Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]=O)=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:33]([S:35][CH2:36][CH2:37][NH2:38])[CH3:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH2:31][NH:38][CH2:37][CH2:36][S:35][CH2:33][CH3:34])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CCSCCN
Reactant: O=Cc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCSCCNCc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carbaldehyde (0.31 g), 2-(ethylsulfanyl)ethanamine (0.14 g), acetic acid (1 drop) and tetrahydrofuran (2 mL) was stirred overnight at 50° C. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was m washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was dissolved in methanol (4 mL), and sodium borohydride (28 mg) was added at 0° C. The reaction mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (0.37 g, quantitatively) was obtained as a yellow oil from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). MS: 471 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](O)=[O:8])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.O.[NH2:30][NH2:31]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([NH:30][NH2:31])=[O:8])[CH3:2]
Reactant: NN
Reactant: CCOc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
3-Ethoxy-4-nitrobenzoic acid (PCT Int Appl. 2008003958, 1.06 g 5.02 mmole) was stirred with dry THF (10 mL) and triethylamine (0.86 mL, 6.1 mmol) and the solution was cooled in an ice bath. Ethyl chloroformate (0.56 mL, 5.85 mmol) was added dropwise and the reaction was stirred in the ice bath for 15 minutes. Hydrazine hydrate (1.27 mL, 26 mmol) was added in one portion and the reaction stirred in the ice bath for 5 minutes and then at 20° C. for 1 hour. The reaction was concentrated in vacuo, partitioned between EtOAc (100 mL) and saturated aqueous sodium bicarbonate (15 mL). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound (1.07 g, 95%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[CH3:21][N:22]1[C:26]([CH:27]=[O:28])=[CH:25][CH:24]=[N:23]1>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:27]([OH:28])[C:26]4[N:22]([CH3:21])[N:23]=[CH:24][CH:25]=4)=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: Cn1nccc1C=O
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: COC(=O)c1nc2n(c1C(O)c1ccnn1C)CCOc1cc(F)c(Br)cc1-2
Yield: 33 %

Procedure:
Methyl 10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxylate was reacted with 1-methylpyrazole-5-carbaldehyde to afford 219 mg (33% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](Cl)[S:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[S:4][N:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(Cl)nsc1Cl
Agent: [Pd+2]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Product: COC(=O)c1c(Cl)nsc1-c1ccc(OC)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3,5-dichloro-1,2-thiazole-4-carboxylate (300 mg, 1.41 mmol, 1.00 equiv) in Tol (5 mL), (4-methoxyphenyl)boronic acid (270 mg, 1.78 mmol, 1.26 equiv), Pd(OAc)2 (17 mg, 0.08 mmol, 0.05 equiv), KF (260 mg), 18-Crown-6 (180 mg, 0.68 mmol, 0.48 equiv). The resulting solution was stirred for 2 h at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:19). This resulted in 330 mg (74%) of methyl 3-chloro-5-(4-methoxyphenyl)-1,2-thiazole-4-carboxylate as a white crystal.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[N:13]=[C:12](Cl)[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1>O.C1COCC1>[Cl:3][C:4]1[N:13]=[C:12]([OH:1])[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1
Reactant: COc1ccc2c(Cl)nc(Cl)nc2c1C
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(O)nc(Cl)nc2c1C
Temperature: 40 °C
Yield: 99.3 %

Procedure:
A solution of NaOH (1.58 g, 39.6 mmol) in water (40 mL) was added to 2,4-dichloro-7-methoxy-8-methylquinazoline (139) (3.2 g, 13.05 mmol) in THF (20 mL). The resulting mixture was heated at 40° C. for 24 h. Then, the reaction mixture was cooled to room temperature, THF was evaporated and additional water (30 mL) was added. The precipitate was filtered off. Then, the pH of the filtrate was adjusted to 5 with AcOH to give a solid which was subsequently filtered off and successively washed with water and isopropylether to give the title compound (2.91 g, 99%) as a yellowish powder: m/z=225 (M+H)+.
Reaction SMILES: C(OC(=O)[CH2:5][NH:6][NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)C.P(Cl)(Cl)(Cl)=[O:21]>>[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([C:8]2[O:18][C:5](=[O:21])[NH:6][N:7]=2)=[CH:10][CH:11]=1)([CH3:17])[CH3:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CNNC(=O)c1ccc(C(C)C)cc1
Product: CC(C)c1ccc(-c2n[nH]c(=O)o2)cc1
Yield: 58 %

