CH2:31][CH2:30][O:36][N:18]([C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[N:8]=[C:7]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:6]=1)[C:19]1[C:20]([C:21]([NH2:23])=[O:22])=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC(=O)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(O)cc12
Reactant: O=C([O-])[O-]
Reactant: CN(C)CCCl
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCON(c1ccccc1C(N)=O)c1nc(-c2cccnc2)nc2ccccc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A suspension of 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (synthesized as described in Scheme 24) (25 mg, 0.07 mmol), 2-chloro-N,N-dimethylethylamine hydrochloride (20 mg, 0.14 mmol) and cesium carbonate (68.4 mg, 0.21 mmol) in DMF (1 mL) was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and extracted with dichloromethane (3×5 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by prep-TLC (silica, 2000 micron plate, 95% dichloromethane-5% methanol-0.1% NH4OH) to yield the desired compound as a brown solid (12.6 mg, 40%). LCMS m/z=428.9 (M+1) (Method C) (retention time=1.41 min). 1H NMR (300 MHz, DMSO) δ 12.99 (s, 1H), 9.59 (d, J=1.3 Hz, 1H), 9.12 (d, J=8.4 Hz, 1H), 8.81-8.66 (m, 2H), 8.52 (s, 1H), 8.06-7.88 (m, 3H), 7.80-7.53 (m, 4H), 7.22 (t, J=7.6 Hz, 1H), 4.46 (s, 2H), 3.35 (s, 2H), 2.69 (s, 6H).
Reaction SMILES: Br[C:2](=[N:12][OH:13])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:4]([CH3:7])([CH3:6])[CH3:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CCOCC>[CH3:5][C:4]([CH3:7])([CH3:6])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:2](=[N:12][OH:13])[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CNC(=O)C(C(Br)=NO)C(C)(C)C
Reactant: C1CCNC1
Solvent: CCOCC
Product: CNC(=O)C(C(=NO)N1CCCC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 12.6 g of 1-bromo-3,3-dimethyl-2-methylcarbamyloximinobutane in 100 ml of anhydrous ether is added, dropwise, 7.8 g (0.11 mol) of pyrrolidine. The mixture is stirred at room temperature for 1 hour and at reflux for 0.5 hour, then cooled and washed with water. The ether solution is separated, dried, and stripped of solvent to give 11.8 g of amber oil which solidifies on standing to an amber solid, m. 43°-46° C. Properties of this and analogous compounds prepared by substantially the same procedure are shown in Table 3.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](CO)=[CH:7][CH:6]=1.[CH:13]([Cl:16])(Cl)Cl.S(Cl)([Cl:19])=O.O>N1C=CC=CC=1>[Cl:19][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:13][Cl:16])=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCCOc1ccc(CO)cc1
Reactant: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: ClCCOc1ccc(CCl)cc1
Yield: 66.6 %

Procedure:
10 Grams (0.06 mol) of 4-(2-hydroxyethoxy)benzyl alcohol, prepared according to L. M. Marson, Il Farmaco ed. sci. 14, 159 (1959)), was dissolved in anhydrous pyridine (80 ml) and anhydrous chloroform (100 ml), then the mixture was ice cooled and thionyl chloride (80 ml) was slowly added, under stirring. Stirring was continued, allowing temperature to raise to the room's one, then the mixture was heated for about 2 hours to complete the reaction. After cooling, the reaction mixture was poured into water (200 ml); the chloroformic layer was separated, washed with a 5% aqueous solution of sodium hydroxyde, dried over Na2SO4 and evaporated. The residue was distilled under vacuum to provide the pure product (8.2 g; 66.6% yield).
