Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:12]([F:13])=[CH:11][C:10]([O:14]CC3C=CC=CC=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C(OCC)(=O)C.[OH-].[Na+]>[Pd].C(O)(=O)C>[F:13][C:12]1[CH:11]=[C:10]([OH:14])[CH:9]=[N:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1cc(OCc2ccccc2)cnc1-c1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1cnc(-c2ccccc2)c(F)c1
Reaction time: 3 h
Yield: 77 %

Procedure:
6.55 g (29.7 mM) of 2-phenyl-3-fluoro-5-(phenylmethoxy)pyridine are added to 160 ml of methanol, 30 ml of ethyl acetate and 30 ml of acetic acid. 0.33 g of 10% palladium-on-charcoal is added. The mixture is stirred under a hydrogen atmosphere for 3 hours. The catalyst is filtered off and the solvents are concentrated to give a white solid, which is taken up with 1 N sodium hydroxide solution. The aqueous phase obtained is washed with dichloromethane and then acidified to pH 5 with 1 N hydrochloric acid solution. The white precipitate obtained is filtered off and washed with water. After drying, the desired product is obtained in the form of a white solid with a yield of 77%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[CH3:8].[F-].[Cs+].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:44][C:45]1[CH:50]=[C:49](Cl)[N:48]=[C:47]([C:52]([O:54][CH3:55])=[O:53])[C:46]=1[Cl:56]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(N(CC)CC)C>[NH2:44][C:45]1[CH:50]=[C:49]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[N:48]=[C:47]([C:52]([O:54][CH3:55])=[O:53])[C:46]=1[Cl:56]
Reactant: COC(=O)c1nc(Cl)cc(N)c1Cl
Reactant: Cc1ccc(B(O)O)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2ccc(C)c(C)c2)cc(N)c1Cl
Yield: 50 %

Procedure:
A solution of 3,4-dimethylphenylboronic acid (2.1 g, 14.0 mmol), cesium fluoride (6.3 g, 41.5 mmol), 1,4-bis(diphenylphosphino)butane (0.5 g, 1.2 mmol), methyl 4-amino-3,6-dichloropyridine-2-carboxylate (2.5 g, 10.0 mmol) and triethylamine (5 mL) in acetonitrile (100 mL) was sparged for thirty minutes with nitrogen. Palladium acetate (0.3 g, 1.2 mmol) was added and the reaction mixture heated under reflux for three hours. After cooling water (200 mL) was added and the mixture extracted with ethyl acetate (2×100 mL). The organic layer was washed with brine (100 mL), dried (NaSO4), and concentrated. The residue was purified by column chromatography (33 percent ethyl acetate in hexane) to give methyl 4-amino-3-chloro-6-(3,4-dimethylphenyl)pyridine-2-carboxylate (1.4 g, 5.0 mmol), mp 154-156° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:31][C:32]#[C:33][CH2:34][CH2:35]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([CH2:35][C:34]#[C:33][CH2:32][Cl:31])[C@@:16]2([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18]3)[CH:4]=[C:3]([C:2]([F:29])([F:1])[F:30])[CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3)cc(C(F)(F)F)c1
Reactant: ClC#CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3CC#CCCl)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of (1R*,2R*,5R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 60; 400 mg, 0.93 mmol) in dimethylformamide (4 ml) was added to 1,4-dichlorobutyne (0.23 ml, 2.33 mmol) and potassium carbonate (386 mg, 2.79 mmol) in dimethylformamide (2 ml) at 60° C. The reaction mixture was stirred under N2 at 60° C. overnight. The mixture was diluted with water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [2.5%-7.5% methanol in dichloromethane] to give the title compound as a brown oil.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22]#[N:23])[CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[OH:26][NH:27][C:28](=N)[CH:29]([CH3:31])[CH3:30]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:17][CH2:18][N:19]([C:22]4[O:26][N:27]=[C:28]([CH:29]([CH3:31])[CH3:30])[N:23]=4)[CH2:20][CH2:21]3)=[CH:24][CH:25]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(C)C(=N)NO
Reactant: N#CN1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(-n4cnnn4)cc3)CC2)n1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
To a solution of 4-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine-1-carbonitrile (Step A, Example 83; 150 mg, 0.444 mmol) and N-hydroxyisobutyrimidamide (54 mg, 0.53 mmol) in tetrahydrofuran (5 mL) was added zinc chloride (1.1 mL, 0.5 M in tetrahydrofuran, 0.53 mmol). The mixture was refluxed for 2 h, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in 2 mL of 4N HCl ethanol and water (1:1). The solution was refluxed for 1 hour, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (5 mL), neutralized by the addition of excess potassium carbonate, mixed with silica gel (2 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (15 g of silica gel) and eluted with dichloromethane/methanol (199:1, 1 L) to provide impure product (72 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[Br:10].S1(CCCC1)(=O)=O.[Li+].CC([N-]C(C)C)C.[Li]CCCC.[C:31](=[O:33])=[O:32]>O1CCOCC1.C(OCC)C.C1COCC1.CN1C(=O)N(C)CCC1.CN(P(N(C)C)(N(C)C)=O)C>[Br:10][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([F:9])=[C:5]([CH:4]=1)[C:31]([OH:33])=[O:32]
Reactant: Fc1ccc(Br)c(F)c1F
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Solvent: CN1CCCN(C)C1=O
Product: O=C(O)c1cc(Br)c(F)c(F)c1F
Reaction time: 1.25 h

