Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][N:12]([CH2:20][CH:21]([OH:37])[CH2:22][O:23][C:24]2[C:29]3[C:30]4[C:35]([NH:36][C:28]=3[CH:27]=[CH:26][CH:25]=2)=[CH:34][CH:33]=[CH:32][CH:31]=4)CC2C=CC=CC=2)=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OCC)(=O)C>[Pd].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][NH:12][CH2:20][CH:21]([OH:37])[CH2:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[NH:36][C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]=12
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 47.5 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
Benzyl carvedilol (205 g) obtained in step 3 was charged to ethyl acetate (2400 ml) and water (240 ml). The contents were stirred and 10% palladium on carbon (20 g) was added at room temperature. Hydrogen gas was bubbled at room temperature. The temperature was raised to 45-50° C. and bubbling was continued for 8 hours. The reaction mass was filtered to remove the catalyst and the filtrate was concentrated to remove solvent (about 2 L). The contents were chilled to 15-20° C., filtered and washed with chilled ethyl acetate (50 ml) to give carvedilol (140 g) (84%).
Reaction SMILES: [CH3:1][C:2]([S:7][CH3:8])([CH3:6])[CH:3]=[N:4][OH:5].C(N(CC)CC)C.[CH3:16][N:17]=[C:18]=[O:19].P(=O)(O)(O)O>O>[CH3:16][NH:17][C:18]([O:5][N:4]=[CH:3][C:2]([CH3:6])([S:7][CH3:8])[CH3:1])=[O:19]
Reactant: CSC(C)(C)C=NO
Reactant: CN=C=O
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)ON=CC(C)(C)SC
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Into a one liter glass resin kettle equipped with an air-driven stirrer, a pressure-equalizing dropping funnel with Teflon® tube for subsurface addition, a thermometer and a dry ice/acetone cold condenser was added 66.5 grams (0.50 mole) of 2-methyl-2-(methylthio) propionaldehyde oxime (aldicarb oxime) and 266 milliliters of water. After cooling the mixture to a temperature of 5° C. with a water/salt/ice bath, 0.52 grams (0.005 mole) of triethylamine was added to the kettle under a nitrogen atmosphere. A stoichiometric amount of methyl isocyanate (29.5 milliliters, 0.50 mole) was then added over a period of 30 minutes at a temperature of 5° C.-10° C. with vigorous stirring. The water/salt/ice bath was removed and the mixture was stirred for an additional 60 minutes at a temperature of 15° C.-20° C. after which an additional 2.0 milliliters (0.03 mole) of methyl isocyanate was added and the mixture stirred for an additional period of 30 minutes. The water/salt/ice bath was then put back in place and 2.9 grams of phosphoric acid in 10 milliliters of water was added in a slow stream subsurface. The resulting solid product was filtered off on a sintered glass funnel to give 107.1 grams (wet weight) of a fluffy white powder. High pressure liquid chromatographic analysis (internal standard) indicated the following: 76.00 percent 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime (aldicarb) (89percent yield based on aldicarb oxime) and 0.36 percent 2-methyl-2-(methylthio) propionaldehyde oxime (aldicarb oxime); 23.64 percent water content was determined by Karl Fischer titration.
Reaction SMILES: [OH-].[Na+].CS(C)=O.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:16][C:15]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[OH:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A stirred solution of sodium hydroxide (16.8 g) in water (32 mL) at 20° C. is treated with dimethyl sulfoxide (560 mL). It is then treated with 3,4-dihydroxy-benzaldehyde (56.9 g), portionwise during 5 minutes, while keeping the temperature at 20° C. It is then treated with benzyl bromide (49.7 mL), portionwise, at 20° C. The solution is then heated at 80° C. for 6 hours and then allowed to stand at room temperature overnight. After dilution with ice-water (2240 mL) the solution is extracted with diethyl ether (1×1000 mL, 2×250 mL). The combined ether extracts are washed with water, dried over magnesium sulfate and concentrated, to give an oily solid, which is recrystallized from a mixture of ethyl acetate and isopropanol, to give 4-benzyloxy-3-hydroxybenzaldehyde (60.9 g), in the form of pale yellow crystals, m.p. 118°-120° C.