Reaction SMILES: C(N1CCCC1C[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][C:12]=1Cl)C.[CH3:20][O-:21].[Na+].[Na]>CO>[CH3:20][O:21][C:12]1[N:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:10]([NH2:9])=[O:19]
Reactant: C[O-]
Reactant: CCN1CCCC1CNC(=O)c1ccc(Cl)nc1Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1nc(Cl)ccc1C(N)=O
Reaction time: 1 h

Procedure:
10.5 g (0.33 mole) of N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2,6-dichloronicotinamide are dissolved in 50 ml of absolute methanol and to this solution is added dropwise a sodium methoxide solution prepared from 0.75 g (0.33 mole) of sodium and 100 ml of absolute methanol in the course of 90 minutes at 40°-45° C. The reaction mixture is kept for 1 hour at 40°-45° C and the methanol is thereafter evaporated in vacuo to a volume of 50 ml. The concentrate is poured onto ice-water, saturated with potassium carbonate and extracted twice with benzene. The organic phases are dried over magnesium sulphate and the solvent is then evaporated in vacuo. The oily residue is chromatographed through a column of basic silica gel with benzene to which 0.5% of methanol is added. Pure N-[1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxy-6-chloronicotinamide is obtained as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][CH:33]=1.O.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:40][CH:41]=1
Reactant: COC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.4 g, 0.72 mmol) in methanol (6 mL) was added lithium hydroxide monohydrate (0.061 g, 1.44 mmol) in water (2 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.05 g, 13%); 1H NMR (DMSO-d6): δ 1.60 (d, 2H, J=6.8 Hz), 1.82 (t, 2H, J=6.8 Hz), 2.35 (t, 2H, J=6.8 Hz), 2.50-2.71 (m, 7H), 3.85 (t, 2H, J=6.8 Hz), 4.55-4.56 (m, 4H), 6.75 (t, 1H, J=7.2 Hz), 6.84 (d, 2H, J=8.4 Hz), 6.96 (d, 3H, J=2.4 Hz), 7.17-7.26 (m, 5H), 7.85 (d, 2H, J=8 Hz); MS for C31H33N5O4 m/z 540.05 (M+H)+.
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[C:9]([NH2:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].O>C(Cl)(Cl)Cl>[C:1]([NH:14][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: C=C(C)C(N)=O
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=C(C)C(=O)NC(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
Into the same reaction vessel as used in Example 1, ethoxalyl chloride (12.3 g; 0.09 mol) was charged, and the reaction vessel was cooled in an ice bath. A solution of methacrylamide (20.3 g; 0.24 mol) in chloroform (90.0 ml) was dropwise added thereto in 30 minutes, followed by stirring at room temperature for 3 days. The reaction mixture was shaken with chloroform (500 ml) and water (500 ml), and the chloroform layer was separated and dried over anhydrous magnesium sulfate, followed by removal of chloroform. Hydroquinone (0.01 g) was added thereto, and distillation under reduced pressure was carried out to give N-ethoxalylmethacrylamide (4.8 g). Yield, 29%.
Reaction SMILES: Cl.[C:2]1(=O)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[Na+].[Na+].[CH3:22][O:23][C:24]([CH:26]([C:31](OC)=[O:32])[C:27](OC)=[O:28])=[O:25]>C(OCC)(=O)C>[CH2:11]([N:15]1[C:27](=[O:28])[C:26]([C:24]([O:23][CH3:22])=[O:25])=[C:31]([OH:32])[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:2]1=2)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN
Reactant: COC(=O)C(C(=O)OC)C(=O)OC
Reactant: O=C1CCCCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCn1c2c(c(O)c(C(=O)OC)c1=O)CCCCCC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A concentrated hydrochloric acid was added to a mixture of cyclooctanone (3.84 g, 30.43 mmol) and butylamine (3.01 mL, 30.43 mmol) by two drops, and the mixture was stirred at room temperature for 15 hours. Diluted sodium carbonate aqueous solution and ethyl acetate were added in the reaction mixture to separate the mixture, and the organic layer was washed with water and saturated saline. After the organic layer had been dried, the solvent was removed by distillation and 4.72 g of colorless oily matter was obtained (86%). This imine (4.67 g, 25.76 mmol) was reacted as mentioned above together with trimethylmethane tricarboxylic acid (3.42 g, 18 mM) in trigrim (40 mL), and viscous yellow oily matter (AA17, 2.62 g, 47%) was obtained.