Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([OH:16])[CH2:15][C@@:9]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:10]([O:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39]I.[H-].[Na+]>C1COCC1>[CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([O:16][CH3:39])[CH2:15][C@@:9]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:10]([O:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:20]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-ol (Example 43; 22 mg 0.041 mmol), methyl iodide (0.5 ml), sodium hydride (40 mg, 1 mmol) and THF (2 ml) was stirred at room temperature for 24 hours, quenched quenched with saturated aqueous NH4Cl and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by preparative TLC on silica gel (iso-hexane:diethyl ether 30%) to give the title compound (17 mg, 75%).
Reaction SMILES: [CH3:1][C:2]1[C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[F:39][C:40]([F:74])([F:73])[C:41]1[CH:42]=[C:43]([C:51]([CH3:72])([CH3:71])[C:52]([N:54]([C:56]2[CH:57]=[N:58][C:59]([N:63]3[CH2:67][C@H:66]([OH:68])[CH2:65][C@H:64]3[CH2:69][OH:70])=[CH:60][C:61]=2I)[CH3:55])=[O:53])[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[F:50][C:47]([F:48])([F:49])[C:45]1[CH:44]=[C:43]([C:51]([CH3:71])([CH3:72])[C:52]([N:54]([C:56]2[CH:57]=[N:58][C:59]([N:63]3[CH2:67][C@H:66]([OH:68])[CH2:65][C@H:64]3[CH2:69][OH:70])=[CH:60][C:61]=2[C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH3:55])=[O:53])[CH:42]=[C:41]([C:40]([F:74])([F:39])[F:73])[CH:46]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1I
Reactant: Cc1ncccc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1-c1cc(N2C[C@H](O)C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 38.8 %

Procedure:
A mixture of 0.12 g (0.48 mmol) trifluoro-methanesulfonic acid 2-methyl-pyridin-3-yl ester, 0.13 g (0.52 mmol) bis(pinacolato)diboron, 0.14 g (1.4 mmol) potassium acetate and 0.02 g (0.02 mmol) dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(II) dichloromethane adduct in 2.5 ml N,N-dimethylformamide was heated at 80° C. over night under argon. After cooling to room temperature 0.10 g (0.16 mmol) (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide and 1.3 ml of a deoxygenated 2 M aqueous solution of sodium carbonate were added. The reaction mixture was heated at 80° C. for 6 h. After cooling to room temperature the mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 37 mg (39%) of the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:4].[C:33]([O:37][C:38]([NH:40][C@H:41]([CH3:45])[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[CH3:31][CH:30]([CH3:32])[CH2:29][C@@H:2]([NH:1][C:42](=[O:43])[C@H:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])[CH3:45])[C:3](=[O:4])[NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@@H](N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Product: CC(C)C[C@@H](NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Yield: 100.7 %

