Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][OH:22])[CH2:8][O:7][C:6]2([CH2:13][C:12]([CH2:15][CH3:16])([CH3:14])[NH:11][C:10]([CH2:18][CH3:19])([CH3:17])[CH:9]2[CH3:20])[O:5][CH2:4]1)[CH3:2].[C:23](Cl)(=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>N1C=CC=CC=1.O>[C:23]([O:22][CH2:21][C:3]1([CH2:1][CH3:2])[CH2:4][O:5][C:6]2([CH2:13][C:12]([CH2:15][CH3:16])([CH3:14])[N:11]([O:7][C:6](=[O:5])[CH3:9])[C:10]([CH2:18][CH3:19])([CH3:17])[CH:9]2[CH3:20])[O:7][CH2:8]1)(=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCC1(CO)COC2(CC(C)(CC)NC(C)(CC)C2C)OC1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC1(CC)COC2(CC(C)(CC)N(OC(C)=O)C(C)(CC)C2C)OC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
12 g (0.037 mol) of 3,8,10-triethyl-7,8,10-trimethyl-1,5-dioxa-9-azaspiro[5.5]undec-3-ylmethanol (for method of preparation, see U.S. Pat. No. 4,105,626) are dissolved in 40 ml of pyridine and admixed with 11.7 g (0.039 mol) of stearoyl chloride. After stirring for 18 hours at room temperature, the reaction mixture is diluted with 200 ml of water and extracted with 2×50 ml of methyl-t-butylether. After distilling off the solvent, the resulting stearoyl nitroxide is converted by a method analogous to Example A 30 into the compound 144 which is obtained in the form of a colourless oil.
Reaction SMILES: [C:1](=[O:27])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3](C(OC(C)(C)C)=O)[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[C:37]1([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[C:37]1([N:43]2[CH2:48][CH2:47][N:46]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]3)=[O:27])[CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)C(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCC1CCNCC1)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
(1-(tert-Butoxycarbonyl)piperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 2; 5.0 g, 13.1 mmol) was dissolved in DMF (30 mL). DIPEA (4.58 mL, 26.3 mmol) and 1-phenylpiperazine (2.01 mL, 13.1 mmol) were added. The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed sequentially with sat aq NaHCO3 solution (6×200 mL), 10% citric acid solution (50 mL) and brine (50 mL). The solution was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (20 mL) and TFA (10 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was dissolved in water (20 mL), sat aq NaHCO3 solution (100 mL) was added and the aqueous layer was extracted with DCM (3×200 mL). The combined organic layers were then washed with brine (50 mL), dried (MgSO4) and the solution was concentrated in vacuo to give (piperidin-4-yl)methyl 4-phenylpiperazine-1-carboxylate (3.825 g, 95.9% yield) as a yellow solid.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([OH:9])[CH2:2]1.O1[C@H]2OCC[C@H]2[C@H](O)C1.P([O-])([O-])(O)=O.[K+].[K+].Cl[O-].[Na+]>C(OCC)(=O)C.O1[C@@H]2OCC[C@@H]2[C@H](O)C1.O1[C@@H]2OCC[C@@H]2[C@@H](O)C1.[Br-].[K+].CC(O)C>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C:3](=[O:9])[CH2:2]1
Reactant: O[C@H]1CO[C@H]2OCC[C@H]21
Agent: O=P([O-])([O-])O
Agent: O[C@@H]1CO[C@@H]2OCC[C@@H]21
Agent: O[C@@H]1CO[C@H]2OCC[C@H]21
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=C1CO[C@H]2OCC[C@@H]12
Reaction time: 1 h
Yield: 94.8 %

