Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.CO.[OH-].[Na+].Cl>O>[OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(F)(F)F)cc3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To methyl 4-{[2-(1-{4-hydroxy-1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}ethylidene)hydrazino]carbonyl}benzoate (0.116 mmol, 53.4 mg), methanol (2 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.580 mL) was added at room temperature. After 30 minutes of stirring at room temperature and 1 hour of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.580 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a yellow solid (37.7 mg, yield 73%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH:38]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:38][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][CH:24]=4)=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc[nH]1
Reactant: Cc1ccc(C(=O)Nc2ccc(N3CCNCC3)cc2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(C(=O)Nc2ccc(N3CCN(Cc4ccc[nH]4)CC3)cc2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
To a solution of 5-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (329 mg) in 1,2-dichloroethane (20 mL) was added 1H-pyrrole-2-carboxaldehyde (86 mg) and acetic acid (54 mg). The solution was cooled at 0° C. and sodium triacetoxy borohydride (238 mg) was added portionwise and the mixture was stirred at room temperature for 16 hours. The solution was then washed with a saturated solution of NaHCO3, with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2/MeOH (95/5) and the oily residue obtained was crystallized from diisopropyl ether to give the title compound (210 mg) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16]CC2C=CC=CC=2)[CH:7]=1)[CH3:2]>CCO>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:14])([F:13])[F:15])[CH:9]=[C:8]([OH:16])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Solvent: CCO
Product: CCOC(=O)Cc1cc(O)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(3-Benzyloxy-5-trifluoromethyl-phenyl)-acetic acid ethyl ester (1.7 g, 5.6 mmol) was dissolved in EtOH (30 mL) and degassed with N2. 5% Palladium on carbon (1 g) was added, and the reaction was purged with H2 and then stirred under an H2 balloon at 50° C. overnight. The mixture was filtered and concentrated to give (3-Hydroxy-5-trifluoromethyl-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:20]2[CH:19]=[CH:18][N+:17]([O-])=[CH:16][C:15]=2[CH:14]=[CH:13]1.C[Si](C#N)(C)C>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[CH:14]=[CH:13]1
Reactant: [O-][n+]1ccc2c(ccn2-c2ccc(C(F)(F)F)cc2Cl)c1
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(-n2ccc3cnccc32)c(Cl)c1
Reaction time: 5 h
Yield: 50.6 %

Procedure:
A solution of 1-(2-chloro-4-trifluoromethylphenyl)-pyrrolo[3,2-c]pyridine 5-oxide (3.5 g, 12 mmol) in triethylamine (50 ml) was cooled in an ice-bath and trimethylsilyl cyanide (10.7 ml, 80 mmol) added dropwise. The ice-bath was removed and the mixture stirred for 5 hours. The precipitate was collected and dried to afford 1-(2-chloro-4-trifluoromethylphenyl)pyrrolo[3,2-c]pyridine (1.8g) as a colorless solid, m.p. 160°-161° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].C(OCC)(=O)C>O1CCCC1>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[CH:3]=2)[NH:7]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 88.9 %

Procedure:
A stirred solution of 5-amino-1,3-dihydro-indol-2-one (3.5 g, 23.6 mmol, prepared according to U.S. Pat. No. 6,114,371) in 20 ml of tetrahydrofuran was added with triethylamine (1.3 ml, 9 mmol). The solution was cooled down to −30° C. in an acetone-dry ice bath and added with acetyl chloride (1.3 ml, 9 mmol) dropwise. Upon the completion of the addition, the resulting mixture was stirred for 20 minutes at room temperature and added with ethyl acetate (20 ml) until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (4 g, 88.9%) as a white solid.
Reaction SMILES: O.NN.[CH2:4]([N:11]([C:15]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])C(=O)C)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C.[Cl-].[Na+]>C(OCC)(=O)C>[CH2:4]([NH:11][C:15]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)N(Cc1ccccc1)c1cc(Oc2ccccc2)ccc1C(=O)O
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(Oc2ccccc2)cc1NCc1ccccc1
Temperature: 25 °C
Yield: 22.6 %

