Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)=[O:25])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.Cl>C1COCC1.O.[OH-].[Li+]>[F:36][C:34]([F:35])([F:37])[O:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:24](=[O:25])[NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:38])=[O:2])[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)=[N:18][CH:19]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(NC(=O)Nc4ccc(OC(F)(F)F)cc4)cn3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCC(c2ccc(-c3ccc(NC(=O)Nc4ccc(OC(F)(F)F)cc4)cn3)cc2)CC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To 210 mg (0.4 mmol) [4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)-ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-acetic acid methyl ester in THF/H2O (10 mL; 4:1), 5 mL (4M) aqueous Lithium Hydroxide solution was added and the mixture stirred at 60° C. for 5 hours. Acidified with concentrated hydrochloric acid which precipitated the desired compound. Filtered and dried under vacuum to afford [4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)-ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-acetic acid, which was subsequently dissolved in methanol (5 mL) one equivalent of potassium hydroxide and 2 mL of H2O were added and the resulting mixture was stirred at 40° C. for 2 hours. Evaporated to dryness to afford [4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)-ureido]-pyridin-2-yl}phenyl)-cyclohexyl]-acetic acid as the potassium salt: 1H NMR (400 MHz, MeOD) δ ppm 1.03-1.14 (m, 2H) 1.45 (td, J=12.57, 9.98 Hz, 2H) 1.75-1.87 (m, 5H) 2.03 (d, J=7.07 Hz, 2H) 2.37-2.47 (m, 1H) 7.12 (d, J=8.34 Hz, 2H) 7.21 (d, J=8.34 Hz, 2H) 7.43-7.51 (m, 2H) 7.64-7.73 (m, 3H) 7.96 (dd, J=8.72, 2.65 Hz, 1H) 8.58 (d, J=2.27 Hz, 1H); (M+H)+514.2.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:13](O)[CH2:14][OH:15].C[Si](Cl)(C)C>C(Cl)Cl>[O:1]1[CH2:13][CH2:14][O:15][C:2]1([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: OCCO
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: COC(=O)CC1(CC(=O)OC)OCCO1
Temperature: 50 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
To a solution of 4.2 g (24 mmol) of dimethyl 3-oxopentanedioate and 2.7 ml (48 mmol) of ethylene glycol in 50 mL of methylene chloride was added 12 mL (96 mmol) of TMSCl at room temperature. The reaction mixture was stirred at 50° C. for 3 days. The reaction was quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over Na2SO4, evaporated under reduced pressure. Chromatography on silica gel gave the desired product, dimethyl 2,2′-(1,3-dioxolane-2,2-diyl)diacetate (2.6 g, 12 mmol, yield: 50%): MS (m/e): 219 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:34][C:35]([F:38])([F:37])[F:36])(=O)=O.O>CN(C)C=O>[F:36][C:35]([F:38])([F:37])[CH2:34][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(O)c2)CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a stirred solution of tert-butyl 4-(3-hydroxyphenoxy)piperidine-1-carboxylate (2.00 g, 6.82 mmol) and cesium carbonate (4.44 g, 13.6 mmol) in N,N-dimethylformamide (25 mL) was added 2,2,2-trifluoroethyl trifluoromethane-sulfonate (1.74 g, 7.50 mmol) at room temperature. After stirring at room temperature for 2 hours, the mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (4:1) to give 2.42 g (95%) of the title compound as colorless oil.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:22]
Reactant: COC(=O)c1ccccc1S
Reactant: CCOc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 14.1 %

Procedure:
A mixture of methyl thiosalicylate (0.17 g, 1.0 mmol), 2-cyano-6-ethoxypyridine (0.15 g, 1.0 mmol), triethylamine (0.21 ml, 1.5 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure. The residue was subjected to a column chromatography and eluted with hexane-ethyl acetate (3:1, v/v). The obtained crystals were recrystallized from ethyl acetate-hexane to give the titled compound (0.04 g, 14%).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:35])[N:21]([CH3:34])[C@@H:22]([C:30](=[O:33])[NH:31][CH3:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:34][N:21]([C@@H:22]([C:30](=[O:33])[NH:31][CH3:32])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:20](=[O:35])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Yield: 87.5 %

Procedure:
N-Methyl-N-{(1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl}carbamic acid tert-butyl ester (600 mg, 1.19 mmol) was stirred in trifluoroacetic acid/methylene chloride (1:1, 5 mL) for 10 min and the volatiles were removed in vacuo. The residue was stripped with diethylether (2×5 mL) and dissolved in methanol (2 mL) and mixed with sodium hydrogen carbonate (10 mL) and ethylacetate (15 mL). The organic phase was separated and dried (magnesium sulfate) to afford 420 mg of (2R)-N-methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](Cl)=[O:5].Cl.[CH2:8]([NH2:17])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>CN(C)C=O>[CH2:8]([NH:17][C:4](=[O:5])[CH2:3][CH2:2][Br:1])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(Cl)CCBr
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CCBr)NCC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
3-Bromopropionyl chloride (25 g; 0.146 mole) was added slowly to a stirred suspension of phenacylamine hydrochloride (17.15 g; 0.1 mole) in dry dimethylformamide (50 ml) at room temperature. The internal temperature rose to ca. 40° C. The mixture was stirred for 2 hours and the DMF removed under vacuum. The residue was diluted with water (200 ml) and the crystalline solid collected, washed with water and dried. Weight of product = 9.49 g (35%), m.p. 114° C.
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][CH2:6][N:7](C)[CH3:8])[CH2:3][CH2:2]1.CN>C1C=CC=CC=1>[CH:1]1([C:4](=[O:10])[CH2:5][CH2:6][NH:7][CH3:8])[CH2:3][CH2:2]1
Reactant: CN(C)CCC(=O)C1CC1
Agent: CN
Solvent: c1ccccc1
Product: CNCCC(=O)C1CC1