Procedure:
The mixture (18.9 g) containing (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (7.93 g, 60.9 mmol), (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (2.07 g, 15.9 mmol), (3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol (0.05 g, 0.4 mmol) and (3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol (0.05 g, 0.4 mmol) obtained in Example 4 was dissolved in ethyl acetate (112 ml), and dipotassium hydrogen phosphate (27.1 g, 155.3 mmol), potassium bromide (0.5 g, 3.9 mmol) and 2,2,6,6-tetramethylpiperidinyl-1-oxy (61 mg, 0.4 mmol) were added, and the mixture was cooled to 0. Into this was dropped a sodium hypochlorite aqueous solution (123.9 g, effective chlorine concentration 14%, 0.23 mol) at 15° C. or less, and after completion of dropping, the mixture was stirred for 1 hour. After completion of the reaction, 2-propanol (10 ml) was added, and the mixture was stirred for 30 minutes and liquid-partitioned. Further, the aqueous layer was extracted with ethyl acetate (50 ml) and the organic layers were combined, and dried over anhydrous sodium sulfate (1.0 g) added. Sodium sulfate was filtrated, then, the solvent was distilled off, and 2-propanol (30 ml) was added to the concentrated residue and recrystallization was performed, to obtain a pale brown white crystal (3aR,6aR)-tetrahydrofuro[2,3-b]furan-3(2H)-one (7.4 g, purity 98%, yield 73%). At this stage, the enantiomer excess was 100% ee.
Reaction SMILES: Cl[CH:2]([C@H:7]([OH:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].C[O-].[Na+]>CO>[O:10]1[C@H:7]([CH2:8][CH3:9])[C@H:2]1[C:3]([O:5][CH3:6])=[O:4]
Reactant: CC[C@@H](O)C(Cl)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H]1O[C@@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.87 %

Procedure:
To 130 ml of a methanol solution of 25.5 g (0.153 mol) of the methyl (3R)-2-chloro-3-hydroxypentanoate obtained in (2) above was added dropwise 30 g (0.155 mol) of a 28% methanol solution of sodium methoxide at 0 to 5° C., followed by stirring at room temperature for 1 hour. After confirming disappearance of the methyl (3R)-2-chloro-3-hydroxypentanoate by TLC, methanol was evaporated. The concentrate was cooled, adjusted to pH 8 to 9 with 120 ml of a phosphate buffer, and extracted with 300 ml of isopropyl ether. The isopropyl ether was evaporated, and the residue was purified by column chromatography to give 16.5 g (0.126 mol; yield: 82.87%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.CCN=C=NCCCN(C)C.[Cl:25][C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[N:30][CH:31]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C1COCC1>[Cl:25][C:26]1[C:27]([C:32]([NH:9][C:8]2[C:3]([NH:2][CH3:1])=[N:4][CH:5]=[C:6]([C:10]([F:13])([F:11])[F:12])[CH:7]=2)=[O:33])=[N:28][CH:29]=[N:30][CH:31]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=C(O)c1ncncc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CNc1ncc(C(F)(F)F)cc1NC(=O)c1ncncc1Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of N2-methyl-5-trifluoromethylpyridine-2,3-diamine (2.65 g), WSC (2.66 g), 4-dimethylaminopyridine (0.10 g), THF (10 ml), and pyridine (10 ml), 5-chloropyrimidine-4-carboxylic acid was added under ice-cooling, and the reaction mixture was stirred at 50° C. for 8 hours. After standing to cool the reaction mixture to room temperature, to the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.77 g of 5-chloro-N-(2-methylamino-5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[CH3:9]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(O)ccc1Br
Solvent: ClCCl
Product: Cc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C

