Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([C@@H:4]1[C@@H](CO)O[C@@H](N2C=C(C)C(=S)NC2=O)[CH2:5]1)=[N+]=[N-].C([CH:23]([OH:41])[C@H:24]1[O:28][C@@H:27]([N:29]2[CH:36]=[C:35](I)[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:26][C@@H:25]1[N:38]=[N+:39]=[N-:40])(=O)C.C[Si](C#C)(C)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[N:38]([C@@H:25]1[C@@H:24]([CH2:23][OH:41])[O:28][C@@H:27]([N:29]2[CH:36]=[C:35]([C:4]#[CH:5])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:26]1)=[N+:39]=[N-:40]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=S
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Product: C#Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
The title compound was prepared in a manner analogous to the procedure described in (1). 5'-Acetyl-3'-azido-2',3'-dideoxy-5-iodouridine (0.4 g, 0.94 mMol) was dissolved in anhydrous, deoxygenated triethylamine (50 mL) and treated with trimethylsilyl acetylene (0.37 g, 3.8 mMol), bis(triphenylphosphine)palladium(II)chloride (14 mg), and CuI (14 mg) at 55° C. under N2 for 4 hours. The reaction was evaporated to dryness and the residue dissolved in CHCl3. The CHCl3 was washed with 5% EDTA (2×25 mL) then H2O (1×25 mL) followed by drying over Na2SO4. The CHCl3 solution was filtered and evaporated to a solid which was dissolved in 0.5N NaOCH3 in MeOH (50 mL) at ambient temperature. After 1 hour the solution was neutralized DOW 50 H+, filtered and evaporated in vacuo. The residue was chromatographed on silica gel and eluted with 9:1 CHCl3/MeOH (v/v). Combination and evaporation of the appropriate fractions yields the title compound as a solid, 80 mg(0.29 mMol, 30%): mp=134°-136° C.; UV(nm): at pH 1 λmax=286,225(ε=11300,10700), λmin=251(ε=3100); at pH 13 λmax=282(ε=9700), λmin=255(ε=5000); H NMR(DMSO-d6) δ11.6(s,1H,--NH), 8.26(s,1H,H6), 6.01(t,1H,H1',J=6.01 Hz), 5.35-5.30(m,1H,5'OH), 4.4-4.3(m,1H,H3'), 4.08(s,1H,C CH), 3.85-3.80(m,1H,H4'), 3.7-3.6(m,2H,H5'), 2.5-2.3(m,2H,H2').
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][CH2:11][C:12]([NH2:14])=O)[C:4]=2[CH2:3][CH2:2]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.C(=O)([O-])O.[Na+]>[O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][CH2:11][C:12]#[N:14])[C:4]=2[CH2:3][CH2:2]1
Reactant: NC(=O)CCc1nccc2c1CCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CCCc1nccc2c1CCO2
Temperature: 25 °C
Reaction time: 0.22 h
Yield: 33.5 %