Procedure:
Ethyl[2-(4-isopropylbenzoyl)hydrazino]acetate (4.85 g, 19.4 mmol) is treated with phosphorus oxychloride (50 mL), heated to reflux for 3 h, and then poured onto ice. The precipitate is collected and washed thoroughly with water and dried in the air to furnish 5-(4-isopropylphenyl)-1,3,4-oxadiazol-2(3H)-one (2.30 g, 58%) MS (ES+): m/e 205.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:23]
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: O=C(O)c1ccccc1Br
Product: O=C(c1ccccc1Br)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-bromobenzoic acid. MS (ESI) mass calcd. for C21H19BrN4O, 423.31; m/z found, 423.0, 425.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O=[Pt]=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#CCO)CC1
Agent: O=[Pt]=O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Yield: 99.3 %

Procedure:
1.63 g (6.83 mmol) of 4-(3-Hydroxy-prop-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 50 ml of ethanol, treated with 350 mg of PtO2.H2O and hydrogenated (1 atm) for 7 h. The reaction was filtered and evaporated to give 1.65 g (99%) of 4-(3-Hydroxy-propyl)-piperidine-1-carboxylic acid tert-butyl ester, MS: 244 (MH1, 1Cl).
Reaction SMILES: C([O:8][C:9](=[O:38])[C:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:37])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=3)[CH2:21]2)[CH:15]=1)([CH3:12])[CH3:11])C1C=CC=CC=1>[Pd].CO>[CH:34]([C:31]1[CH:32]=[CH:33][C:28]([CH2:27][C:26]([N:22]2[CH2:23][CH2:24][CH2:25][CH:20]([C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=3)[O:13][C:10]([CH3:11])([CH3:12])[C:9]([OH:38])=[O:8])[CH2:21]2)=[O:37])=[CH:29][CH:30]=1)([CH3:36])[CH3:35]
Reactant: CC(C)c1ccc(CC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)OCc4ccccc4)c3)C2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(CC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)O)c3)C2)cc1
Reaction time: 3 h
Yield: 78.5 %

Procedure:
10% Palladium on carbon (50 mg, 10 wt %) was added to a solution of 2-(3-{1-[(4-isopropyl-phenyl)-acetyl]-piperidin-3-yl}-phenoxy)-2-methyl-propionic acid benzyl ester (494 mg, 0.96 mmol) in methanol (15 mL) and the resulting mixture hydrogenated at atmospheric pressure for 3 h. The reaction mixture was filtered through a plug of celite and the celite plug washed thoroughly with ethyl acetate. The combined filtrates were concentrated under reduced pressure to provide 319 mg (78%) of 2-(3-{1-[(4-Isopropyl-phenyl)-acetyl]-piperidin-3-yl}-phenoxy)-2-methyl-propionic acid as a clear oil.
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[C:7](\[CH3:21])/[CH2:8][CH2:9][C:10]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([CH3:18])[C:12](=[O:19])[C:11]=1[CH3:20])(=[O:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:1]([O:4][CH2:5]/[CH:6]=[C:7](\[CH3:21])/[CH2:8][CH2:9][C:10]1[C:11]([CH3:20])=[C:12]([OH:19])[C:13]([CH3:18])=[C:14]([CH3:17])[C:15]=1[OH:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C=C(\C)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OC/C=C(\C)CCc1c(C)c(O)c(C)c(C)c1O
Yield: 89 %

