Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[K+:17].[S:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([O-])=O)=[CH:24][CH:23]=1)([OH:21])(=[O:20])=[O:19].[OH-].[K+].C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>O>[K+:17].[CH2:13]([N:4]1[C:3](=[O:16])[C:2]2[NH:1][C:26]([C:25]3[CH:24]=[CH:23][C:22]([S:18]([O-:21])(=[O:20])=[O:19])=[CH:30][CH:29]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH2:10][CH3:11])[C:5]1=[O:12])[CH2:14][CH3:15]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C([O-])c1ccc(S(=O)(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)[O-])cc3)nc2n(CCC)c1=O
Yield: 17 %

Procedure:
A mixture of 5,6-diamino-1,3-dipropyl-2,4-(1H,3H)pyrimidinedione (16.0 g, 0.07 moles), 4-sulfobenzoic acid monopotassium salt (17.0 g, 0.0707 moles) and water (250 ml) is prepared, and the pH adjusted to 5.0 by the addition of 10% potassium hydroxide. To this solution is added ethyl-3-(3-dimethylaminopropyl)carbodiimide (13.6 g, 0.0707 moles) in one portion, and the pH maintained at 5.0±0.5 by the dropwise addition of 4 N hydrochloric acid. When the pH stabilizes, the reaction mixture is treated with sodium hydroxide (100 ml, 50%), boiled under reflux for ten minutes, treated with activated carbon, and filtered warm. The resulting solution is chilled in ice, treated with hydrochloric acid (12 N, 1350 ml), and filtered. The solids are dried, recrystallized from methanol, and dried at 78° to yield 5.12 grams of 4-(1,3-dipropyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid potassium salt, mp greater than 360°.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][CH:45]=[C:44]([NH:49][C:50]([CH3:57])([CH3:56])[CH2:51][C:52]([CH3:55])([CH3:54])[CH3:53])[N:43]=1>C(Cl)(Cl)Cl>[F:48][C:47]1[C:42]([N:41]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)=[N:43][C:44]([NH:49][C:50]([CH3:57])([CH3:56])[CH2:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[CH:45][CH:46]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: CC(C)(C)CC(C)(C)Nc1ccc(F)c(N)n1
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)CC(C)(C)C)ccc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To 3 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.84 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 0.75 g of 2-amino-3-fluoro-6-(1,1,3,3-tetramethylbutylamino)pyridine. The solution was concentrated under reduced pressure, and to the residue were added 0.65 g of anhydrous potassium carbonate and 1.5 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 1 hour and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 0.45 g of the title compound as a pale yellow powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl-].[NH4+]>CO.[Zn]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2])=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
Step B To a solution of 2-(tert-butyldimethylsilyloxy)-1-(4-nitrophenyl)ethanone (0.54 g, 1.83 mmol) in methanol (60 mL) was added an aqueous solution (15 mL) of ammonium chloride (0.98 g, 18.3 mmol), followed by the addition of Zinc (1.2 g, 18.3 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to a small volume, then when partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated to give 1-(4-amino-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-ethanone as a white foam (0.4 g, 82%)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[O:23][C:22]([C:24]3[CH:33]=[CH:32][C:27]([C:28](OC)=[O:29])=[CH:26][CH:25]=3)=[N:21][N:20]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[N:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.CC(C[AlH]CC(C)C)C.Cl.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[C:3]([C:19]2[O:23][C:22]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][OH:29])=[CH:32][CH:33]=3)=[N:21][N:20]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nnc(-c3nc(-c4ccc(C(=O)N(C)C)cc4)cnc3N)o2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CO)cc4)o3)n2)cc1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 9.4 %

Procedure:
Methyl 4-[5-[3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]benzoate (154 mg, 0.3465 mmol) in dry THF (1.5 mL) was cooled in ice-bath then treated dropwise with DIBAL (346.5 μL of 1 M solution in hexanes, 0.3465 mmol). The resulting mixture was stirred 0-20° C. over 90 min and then at room temperature overnight. Additional DIBAL (1.732 mL of 1 M solution in hexanes, 1.732 mmol) was added at room temperature. The reaction mixture was poured onto water (10 mL) and acidified with 2M HCl, adjusted to pH 10 with aq NaOH solution and extracted EtOAc (6×10 mL) to give an orange solid. This was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were combined and passed through a bicarbonate cartridge. The eluent was concentrated in vacuo and taken up in acetonitrile and water and lypholised to leave the product as a yellow powder (13.1 mg, 33% yield); 1H NMR (400 MHz, DMSO) d 2.18 (s, 6H), 4.64 (s, 2H), 5.43 (br s, 1H), 4.43-4.45 (m, 2H), 7.65-7.63 (m, 2H), 7.69 (br s, 2H), 8.05-8.30 (m, 4H) and 8.92 (s, 1H) ppm; MS (ES+) 403.18
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH:22]=1>C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH:9]2[CH2:10][CH2:11][N:12]([C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(CC2CCNCC2)c2ccccc2)cc1
Reactant: O=C(O)CCCc1cccnc1
Solvent: Cc1ccccc1
Product: O=C(CCCc1cccnc1)N1CCC(CC(c2ccccc2)c2ccccc2)CC1