Procedure:
To a solution of 3-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)propanamide (435 mg, 2.26 mmol) in dichloromethane (10 mL) were added pyridine (384 μL, 4.75 mmol) and trifluoroacetic anhydride (384 μL, 2.72 mmol), and the mixture was stirred at room temperature for 13 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=30/70→70/30) to give the title compound (132 mg, yield 33%).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:12])=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)OC2
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C1OCc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
A solution of 6-methoxy-3H-isobenzofuran-1-one (50 g, 0.3 moles), prepared as described in example 34, in CH2Cl2 (250 ml) under N2 at −5° C., was dropwise added with BBr3 (360 ml, 0.36 moles). At the end of the addition the solution was stirred at room temperature overnight, then cooled and added with further BBr3 (60 ml, 60 mmoles). The stirring was kept on for 4 hours at room temperature. The mixture was cooled and added with CH3OH (250 ml), then dried under vacuum to give a solid which was triturated in ethyl ether and washed with ethyl ether and ethyl acetate. After drying under vacuum at 40° C. a solid was obtained which was joined to the solid yielded by drying the mother liquors, discolouring and triturating in ethyl ether. There were obtained 33.51 g of the title compound (yield: 73%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:28](O)(=[O:32])[CH2:29][CH:30]=[CH2:31].N(C(OCC)=O)=NC([O-])=O>CCOCC>[C:28]([O:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:32])[CH2:29][CH:30]=[CH2:31]
Reactant: C=CCC(=O)O
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: C=CCC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
138 g (535 mmol) Triphenylphosphine and 84 ml (812 mmol) benzyl alcohol were added dropwise to 46 g (535 mmol) 3-butenoic acid dissolved in 500 ml ether and 87 ml (535 mmol) ethyl azodicarboxylate and the mixture stirred for 7 hours and allowed to stand overnight. After evaporation of the solvent, the residue was purified by column chromotography (silica gel, hexane/ethyl acetate=95:5) and a sample analysed by thin layer chromatography (hexane:ethyl acetate=1:1) (Rf=0.61).
Reaction SMILES: [H-].[Na+].C(O)C.[CH3:6][SH:7].Br[CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([N+:18]([O-:20])=[O:19])=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:14]=2[CH:27]=1>O>[CH3:6][S:7][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([N+:18]([O-:20])=[O:19])=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:14]=2[CH:27]=1
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Reactant: CS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSCc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
To a stirred mixture of 1.4 g. of sodium hydride in 150 ml. of ethanol is added 6 ml. of methyl mercaptan, then 6.6 g. (0.02 mole) of 5-bromomethyl-2-nitro-3-phenylbenzofuran. After four hours the mixture is poured into cold water, this mixture is extracted with diethyl ether, the extracts are washed with 5 percent sodium hydroxide solution, water and saturated sodium chloride solution, then dried. Evaporation provides yellow 5-methylthiomethyl-2-nitro-3-phenylbenzofuran. The structural assignment is supported by infrared spectral analysis.
Reaction SMILES: [C:1]1(=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[N:11]O.[C:14](O)(=[O:16])[CH3:15]>C(OC(=O)C)(=O)C.[Zn]>[O:13]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[NH:11][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)O
Reactant: O=C1C(=NO)CCc2ccccc21
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC1CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
Zinc powder (24 g, 367 mmol) was added to a solution of 3,4-dihydro-[1,2]naphthoquinone 2-oxime (21.5 g, 123 mmol) in acetic acid (200 mw) and acetic anhydride (150 ml), and the solution was stirred at room temperature for 12 hours. After filtration and removal of the solvents under reduced pressure, the residue was partitioned between water and chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was washed with ethyl acetate and dried to afford N-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (16.5 g, 81 mmol, 66%) as brown crystals.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:27][C:26]([CH2:28]O)=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[S:27][C:26]([CH2:28][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[CH:25][CH:24]=1
Reactant: OCc1ccc(Cl)s1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)s4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 3.2 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chloro-2-thienyl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (7 mg) as a white solid.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>CCO>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: C1CCNC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCCC1)OC2
Temperature: 130 °C
Yield: 76.3 %

Procedure:
A mixture of 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (0.5 g, 1.63 mmol), pyrrolidine (2.0 ml, 24.0 mmol) and EtOH (4.0 ml) was heated in a micro wave oven at 130° C. for 30 min. The mixture was evaporated to dryness. The residue was chromathographed on a silica column using EtOAc/MeOH (10:1) as eluent, affording the title compound (0.37 g, 76%). The title compound (0.26 g) was converted into the hydrochloric acid salt and crystallized from EtOH/DEE. M.p. 199° C. 1H-NMR (400 MHz, MeOH): δ 7.49 (1H, dd, J 18 Hz, J 21.6 Hz), δ 7.40 (1H, d, J 1.6 Hz), δ 7.31 (1H, d, J 8 Hz), 5.29 (1H, t, J 4.4 Hz), δ 5.03 (2H, dd, J 56 Hz, 16 Hz), δ 3.1 (3H, s), 2.92 (2H, m), δ 2.70 (4H, m), δ 1.83 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]([N+:15]([O-])=O)=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7]>[Ni].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]([NH2:15])=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c(OC)cc1N
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
In an hydrogenating autoclave, there are placed 144 g of methyl 3,4-dimethoxy-6-nitro-benzoate, 300 ml of tetrahydrofuran and 3 coffee spoonfuls of Raney nickel. Hydrogenation occurs at about 35°C. In 20 minutes, the pressure drop is 80 kg. It is cooled, the nickel filtered, and the tetrahydrofuran removed under vacuum. There are obtained 123 g (97%) of methyl 3,4-dimethoxy-6-aminobenzoate. (m.p.: 130°C).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20].O1CCC[CH2:22]1.[H-].[Na+].IC>C(OCC)C>[CH3:20][O:19][CH:3]1[CH:2]([O:1][CH3:22])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:10]1([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]1
Reactant: C1CCOC1
Reactant: COC1C(O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Product: COC1CCC2(CO2)C(C2(C)OC2CC=C(C)C)C1OC

