Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[C:5]=1[F:12])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:37])=[C:31]([F:38])[C:30]=2[F:39])=[CH:25][CH:24]=1>CN(C=O)C>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:27]=[CH:28][C:23]([CH2:22][O:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:12])[C:6]=3[F:11])=[CH:24][CH:25]=2)=[C:30]([F:39])[C:31]=1[F:38])[CH3:37]
Reactant: CCOc1ccc(-c2ccc(CCl)cc2)c(F)c1F
Reactant: CCOc1ccc(O)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2ccc(-c3ccc(OCC)c(F)c3F)cc2)c(F)c1F
Temperature: 30 °C
Reaction time: 7 h
Yield: 74 %

Procedure:
4-Ethoxy-2,3-difluorophenol (6) (1.5 g) and tripotassium phosphate (K3PO4) (7.5 g) were added to DMF (100 ml) under a nitrogen atmosphere, and the stirring was continued at 70° C. The compound (5) (2.0 g) was added thereto and the stirring was continued at 70° C. for 7 hours. After the reaction mixture obtained had been cooled to 30° C. and then separated from the solid by filtration, toluene (100 ml) and water (100 ml) were added thereto and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases. The extraction into an organic phase was carried out. The organic phase obtained was washed with brine and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off, and the residue obtained was purified by means of column chromatography (silica gel; heptane: toluene=1:2 by volume). The product was further purified by means of recrystallization from a mixed solvent of Solmix A-11 and heptane (Solmix A-11: heptane=1:2 by volume) and dried, giving 2.2 g of 4-ethoxy-2,3-difluoro-4′-(4-ethoxy-2,3-difluorophenoxymethyl)-1,1′-biphenyl (No. 678). The yield based on the compound (5) was 74.0%.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.OC[CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:28][S:27][C:16]=3[N:17]=[C:18]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])[N:19]=2)[CH2:10][CH2:9]1>ClCCl>[Br:5][CH2:2][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:28][S:27][C:16]=3[N:17]=[C:18]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])[N:19]=2)[CH2:12][CH2:13]1
Reactant: O=C1CCCN1Cc1nc(N2CCC(CO)CC2)c2c(-c3ccccc3)csc2n1
Reactant: BrC(Br)(Br)Br
Solvent: ClCCl
Product: O=C1CCCN1Cc1nc(N2CCC(CBr)CC2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 136.5 %

Procedure:
Tetrabromomethane (120 mg) was added to a solution of 1-[[4-[4-(hydroxymethyl)-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]methyl]pyrrolidin-2-one (102 mg) in dichloromethane (10 mL). Polystyrene-supported triphenylphosphine (0.35 g, 2.04 mmol g-1) was added and the mixture was stirred overnight at room temperature. The solid material was filtered off and the solvent was evaporated to give the target compound as a yellow solid (160 mg). m/z [M+H]+ 484.9/486.9. Retention time 4.97 min (LCMS method+ve 6 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)([CH2:13][CH3:14])[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25]([CH3:26])=[O:38])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)([CH2:13][CH3:14])[CH2:9][CH2:10][C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: CCC(CCC#N)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CCC(CCC#N)(c1ccc(Cl)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
120 mg (0.31 mmol) of the compound from Example 157 were introduced into 12 ml of dichloromethane at 0° C., 77 mg (0.31 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 120 mg (96% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: C[O:2][CH:3]=[CH:4][C:5]1[C:6]([CH3:17])=[N:7][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]=1[CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>C(O)(C)C.O>[CH3:17][C:6]1[C:5]([CH2:4][CH:3]=[O:2])=[C:9]([CH3:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: COC=Cc1c(C)nn(-c2ccccc2)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1nn(-c2ccccc2)c(C)c1CC=O
Temperature: 60 °C
Yield: 60.5 %