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of Example 10 starting with 5.3 g of 4-(2,2-diphenylethyl)piperidine free base and the acid chloride prepared from 5.0 g of 3-pyridine butanoic acid, there was obtained 7.0 g of oil from the toluene extracts. Crystallization from methylene chloride/ether provided 6.3 g (76%) of 4-(2,2-diphenylethyl)-1-[1-oxo-4-(3-pyridinyl)butyl]piperidine, mp 98°-100° C. Analysis Calculated for C28H32N2O: C, 81.51; H, 7.82; N, 6.79. Found: C, 81.43; H, 7.88; N, 6.53.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)C(N=[N+]=[N-])=O)([O-:3])=[O:2].S(=O)(=O)(O)O.[NH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[NH2:23])([O-:3])=[O:2]
Reactant: N
Reactant: [N-]=[N+]=NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
The 3,5-dinitrobenzoyl azide thus obtained (5 g., 0.021 mol) was heated gently in 20 ml. of concentrated sulfuric acid until nitrogen evolution was complete. The resulting solution was poured over 200 ml. of ice/water and then made basic to pH 10 with concentrated aqueous ammonia solution. The solid was filtered to give 3,5-dinitroaniline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([S:18]([CH3:21])(=[O:20])=[O:19])=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=2)[C:9]1=[O:47].[F-].[NH4+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([S:18]([CH3:21])(=[O:20])=[O:19])=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][OH:29])[CH:23]=2)[C:9]1=[O:47]
Reactant: CC(C)(C)[Si](OCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(S(C)(=O)=O)nc32)c1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CO)c1)C(=O)N(c1ccccc1Br)C2
Yield: 95.5 %

Procedure:
A solution of 400 mg (0.55 mmol) of 3-(2-bromophenyl)-1-[3-(tert-butyldiphenylsilyloxymethyl)phenyl]-3,4-dihydro-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one in 30 ml of methanol was treated with 400 mg (11 mmol) of ammonium fluoride and the mixture heated at reflux for 1 hour. The mixture was evaporated and the product purified by flash chromatography on silica gel eluting with dichloromethane/methanol in a ratio of 20:1. The product-containing fractions were combined and evaporated to afford 257 mg (96%) of 3-(2-bromophenyl)-3,4-dihydro-1-[3-(hydroxymethyl)phenyl]-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid. [Mass spectrum (ESI) MH+ =490].
Reaction SMILES: [Cl:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14]O>>[Cl:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CO
Reactant: COc1cc(Cl)c(I)cc1C(=O)O
Product: COC(=O)c1cc(I)c(Cl)cc1OC
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 4-chloro-5-iodo-2-methoxybenzoic acid (2 g, 6.41 mmol) concentrated sulfuric acid (1.5 mL) in MeOH (50 mL) was stirred at reflux for 16 h. The mixture was allowed to cool to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to afford the desired product (1.85 g, 85% yield) as a yellow oil.
Reaction SMILES: [C:1]([N:4]1C2C=CC=CC=2C2C1=CC=CC=2)(=[O:3])[CH3:2].Cl[C:18]1[CH:19]=[CH:20][C:21]2[NH:22][C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][C:26](Cl)=[CH:25][CH:24]=3>C(O)C>[C:1]([NH:4][C:20]1[C:21]2[NH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:18][CH:19]=1)(=[O:3])[CH3:2]
Reactant: Clc1ccc2[nH]c3ccc(Cl)cc3c2c1
Reactant: CC(=O)n1c2ccccc2c2ccccc21
Solvent: CCO
Product: CC(=O)Nc1cccc2c1[nH]c1ccccc12

Procedure:
Condensation of cyclohexane-1,4-dione 2 with phenylhydrazine 1 in ethanol affords the bishydrazone 3. Treatment of 3 with sulfuric acid and acetic acid produces 3-aminocarbazole 4 (Tetrahedron 2003, 59, 1265).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([O:14][CH3:15])=[O:13])=[C:6]2[C:10]=1[O:9][C:8](=S)[NH:7]2.P(Cl)(Cl)(Cl)(Cl)[Cl:17].P(Cl)(Cl)(Cl)=O>>[Cl:17][C:8]1[O:9][C:10]2[C:6](=[C:5]([C:12]([O:14][CH3:15])=[O:13])[CH:4]=[CH:3][C:2]=2[F:1])[N:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(F)c2oc(=S)[nH]c12
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(F)c2oc(Cl)nc12
Temperature: 95 °C
Yield: 99 %