Procedure:
A solution of 3.27 g (11.3 mmol) of (E)-3-methyl-5-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)-2-pentenyl acetate in 60 ml of THF was treated dropwise with 40 ml of a freshly Prepared 0.5M sodium dithionite solution. After completion of the addition the mixture was diluted with water and extracted with chloroform. The combined extracts were washed with water and freed from solvent. The solid residue was washed with hexane and dried under oil pump vacuum, yielding 2.94 g of (E)-5-(2,5-dihydroxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl acetate as a colourless powder; m.p. 94.5°-96° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:11]C(=O)C(C)(C)C)=[N:8][C:9]=1[CH3:10].[OH-].[Na+]>>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[N:8][C:9]=1[CH3:10]
Reactant: COCc1ccc(NC(=O)C(C)(C)C)nc1C
Agent: [Na+]
Agent: [OH-]
Product: COCc1ccc(N)nc1C

Procedure:
This material was prepared in analogy to example 86 step B) from N-(5-methoxymethyl-6-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.4 g) and 3M aqueous NaOH (2.68 mL) as a crystalline orange solid (0.174 g). MS (EI): 152.2 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([NH2:11])=[O:10].[CH3:12][C:13]#N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:3][CH2:2][CH2:7][CH2:6][CH2:5][CH2:4][CH2:13][CH3:12])=[CH:4][C:3]=1[C:9]([NH2:11])=[O:10]
Reactant: CC#N
Reactant: NC(=O)c1cc(O)ccc1Cl
Product: CCCCCCCCCOc1ccc(Cl)c(C(N)=O)c1
Yield: 80 %

Procedure:
Synthesised from 2-chloro-5-hydroxybenzenecarboxamide according to Method B, scheme 2. Yield 80%, HPLC-MS (method 1): m/z 339 [M+H+CH3CN]+, Rt=5.29 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[CH:16][CH:17]=[C:4]2[N:3]=1.[CH3:18][O-:19].[Na+]>CO.ClCCl.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([O:19][CH3:18])[N:5]2[N:15]=[CH:16][CH:17]=[C:4]2[N:3]=1
Reactant: C[O-]
Reactant: Clc1nc2ccnn2c(Cl)c1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1c(-c2ccccc2)c(Cl)nc2ccnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.00 g 5,7-dichloro-6-phenylpyrazolo[1,5-a]pyrimidine (prepared as described above) were dissolved in 20 mL methanol and 20 mL dichlormethane. 1.2 g sodium methylate was added at 0° C. and stirred at room temperature for 2 h. The solution was diluted with water and dichloromethane. The organic phase was separated and the water phase was extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The crude product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Cl:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]([C:13]4[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=4[F:19])=[O:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:31][CH:30]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: OB(O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)nc4)cc23)c1F
Reaction time: 0.27 h