Procedure:
To a stirred solution of 4-(2-methoxy-vinyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (7.09 g, 31.1 mmol) in 100 mL isopropanol-water (1:1 v/v) was added p-toluenesulfonic acid monohydrate (1.5 g, 7.76 mmol). After the reaction was heated at 60° C. for 16 h, 1.9 mL concentrated hydrochloric acid was added and the reaction mixture was heated at 60° C. for 20 h. The organic solvent was removed in vacuo and the remaining aqueous suspension was neutralized with an aqueous sodium bicarbonate solution and extracted several times with a dichloromethane-ethyl acetate mixture. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to produce a residue, which was purified via silica gel column chromatography (0-50% ethyl acetate in heptane) to give the title compound as a yellow solid (4.02 g, 18.8 mmol, 60% yield).
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@H:16]([CH3:30])[NH:17][C:18](=[O:29])[C@H:19]([CH3:28])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])C1C=CC=CC=1.[H][H].C(O)C>C(O)(C)(C)C>[C:21]([NH:20][C@H:19]([C:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:32])=[O:8])=[O:31])[CH3:30])=[O:29])[CH3:28])([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A Parr flask was flushed with argon and charged with 10% palladium on charcoal (0.74 g), followed by the addition of Boc-L-alanyl-L-alanyl-L-proline benzyl ester (1.8 g, 4.0 mmol) dissolved in tert-butanol (300 ml). The reaction mixture shaken under 30 psi of hydrogen at 35° C. for 5 hr. After cooling to room temperature, ethanol (50 ml) was added and the solution was filtered through celite and the filtrate concentrated on a rotary evaporator. The residue was azeotroped with chloroform-hexane to remove the last traces of tert-butanol and then dried under high vacuum to give Boc-L-alanyl-L-alanyl-L-proline (1.40 g, 3.9mmol) in 98% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5]2.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([F:27])([F:26])[F:15])=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCCn1ccc2cc(Br)ccc21
Product: CCCCn1ccc2cc(-c3ccc(C(F)(F)F)cc3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-butyl-1H-indole (Step 1 of Example 29) and 4-trifluoromethylphenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil, mp: 52-53° C. Mass spectrum (APCI, [M+H]+) m/z 318. 1HNMR (400 MHz, DMSO-d6): δ 7.91-7.88 (m, 3H), 7.76 (d, 2H, J=8.24 Hz), 7.59 (d, 1H, J=8.55 Hz), 7.49 (d, 1H, J=8.56 Hz), 7.43 (d, 1H, J=3.06 Hz), 6.51 (d, 1H, J=3.05 Hz), 4.20 (t, 2H, J=7.01 Hz), 1.74 (p, 2H, J=7.19 Hz), 1.25 (h, 2H, J=7.48 Hz), and 0.88 ppm (t, 3H, J=7.32 Hz).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.CO.[ClH:29]>C1(C)C=CC=CC=1>[ClH:29].[ClH:29].[N:14]1([C:13]2[C:8]([N:5]3[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccnc2N2CCC(O)CC2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: OC1CCN(c2ncccc2N2CCNCC2)CC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 99.47 %

Procedure:
Add t-Butyl 4-(2-(4-hydroxypiperidin-1-yl)pyridin-3-yl)piperazine-1-carboxylate (306.5 g, 0.846 mol) to a 12-liter flask, followed by methanol (613 ml) and toluene (3.06 L). Stir the mixture to give a solution and then add the methanolic HCl solution (579 mL). Heat the solution to 35° C. for 2 hr. followed by 4 hr. at ambient temperature. Filter off the resulting crystalline product, wash the crystals with toluene, and then dry in a vacuum oven at 40-45° C. to provide 1-(3-(piperazin-1-yl)pyridin-2-yl)piperidin-4-ol dihydrochloride as a crystalline solid (283.5 g, 99.47%). 1H NMR 300 MHz (DMSO) δ 9.624 (bs, 2H) 7.890 (dd, J=6.4 Hz, 1H), 7.633 (d, J=7.75 Hz, 1H), 7.137 (m, 1H), 3.916 (bm, 2H), 3.727 (bm, 1H), 3.236 (bs, 9H), 1.877 (bm, 2H), 1.515 (bm, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][CH:15]=[N:14][CH:13]=2)=[C:8]([O:17][CH3:18])[CH:7]=1)=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH3:18][O:17][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=[CH:10][C:9]=1[C:12]1[O:16][CH:15]=[N:14][CH:13]=1
Reactant: COc1cc(NC(=O)CCl)ccc1-c1cnco1
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)CNc2ccccc2)ccc1-c1cnco1