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CCOCC>C1COCC1>[NH2:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: N#CCCN1CCC(Cc2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCCN1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of 3-(4-benzylpiperidin-1-yl)propionitrile (8.20 g, 35.9 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0M, 126 mL, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours, then cooled to room temperature and concentrated to a volume of about 30 mL. Aqueous HCl (6 N, 80 mL) was added and stirring was continued for 2 hours at 55°-60° C. The mixture was basified to pH 9 by addition of 6N aq. NaOH and extracted with CH2Cl2 (3×150 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and treated with HCl in ether (1.0M, 75 ml, 2.1 equiv). The solvents were removed, ether (60 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2×30 mL). Water (40 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1M NaOH, and the aqueous phase was extracted with CH2 Cl2 (3×80 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 7.59 g (91%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=1)=[N:6][N:5]([CH3:11])[CH:4]=2.C([Li:16])CCC.[S:17](=O)([OH:19])[OH:18]>C(OCC)C>[Cl:1][C:2]1[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=1)=[N:6][N:5]([CH3:11])[C:4]=2[S:17]([O-:19])=[O:18].[Li+:16]
Reactant: [Li]CCCC
Reactant: Cn1cc2c(Cl)cccc2n1
Reactant: O=S(O)O
Solvent: CCOCC
Product: Cn1nc2cccc(Cl)c2c1S(=O)[O-]
Product: [Li+]
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution containing 16 g (0.1 mol) of 4-chloro-2-methyl-2H-indazole in 300 ml of ethyl ether, was cooled to -30° C., and 85.4 g (0.2 mol) of n-butyl lithium (15% hexane solution) was dropwise added thereto. The mixture was stirred for one hour at the same temperature. Then, an excess amount of sulfurous acid gas was blown thereinto at a temperature of not higher than -20° C. for 3 hours. After completion of the reaction, the mixture was returned to room temperature and diluted with ethyl ether, and the product was subjected to filtration. Crystals were dried to obtain crude lithium 4-chloro-2-methyl-2H-indazole-3-sulfinate. This product was used for the subsequent reaction without purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:28]1([C:34]2[CH:38]=[C:37]([C:39]([OH:41])=O)[O:36][N:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:39]([C:37]3[O:36][N:35]=[C:34]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:38]=3)=[O:41])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc(-c2ccccc2)no1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3cc(-c4ccccc4)no3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 3-phenylisoxazole-5-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=2[Cl:39])[C:10](=[O:40])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:39][C:16]1[CH:17]=[CH:18][C:19]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2Cl)C(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](Oc1ccc(Cl)c(CN2CCNCC2=O)c1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of product from Step E (2.10 g, 3.74 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL). The resulting solution was stirred for 2 hours, then poured onto saturated aqueous sodium bicarbonate, and extracted with methylene chloride (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the title product without further purification.
Reaction SMILES: C[O:2][CH:3](OC)/[CH:4]=[CH:5]/[CH:6]=[CH:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH3:12].O>CC(C)=O.CCOCC>[CH:3](=[O:2])/[CH:4]=[CH:5]/[CH:6]=[CH:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH3:12]
Reactant: CC/C=C\CC=C/C=C/C(OC)OC
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: CC/C=C\CC=C/C=C/C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 9.8 g of a mixture of (2E,7Z)-1,1-dimethoxy-2,4,7-decatriene as obtained in example 1 (50 mmoles) and 2.7 ml of water (150 mmoles) in 150 ml of acetone were added 0.2 g of AMBERLITE®, and the reaction mixture so obtained was stirred for 1 hour at room temperature. Afterwards, the reaction mixture was filtered and neutralized with 1 ml of a saturated aqueous solution of NaHCO3, and then concentrated. The crude product thus obtained was dissolved in Et2O and the organic phase has been washed twice with brine, dried over Na2SO4 and concentrated to yield 8.8 g of an extract. The extract has been further purified by distillation over a Vigreux column (52–54° C./0.1 mbar) to yield 7.2 g of a mixture of (2E,7Z)-2,4,7-decatrienal (4Z:4E=88:8)(purity=96%, yield=96%). The product thus obtained had the same spectroscopic data as described in WO 01/58282.