Procedure:
To a solution of 6-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (14.1 mg) in freshly distilled tetrahydrofuran (0.5 ml) was added sodium hydride (60% oil dispersion, 2.0 mg) in one portion in an ice bath. The suspension was stirred for half an hour at the same temperature and thereto iodomethane (71 mg) was added. After stirring for 2 hours at ambient temperature, the mixture was diluted with diethyl ether and washed with water. The organic layer was dried and evaporated to give a crude oil which was purified by column chromatography on silica gel eluted by a mixture of diethyl ether and n-hexane (1:2) to yield 5,6-dimethoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (14.2 mg) as an oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([O:16][CH:17]([F:19])[F:18])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[N:12]2)=[CH:7][CH:6]=1)C.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[F:19][CH:17]([F:18])[O:16][C:15]1[N:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][CH:9]=2)[N:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=1
Reactant: CCOC(=O)c1ccc(-n2nc(C(F)(F)F)cc2OC(F)F)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCc1ccc(-n2nc(C(F)(F)F)cc2OC(F)F)cc1
Yield: 112.1 %

Procedure:
A solution of 4-(5-difluoromethoxy-3-trifluoromethyl-pyrazol-1-yl)-benzoic acid ethyl ester (0.4 g, 1.1 mmol) in dry toluene (8.0 mL) was stirred and 1 M solution of DIBAL-H in toluene (1.33 mL, 1.33 mmol) was added. The resultant solution was stirred at room temperature for 10 minutes. The mixture was quenched with saturated aqueous NH4Cl (40 mL) and extracted with EtOAc (3×40 mL). The organics were washed with water and brine. The solvent was removed under reduced pressure and purification of the resulting residue by chromatography (SiO2, 10:1 Hexane/EtOAc) gave [4-(5-difluoromethoxy-3-trifluoromethyl-pyrazol-1-yl)-phenyl]-methanol (380 mg, 99% yield) as a syrup.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-].C([O-])(=O)C>ClCCCl.C1C=CC=CC=1>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: c1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R, 3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.5 g) in 1,2-dichloroethane (10 ml) was added rhodiim(II) acetate (2 mg) under refluxing. After refluxing for 30 minutes, the reaction mixture was cooled and evaporated in vacuo to give a residue. The residue was dissolved in anhydrous benzene (10 ml) and then evaporated. This operation was repeated once again and the residue was dried in vacuo to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The compound obtained above was dissolved in anhydrous acetonitrile (10 ml) and cooled to 0° C. under an atmosphere of nitrogen. To this solution were added N,N-diisopropyl-N-ethylanine (0.27 ml) and diphenyl phosphorochloridate (0.28 ml) successively, and the solution was stirred at 0° C. for 40 minutes. To the resulting solution were added dropwise a solution of (2S,4S)-2-(difluoromethyl)thiomethyl-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.54 g) in anhydrous acetonitrile (3 ml) and N,N-diisopropyl-N-ethylamine (0.29 ml) at 5° C. with stirring, and the stirring was continued at the same temperature for 2 hours. To the reaction mixture was added ethyl acetate (30 ml). The solution was washed twice with saturated aqueous sodium chloride (20 ml), dried over anhydrous magnesium sulfate and evaporated. The oily residue was chromatographed on silica gel (60 g) eluting with a mixture of dichloromethane and acetone (5:1,V/V) to give 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(difluoromethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.58 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:3]=1[C:14](=[O:16])[CH3:15].[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19]1>>[C:14]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]2[N:25]=[C:26]3[C:21]([CH2:20][CH2:19][C:18](=[O:17])[NH:27]3)=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)(=[O:16])[CH3:15]
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: CC(=O)c1c(F)cccc1N1CCNCC1
Product: CC(=O)c1c(F)cccc1N1CCN(CCCCOc2ccc3c(n2)NC(=O)CC3)CC1