Procedure:
A suspension of hydrazine monohydrate 2.0 mL of 2-(N-benzylacetamido)-4-phenoxybenzoic acid 0.10 g was heated and refluxed for 3 hours. After the reaction mixture was cooled to room temperature, acetic acid 5.0 mL was added to it, and ethyl acetate and saturated sodium chloride aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate:acetic acid=80:20:1] to give 2-(benzylamino)-4-phenoxybenzoic acid 20 mg of white solid.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=2)[CH2:2][CH3:3].[Sn](Cl)(Cl)(Cl)Cl.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[CH3:22][O:23][CH2:24][C:25]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:1][CH2:2][CH3:3])=[O:26]
Reactant: CCCc1cc2ccc(C(=O)OC)cc2[nH]1
Reactant: COCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)COC
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-propylindole-6-carboxylate (300 mg) in dichloromethane (10 ml) was added a 1M solution of tin(IV) chloride in dichloromethane (2.76 ml) at 20° C. The mixture was stirred at 20° C. for 30 minutes, then methoxyacetyl chloride (0.25 ml) was added. After stirred at 20° C. or 30 minutes, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:10-1:1) to give methyl 3-methoxyacetyl-2-propylindole-6-carboxylate (135 mg) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]([CH3:31])([CH3:30])[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH:21]([C:26]([O:28]C)=[O:27])[C:22]([O:24]C)=[O:23])[C:18]#[C:19][CH3:20])=[CH:13][CH:12]=2)=[O:9])=[C:4]([Cl:34])[CH:3]=1.Cl>C(#N)C.[OH-].[Na+]>[Br:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]([CH3:30])([CH3:31])[C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]([CH:21]([C:26]([OH:28])=[O:27])[C:22]([OH:24])=[O:23])[C:18]#[C:19][CH3:20])=[CH:15][CH:16]=2)=[O:9])=[C:4]([Cl:34])[CH:3]=1
Reactant: CC#CC(c1ccc(NC(=O)C(C)(C)Oc2ccc(Br)cc2Cl)cc1)C(C(=O)OC)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC#CC(c1ccc(NC(=O)C(C)(C)Oc2ccc(Br)cc2Cl)cc1)C(C(=O)O)C(=O)O

Procedure:
A solution of 180 mg of dimethyl 2-(1-{4-[2-(4-bromo-2-chlorophenoxy)-2-methylpropionylamino]phenyl}but-2-ynyl)malonate in 5 ml of acetonitrile and 3.5 ml of 1 N sodium hydroxide solution (aq) was stirred at room temperature for 18 h. The reaction mixture was adjusted to pH=1 with 1 N HCl (aq) and then extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under high vacuum. This gave 171 mg of 2-(1-{4-[2-(4-bromo-2-chlorophenoxy)-2-methylpropionylamino]phenyl}but-2-ynyl)malonic acid in quantitative yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.O>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(O)c1
Solvent: C1CCOC1
Solvent: O
Product: OCCc1cccc(O)c1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 3-hydroxyphenylacetic acid (3.04 g, 20.0 mmol) in tetrahydrofuran (30 ml) was added at 0° C. borane-tetrahydrofuran complex (1M, 30.0 ml, 30.0 mmol) under an atmosphere of nitrogen. The mixture was stirred for 1 hour, followed by addition of water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give the subject compound (2.76 g, 100%).
Reaction SMILES: C(P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:28][C:29]1[CH:34]=[C:33]([CH2:35][OH:36])[CH:32]=[CH:31][N:30]=1.[C:37]1(O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[Cl:28][C:29]1[CH:34]=[C:33]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=[CH:31][N:30]=1
Reactant: Oc1ccccc1
Reactant: OCc1ccnc(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: Clc1cc(COc2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
To a solution of tributylphosphine (4.57 g, 22.63 mmol) in anhydrous tetrahydrofuran (20 mL) was added diisopropyl azodicarboxylate (4.57 g, 22.63 mmol) at 0° C. The reaction mixture was stirred for 10 minutes at 0° C., then added to a solution of (2-chloropyridin-4-yl)methanol and phenol in anhydrous tetrahydrofuran (50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes then at ambient temperature for 16 hours. The reaction was quenched with saturated ammonium chloride solution (10 mL). The solvent was evaporated in vacuo. The residue was diluted with ethyl acetate (350 mL), washed with 1 N sodium hydroxide solution (3×40 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/9) to afford 2-chloro-4-(phenoxymethyl)pyridine as a gummy solid in 61% yield (2.34 g): 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J=5.1 Hz, 1H), 7.40 (s, 1H), 7.32-7.24 (m, 3H), 7.01-6.91 (m, 3H), 5.05 (s, 2H); MS (ES+) m/z 220.2 (M+1).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:18][CH2:19][C:20]#[N:21])[CH2:6][CH:7]([N:9]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:11][C:12]#[N:13])[CH3:8])#[N:2].[H][H]>O1CCOCC1>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:6][CH:7]([N:9]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:11][CH2:12][NH2:13])[CH3:8]
Reactant: [H][H]
Reactant: CC(CN(CCC#N)CCC#N)N(CCC#N)CCC#N
Solvent: C1COCCO1
Product: CC(CN(CCCN)CCCN)N(CCCN)CCCN
Yield: 96.9 %