Procedure:
The procedure of Example 14(a) was repeated, except that (2R)-2-amino-4-methyl-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]pentanamide (600 mg) and (R)-2-(tert-butoxycarbonylamino)propanoic acid (279 mg) were used, whereby tert-butyl (2R)-1-[(2R)-4-methyl-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino]pentan-2-ylamino]-1-oxopropan-2-ylcarbamate (832 mg) was yielded. Subsequently, the procedure of Example 25(a) was repeated, except that the compound prepared as described above was used, whereby the title compound (460 mg) was yielded.
Reaction SMILES: C([O:3][CH:4]1[CH2:7][CH:6]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=2)[C:5]1([CH3:20])[CH3:19])C.BrB(Br)Br>C(Cl)Cl>[OH:3][CH:4]1[CH2:7][CH:6]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=2)[C:5]1([CH3:20])[CH3:19]
Reactant: CCOC1CC(Nc2nc(SC)ncc2C#N)C1(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CSc1ncc(C#N)c(NC2CC(O)C2(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
A cooled (0° C.), stirred solution of 4-((3-ethoxy-2,2-dimethylcyclobutyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (1.0 equiv.) in DCM (0.7 M) was treated with 1.0 M tribromoborane in DCM (3.0 equiv.). The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with MeOH. DCM and saturated sodium bicarbonate were added. The separated aqueous layer was extracted with DCM. The organic extract was dried over sodium sulfate, filtered and concentrated to give a brown oil, which was purified by silica gel column chromatography (0-45% ethyl acetate in hexane, 25 g column) to give (37% yield) of yellow solid. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.24 (s, 1H), 5.42 (d, J=7.03 Hz, 1H), 4.09 (dt, J=7.62, 9.37 Hz, 1H), 3.80-3.89 (m, 1H), 2.77 (dt, J=7.42, 11.72 Hz, 1H), 2.48-2.54 (m, 3H), 1.84 (ddd, J=8.20, 9.47, 11.62 Hz, 1H), 1.74 (d, J=6.25 Hz, 1H), 1.23-1.28 (m, 3H), 0.99-1.03 (m, 3H). MS (ESI) m/z 264.8 [M+1]+.
Reaction SMILES: [C:1]([CH:3]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[NH4+].[OH-].[CH2:22]([O:29][C:30](=[O:40])[CH2:31][C:32]1([C:37](O)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CCO.CN(C=O)C.[Ni]>[CH2:22]([O:29][C:30](=[O:40])[CH2:31][C:32]1([C:37]([NH:2][CH2:1][CH:3]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:4]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:5])=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)C(C#N)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(CC1(C(=O)O)CCCC1)OCc1ccccc1
Agent: [Ni]
Agent: On1nnc2cccnc21
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(CNC(=O)C1(CC(=O)OCc2ccccc2)CCCC1)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.3 %

Procedure:
A suspension of tert-butyl 2-cyano-3-(3,4-dichlorophenyl)propanoate (100 mg, 0.333 mmol), Raney 2800 nickel (slurry in water) (156 mg, 2.67 mmol) and NH4OH (1.297 ml, 33.3 mmol) in EtOH (3 ml) was allowed to stir under hydrogen at room temperature for 14 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a crude material (93 mg). A solution of the crude material, 1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic acid (87 mg, 0.333 mmol), EDC (83 mg, 0.433 mmol) and HOAt (58.9 mg, 0.433 mmol) in DMF (1 ml) was allowed to stir at room temperature for 2 hours. The reaction was quenched with H2O, and the product was extracted with EtOAc and washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 20:80) to give tert-butyl 3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-2-(3,4-dichlorobenzyl)propanoate (84.5 mg); Retention time=1.70 minutes (condition B); MS (m+1)=548.2; 1H NMR (400 MHz, CDCl3, data for major rotamer) δ ppm 1.37 (s, 9H) 1.61-1.70 (m, 6H) 2.00-2.07 (m, 2H) 2.66-2.84 (m, 5H) 3.26-3.48 (m, 2H) 5.08 (s, 2H) 6.43-6.46 (app t, 1H) 7.02-7.05 (m, 1H) 7.29-7.36 (m, 7H).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])=[O:28])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:29][C:27]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:38])=[O:2])[CH:6]=1)[CH2:25][CH3:26])=[O:28]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)OCc1ccccc1Cl

Procedure:
(2′-{[(2-Chloro-benzyloxycarbonyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.27 mmol) in THF (1 mL) and MeOH (0.8 mL) was hydrolyzed with 1N aqueous NaOH (0.7 mL) for 1 hour. The mixture was acidified with 1N aqueous HCl and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound. M+H is 536.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(N(CC)CC)C.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[C:27]([F:31])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>O1CCOCC1>[CH2:11]([N:3]([CH2:1][CH3:2])[CH:4]=[C:5]([C:23](=[O:24])[C:22]1[CH:26]=[C:27]([F:31])[C:28]([Cl:30])=[CH:29][C:21]=1[Cl:20])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:12]
Reactant: CCOC(=O)C=CN(CC)CC
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CN(CC)CC)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 80.2 %