Procedure:
Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (56, 10 mg, 0.022 mmol) was weighed into a 5 mL microwave vial and combined with 6-chloro-pyridine-3-boronic acid (72, 4.4 mg, 0.028 mmol), followed by the addition of 600 μL of acetonitrile and 500 μL of 1M potassium carbonate and a spatula tip (˜1 mg) of [1,1″-bis(diphenylphosphino)-ferrocene]dichloropalladium(II). The reaction mixture was irradiated in a microwave at 160° C. for 5 minutes. The solution was neutralized with 100 μL of acetic acid and all material was transferred to a 4 mL vial and the solvents were removed under vacuum. The crude material was dissolved in 400 μL of dimtheylsulfoxide and purified by reverse phase HPLC, eluting with 0.1% trifluoroacetic acid in water and 0.1% trifluoroacetic acid in acetonitrile, 20-100% acetonitrile over 16 minutes at 6 mL per minute. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound. MS (ESI) [M+H+]+=491.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([CH2:10][CH3:11])[CH:3]=1.C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CBr
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cc(Br)ccc1CN1CCOCC1
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-ethyl-benzene (3.67 g, 13.2 mmol) in CH3CN (66 mL) was added triethylamine (2.76 mL, 19.8 mmol) and morpholine (1.38 mL, 15.8 mmol). The mixture was stirred for 1.5 hours, at which time the volatiles were removed in vacuo to yield a pale yellow solid (3.7 g, 97%). 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J=7.5 Hz, 3 H), 2.40 (m, 4 H), 2.68 (q, J=7.7 Hz, 2 H), 3.40 (s, 2 H), 3.65 (m, 4 H), 7.13 (m, 1 H), 7.22 (d, J=2.1 Hz, 1 H), 7.30 (d, J=2.1 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([O:21][CH2:22][O:23][CH3:24])[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH:15]=2)[CH:10]([CH2:25]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)(Cl)[Cl:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([O:21][CH2:22][O:23][CH3:24])[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH:15]=2)[CH:10]([CH2:25][Cl:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1c2c(cc3ccccc13)N(C(=O)OC(C)(C)C)CC2CO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCOc1c2c(cc3ccccc13)N(C(=O)OC(C)(C)C)CC2CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
From 27: A solution of 27 (55 mg, 0.16 mmol) in 3 mL anhydrous CH2Cl2 was treated with CCl4 (155 μL, 1.6 mmol) and Ph3P (212 mg, 0.81 mmol) and the mixture was stirred at 25° C. for 2 h. The solution was concentrated in vacuo. Flash chromatography (SiO2, 1.5×15 cm, 0-12% EtOAc/hexane gradient) provided 28 (52 mg, 90%) as a white solid: mp 99-101° C.; 1H NMR (CDCl3, 250 MHz) δ8.03 (br s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.37 (m, 2H), 5.24 (d, J=6.1 Hz, 1H), 5.15 (d, J=6.1 Hz, 1H), 4.06 (m, 4H), 3.65 (s, 3H), 3.51 (app t, J=10.1 Hz, 1H), 1.59 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ152.3, 150.5, 141.1, 136.2, 127.9, 126.6, 124.6, 124.1, 122.4, 121.4, 107.7, 100.0, 81.2, 57.5, 52.1, 45.9, 40.8, 28.4; IR (film) νmax 2976, 1704, 1634, 1449, 1336, 1147, 1055, 983 cm−1; FABHRMS (NBA) m/z 378.1463 (C20H24ClNO4+H+ requires 378.1472).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[FH:16].[F-].[K+]>>[F:16][CH2:3][C@H:2]([OH:1])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1CO1
Reactant: F
Agent: [F-]
Agent: [K+]
Product: O=C1c2ccccc2C(=O)N1C[C@@H](O)CF

Procedure:
A sample of 2-[(2R)-Oxiranylmethyl)-1H-isoindole-1,3-dione (G. Alexander et al. Tetrahedron Asymmetry, 7, 1641-8, 1996) is treated with potassium hydrogen difluoride to give 2-[(2R)-3-fluoro-2-hydroxypropyl]-1H-isoindole-1,3-dione in the presence of catalyst nBu4NH2F3. The procedures and methods used in this synthesis are identical to those of Example 3, except that in step Example-3B 2-[(2R)-3-fluoro-2-hydroxypropyl]-1H-isoindole-1,3-dione is used instead of (S)-1-[(benzyloxycarbonyl)amino]-2-propanol to produce the title product.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>CCCCCC>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: C1=COCCC1
Reactant: Oc1ccc(I)cc1
Solvent: CCCCCC
Product: Ic1ccc(OC2CCCCO2)cc1
Reaction time: 1 h
Yield: 77 %

Procedure:
In 1 l of four-necked flask, 178 g (0.81 mol) of p-iodophenol, 81.68 g of dihydropyran and hexane were introduced and stirred for one hour. Then, 15 g of a cation exchange resin Amberlyst 15 (Rohm & Haas Co. "Amberlyst"®) was added thereto and stirred at room temperature overnight. Amberlyst 15 was removed by filtration and the filtrate was washed with an alkali and then with water. The oil layer was dried over sodium hydroxide and the solvent was distilled off to obtain 189.7 g (yield: 77%) of 4-[(tetrahydropyran-2-yl)oxy]iodobenzene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[CH3:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:15][N:16]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]1[CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]=2[CH2:11]1
Reactant: O=C1CCc2ncc([N+](=O)[O-])cc2C1
Reactant: CNCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(CCc1ccccc1)C1CCc2ncc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 18 %