Procedure:
20.05 g of N,N,N′,N′-tetrakis(2-cyanoethyl)-1,2-diaminopropane, 2.01 g of Raney Co and 100 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 9.0 MPa at 160° C. for 3 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 20.52 g of the title compound as a white solid.
Reaction SMILES: [CH:1]([OH:6])=[CH:2][C:3](=[CH2:5])[CH3:4].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C(Cl)Cl.CS(O)(=O)=O>[CH3:5][C:3](=[CH2:4])[CH2:2][CH2:1][O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1
Reactant: C=C(C)C=CO
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CCOC1CCCCO1
Yield: 100.5 %

Procedure:
To isoprenyl alcohol (80.0 g, 929 mmol) in CH2Cl2 (500 ml) at 0° C. was added one drop of methanesulfonic acid. To this solution was added 2,3-dihydropyran (100 ml, 1.10 mol) dropwise over 3 h. After the addition was complete triethylamine (5 ml) was added and the resulting mixture was filtered through a thin pad of SiO2 and concentrated to afford 159 g (100%) of 2-(3-methyl-3-butenyloxy)tetrahydropyran as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][N:9]=[C:8]([I:12])[C:7]2=[O:13].[CH3:14][O:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:18][CH2:17][C:16]([O:15][CH3:14])([CH3:21])[CH3:20])[N:9]=[C:8]([I:12])[C:7]2=[O:13]
Reactant: O=c1c(I)n[nH]c2c(F)cccc12
Reactant: COC(C)(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(C)(C)CCn1nc(I)c(=O)c2cccc(F)c21
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A mixture of 0.72 g of 8-fluoro-3-iodocinnolin-4(1H)-one and 0.48 ml of 3-methoxy-3-methylbutan-1-ol in 20 ml of THF is cooled to 5° C., 0.97 g of triphenylphosphine is added and then 0.65 g of diethyl azodicarboxylate is slowly added, and the mixture is left stirring overnight at AT. The reaction mixture is concentrated under vacuum and the residue is chromatographed on silica gel, elution being carried out with the cyclohexane/AcOEt mixture (75/25; v/v) and then with AcOEt. The expected compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([S:28]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidin-4-ol, triethylamine, benzenesulfonyl chloride, and methylene chloride was stirred at ambient temperature for 2 days to yield 1-tert-butoxycarbonylpiperidin-4-yl benzenesulfonate. A mixture of 1-tert-butoxycarbonylpiperidin-4-yl benzenesulfonate obtained, diethyl malonate, 20% NaOEt-EtOH, and EtOH was heated under reflux with stirring for 22 hours to yield diethyl[1-(tert-butoxycarbonyl)piperidin-4-yl]malonate. A mixture of diethyl [1-(tert-butoxycarbonyl)piperidin-4-yl]malonate obtained, lithium borohydride, toluene, and THF was stirred at 60° C. for 18 hours to yield 2-(1-tert-butoxycarbonylpiperidin-4-yl)propane-1,3-diol, which was stirred together with 4M HCl-dioxane solution in MeOH at ambient temperature for 1 hour to yield 2-piperidin-4-ylpropane-1,3-diol hydrochloride.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl[Si:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[CH3:29][Si:28]([CH3:31])([CH3:30])[O:26][C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH2:13]
Reactant: CCCCCCCCCCCC(C)=O
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C(CCCCCCCCCCC)O[Si](C)(C)C
Temperature: 10 °C
Yield: 99.1 %