Procedure:
First 17.1 g of ethyl 3-diethylaminoacrylate are added dropwise and then 10.5 g of triethylamine are added to a solution of 22.75 g of 2,4-dichloro-5-fluorobenzoyl chloride in 80 ml of anhydrous dioxane, while cooling in ice and stirring. The mixture is stirred at room temperature for one hour, heated to boiling under reflux for 45 minutes, and the solvent is removed by distillation in vacuo, and the oily residue is taken up in methylene chloride/water. The phases are separated, and the aqueous solution is again extracted with methylene chloride. The combined organic phases are washed with water, dried with sodium sulphate, and the methylene chloride is removed in vacuo. 29 g of ethyl 3-diethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate are obtained as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]2[C:8](=[C:9](F)[CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:23].[Na].[CH2:29]([OH:31])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]2[C:8](=[C:9]([O:31][CH2:29][CH3:30])[CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:23]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(F)cccc12
Reactant: CCO
Agent: [Na]
Product: CCOC(=O)Cc1nn(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(OCC)cccc12

Procedure:
Ethyl 2-(3,4-dichlorobenzyl)-8-fluoro-1,2-dihydro-1-oxophthalazin-4-ylacetate (1.8 g.) was added to a solution of sodium (1.5 g.) in dry ethanol (150 ml.). The solution obtained was heated under reflux for 3 hours and then evaporated. Water (100 ml.) was added to the residue and the solid obtained was collected by filtration and dried to give ethyl 2(3,4-dichlorobenzyl)-8-ethoxy-1,2-dihydro-1-oxophthalazin-4-ylacetate (0.5 g.).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]([C:23]([CH3:29])([CH3:28])[C:24]([O:26]C)=O)=[C:20](O)[N:21]=3)=[N:14][N:13]([CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[C:10]2=[N:11][CH:12]=1.[NH3:39]>C(#N)C>[F:6][C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]4[C:23]([CH3:29])([CH3:28])[C:24](=[O:26])[NH:39][C:20]=4[N:21]=3)=[N:14][N:13]([CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:34])([F:36])[F:35])[C:10]2=[N:11][CH:12]=1
Reactant: N
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(CCC(F)(F)C(F)(F)F)c3ncc(F)cc23)nc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncc(F)cc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.172 ml of phosphoryl chloride were added to 290 mg (0.606 mmol) of the compound from Example 17A, and the mixture was stirred at RT overnight. The reaction mixture was dissolved in 40 ml of acetonitrile and, with ice-cooling, stirred into 27 ml of concentrated aqueous ammonia solution (33% strength). The mixture was stirred at room temperature for 2 days. The mixture was then concentrated. The residue was taken up in water and ethanol and treated in an ultrasonic bath. A precipitate was formed, which was filtered off with suction and washed with water, ethanol and then with diethyl ether. DMF was added to this residue, acetonitrile and water were added and the mixture was then once more filtered off with suction. The precipitate was washed with acetonitrile and water and then dried under high vacuum. This gave 149 mg of the title compound (52% of theory, purity 94%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1COCC1>[C:3]1([CH:9]([CH2:10][O:11][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:12][OH:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(CO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(CO)c1ccccc1
Reaction time: 0.75 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 525 mg, 13 mmol) was added to a round bottom flask and washed with 3×5 mL of dry hexane. Dry THF (25 mL) was then added, followed by 2-phenyl-1,3-propanediol (2.0 g, 13 mmol). Another 25 mL of dry THF was added to facilitate stirring of the resulting thick suspension. After 45 min., tert-butyldimethylsilyl chloride was added in one portion. After stirring for 2 h, the mixture was partitioned between 100 mL of ethyl ether and 60 mL of 10% aqueous potassium carbonate. The aqueous layer was extracted with 2×30 mL of ethyl ether. The combined organic layers were washed with 40 mL of brine, dried over sodium sulfate, and evaporated. Purification by flash column chromatography, eluting with 10% ethyl acetate in hexane, gave the 3.36 g of the title compound as a colorless liquid. 1NMR (400 MHz,CD3OD): δ 7.30-7.16(m, 5H), 3.90 (dd, 1H, J=11, 7 Hz), 3.88 (dd, 1H, J=10, 6 Hz), 3.83 (dd, 1H, J=10, 6 Hz), 3.76 (dd, 1H, J=11, 7 Hz), 2.91 (quintet, 1H, J=6 Hz), 0.84 (s, 9H),-0.04 (s, 3H),-0.05 (s, 3H). Mass spectrum (NH3 /CI): m/z=267 (M+1).
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH3:23])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2].[BH4-].[Na+].[C:26](O)(=O)[CH2:27][CH3:28]>>[CH2:1]([N:3]([CH2:26][CH2:27][CH3:28])[CH:4]([CH3:23])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2]
Reactant: CCNC(C)CN1CCc2c(c(=O)oc3cc(OC)ccc23)C1
Reactant: CCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCCN(CC)C(C)CN1CCc2c(c(=O)oc3cc(OC)ccc23)C1