Procedure:
To a solution of 2,3,4-trifluorobromobenzene in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), sulfolane, HMPA, DMPU, prefer anhydrous THF, ethyl ether and dioxane) was added strong base (such as LDA, nBuLi, LiHDMS) at low temperature (−50-−80° C., prefer −78° C.) under nitrogen atmosphere. The reaction is kept stirring for some time (0.5-12 h, prefer 0.5-2 h) and is added dry ice. After several hours (3-12 h, prefer 5-10 h), 5-bromo-2,3,4-trifluorobenzoic acid is obtained after conventional workup.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17]C)=[O:16])[N:5]=2.C(N(CC)CC)C.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>O1CCCC1.O>[CH:29]1([C:32]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([OH:17])=[O:16])[N:5]=3)=[O:33])[CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1cccc(Oc2ccc3nc(N)sc3n2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Yield: 79 %

Procedure:
To a solution of methyl 3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]benzoate (4.20 g, 13.9 mmol) and triethylamine (3.47 μL, 25.1 mmol) in tetrahydrofuran (40 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (1.52 mL, 16.7 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethanol (50 mL). 8N Aqueous sodium hydroxide solution (7 mL) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was adjusted to pH 4 with 6N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to give the title compound (3.90 g, 79%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(Cl)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-chlorophenol and N-{3-[1-(6-hydroxy-6-phenylhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.28 (s, 1H), 7.78–6.70 (m, 13H), 5.08–4.98 (m, 1H), 3.64–3.46 (m, br, 2H), 3.02–2.82 (br, 2H), 2.82–2.56 (m, br, 4H), 2.56–2.34 (m, br, 2H), 2.05–1.75 (m, br, 6H), 1.64–1.48 (m, br, 1H), 1.48–1.34 (br, 3H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 533.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17](Cl)(=[O:28])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[C:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:28])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
4'-Hydroxybiphenyl-4-carboxylic acid (3.5 g) and triethylamine (2.4 g) were dissolved in dichloromethane (30 ml). Undecanoyl chloride (4.3 g) and dimethylaminopyridine (0.2 g) were added to the solution, and the mixture was stirred at room temperature for about 20 hours. Dilute hydrochloric acid was added thereto, and the organic layer was separated in a separating funnel. The solvent was removed by evaporation, and the residue was dried after washing with n-hexane to give the titled compound (5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[C:4]([F:13])[CH:3]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1>C(#N)C>[Cl:14][C:15]1[N:20]=[C:19]([N:9]2[CH2:10][CH:7]([O:6][C:5]3[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][C:4]=3[F:13])[CH2:8]2)[N:18]=[CH:17][N:16]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Fc1cc(Cl)ccc1OC1CNC1
Solvent: CC#N
Product: Fc1cc(Cl)ccc1OC1CN(c2ncnc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
To a solution of 3-(4-chloro-2-fluorophenoxy) azetidine (3.6 g, 18.0 mmol) in acetonitrile (60 mL, 3 mL/mmol) was added TEA (7.2 mL, 50.0 mmol) and 2, 4-dichloro-1, 3, 5-triazine (3.0 g, 20.0 mmol) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×50 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-1,3,5-triazine (0.800 g, 20%) as a solid. Observed mass (M+1): 315.0
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[C:20]([C:22]1([OH:26])[CH2:25][CH2:24][CH2:23]1)#[CH:21]>>[OH:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:21]#[C:20][C:22]2([OH:26])[CH2:25][CH2:24][CH2:23]2)[CH:3]=1)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Reactant: C#CC1(O)CCC1
Product: CC(C)(C)OC(=O)NCCC(O)c1cccc(C#CC2(O)CCC2)c1