Procedure:
Into a 100 mL round bottom flask was added 4-bromo-3-methylphenol (0.90 g, 0.0048 mol), phenylboronic acid (2.4 g, 0.019 mol), cupric acetate (1.4 g, 0.0077 mol) and DCM (49.99 mL). TEA (4.0 mL, 0.029 mol) was then added followed by 4 A° molecular sieves and the reaction mixture was stirred at rt over night. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=2.35 (s, 3H), 6.72 (dd, J=8.59, 3.03 Hz, 1H), 6.91 (d, J=2.78 Hz, 1H), 6.98-7.05 (m, 2H), 7.08-7.16 (m, 1H), 7.31-7.38 (m, 2H), 7.46 (d, J=8.59 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([C@H:18]([CH:20]2[S:25][CH2:24][CH2:23][CH2:22][S:21]2)[OH:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:26]([CH3:28])[CH3:27])[S:14]2)[C@H:10]1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([C@@H:18]([O:19][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:20]2[S:25][CH2:24][CH2:23][CH2:22][S:21]2)[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:26]([CH3:28])[CH3:27])[S:14]2)[C@H:10]1[O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@@H](O)C3SCCCS3)O[C@@H]2S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@@H](OCc3ccccc3)C3SCCCS3)O[C@@H]2S1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A solution of 96 (3.3 g, 6 mmol) in DMF (40 mL) was treated with sodium hydride (830 mg, 24 mmol, 70% mineral oil dispersed) for 30 min at room temperature, followed by the addition of (bromomethyl)benzene (2.1 g, 12 mmol). After additional 1 hour at room temperature, the reaction was quenched by water (100 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layer was washed with brine (5×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 10%-30% ethyl acetate in petroleum ether to afford 97 as a brown syrup (2.8 g, 73%); (ES, m/z) [M+H]+ 637.1; 1H NMR (300 MHz, CDCl3) δ 7.24-7.41 (m, 15H), 6.32-6.34 (d, J=6.3 Hz, 1H), 4.65-4.82 (m, 5H), 4.37-4.39 (m, 3H), 4.05-4.25 (m, 3H), 3.76-3.89 (m, 1H), 3.02 (s, 6H), 2.77-2.92 (m, 4H), 1.64-1.68 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:25])=[N-]>CO>[CH3:25][O:14][C:13](=[O:15])[CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C(NC(=O)OCc1ccccc1)C1CC(=O)NC1=O

Procedure:
In 300 ml of methanol was dissolved 2 g of benzyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)glycine and under ice-cooling an excess of an ethereal solution of diazomethane was added. The mixture was stirred under ice-cooling for 2 hours and then concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-acetone (4:1). The eluate was concentrated under reduced pressure and after addition of ethyl ether to the residue, the mixture was allowed to stand in a refrigerator overnight to give crystals. Yield 1.3 g.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:27])([F:26])[C:9]1[CH:25]=[CH:24][C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:15]=3[CH2:16][CH:17](Cl)[C:11]=2[CH:10]=1.O.[OH-].[Al+3].[Li+].[OH-].[OH-].[OH-]>O1CCCC1>[F:27][C:8]([F:7])([F:26])[C:9]1[CH:25]=[CH:24][C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:15]=3[CH2:16][CH2:17][C:11]=2[CH:10]=1
Reactant: FC(F)(F)c1ccc2c(c1)C(Cl)Cc1c(Cl)cccc1S2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)CCc1c(Cl)cccc1S2
Temperature: 25 °C
Yield: 18 %

Procedure:
To the mixture of 0.2 g of lithium aluminum hydride and 20 ml of anydrous tetrahydrofuran was added with stirring under ice-cooling 400 mg of 2-trifluoromethyl-9-chloro-11-chloro-10,11-dihydrodibenzo[b,f]thiepin dissolved in 10 ml of anhydrous tetrahydrofuran. Thereafter, the mixture was reacted under cooling for 0.5 hr. at the room temperature and further under reflux condition for 3.5 hrs. After cooling, to the mixture was added water with stirring under cooling to decompose an excess of lithium aluminum hydroxide and the resulting mixture was filtered with the use of celite. The filtrate was extracted with chloroform, chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 372 ml of an oily substance, which was chromatographed on a silica gel, eluted with n-hexane, and there was obtained 65 mg of 2-trifluoromethyl-9-chloro-10,11-dihydrodibenzo[b,f]thiepin.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li:14])CCC.CCCCCC>O1CCCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Li:14]
Reactant: COc1ccccc1I
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]c1ccccc1OC
Reaction time: 0.75 h