Procedure:
A100 mL flask, equipped with a magnetic stirbar, was charged with 3-nitro-7,8-dihydroquinolin-6(5H)-one (2.5 g, 13.0 mmol), N-methyl-2-phenylethanamine (1.76 g, 13.0 mmol), and 1,2-dichloroethane (73 mL). Sodium triacetoxyborohydride (4.13 g, 19.5 mmol) was added as a solid. The mixture was stirred at ambient temperature for 40 hours. Saturated NaHCO3 (aq) was added until the pH=8. The mixture was extracted with dichloromethane (3×50 mL). The combined organic portions were dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (0 to 10% MeOH in dichloromethane) to provide the title compound (0.73 g, 18%). 1H NMR (400 MHz, CD3OD), δ9.16 (d, 1H, J=2.6), 8.13 (d, 1H, J=2.6), 7.30-7.17 (m, 5H), 3.19 (ddd, 2H, J=19, 6, 4), 2.96-2.89 (m, 6H), 2.45 (s, 3H), 2.21-2.12 (m, 2H), 1.89-1.84 (m, 1H). MS [M+H]+=312.2 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[CH2:25]([OH:30])[CH2:26][CH2:27][C:28]#[CH:29].CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:29]#[C:28][CH2:27][CH2:26][CH2:25][OH:30])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: C#CCCCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCCCO)cc2c1O
Temperature: 25 °C

Procedure:
A solution of the title compound of Example 5 (540.3 mg), 4-pentyn-1-ol (0.16 mL), PdCl2 (PPh3)2 (21.1 mg), and 0.75 mL Et3N in 3 mL DMF is heated at 90° C. for 1 hr. The reaction mixture is cooled to room temperature and partitioned between EtOAc and H2O. The aqueous layer is washed with EtOAc (3×). The combined organic layers are dried over Na2SO4 and condensed to obtain a red-brown residue. The residue is diluted with CH2Cl2 and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined, condensed and recrystallized from EtOAc/hexanes to yield 0.296 g of the desired product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=O)[CH3:10].[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.C(O)(=O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1/[C:9](=[N:21]/[NH:20][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[CH3:10]
Reactant: CC(=O)c1c(O)cccc1O
Reactant: NNC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1ccccc1)c1c(O)cccc1O
Temperature: 120 °C
Yield: 56.3 %

Procedure:
1-(2,6-Dihydroxyphenyl)ethanone (100 mg, 0.657 mmol) and benzohydrazide (89 mg, 0.657 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (100 mg) as a solid. 1H NMR (400 MHz, CD3OD): δ 7.59 (m, 2H), 7.49 (m, 1H), 7.39 (m, 2H), 7.11 (t, 1H, J=8.0 Hz), 6.45 (m, 2H), 2.35 (s, 3H). ESI-MS: 271.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[CH:4][CH:3]=[N:2]1.C(O[CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])C>>[NH:1]1[C:5]([NH:6][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=[N:2]1
Reactant: Nc1ccn[nH]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccn[nH]1)C(=O)OCC
Temperature: 200 °C

Procedure:
A mixture of 1H-pyrazol-5-amine 1 (2 g, 24.1 mmol) and diethyl 2-(ethoxymethylene)malonate (10.4 g, 48.2 mmol) was heated at 200° C. until the starting material was consumed completely. The reaction mixture was allowed to cool to room temperature and EtOH (10 mL) was added. A precipitate formed, which was removed by filtration, washed with EtOH and dried under vacuum to give diethyl 2-((1H-pyrazol-5-ylamino)methylene)malonate; 4.0 g (66%). 1H NMR (300 MHz, CDCl3) δ 10.95 (d, J=13.5 Hz, 1H), 8.60 (d, J=13.8 Hz, 1H), 7.52 (d, J=2.4 Hz, 1H), 6.08 (d, J=2.4 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 4.22 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H).