Procedure:
Prepared by the method described for Example 59 from 3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.0 g, 0.009 moles), propionic acid (20 ml), and sodium borohydride (2.0 g, 0.053 moles). The free base is obtained crystalline. Recrystallization from acetonitrile gave the product (2.0 g), mp 100°-101° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[S:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)(Cl)Cl>[C:1]1([CH2:7][CH2:8][N:9]2[S:10](=[O:23])[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(CCN2Sc3ccccc3S2)cc1
Solvent: ClC(Cl)Cl
Product: O=S1c2ccccc2SN1CCc1ccccc1
Temperature: 0 °C
Yield: 70.6 %

Procedure:
To a solution of 2-(2-phenylethyl)-1,3,2-benzodithiazole (0.538 g, 2.08 mmol), from Step 2, in 30 mL of chloroform at -20° C., was added portionwise 56% meta-chloroperoxybenzoic acid (mCPBA) (0.64 g, 2 mmol). The reaction mixture was allowed to warm to 0° C. over a 2 hour period and then the reaction was quenched at 10° C. with 20 mL of 1M aqueous sodium bicarbonate solution. The organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with chloroform (CHCl3) to give 389 mg (65.7% yield) of the title compound. Analysis calculated for C14H13NOS2 : C, 61.08; H, 4.76; N, 5.09. Found: C, 60.92; H, 4.75; N, 5.04.
Reaction SMILES: C([Li])CCC.[O:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:8][CH2:7]1.[Cl:22][C:23]1[CH:41]=[CH:40][C:26]([CH:27]=[C:28]2[C:32](=[O:33])[C:31]3[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:30]=3[O:29]2)=[CH:25][CH:24]=1.[K+].[Br-]>C1COCC1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH:27]=[C:28]2[O:29][C:30]3[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=3[C:32]2([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][N:9]3[CH2:10][CH2:11][O:6][CH2:7][CH2:8]3)=[CH:16][CH:17]=2)[OH:33])=[CH:40][CH:41]=1
Reactant: COc1ccc2c(c1)OC(=Cc1ccc(Cl)cc1)C2=O
Reactant: Brc1ccc(OCCN2CCOCC2)cc1
Agent: [Br-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)OC(=Cc1ccc(Cl)cc1)C2(O)c1ccc(OCCN2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (2.87 mi of a 1.28M solution, 3.68 mmol) was added dropwise to a solution of 4-[2-morpholinoethoxy]phenyl bromide (0.80 ml, 3.68 mmol) in THF (10 ml) at -78° C. under nitrogen atmosphere. After stirring for 1 hour at -78° C., 2-(p-chlorobenzylidene)-6-methoxy-3(2H)-benzofuranone (1.0 g, 3.50 mmol) in THF (5 m was added dropwise to the mixture at -78° C. The reaction mixture was left overnight at room temperature. It was quenched with saturated ammonium chloride, THF was evaporated off to yield an oil which was extracted with ethyl acetate (2×20 ml). The ethyl acetate extract was washed with water followed by brine (2×20 ml), dried (anhydrous magnesium sulfate) and the solvent was evaporated to give an oil which was chromatographed on silica gel. Elution with (chloroform:hexane:triethylamine=1:1:0.2) yielded a solid of the free base (Rf =0.3). Yield (56%); m.p. 69-70° C.; 1H-NMR (CDCl3) δ 1.55 (brs, 1H, OH), 2.54-2.58 (m, 4H, N(CH2CH2)20 (ring)), 2.79 (t, 2H, OCH2CH2N), 3.7-3.74 (m, 4H, N(CH2CH2)2 (ring)), 3.84 (3H, OCH3), 4.09 (2H, OCH2CH2N), 5.64 (benzylidene proton), 6.72-7.60 (m, 11H, ArH). 