Procedure:
A solution of 2A (30.0 mg, 0.11 mmol) and aniline (30 μL, 0.33 mmol) in DMF (0.1 mL) was heated at 100° C. for 2.5 h. After the reaction had cooled, the solvent was removed under reduced pressure, and the residue was subjected to preparative HPLC to give 2 as a yellow solid. LC/MS: ret. timeA=3.576 min., MS (M+H)+=324.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:32])[CH2:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[Cl:31])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:31][C:30]1[CH:29]=[CH:28][S:27][C:26]=1[C:24]1[CH2:23][C:22](=[O:32])[NH:21][C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1sccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2sccc2Cl)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {3-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K61) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (232 mg).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:17]=[CH:18][C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=O>C(O)(=O)C>[C:9]1([C:7]([C:6]2[CH:5]=[N:4][N:3]3[C:19]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:18][CH:17]=[N:1][C:2]=23)=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
A reaction mixture of 1.87 g of (3-amino-1H-pyrazol-4-yl)phenyl-methanone and 1.76 g of 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one in 25 ml of glacial acetic acid was refluxed for 6 hours and then the solvent was removed in vacuo giving a crystalline residue. This residue was partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The organic layer was dried with anhydrous sodium sulfate and then passed through a short pad of hydrous magnesium silicate. The addition of hexane to the refluxing eluate induced crystallization. After cooling, the desired product was collected, giving 2.45 g, mp 202°-203° C.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:3][C:2]([CH3:1])([N:6]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]2)[CH3:5])[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Product: CN1CCN(CC(C)(C)n2cnc([N+](=O)[O-])c2)CC1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with N-methyl piperazine to provide the title compound: MS m/z 268.2 (M+1).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH3:4].[NH:17]([C:24]1([C:30]([NH2:32])=[O:31])[CH2:29]CNC[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][CH:6]1[CH2:5][N:3]1[CH2:2][CH2:25][C:24]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]([NH2:32])=[O:31])[CH2:29][CH2:4]1
Reactant: CN(C)CC1CCc2ccccc2C1=O
Reactant: NC(=O)C1(Nc2ccccc2)CCNCC1
Agent: Cl
Solvent: CCO
Product: NC(=O)C1(Nc2ccccc2)CCN(CC2CCc3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[(Dimethylamino)methyl]-3,4-dihydro-1(2H)-naphthalenone, hydrochloride (10.0 g) and 4-anilino isonipecotamide (10.2 g) are dissolved in absolute ethanol (150 ml) by brief heating. The reaction mixture is stirred at room temperature under nitrogen for 16 hours. The resulting precipitate is collected by filtration, washed with additional absolute ethanol, and dried in vacuo to give the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][C:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=3)[CH:8]=2)=[CH:3]1>[Pd].C(OCC)(=O)C.C(O)C>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=3)[CH:8]=2)[CH2:3]1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(C3=CC(O)CC3)nc3c2CCC3)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Nc2cc(C3CCC(O)C3)nc3c2CCC3)cc1
Reaction time: 4 h

Procedure:
A 250-mL round bottom flask was charged with ethyl 2-(4-((2-(3-hydroxycyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.109 g, 0.29 mmol) and 10% palladium on carbon (0.028 g) in 1:1 ethyl acetate/ethanol (12 mL). This mixture was vigorously stirred under H2 (1 atm) for 4 h. After this time, the mixture was filtered through celite and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford two diastereomers of the title compound:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][NH:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH2:14][C@H:15]([CH3:17])[CH2:16][C@H:11]([CH3:10])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CNC[C@@H](C)C1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](C)CN(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
A suspension of 4-bromobenzyl bromide (4.0 g, 16.0 mmol), cis, trans-(3,5-dimethylpiperidine) (1.81 g, 16.0 mmol) and potassium carbonate (2.65 g, 19.2 mmol) in THF (160 mL) was heated under reflux for 24 h. The reaction mixture was allowed to cool to ambient temperature, the solid removed by filtration and the filtrate evaporated in vacuo. The resultant residue was loaded onto a 50 g SCX-2 cartridge which was washed with methanol then eluted with 2N ammonia in methanol. Concentration of the combined basic fractions in vacuo followed by flash chromatography of the resultant residue (silica, 330 g column, ISCO, 0-25% ethyl acetate in pentane) afforded cis-1-(4-bromobenzyl)-3,5-dimethylpiperidine (1.60 g, 35%) as a colourless oil. 1H NMR (CDCl3, 300 MHz): 7.47-7.39 (m, 2H); 7.20 (d, J=8.0 Hz, 2H); 3.42 (s, 2H); 2.82-2.71 (m, 2H); 1.76-1.61 (m, 4H); 1.51-1.37 (m, 2H); 0.82 (d, J=6.4 Hz, 6H).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[CH2:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:20]([O:22][CH3:23])=[O:21])[CH2:24][O:9]2)=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(c2ccc(Cl)cc2)CO1
Temperature: 25 °C