Procedure:
Sonogashira reaction of 39 with 1-ethynyl-cyclobutanol yielded tert-butyl 3-hydroxy-3-(3-(2-(1-hydroxycyclobutyl)ethynyl)phenyl)propylcarbamate as yellow oil. Yield (1.5 g, 70%): 1H NMR (400 MHz, DMSO-d6) δ 7.45 (s, 1H), 7.27-7.34 (m, 3H), 4.85 (bs, 1H), 4.71 (m, 1H), 3.48-3.51 (m, 2H), 3.14-3.16 (m, 1H), 2.50-2.52 (m, 2H), 2.30-2.49 (m, 3H), 1.80-1.90 (m, 4H), 1.45 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].C(O[CH:14](N(C)C)[N:15]([CH3:17])[CH3:16])(C)(C)C>CCCCCC>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:2]/[C:1]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1ccc[nH]1
Solvent: CCCCCC
Product: CN(C)/C=C/C(=O)c1ccc[nH]1
Reaction time: 6 h
Yield: 42.1 %

Procedure:
A mixture of 39.6 g of 2-acetylpyrrole and 104 ml (87.7 g) of tert-butoxy bis(dimethylamino)methane was heated on a steam bath for 20 minutes. The reaction was allowed to subside, then heating was continued for 6 hours. The mixture solidified then was slurried in hexane with chilling. The crude product was collected, washed with hexane and dried. The solid was dissolved in chloroform containing 5% methanol and filtered through magnesium silicate. The eluent was evaporated in vacuo and the residue was recrystallized from dichloromethane/hexane containing a small amount of methanol. The solid was collected, washed with hexane then dried in vacuo giving 25.1 g of the desired compound as yellow crystals, mp 192°-193° C. (dec.).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25](O)[CH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][CH3:41])[CH2:35][CH2:34]2)[CH2:29][CH2:28]1.O>C1(C)C=CC=CC=1>[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25]=[CH:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][CH3:41])[CH2:35][CH2:34]2)[CH2:29][CH2:28]1
Reactant: CCCC1CCC(C2CCC(CC(O)c3c(C)cc(OCC)c(F)c3F)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1CCC(C2CCC(C=Cc3c(C)cc(OCC)c(F)c3F)CC2)CC1

Procedure:
0.55 g of p-toluenesulfonic acid monohydrate was added to the compound (8) having been dissolved in 120 mL of toluene, and the mixture was heated under stirring by using a Dean-Stork trap until completion of azeotrope of water. After terminating the reaction by adding water, the aqueous layer was extracted with toluene, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography and then subjected to recrystallization to obtain 11.2 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-(4-propylcyclohexyl)cyclohexyl)ethene (Compound 1-3-3-9) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[C:5]=1[CH2:14][CH:15]=C.[O:18]=[O+][O-].CSC>ClCCl.CO>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]2[O:13][CH:15]([OH:18])[CH2:14][C:5]=12)=[O:17]
Reactant: O=[O+][O-]
Reactant: C=CCc1c(C(=O)OC)ccc([N+](=O)[O-])c1O
Solvent: CSC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc([N+](=O)[O-])c2c1CC(O)O2
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
Into a solution of 2-allyl-3-hydroxy-4-nitro-benzoic acid methyl ester (6.11 g 25.6 mmol) in dichloromethane (100 mL) and methanol (10 mL) at −78° C. was bubbled with ozone for 40 minutes. After stirring for another 20 min at −70° C., a stream of nitrogen gas was passed through the reaction mixture. Dimethyl sulfide (5 mL, 68.1 mmol) was added at −78° C. The reaction solution was allowed to warm up gradually to room temperature overnight. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was further extracted twice with dichloromethane. The organic extract was washed with brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure to give 2-hydroxy-7-nitro-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester as a yellow solid (6.0 g). 1H NMR (CDCl3) &: 3.51-3.74 (m, 2H), 3.96 (s, 3H), 6.43 (dd, 1H, J=6.4 Hz, 2.6 Hz), 7.63 (d, 0.1H, J=8.8), 8.01 (d, 1H, J=8.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:13]1[C:21]2[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][CH2:11][OH:12].ClCCl.ClC1C=CC=C(C(OO)=[O:36])C=1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:13]1[C:21]2[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:36])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][CH2:11][OH:12]
Reactant: CSCc1cccc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75.9 mg (0.20 mmol) of the compound from Example 7 were introduced into 11 ml of dichloromethane at 0° C., 49.2 mg (0.20 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. 2 ml of methanol were added, the residue after concentration was taken up in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases were separated, the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 50 mg (63% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([CH2:19]O)[CH:16]=[CH:17][CH:18]=3)=[N:9]2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:24]>ClCCl>[Br:24][CH2:19][C:15]1[CH:14]=[C:13]([C:10]2[N:11]=[N:12][N:8]([CH2:7][C:6]3[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(Cn2nnc(-c3cccc(CO)c3)n2)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2nnc(-c3cccc(CBr)c3)n2)cc1
Reaction time: 16 h
Yield: 96.6 %