Procedure:
To a solution of 2-iodoanisole (4.97g, 21.24 mmol, Aldrich 98%) in anhydrous tetrahydrofuran (33 mL) at −78° C., was added a solution of n-butyllithium in hexane (2.5 M, 8.5 mL, 21.25 mmol, Aldrich). The reaction was stirred at −78 OC for 0.5-1 hr to give a solution of the 2-methoxyphenyl lithium for the following reaction.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[C:29]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([Si:33]([O:5][C:4]([O:6][CH3:7])=[C:3]([O:2][CH3:1])[CH3:8])([CH3:35])[CH3:34])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C(C)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(C)=C(OC)O[Si](C)(C)C(C)(C)C
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of methyl 2-methoxypropionate (177 mg, 1.5 mmol) in THF (1 mL) was added to a solution of LDA prepared from diisopropylamine (0.212 mL, 1.50 mmol) and butyllithium (0.60 mL, 1.50 mmol) in THF (2 mL) at −78° C. under nitrogen. The mixture was gradually allowed to warm to −20° C. over 1 h, re-cooled to −78° C. and then a solution of tert-butylchlorodimethylsilane (233 mg, 1.50 mmol) in THF (1 mL) was added. The mixture was allowed to warm to rt over 2 h and stirred overnight. The reaction was quenched with satd. NaHCO3 (5 mL), diluted with DCM (10 mL). The organic layer was separated, washed with water, brine and dried (MgSO4). Evaporation of solvents afforded tert-butyl((1,2-dimethoxyprop-1-en-1-yl)oxy)dimethylsilane as a clear oil and used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]1[C:9](=[CH2:10])[CH2:8][C@H:7]2[C@@H:3]1[CH2:4][C@@H:5]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C@H:6]2/[CH:11]=[CH:12]/[C@@H:13]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1.O>C(Cl)Cl.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[O:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH:40]1[O:1][CH:2]1[C:9](=[CH2:10])[CH2:8][C@H:7]2[C@@H:3]1[CH2:4][C@@:5]([C:3]([CH3:7])([CH3:4])[CH3:2])([O:27][Si:28]([C:31]([CH3:33])([CH3:32])[CH3:34])([CH3:29])[CH3:30])[C@H:6]2/[CH:11]=[CH:12]/[C@@H:13]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2C1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: ClCCl
Solvent: O
Product: C=C1C[C@H]2[C@H](C[C@](O[Si](C)(C)C(C)(C)C)(C(C)(C)C)[C@H]2/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)C1OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 176 %

Procedure:
(1S,2RS,5S,6S,7R)-2-hydroxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane (127 mg, 0.25 mmole) obained in Example 3 was dissolved in 2 ml of methylene chloride. Dihydropyrane (42 mg, 0.50 mmole) and pyridium p-toluenesulfonate (5 mg) were added to the solution, and the mixture was stirred at room temperature for 8 hours. Water and methylene chloride were added to the reaction mixture to perform extraction. The resulting organic layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The resulting crude product was subjected to column chromatography (silica gel 15 g, hexane/ethyl acetate=30/1) to give (1S,2RS,5S,6S,7R)-2-(2-tetrahydropyranyloxy)-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-7-t-butyl-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane (130 mg, 0.22 mmole, 88%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[CH:6][CH:7]=1.O.N>C(O)C.[Pd]>[OH:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:5]1[N:4]=[N:3][CH:2]=[CH:7][CH:6]=1
Reactant: Oc1cccc(Oc2ccc(Cl)nn2)c1
Agent: [Pd]
Agent: N
Solvent: CCO
Solvent: O
Product: Oc1cccc(Oc2cccnn2)c1

Procedure:
11.1 g of 3-chloro-6-(3-hydroxyphenoxy)pyridazine are dissolved in 100 ml of ethanol, followed by addition of 6 ml of concentrated ammonia water and 1.0 of 5% Pd-C. Then catalytic reduction is carried out at 50° C. under atmospheric pressure. The theroretical amount of hydrogen gas is almost completely absorbed in about 1 hour. The reaction mixture is filtered and the filtrate is concentrated to dryness.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:18]([C:24]([CH3:26])=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)(O)[O-].[Na+].C(COC)OC>CCCCCC>[CH2:22]([O:21][C:19]([C:18]1[N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:2]2=[N:1][C:24]=1[CH3:26])=[O:20])[CH3:23]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncccc1OCc1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CCOC(=O)c1c(C)nc2c(OCc3ccccc3F)cccn12
Reaction time: 0.5 h