Procedure:
MCPBA (35 g, 77%, 156 mmol) was added to a solution of methyl 2-(4-chlorophenyl)-acrylate (20 g, 102 mmol) in CHCl3 (200 mL). The mixture was refluxed for 24 hours. The reaction was cooled to room temperature, diluted with chloroform (200 mL) and washed with 10% Na2S2O3, 10% NaHCO3 and water. The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (9:1) to give methyl 2-(4-chlorophenyl)oxirane-2-carboxylate. Methyl 2-(4-chlorophenyl)oxirane-2-carboxylate (2 g, 9.4 mmol) and ethanol (10 mL) and isopropylamine (1 mL, 11.7 mmol) were added to a 50 mL high pressure bomb. The mixture was heated to 90° C. for 12 hours in the bomb. After cooling, the solvent was removed, and the residue was dissolved in DCM (20 mL) and TEA (2 mL). (Boc)2O (4 g, 23.0 mmol) was added to it. The mixture was stirred at room temperature for 48 hours. The solvent was removed, and the residue was dissolved in THF (20 mL). LiOH (3M, 14 mL) was added to the mixture. The mixture was stirred at room temperature for 16 hours and refluxed for 2 hours. After cooling, the mixture was quenched with 2N HCl (21 mL). The solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (1:1) to give 3-(tert-butoxycarbonykisopropyl)amino)-2-(4-chlorophenyl)-2-hydroxypropanoic acid. LCMS (APCI+) [M−Boc+H]+ 258.1; Rf: 3.66 min.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]([C:12](OCC)=[O:13])[C:7](OCC)=[O:8])#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].O>C(OCC)C>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH:6]([CH2:12][OH:13])[CH2:7][OH:8]
Reactant: CCOC(=O)C(CCCC#N)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCCCCC(CO)CO
Temperature: 25 °C

Procedure:
6 g of diethyl 2-(3-cyanopropyl)malonate are added dropwise, at -10° C., to a suspension of 3 g of LiAlH4 in 100 ml of dry diethyl ether under N2. The mixture is slowly warmed to room temperature and then refluxed for 3 h. After renewed cooling to -10° C., the excess hydride is decomposed with water. The precipitate is removed on a frit and washed several times with diethyl ether. The ether solution is dried over MgSO4, filtered and evaporated in a rotary evaporator. Yield 0.66 g of 2-(4-aminobutyl)-1,3-propanediol, detectable in the 1H NMR and by C and H analysis. Glassy solid, melting point 126° C. (honey-like above 60° C.).
Reaction SMILES: [S:1]1[C@H:12]2[CH2:13][C@@H:14]([OH:25])[C@H:15](/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:11]2[CH2:10][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[O:26]1CC[CH2:28][CH2:27]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>OCCO>[OH:26][CH2:27][CH2:28][O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[S:1][C@H:12]2[CH2:13][C@@H:14]([OH:25])[C@H:15](/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:11]2[CH2:10]1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)O)S[C@H]2C[C@H]1O
Reactant: C1CCOC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: OCCO
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)OCCO)S[C@H]2C[C@H]1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 70 mg of (13E)-(6RS,9α,11α,15S)-6,9-epithio-11,15-dihydroxyprost-13-enoic acid (prepared as described in Example 2), 3 ml of tetrahydrofuran and 34.5 μl of triethylamine was stirred at room temperature for 5 minutes, and then stirred with 27.7 μl of pivaloyl chloride. To the mixture were added 70 μl of triethylamine and 0.5 ml of 2-hydroxyethanol, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (2:1) as eluent to give 92 mg of the title compound having the following physical characteristics:
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:11][CH3:12])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[C:13]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:11][CH3:12])[C:8]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH:30]=3)[CH2:25][CH2:24]2)=[O:9])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(CC)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 15 was prepared from 2,2-diphenylbutanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.43–7.38 (m, 1H), 7.37–7.29 (m, 9H), 7.28–7.21 (m, 4H), 6.90 (d, 1H, J=8.2 Hz), 6.43 (t, 1H, J=4.1), 3.32 (q, 2H, J=6.5 Hz), 2.95–2.89 (m, 2H), 2.45 (q, 2H, J=7.9 Hz), 2.43–2.35 (m, 3H), 2.27 (t, 2H, J=6.5 Hz), 2.01–1.92 (m, 2H), 1.78–1.59 (m, 6H), 1.24 (t, 3H, J=7.9 Hz), 0.79 (t, 3H, J=6.5 Hz); ESMS m/e: 512.3 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.[C:20]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:21][C:22]([CH3:24])=O>C1C=CC=CC=1>[CH2:27]([O:26][C:20](=[O:25])[CH:21]=[C:22]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([CH3:12])=[CH:14][CH:15]=1)[CH3:24])[CH3:28]
Reactant: Cc1ccc(N)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C=C(C)Nc1ccc(C)cc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
p-Toluenesulfonic acid (catalytic amount) was added to a solution of p-methylaniline (10.7 g, 100 mmol) and ethyl acetoacetate (13.0 g, 110 mmol) in benzene (250 mL) at room temperature. The reaction mixture was refluxed with a Dean-Stark apparatus over night. After cooling down to room temperature, the reaction mixture was concentrated and purified by column chromatography (5% ethyl acetate in n-hexane) to give 3-p-tolylamino-but-2-enoic acid ethyl ester (18.6 g, 85% yield).