Procedure:
A mixture of methyl 7-fluoro-2-thioxo-2,3-dihydrobenzoxazole-4-carboxylate (1.3 g, 5.72 mmol) and phosphorus pentachloride (1.2 g, 5.72 mmol) in phosphorus oxychloride (2.6 mL, 10.25 mmol) was heated to 95° C. for 3.5 h. After cooling to room temperature, the reaction mixture was concentrated and dried under vacuum to afford methyl 2-chloro-7-fluorobenzoxazole-4-carboxylate (1.3 g, quantitative) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 8.08-8.04 (m, 1H), 7.21 (t, J=9.3 Hz, 1H), 4.02 (s, 3H); MS (ESI+) m/z 229 (M+H).
Reaction SMILES: [ClH:1].[F:2][C:3]([F:18])([F:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=CC=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[S:19](C(C)C(=O)C)[C:20]#[N:21]>>[ClH:1].[CH3:16][C:11]1[N:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][CH:8]=2)[C:20](=[NH:21])[S:19][C:12]=1[CH3:13]
Reactant: FC(F)(F)c1ccc(Nc2ccccc2)cc1
Reactant: CC(=O)C(C)SC#N
Agent: Cl
Product: Cc1sc(=N)n(-c2ccc(C(F)(F)F)cc2)c1C

Procedure:
The title compound was prepared from 4-trifluoromethylphenylaniline hydrochloride and 3-thiocyano-2-butanone as described for Example 160A.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[OH:15])=[N+:2]=[N-:3].O=[C:17]([CH3:23])[CH2:18][C:19]([O:21]C)=[O:20].[O-]CC.[Na+].[OH-].[Na+]>C(O)C>[CH2:11]([NH:10][C:8]([C:7]1[CH:13]=[CH:14][C:4]([N:1]2[C:17]([CH3:23])=[C:18]([C:19]([OH:21])=[O:20])[N:3]=[N:2]2)=[C:5]([OH:15])[CH:6]=1)=[O:9])[CH3:12]
Reactant: COC(=O)CC(C)=O
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])c(O)c1
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2C)c(O)c1
Temperature: 60 °C
Reaction time: 9 h
Yield: 55 %

Procedure:
To a solution of 4-azido-N-ethyl-3-hydroxybenzamide (0.41 g) obtained in Example 133b) and methyl 3-oxobutanoate (0.27 ml) in ethanol (10 ml) was added 28% sodium ethoxide in ethanol solution (1.0 ml) at room temperature, and the mixture was stirred overnight and at 60° C. for 9 hr. After allowing to cool to room temperature, 1N aqueous sodium hydroxide solution (4.0 ml) was added to the reaction mixture and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained residue was diluted with water. The obtained aqueous solution was washed with ethyl acetate, acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product of the title compound as a brown solid (0.32 g, 55%). The obtained crude product was used for the next reaction without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][O:17][C:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Product: COc1ccc2ccc(-c3ccccc3)cc2c1

Procedure:
The title compound was prepared by reacting 7-methoxy-2-naphthyl trifluoromethanesulfonate (3.01 g, 9.83 mmol) with phenylboronic acid (1.4 g, 12 mmol) according to method A to yield 1.95 g (85%) of a white solid mp 62-64° C.; 1H NMR (CDCl3) δ 3.95 (3H, s), 7.15 (1H, dd, J=2.56 Hz, J=8.79 Hz), 7.20 (1H, d, J=2.56 Hz), 7.36-7.39 (1H, m), 7.46-7.50 (2H, m), 7.60 (1H, dd, J=1.83 Hz, J=8.42 Hz), 7.70-7.73 (2H, m), 7.76 (1H, d, J=8.79 Hz), 7.84 (1H, d, J=8.42 Hz), 7.94 (1H, d, J=1.46 Hz); MS (EI) m/z 234 (M)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1)[CH3:2].C([Li])(C)(C)C.[CH3:15][C:16]1([CH3:47])[CH:25]=[C:24](OS(C(F)(F)F)(=O)=O)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:35][C:36]3[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=3)[CH:22]=2)[O:17]1>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:35][C:36]4[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=4)[CH:22]=3)[O:17][C:16]([CH3:15])([CH3:47])[CH:25]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)O3)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)O3)cc1
Temperature: 25 °C