Procedure:
A mixture of 25.0 g of 2-amino-3-(2-fluorobenzyloxy)pyridine, 20.5 g ethyl 2-chloroacetoacetate, 10.0 g of sodium bicarbonate and 250 ml dimethoxyethane was heated under reflux for 48 hrs. An additional 5.0 g ethyl 2-chloroacetonacetate was added and refluxed for another 24 hrs., followed by another 5.0 g and refluxed for a further 66 hrs. The mixture was cooled and suctionfiltered. The solids collected were washed with tetrahydrofuran, and the combined filtrate and washings were evaporated invacuo to leave a dark-colored oil. Hexane (200 ml) was added to the oil with vigorous stirring, and the resulting precipitate filtered off. To this solid was added (with vigorous stirring) acetonitrile (50 ml) and diisopropyl ether (200 ml) and stirring was continued for 0.5 hr. The suspended solid was filtered and crystallized from acetonitrile to give the desired ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>[O-]CC.[Na+]>[C:9]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccc(CC#N)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(C#N)c1ccc(C)cc1

Procedure:
Following the procedures outlined in Examples 1 and 3, p-methylphenylacetonitrile and diethyl oxalate are reacted in alcoholic sodium ethoxide to obtain ethyl 3-cyano-3-(p-methylphenyl)-pyruvate, m.p. 86°-88° C. The latter is reacted with p-methylphenylacetonitrile to give 2,5-di-(p-methylphenyl)-3,4-dioxoadiponitrile, m.p. 270°-272° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.Br[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:8]([N:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCc1ccccc1
Reactant: O[C@@H]1CCNC1
Product: O[C@@H]1CCN(CCc2ccccc2)C1
Yield: 83.5 %

Procedure:
Prepared as in Intermediate I-15 from (3R)pyrrolidin-3-ol (commercially available) and (2-bromoethyl)benzene. The yield was 0.91 g (83.5%) of the title compound.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1.CCCC[N+](CCCC)(CCCC)CCCC.[FH:39].F.[F-]>>[F:39][CH2:3][CH:2]([OH:1])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCC(OCC2CO2)CC1
Reactant: F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(OCc1ccccc1)N1CCC(OCC(O)CF)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
A mixture of benzyl 4-(oxiran-2-ylmethoxy)piperidine-1-carboxylate (1.81 g) and tetrabutylammonium dihydrogen trifluoride (3.74 g) was stirred at 120° C. overnight. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (960 mg).
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:22](=[O:23])[CH:16]3[CH2:17][CH:18](O)[CH2:19][CH2:20][N:15]3[C:14]2=[O:24])[C:10]([F:25])=[CH:9][C:8]=1[Cl:26])(=[O:5])=[O:4].C(N(S(F)(F)[F:33])CC)C>ClCCl>[Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:22](=[O:23])[C@@H:16]3[CH2:17][C@@H:18]([F:33])[CH2:19][CH2:20][N:15]3[C:14]2=[O:24])[C:10]([F:25])=[CH:9][C:8]=1[Cl:26])(=[O:5])=[O:4]
Reactant: O=C1C2CC(O)CCN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C1[C@@H]2C[C@@H](F)CCN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Example 11, Step A (771 mg, 1-80 mmol) in dichloromethane (10 mL) was added dropwise diethylaminosulfur trifluoride (0.48 mL, 3.60 mmol) at 0° C. The reaction was stirred at 0° C. for 1 hour, quenched with cold water, and extracted with dichloromethane. The combined organic layers were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The title compound of Step A, a compound of this invention, was isolated by flash chromatography (332 mg) as a foam melting at 60-64° C. 1H NMR (CDCl3) 87.7 (d, 1H), 7.4 (d, 1H), 7.1 (br s, 1H), 5.28 and 5.12 (two br s, 1 H), 4.6 (s, 2H), 1H), 4.2 (dd, 1H), 3.3 (ddd, 1H), 2.65 (m, 1H), 2.2 (m, 1H), 1.9-1.6 (m, 2H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:27][NH:28][CH2:29][CH3:30].CC(C)(C)CNC[C@@H]1OC2C=C(S(C)(=O)=O)C=CC=2OC1>C(#N)C>[CH3:27][N:28]([CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][CH:19]=2)[O:14]1)[CH2:29][CH3:30]
Reactant: CCNC
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Agent: CC(C)(C)CNC[C@H]1COc2ccc(S(C)(=O)=O)cc2O1
Solvent: CC#N
Product: CCN(C)CC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-methylethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 283 (M+, 2), 131 (4), 77 (4), 73 (5), 72 (bp), 63 (2).