Procedure:
A solution of n-butyllithium (12.6 mL, 27.7 mmol, 2.2 M in hexane) was added dropwise via syringe to a cooled (-78° C.) solution of diisopropylamine (4.1 mL, 29 mmol) in dry THF (200 mL). The resulting solution was stirred (15 minutes -78° C.), then a solution of 2-tridecanone (5.0 g, 25 mmol) in dry THF (50 mL) was added dropwise via a drop-in funnel. The resulting mixture was stirred (30 minutes, -78° C.), then a solution of chlorotrimethylsilane (3.5 mL, 28 mmol) in dry THF (40 mL) was added in one portion. The dry ice bath was removed and the resulting mixture was warmed to 10° C., then quenched with saturated sodium bicarbonate (100 mL). Dichloromethane (400 mL) and water (80 mL) were added and the layers were separated. The organic layer was washed with brine (1×200 mL), dried (MgSO4), and concentrated in vacuo to yield 6.7 g (98%) of the title compound as a milky oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[S:18][CH2:17][CH2:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][C:13]=3[CH:23]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[S:18][CH2:17][CH2:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[CH:23]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(OC)cc3)ccc2SCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3)cc1
Reaction time: 18 h
Yield: 106.2 %

Procedure:
To a solution of methyl 7-(4-methoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (0.50 g) in ethanol/THF (10/10 ml) was added at room temperature 1N sodium hydroxide solution (2 ml), and the mixture was stirred for 18 hours. To the mixture was added 1N hydrochloric acid (2 ml). Under reduced pressure, the mixture was concentrated. To the mixture was added water, and the precipitates were collected by filtration, which were washed with 2-propanol, diethylether and hexane to give pale yellow solid of 7-(4-methoxyphenyl)-2,3-dihydro-1-benzo-thiepine-4-carboxylic acid (508 mg). This compound was used for the following reaction, without subjecting further purification.
Reaction SMILES: [NH+]12CC[NH+](CC1)C[CH2:2]2.OO.[N:11]12[CH2:18][CH2:17][N+:14]([O-:19])([CH2:15][CH2:16]1)[CH2:13][CH2:12]2.IC.[F:22][B-:23]([F:26])([F:25])[F:24].[Na+]>C1COCC1.C(#N)C>[F:22][B-:23]([F:26])([F:25])[F:24].[CH3:2][O:19][N+:14]12[CH2:17][CH2:18][N:11]([CH2:16][CH2:15]1)[CH2:12][CH2:13]2
Reactant: [O-][N+]12CCN(CC1)CC2
Reactant: C1C[NH+]2CC[NH+]1CC2
Agent: F[B-](F)(F)F
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CC#N
Product: CO[N+]12CCN(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-fluoro-4-methoxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) 1,4-Diazoniabicyclo[2.2.2]octane N-oxide is prepared by the reaction of 1,4-Diazoniabicyclo[2.2.2]octane with hydrogen peroxide as described by Farkas in J. Chem. Eng. Data (1968) 13, 278. 1,4-Diazabicyclo[2.2.2]octane N-oxide (12.8 g, 10 mmol) in THF (100 mL) is reacted with iodomethane (14.1 g, 10 mmol) until the reaction is complete by TLC. The reaction is evaporated, diluted with acetonitrile (100 mL) and sodium tetrafluoroborate (40 g, 20 mmol) added. The solution is stirred overnight at room temperature and then filtered to remove all undissolved salts. The filtrate is evaporated to afford 1-methoxy-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[C:27]([O:26][C:24]([N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=1)[C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)c1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C3CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1)c1ccc(C2CCCCC2)cc1
Reaction time: 8 h

Procedure:
4-{[tert-Butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoic acid methyl ester was suspended in ethanol (30 mL) and sodium hydroxide (4 N, 8.1 mL) was added. The reaction mixture was stirred overnight. The mixture was concentrated to dryness, suspended in water (100 mL), acidified with hydrochloric acid (8.5 mL, 4 N) and extracted with ethyl acetate (100 mL). The aqueous phase was extracted once more with ethyl acetate (30 mL) and the combined organic phases were washed with water (3×50 mL), dried with magnesium sulphate and concentrated in vacua. The residue was crystallised from a mixture of ethyl acetate and n-heptane to afford 1.75 g of 4-{[tert-butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}-benzoic acid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]=O)=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2].N1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.[CH3:54][O:55][NH2:56]>C(O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH:35]=[N:56][O:55][CH3:54])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Yield: 64.5 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2-oxoethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (145 mg, 0.25 mmol), in ethanol (10 mL) under nitrogen atmosphere, were added pyridine (0.099 mL, 1.28 mmol), sodium acetate (201.3 mg, 2.45 mmol) and O-methylhydroxylamine hydrochloride (102 mg, 1.22 mmol). The reaction mixture was refluxed for 5 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was extracted with ethyl acetate (50 mL). The organic layer was separated, washed with water (2×10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1.8:8.2 Acetone:Pet. Ether) to afford title compound (100 mg, 64.4%).