Procedure:
A solution of 4-ethylbromobenzene (280.0 mg, 1.51 mmol) in 3.0 mL of THF was cooled to -78° C. and tert-butyllithium (198.6 mg, 3.10 mmol, 1.9 ml of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (408.0 mg, 3.10 mmol) in 5.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 4-(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-chromen-6-ylethynyl)-benzoate (Compound 264, 150.0 mg, 0.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (24.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. This solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 123.0 mg (91%), was isolated by column chromatography (2.5% EtOAc/hexanes) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.00 (2H, d, J=8.4 Hz), 7.52 (2H, d, J=8.4 Hz), 7.36 (1H, dd, J=2.0, 8.3 Hz), 7.31-7.25 (5H, m), 6.88 (1H, d, J=8.3 Hz), 5.65 (1H, s), 4.38 (2H, q, J=7.1 Hz), 2.73 (2H, q, J=7.6 Hz), 1.52 (6H, s), 1.41 (3H, t, J=7.1 Hz), 1.31 (2H, t, J=7.6 Hz).
Reaction SMILES: [N+:1]([C:4]1[C:9](OC)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=[O:2].[NH2:12][NH2:13].O>CN(C=O)C>[CH:7]1[CH:6]=[N:5][C:4]2[N:1]([OH:2])[N:12]=[N:13][C:9]=2[CH:8]=1
Reactant: COc1cccnc1[N+](=O)[O-]
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: On1nnc2cccnc21
Reaction time: 24 h
Yield: 52.1 %

Procedure:
To 13.58 g of 2-nitro-3-methoxypyridine was added 26.4 mL of 95% hydrazine, 10.4 mL of water and 15.3 mL of DMF. The mixture was carefully warmed to about 70° on a hot plate. Spontaneous warming then set in, the temperature rising to about 80° as the solid dissolved. The solution was set aside for 24 hr and then evaporated from a water bath with the aid of a water aspirator to remove excess hydrazine and water. The dark green residue was cooled in an ice bath, diluted with 50 mL of water and acidified to Congo Red with concentrated hydrochloric acid (ca. 17 ml). A yellow-straw-colored solid separated and was filtered and washed with a little cold water to give 6.25 g (52.1%) of HOAt upon recrystallization from 75 mL of water gave 5.46 g (45.5%) of nearly colorless crystals, mp 216°-217° 1H NMR (CDCl3 -DMSO-d6): δ7.35 (dd, 1, β-H), 8.3 (dd, 1, γ-H), 8.66 (dd, 1, α-H); Jα,β =4.2 Hz, Jβ, γ=8.2 Hz, Jα, γ=1.6 Hz. Evaporation of the filtrate gave an additional 0.14 g of the pure hydroxy compound so the total yield was 5.6 g (46.7%).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([O:8][C:9]([C:11]1([CH3:35])[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=2[O:33]C)[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])[CH2:13][CH2:12]1)=[O:10])[CH:6]=[CH2:7].[Cl-].[NH4+]>C(Cl)Cl>[CH2:5]([O:8][C:9]([C:11]1([CH3:35])[CH2:12][CH2:13][CH:14]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=2[OH:33])[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])[CH2:15][CH2:16]1)=[O:10])[CH:6]=[CH2:7]
Reactant: C=CCOC(=O)C=Cc1ccc(OC)c(OCC2CCC(C)(C(=O)OCC=C)CC2)c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C=CCOC(=O)C=Cc1ccc(O)c(OCC2CCC(C)(C(=O)OCC=C)CC2)c1
Yield: 38.4 %

Procedure:
At -78° C., 0.3 ml of boron tribromide was added to a solution of 0.7 g of allyl 3-[1-(4-allyloxycarbonyl-4-methylcyclohexyl)methoxy]-4-methoxycinnamate (Example 47) in 10 ml of methylene chloride. The solution was reacted for 20 minutes in this state. After reaction, 20 ml of an aqueous ammonium chloride solution was added to the reaction solution. The solution was extracted three times with 30 ml of ethyl acetate. The oily substance obtained was washed three times with an aqueous sodium chloride solution and was dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo, yielding 0.26 g of allyl 3-{1-[4-(allyloxycarbonyl)-4-methylcyclohexyl]methoxy}-4-hydroxycinnamate (a compound of the present invention) as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[N:1]1([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6]1
Reactant: C1=CCNCC1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(c1ccccc1)N1CC=CCC1

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: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].[CH:10](O)=[O:11]>>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:10]=[O:11])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=CO
Product: N#Cc1ccc(NC=O)cc1

Procedure:
Was prepared according to Example 2 from 4-cyanoaniline and formic acid.