Procedure:
The alcohol (1 g, 3.37 mmol) of Step (a) was dissolved in dichloromethane (25 mL) and added dropwise at room temperature to a solution of phosphorous tribromide (1 g, 3.7 mmol) in dichloromethane (75 mL). The solution was stirred for 16 hours, then concentrated in vacuo. The residue obtained was triturated with hexane and collected by filtration to yield a white solid (1.17 g, 92%). 1H NMR (CDCl3) δ 8.2 (d, 1H), 7.7 (m, 2H), 7.5 (m, 1H), 7.4 (d, 2H), 6.8 (d, 2H), 5.8 (s, 2H), 4.5 (s, 2H), 3.7 (s, 3H) ppm.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[CH2:7])CCC>CN(C=O)C.C(OCC)(=O)C.Cl[Cu]>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:13]=2)=[CH2:7])=[CH2:7])=[CH:9][CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=C(c1ccc(OCc2ccccc2)cc1)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C(=C)c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of tributyl-[1-(4-benzyloxy-phenyl)-vinyl]-stannane (26.2 g, 52.6 mmol) in DMF (180 mL) at 0° C. was added CuCl (8.6 g, 87.7 mmol) and CuCl2 (1.00 g, 8.13 mmol), which was then stirred at 25° C. for 2 h. The reaction mixture was then diluted with ethyl acetate (500 mL) and washed with brine (3×300 mL). The reaction mixture was then dried over MgSO4 and purified by SiO2 (20% ethyl acetate/hexane) to yield 2,3-di(4-benzyloxy-phenyl)-1,3-butadiene.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH2:6][O:7][P:8]([O:11][P:12]([O:15][CH2:16][CH:17]1[O:21][CH:20]([N:22]2[C:27](=[O:28])[N:26]=[C:25]([NH2:29])[CH:24]=[CH:23]2)[C@H:19]([OH:30])[C@@H:18]1[OH:31])([O-:14])=[O:13])([O-:10])=[O:9])([CH3:4])[CH3:3].[Na+:32].CN(N=O)C(N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O)=O>O>[CH3:4][N+:2]([CH2:5][CH2:6][O:7][P:8]([O:11][P:12]([O:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[C:27](=[O:28])[N:26]=[C:25]([NH2:29])[CH:24]=[CH:23]2)[C@H:19]([OH:30])[C@@H:18]1[OH:31])([O-:14])=[O:13])([O-:10])=[O:9])([CH3:1])[CH3:3].[Na+:32]
Reactant: C[N+](C)(C)CCOP(=O)([O-])OP(=O)([O-])OCC1OC(n2ccc(N)nc2=O)[C@H](O)[C@@H]1O
Agent: CN(N=O)C(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: O
Product: C[N+](C)(C)CCOP(=O)([O-])OP(=O)([O-])OC[C@H]1O[C@@H](n2ccc(N)nc2=O)[C@H](O)[C@@H]1O

Procedure:
CDP-choline Na was dissolved in distilled water and orally administered at a dose of 100 mg/kg once a day starting from the time point when 8 weeks passed from the administration of streptozotocin.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH:16]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.CN(C=O)C.CCOC(C)=O>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1ccc2c(c1)COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccc3c(c2)COC3=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
To a stirred solution of 5-aminophthalide (11.7 g, 78 mmol) and 2,4-dimethoxybenzaldehyde (15.5 g, 93.6 mmol) in 1% AcOH/DMF (60 ml), was added sodium triacetoxyborohydride (50.0 g, 236 mmol). The mixture was stirred at room temperature for 16 hours, diluted with EtOAc (400 ml), washed with saturated NaHCO3 solution (3×400 ml) and water (400 ml), dried over anhydrous Na2SO4, and evaporated to provide a crude product. Trituration of the crude product with MEOH gave 5-(2,4-dimethoxy-benzylamino)-3H-isobenzofuran-1-one as an off-white powder (19.0 g, 82%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]=2)=[CH:2]1.[ClH:23]>ClCCl.O1CCOCC1>[ClH:23].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2coc3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C1=C(c2coc3ccccc23)CCNC1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a stirred solution of tert-butyl 4-(benzofuran-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.06 g, 6.88 mmol) in dichloromethane (50 ml) was added at room temperature hydrochloric acid solution (4M in dioxane, 25.8 ml, 103 mmol) and the reaction mixture was allowed to stir for 2 h. The reaction mixture was diluted with dioxane (25 ml), the precipitate was collected by filtration, washed with dioxane and dried to yield 4-(benzofuran-3-yl)-1,2,3,6-tetrahydropyridine hydrochloride as off-white solid (1.37 g, 85%), MS (ISP) m/z=200.2 [(M+H)−], mp 276° C.