13C-NMR δ(ppm) 104.4 (benzylidene carbon), 133.1 (C-2), 81.0 (C-3), 54.1 (OCH3); IR (KBr) 1680 cm-1 (C=C), 3400 cm-1 (broad OH); m/z (%) 495(5), 493(10), 100(100). (Found: C, 68.14, H, 5.89, N, 2.75, Cl, 7.30. C28H28ClO5N required C, 68.15, It, 5.68, N, 2.84, Cl, 7.10).
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: CC(C)=O
Solvent: O
Solvent: CCOCC
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: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([F:13])[CH:3]=1.O=[As](O[As](=O)=O)=O.P(=O)(O)(O)O.[CH:26]([C:28]([CH3:30])=O)=[CH2:27]>[OH-].[NH4+]>[CH3:30][C:28]1[C:3]2[C:2](=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=2[F:13])[N:1]=[CH:27][CH:26]=1
Reactant: COc1cc([N+](=O)[O-])c(N)cc1F
Reactant: C=CC(C)=O
Agent: O=P(O)(O)O
Agent: O=[As](=O)O[As](=O)=O
Agent: [NH4+]
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a hot (92°), stirred mixture of 54.4 g (0.292 mol) of 4-amino-2-fluoro-5-nitroanisole (XIII), 50.2 g (0.218 mol) of arsenic pentoxide, and 300 mL of 88% phosphoric acid was added 24.5 g (0.349 mol) of methyl vinyl ketone, during 0.5 hour. The reaction mixture was heated at 95° for 2.5 hours, cooled, diluted with 2.0 L of ice-water, then basified with 700 mL of concentrated ammonium hydroxide. The solid which separated was collected on a filter, washed with water (4×1.0 L), then air dried; yield, 140.6 g. The material was extracted with chloroform (2.0 L). The extract was concentrated to 500 mL then chromatographed on a column of silica gel (900 g) using chloroform as the eluent. The fractions containing product were combined then concentrated in vacuo to a solid; yield, 21.8 g (31.6%). The product was suitable for further transformation. Additional material (40.2 g) was obtained from a similar run and a scouting run.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:3]=1.Cl.C([O-])(O)=O.[Na+]>O.C(O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:11][CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1NCC1CCCCC1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)cc1NCC1CCCCC1
Yield: 37.7 %

Procedure:
A solution of 21.5 g of the product obtained in step A) and 13.4 g of iron powder in a mixture of 25 ml of water and 25 ml of ethanol is brought to the reflux point. A solution of 50 ml of concentrated hydrochloric acid in a mixture of 34 ml of water and 34 ml of ethanol is then added slowly. Reflux is maintained for 2 hours. The reaction medium is then poured onto ice, treated with a saturated solution of NaHCO3 and then extracted with DCM, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM as the eluent. 7.2 g of the expected product are obtained after crystallization from heptane. M.p.=62° C.