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][S:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>ClCCl.C1(C)C=CC=CC=1>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[S:22][S:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:6]([OH:29])=[O:5]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCSSc1ccccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(O)CCOCCOCCOCCOCCSSc1ccccn1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of 140 mg of 15-(2-pyridyldithio)-4,7,10,13-tetraoxapentadecanoic acid tert-butyl ester (13a) in 5 ml of dichloromethane was added 1.0 ml of TFA and 250 μl of Et3SiH. After stirring for 2 hrs, the mixture was diluted with 5 ml of toluene. The mixture was evaporated and then co-evaporated three times with 5 ml of toluene and dried under vacuum to yield of 122 mg (99% yield) of the title compound 14a (FIG. 7). 1H NMR (CDCl3) 13.331 (s, OH), 8.770 (d, 1H, J=5.4 Hz), 8.299 (t, 1H, J=7.7+7.7 Hz), 8.130 (d, 1H, J=8.2 Hz), 7.677 (t, 1H J=6.3+6.4 Hz), 3.703˜3.556 (m, 16H), 3.109 (t, 2H, J=6.4+6.4 Hz), 2.538 (t, 2H, J=6.1+6.1 Hz); 13C NMR 175.900, 157.402, 144.807, 129.114, 124.746, 123.635, 70.452, 70.327, 70.206, 70.184, 69.881, 69.862, 67.229, 66.407, 39.320, 34.866; MS 392.73 (M+H)+, 390.76 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=O)[CH3:2].[Na+].[Cl-].[CH2:18]([O:20][CH2:21][CH3:22])[CH3:19].C([OH:25])C>>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[CH:19][C:18]([O:20][CH2:21][CH3:22])=[O:25])[CH3:2]
Reactant: CCOCC
Reactant: CCO
Reactant: CCOC(=O)C(=O)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Product: CCOC(=O)C=C(C(=O)OCC)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 53 %

Procedure:
An ethanolic solution of sodium ethylate, obtained from sodium (3.35 g; 0.1457 moles) and dry ethanol (276 ml), kept under stirring in inert atmosphere, was added at 20° C. with a solution of (2,4-dichloro-phenyl)-oxo-acetic acid ethyl ester obtained as described in example 2 (36 g; 0.147 moles), and triethyl phosphonoacetate (34.2 g; 0.152 moles) in dry ethanol (70 ml). The reaction mixture was then brought and kept at reflux for 16-20 hours. After cooling to 25° C., the mixture was poured under stirring into a solution of saturated NaCl (500 ml), ethyl ether was added (150 ml) and the phases were separated. The aqueous phase was extracted again with ethyl ether (150 ml). The joined organic phases were washed with water (100 ml), anhydrified over dry Na2SO4, evaporated to dryness. The thus obtained residue was purified by chromatography (SiO2; hexane/ethyl ether 9/1) to give 24.6 g of (E) 2-(2,4-dichlorophenyl)-butendioic acid diethyl ester (yield 53%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:13])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH:7]2O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>[N+](C)([O-])=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:13])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: Nc1ccc(Br)c2c1C(=O)NC2O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Nc1ccc(Br)c2c1C(=O)NC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
7-Amino-4-bromo-3-hydroxyisoindolinone (3.11 g, 12.8 mmol) was dissolved in nitromethane (125 mL), and the solution was added with trifluoroacetic acid (9.90 mL, 128 mmol) and triethylsilane (4.10 mL, 25.6 mmol), followed by stirring at room temperature for 2 hours. The reaction mixture was added with water, extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by slurry using chloroform to obtain 7-amino-4-bromoisoindolinone (2.16 g, yield 74%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:33]=[CH:32][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:31])[C@@:15]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:34](Cl)([CH3:37])(=[O:36])=[O:35].N1C=CC=CC=1>CC(C)=O>[CH3:30][C:27]([CH3:28])([CH3:29])[CH2:26][CH2:25][C@:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:32]=[CH:33][C:3]([NH:2][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:31]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 49G (0.250 g, 0.510 mmol), mesyl chloride (0.158 mL, 2.04 mmol), and pyridine (0.330 mL, 4.08 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.