Procedure:
In a manner similar to that of other examples above, 1-(2-fluoro-6-piperazin-1-yl-phenyl)-ethanone was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 441.3 (Exact Mass: 440.22).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][O:5][C:4]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3S[CH2:13][C:3]1=2.CC(C1C=CC2SCC3C(=O)C(C=O)=C[O:29]C=3C=2C=1)CC.C(C1C=CC2SCC3C(=O)C(C=O)=COC=3C=2C=1)CCC.CC1C2C(=O)C(C=O)=COC=2C2C=CC=CC=2S1.C(C1C2C(=O)C(C=O)=COC=2C2C=CC=C(C)C=2O1)C.[N+](C1C=CC2C3[O+]([O-])C=C(C=O)C(=O)C=3CSC=2C=1)([O-])=O.C(OC1C2C3[O+](=O)([O-])C=C(C=O)C(=O)C=3C(C)SC=2C=CC=1)C.C(C1C2C(=O)C(C=O)=COC=2C2C=CC(C(F)(F)F)=CC=2O1)CC.BrC1C2SC(C(C)C)C3C(=O)C(C=O)=COC=3C=2C=CC=1.C(OC1C=CC2C3OC=C(C=O)C(=O)C=3CSC=2C=1)CCC.C(C1C2C(=O)C(C=O)=COC=2C2C=C(CCCCCC)C=CC=2O1)CCC>>[O:1]=[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][O:5][C:4]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[O:29][CH2:13][C:3]1=2
Reactant: O=Cc1coc2c(c1=O)CSc1ccccc1-2
Reactant: CCC(C)c1ccc2c(c1)-c1occ(C=O)c(=O)c1CS2
Agent: CC(C)C1Sc2c(Br)cccc2-c2occ(C=O)c(=O)c21
Agent: CC1Sc2ccccc2-c2occ(C=O)c(=O)c21
Agent: CCC1Oc2c(C)cccc2-c2occ(C=O)c(=O)c21
Product: O=Cc1coc2c(c1=O)COc1ccccc1-2

Procedure:
In the same manner but replacing 3-acetyl-4-thiochromanone boron difluoride complex with an equivalent amount of another compound of formula V described in Example 1, the following compounds of formula VI are obtained respectively: 4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-3-carboxaldehyde, mp 141°-143° C., 9-(1-methylpropyl)-4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-3-carboxaldehyde, mp 94°-96° C., 9-butyl-4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-3-carboxaldehyde, mp 103°-105° C., 5-methyl-4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-3-carboxaldehyde, 6-chloro-4-oxo-4H,5H-[1]benzopyrano[4,3-b]pyran-3-carboxaldehyde, 5-ethyl-7-methyl-4-oxo-4H,5H-[1]benzopyrano[4,3-b]pyran-3-carboxaldehyde, 8-nitro-4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-3-carboxaldehyde-1 -oxide, 10-ethoxy-5-methyl-4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-3-carboxaldehyde-1,1-dioxide, 5-propyl-8-trifluoromethyl-4-oxo-4H,5H-[1]benzopyrano[4,3-b]pyran-3-carboxaldehyde, 7-bromo-5-(1-methylethyl)-4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-3-carboxaldehyde, 8-butoxy-4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-3-carboxaldehyde and 5-butyl-9-hexyl-4-oxo-4H,5H-[1]benzopyrano[4,3-b]pyran-3-carboxaldehyde.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]=12.Cl.[NH2:23]O>>[CH2:20]([N:17]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:23][O:16][C:8]=3[C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)[C:3]=2[CH:19]=[N:18]1)[CH3:21]
Reactant: NO
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccc(C)cc3)cnc21
Agent: Cl
Product: CCn1ncc2c3noc(-c4ccc(C)cc4)c3cnc21
Reaction time: 2 h
Yield: 60.7 %