Reaction SMILES: [CH:1]1[C:6](N)=[CH:5][CH:4]=[C:3](N)[CH:2]=1.OO.[OH2:11]>CC(O[Na])=O>[C:1]1([OH:11])[C:6]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(N)cc1
Reactant: O
Agent: CC(=O)O[Na]
Agent: OO
Product: Oc1cccc2ccccc12
Reaction time: 1 h

Procedure:
A 0.5 mg/ml solution of a first compound (p-phenylenediamine, "A") and a 0.5 mg/ml solution of a second compound (1-naphthol, "B") was prepared by dissolving the compound in the appropriate amount of 0.1 M CH3COONa, pH 5.5, buffer. A total volume of 100 ml was used in each LOM beaker. 100 ml "A" was added to one beaker and 50 ml "A" and 50 ml "B" were combined to form 100 ml in a second beaker. Swatches of the material listed above were then wetted in DI water and soaked in the precursor solutions. A Coprinus cinereus peroxidase (CiP) with an activity of 180,000 POXU/ml was added to each beaker at a concentration of 0.05 POXU/ml. Either 200 or 500 μM hydrogen peroxide was added to each LOM beaker. The LOM beakers were sealed and mounted in the LOM. After 1 hour at 42 RPM and 30° C., the LOM was stopped. The spent liquor was poured off and the swatches were rinsed in cold tap water for about 15 minutes. The swatches were dried at room temperature and CIELAB values were measured for all of the swatches using the Macbeth ColorEye 7000. The results are given in Tables 42-45.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[CH:10]([OH:11])[CH2:9][O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:18][CH:19]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)COCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 2-benzyloxy-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].Cl[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1>>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:17][CH:18]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Yield: 42 %

Procedure:
As described for example 5, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (200 mg, 1.06 mmol) was converted using methyl 6-chloronicotinate instead of 6-chloronicotinonitrile to the title compound (SiO2, heptane:ethyl acetate=100:0 to 70:30, 191 mg, 42%) which was obtained as a colourless oil. MS: m/e=325.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]2[C:17]3[N:16]=[CH:15][NH:14][C:13]=3[C:12](=[O:18])[NH:11][C:10]2=[O:19])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([N:14]1[C:13]2[C:12](=[O:18])[NH:11][C:10](=[O:19])[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:17]=2[N:16]=[CH:15]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1[nH]c(=O)n(-c2ccccc2)c2nc[nH]c12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(-c2ccccc2)c2ncn(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.2 g (0.1315 mol) of sodium hydride were added in portions to a suspension of 30 g (0.1315 mol) of 3-phenylxanthine in 600 ml of DMF, the mixture was stirred at 25° C. for 30 minutes and then heated to 80° C. 27 g (0.1578 mol) of benzyl bromide were then added and the solution was left at 80° C. for 6 hours. After cooling to 50° C., the reaction mixture was poured into 2000 ml of ice-water, and the precipitate obtained was filtered off with suction, washed well with water and dried under reduced pressure. The dry residue was crystallized from dioxane/methanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:16](=[O:18])=[O:17]>CN(C)CCN(C)C.CCOCC>[C:11]([O:10][C:9]([NH:8][C:5]1[C:4]([C:16]([OH:18])=[O:17])=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Agent: CN(C)CCN(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Temperature: -15 °C

Procedure:
To 13 g of (6-chloro-pyridin-3-yl)-carbamic acid, tert-butyl ester in 24 mL of tetramethylethylenediamine and 300 mL of ether at −78° C. under an inert atmosphere was added slowly 68 mL of 2.5 M n-butyllithium/hexanes (3 eq). After the addition was complete, the reaction was allowed to warm to −15° C. for two hours then recooled to −78° C. Dry ice was allowed to sublime in a separate flask and the vapor was passed over the rapidly stirred reaction mixture while the cooling bath was removed and the reaction allowed to warm to 0° C. Sufficient water was added to dissolve the precipitated product and the resultant aqueous phase was washed twice with ether before acidifying with concentrated HCl. The precipitate was filtered, washed with water, and dried in vacuo to give 10.9 g of 5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid, which was used as is for the next step: melting point 250° C. and higher (slowly decomposed); mass spectrum (negative mode, m/e): M−H 271.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[CH2:7][N:8]([CH2:14][CH3:15])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10].[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:24]=[C:25]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=2[CH2:7][N:8]([C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH2:14][CH3:15])[C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH3:19]
Reactant: CCN(Cc1cc(Br)ccc1I)C(=O)C1CC1
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: cyclopropanecarboxylic acid(5-bromo-2-iodo-benzyl)-ethyl-amide and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: CC(C(Cl)=O)=C.OCC[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26]CCO)=[CH:22][CH:21]=2)([CH3:19])[CH3:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>CC(C)=O>[OH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)([CH3:19])[CH3:18])=[CH:15][CH:16]=1
Reactant: CC(C)(c1ccc(OCCO)cc1)c1ccc(OCCO)cc1
Agent: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
45 g. of methacryl chloride is slowly added to a mixture of 66.2 g. of 2,2-bis[4-(2-hydroxyethoxy)phenyl]-propane, 41 g. of triethylamine and 300 ml. of dry acetone. The temperature is maintained below 32° C with cooling. The resulting amine hydrochloride is filtered off and washed with acetone. The acetone solution is added to 500 ml. of ice and water, the oily layer recovered and washed with sodium bicarbonate, followed by water, and dried at 40° C. in a vacuum with a stream of air passing through the liquid. The infrared spectrum of the product contains only a very small band indicating hydroxyl hydrogens, a large ester carbonyl band, and a carbon double bond band.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[CH:14]([C:16]1[CH:17]=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19](=[O:26])[N:20]2[C:25]=1[CH:24]=[CH:23][CH:22]=[CH:21]2)=[O:15].[Cl-].[NH4+]>C1(C)C=CC=CC=1.ClCCl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]([OH:15])[C:16]2[CH:17]=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19](=[O:26])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)=[N:3][CH:4]=1
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Reactant: Brc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(O)c2ccc(Br)cn2)c2ccccn2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dibromopyridine (2.00 g, 8.44 mmol) in 50 mL of toluene at −78° C. was added n-butyllithium (2.5 M in toluene, 4.05 mL, 10.1 mmol) dropwise. After 2 h, a solution of ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (1.86 g, 7.60 mmoL) in 50 mL of dichloromethane was added dropwise. The mixture was warmed to rt, and after 1 h, treated with saturated aqueous ammonium chloride and concentrated in vacuo. The residue was redissolved in dichloromethane, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 30-100% ethyl acetate in hexanes to provide ethyl 1-[(5-bromopyridin-2-yl)(hydroxyl)methyl]-4-oxo-4H-quinolizine-3-carboxylate that gave a mass ion (ES+) of 404.7 (81Br) for [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([OH:25])=O)[C:14]3=[O:29])[CH:10]=[N:9]2)=[C:5]([CH3:30])[O:4][N:3]=1.Cl.CN.[CH2:34]([N:36](CC)CC)C.C(Cl)CCl>C(#N)C.Cl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH:36][CH3:34])=[O:25])[C:14]3=[O:29])[CH:10]=[N:9]2)=[C:5]([CH3:30])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C(=O)O)c3)C2=O)cn1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCCl
Solvent: CC#N
Product: CNC(=O)c1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 24.7 %

Procedure:
3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzoic acid (100 mg, 0.24 mmol) (example 10-8), methylamine hydrochloride (67 mg, 1 mmol), triethylamine (155 mg, 1.5 mmol), and EDC (57 mg, 0.3 mmol) in acetonitrile (3 mL) were irradiated in the microwave reactor at 80° C. for 10 minutes. The reaction was cooled, diluted with aqueous 1N HCl (100 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in MeOH (3 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 25 minute gradient) to afford 3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)-N-methylbenzamide (25 mg, 25%) as white solid. MS M+H calculated 423.17; found 423.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]([CH:23]=O)=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:23][C:22]1[C:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)=[N:14][C:15]2[C:20]([C:21]=1[CH:25]([CH3:27])[CH3:26])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CC(C)c1c(C=O)c(-c2ccc(F)cc2)nc2ccccc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1c(C=C(Br)Br)c(-c2ccc(F)cc2)nc2ccccc12
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
A solution of carbon tetrabromide (2.958 gm, 8.92 mmol) in CH2Cl2 (10 ml) was added over a 15 minute period to a cold (-10° C.) solution of 2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinecarboxaldehyde (1.744 gm, 5.95 mmol) (the preparation of which is described in Example 2) and triphenylphosphine (4.680 gm, 17.84 mmol) in CH2Cl2 (34 ml). After the addition was complete, the mixture was stirred for 20 minutes then quenched with saturated NaHCO3 and extracted 3× with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), filtered and stripped to give a yellow-orange oil. The oil was chromatographed (flash, Merck SiO2, 30% CH2Cl2 in hexane followed by 1:1 CH2Cl2 in hexane followed by straight CH2Cl2) to give 3-(2,2-dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)quinoline as a colorless foam (2.572 gm, 96%)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[N-:22][N:21]=1
Reactant: Cc1cc(C)[nH]n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(C)[n-]n1
Reaction time: 0.5 h

Procedure:
After 4.98 g of N-benzyloxycarbonyl-D,L-proline was dissolved in 100 ml of dichloromethane, 2.12 g of 3,5-dimethylpyrazole and 4.5 g of dicyclohexylcarbodiimide were added to the solution. The temperature was reverted to room temperature 30 minutes after the addition and stirring was continued for 20 hours. At the end of the reaction, 0.3 ml of acetic acid was added to the reaction mixture. Insoluble matters were filtered off and the solvent was removed by distillation. The residue was dissolved in a small volume of ethyl acetate. After insoluble matters were filtered off, the filtrate was evaporated to dryness under vacuum to give 6.0 g (yield, 91.7%) of N-benzyloxycarbonyl-D,L-proline-3,5-dimethylpyrazolide.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:10])=[C:4]2[CH:3]=[N:2]1.C1C(=O)N([I:18])C(=O)C1>CN(C)C=O>[I:18][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:10])[NH:1][N:2]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ncnc2[nH]ncc12
Solvent: CN(C)C=O
Product: Nc1ncnc2[nH]nc(I)c12
Temperature: 80 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
To a solution of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (1000 mg, 7.40 mmol) in N,N-Dimethylformamide (DMF) (30 mL) stirred under nitrogen at room temperature was added NIS (1998 mg, 8.88 mmol). The reaction mixture was stirred at 80° C. for 5 h. The reaction was allowed to cool to room temperature. The mixture was concentrated, and NH4OH solution (20 ml) and EtOH (20 ml) were added. The precipitated white solid was filtered and dried to give 1.24 g of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. LC/MS (ES) m/z=261.9 [M+H]+.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:20]>>[CH:3]12[O:20][CH:4]1[CH2:5][CH2:6][N:1]([C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[CH2:2]2
Reactant: O=C(c1ccccc1)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=C(c1ccccc1)N1CCC2OC2C1

Procedure:
The target compounds were synthesized as depicted in Schemes 1-3. The synthesis started with 1,2,3,6-tetrahydropyridine, in which the secondary amine was first protected by reacting with benzoyl chloride to form benzamide 10. The alkenyl double bond of compound 10 was oxidized by meta-chloroperoxybenzoic acid (m-CPBA) to form epoxide 11. The epoxide 11 was refluxed with substituted 4-benzoylpiperidine hydrochloride salts, namely (4-(4′-fluorobenzoyl)piperidine hydrochloride or 4-(4′-methoxybenzoyl)piperidine hydrochloride), in ethanol with triethylamine as the base to afford tertiary amino alcohol intermediates. To improve the yield, commercially available 4′-substituted 4-benzoylpiperidine hydrochloride salts were used in excess and the reaction temperature was kept below 75° C. This reaction afforded (3′-hydroxy-1,4′-bipiperidin-4-yl)(4-substituted phenyl)methanone intermediates and their regioisomers, (4′-hydroxy-1,3′-bipiperidin-4-yl)(4-substituted phenyl)methanone intermediates. The separation of these regioisomers by silica gel chromatography was difficult. The mixture of corresponding regioisomers was reacted with acetic anhydride to convert the free hydroxyl group to the corresponding acetates 12a-d. Subsequently, 12a and 12b were separated easily by silica gel chromatography. To confirm the structures of the regioisomers (12a(c) and 12b(d)), in addition to 1D NMR, 2D NMR was performed for regioisomers, 12c and 12d. The 1H, 13C NMR and HMQC spectra showed δH=5.31/2.68, 3.79/3.12, 2.06/1.47, 3.70, 2.48 and δH=4.89/2.66, 4.09/2.82, 1.95/1.41, 3.43 and 2.41 belong to the CH2-a, CH2-c, CH-d and CH-e (FIG. 2). The exact regioisomer (12a(c) or 12b(d)) were further verified by 1H-1H COSY. For regioisomer 12c, the correlations were observed between δH=5.31 (CH-a)/δH=2.68 (CH-a′) and δH=2.48 (CH-e); δH=3.79 (CH-b)/δH=3.12 (CH-b′) and δH=2.06 (CH-c)/δH=1.47 (CH-c′). In contrast, for regioisomer 12d, δH=4.89 (CH-a)/δH=2.66 (CH-a′) has no correlation with δH=2.41 (CH-e), and δH=4.09 (CH-b)/δH=2.82 (CH-b′) and has no correlation with δH=1.95 (CH-c)/δH=1.41 (CH-c′), but it has correlation with δH=1.95 (CH-c)/δH=1.41 (CH-c′) and δH=1.4I(CH-d).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[CH3:13][C:14](=O)/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19]>CS(C)=O.O.Cl>[CH3:13][C:14]1[NH:12][C:10](=[O:11])[C:9]([C:7]#[N:8])=[C:16]([CH2:17][CH2:18][CH3:19])[CH:15]=1
Reactant: N#CCC(N)=O
Reactant: CCC/C=C/C(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1cc(C)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
To a stirred solution of t-BuOK (1 g, 8.9 mmol) in DMSO (15 mL) at rt, was added compound cyanoacetamide (0.824 g, 9.8 mmol) and (E)-hept-3-en-2-one (1 g, 8.91 mmol). Reaction mixture was stirred for 30 min at rt. Additional t-BuOK (3 g, 26.7 mmol) was added and reaction was stirred at rt in presence of air. On completion, it was diluted with H2O and slowly by 4N HCl. Precipitated solid was filtered, washed with water and dried. Crude product was triturated with ether to afford the title compound (0.5 g, 33%).
Reaction SMILES: O.[OH:2][CH2:3][C:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12]O)[OH:11])O)O)=O.[ClH:14]>C1(C)C=CC=CC=1>[Cl:14][CH2:12][C:10]1[O:11][C:4]([CH:3]=[O:2])=[CH:6][CH:8]=1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(CCl)o1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
150 Ml of toluene was introduced to the same flask as used in Example 1, and while introducing a nitrogen gas with slow stirring of toluene, the temperature of the water bath was set at 75° C. Thereafter, a paste-like liquid prepared by well-mixing 18.0 g of crystalline fructose with 2.2 g of water, and then 20.4 g (one equivalent based on the fed fructose) of MgCl2.6H2O were successively added to the stirred toluene layer. After completion of the addition, stirring was carried out at 400 r.p.m. for about 30 minutes. Thereafter, 31.4 g of 35% hydrochloric acid was added dropwise in 5 minutes from the dropping funnel to the stirred solution. After completion of the dropwise addition, stirring was continued at 400 r.p.m. at 75° C. for 1 hour, at which point heating was stopped and the reaction system was immediately lowered to room temperature (about 25° C.). During that period, stirring was still continued. After standing at room temperature, the post treatment of the solution was carried out in the same manner as in Example 1 and was obtained 12.5 g (yield 86.6%) of 5-chloromethylfurfural as product.