Procedure:
4-Chloro-1-ethyl-5-(4-methylbenzoyl)-1H-pyrazolo[3,4-b]pyridine (4.40 g) and hydroxylamine hydrochloride (14.0 g) were mixed dry and then suspended in a solution prepared from 200 ml of glacial acetic acid and 5 ml of concentrated hydrochloric acid. The reaction mixture was then brought to reflux with mechanical stirring. After two hours, the reaction was allowed to cool and then the acetic acid was evaporated. The residue was distributed between dichloromethane and an aqueous sodium bicarbonate solution and then the organic phase was dried and evaporated. The crude product was chromatographed over 230-400 mesh silica gel (10% ethyl acetate/dichloromethane). The appropriate fractions were combined, evaporated, and then washed with pentane, giving 2.48 g of product, mp 221°-222° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.[H-].[Na+].I[CH3:15]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]([CH3:15])[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)ncn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
In an oven dried nitrogen purged 3 neck 50 mL round bottom flask, 5.00 g (37.75 mmol) of 5-methoxybenzimidazole in 20 mL of dry dimethylformamide is reacted with 1.66 g (41.53 mmol) of sodium hydride at room temperature for 4 h. 2.58 mL (41.53 mmol) of iodomethane is added and reaction is allowed to stir at room temperature overnight. Reaction is quenched with water, layers are separated, extracted aqueous 3×50 mL ethyl acetate, dried (MgSO4), and concentrated. The crude mixture is purified by chromatography using dichloromethane: methanol as a solvent system. Product containing fractions are combined to obtain 3.50 g of the title compound which is used as is, 57% yield.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH2:4][CH:5]1[CH2:8][CH:7]([C:9]([O:11]CC)=[O:10])[CH:6]1N1CCCCC1)[CH3:2].C1(C)C=CC(S(OC)(=O)=O)=CC=1>O>[CH2:20]([CH:3]([CH2:1][CH3:2])[CH2:4][CH:5]1[CH2:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6]1)[CH3:21]
Reactant: CCOC(=O)C1CC(CC(CC)CC)C1N1CCCCC1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: O
Product: CCC(CC)CC1C=C(C(=O)O)C1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 47.9 %

Procedure:
Ethyl 3-(2-ethylbutyl)-2-piperidin-1-ylcyclobutanecarboxylate (132 g) and methyl p-toluenesulfonate (41.0 mL) were mixed. The mixture was stirred at 100° C. for 3.5 hr. After an addition of water (70 mL), the mixture was washed with tert-butyl methyl ether/heptane=1/1 (120 mL). To the aqueous layer was added aqueous 8 N potassium hydroxide (140 mL). The mixture was stirred at 105° C. for 3 hr. The reaction mixture was washed with tert-butyl methyl ether (150 mL). The organic layer was extracted with water (50 mL). To the combined aqueous layer was added concentrated hydrochloric acid (105 mL) at ice temperature. The aqueous layer was extracted with ethyl acetate (250 mL×2). The combined organic layer was washed with water (100 mL) and brine (100 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (39.0 g) as a crude product.
Reaction SMILES: [F:1][C:2]([F:25])([C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:3]#[C:4]C(C)(O)C.[OH-].[Na+]>>[F:1][C:2]([F:25])([C:9]([F:23])([F:24])[C:10]([F:21])([F:22])[C:11]([F:19])([F:20])[C:12]([F:17])([F:18])[C:13]([F:16])([F:15])[F:14])[C:3]#[CH:4]
Reactant: CC(C)(O)C#CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: C#CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 100 °C

Procedure:
A flame-dried 50 mL round-bottom flask equipped with distillation apparatus was charged with 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-2-methyldec-3-yn-2-ol (S1) (35.3 g, 88 mmol) and NaOH pellets (2.5 g, 61 mmol) under argon. The pressure was reduced to 400 mmHg and the flask was heated to 100° C. The crude product was collected over an hour in a receiving flask in a brine/ice bath. The product was washed 3 times with distilled water and was subsequently dried over MgSO4. Removal of drying agent via filtration gave S2 (13.4 g, 46%) as a clear liquid. B.p. 92-94° C. 1H NMR (300 MHz, CDCl3): δ 3.07 (t, JH-F=5.7 Hz, 1H). 19F NMR (282 MHz, CDCl3): δ −126.69 (2F), −123.39 (2F), −123.25 (2F), −121.83 (2F), −99.76 (2F), −81.33 (3F).