Procedure:
A solution of 42.5 g. (0.3 mole) of 1-cyclopropyl-3-dimethylamino-1-propanone in 200 ml. of benzene was refluxed while methylamine was bubbled through the solution for 8 hours. The nuclear magnetic resonance spectrum indicated a 90% conversion to 1-cyclopropyl-3-methylamino-1-propanone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCCC1
Reactant: CS(=O)(=O)c1ccc(F)c(Br)c1
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(NC2CCCCC2)c(Br)c1
Temperature: 110 °C
Yield: 66.7 %

Procedure:
A mixture of 2-bromo-1-fluoro-4-(methylsulfonyl)benzene (0.05 g, 0.198 mmol) and cyclohexanamine (0.059 g, 0.593 mmol) in dioxane (1 mL) in a vial was capped and heated at 110° C. for three days. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 40% ethyl acetate in hexanes to afford the title compound (0.044 g, 0.132 mmol, 67.0% yield).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[O-:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+].O>C1COCC1>[C:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC(=O)Cl
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)Oc1ccccc1
Reaction time: 24 h
Yield: 90 %

Procedure:
4-Pentenoyl chloride (8.16 g, 69.1 mmol) was added dropwise to sodium phenoxide (8.02 g, 69.1 mmol) in THF (160 ml) at 20° C. After 24 hours at 20° C. H2O (100 ml) was added and the aqueous phase was extracted with Et2O (3×200 ml). The organic phase was washed with NaHCO3 (2×200 ml), brine (2×200 ml) to neutrality, then dried (Na2SO4), filtered, concentrated and bulb-to-bulb distilled to afford the desired title ester in 90% yield. B.p.: 70° C./0.04 mbar.
Reaction SMILES: [Cl:1][CH:2]([Cl:21])[C:3]([NH:5][C@H:6]([CH2:19][F:20])[C@H:7]([OH:18])[C:8]1[CH:13]=[CH:12][C:11]([Sn](C)(C)C)=[CH:10][CH:9]=1)=[O:4].Br[C:23]1[S:27][C:26]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[N:25][CH:24]=1>>[Cl:1][CH:2]([Cl:21])[C:3]([NH:5][C@H:6]([CH2:19][F:20])[C@@H:7]([C:8]1[CH:13]=[CH:12][C:11]([C:23]2[S:27][C:26]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[N:25][CH:24]=2)=[CH:10][CH:9]=1)[OH:18])=[O:4]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCc1ncc(Br)s1
Product: CC(C)(C)OC(=O)NCc1ncc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1

Procedure:
Following the general procedure of Example 2—Step 1 and making non-critical variations but using 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethyl-stannyl)phenyl)propan-2-yl)acetamide and tert-butyl ((5-bromothiazol-2-yl)methyl)carbamate as starting materials title compound is obtained (346 mg): 1HNMR (400 MHz, DMSO-d6) 1.41 (s, 9H), 4.19-4.22 (m, 1H), 4.26-4.30 (m, 0.5H), 4.36-4.42 (m, 2.5H), 4.54-4.58 (m, 0.5H), 4.66-4.70 (m, 0.5H), 4.86 (t, J=3.4 Hz, 1H), 5.98 (d, J=4.16 Hz, 1H), 6.50 (s, 1H), 7.39 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 7.77-7.82 (m, 1H), 8.05 (s, 1H), 8.60 (d, J=8.8 Hz, 1H) m/z (Cl) 492 [M+H].
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCCC1>[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]([OH:11])[CH:1]=[CH2:2])=[CH:8][C:7]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 280 mL (36.5 g, 0.28 mole) of a 1.0 M solution of vinylmagnesium bromide in tetrahydrofuran diluted with 250 mL of dry tetrahydrofuran under a nitrogen atmosphere was slowly added 60 g (0.28 mole) of 4-fluoro-3-phenoxybenzaldehyde. Upon completion of addition the reaction mixture was allowed to cool to room temperature and was stirred for three hours. Aqueous 10% hydrochloric acid was added, and the mixture was then extracted with diethyl ether. The ether extract was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, leaving 72.0 g of 1-(4-fluoro-3- phenoxyphenyl)-2-propen-1-ol as a brown liquid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[C:16]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)=[C:6]([OH:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Br:58][CH2:59][CH2:60][CH2:61]O>O1CCCC1>[Br:58][CH2:59][CH2:60][CH2:61][O:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=1
Reactant: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3O)n(C)c12
Reactant: OCCCBr
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3OCCCBr)n(C)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a solution of 100 mg (0.27 mmol) of 5-chloro-2-(7-dipropylamino-1-methyl-1H-benzimidazol-2-ylamino)phenol in 4 mL of tetrahydrofuran was added 77 mg (0.30 mmol) of triphenylphosphine and 51 mg (0.30 mmol) of diethylazodicarboxylate and the reaction mixture was stirred for 90 minutes at room temperature. To the reaction mixture was added 41 mg (0.30 mmol) of 3-bromopropan-1-ol and the reaction was stirred overnight. The reaction was concentrated in vacuo and the resulting residue was purified by flash chromatography eluting with 20% ethyl acetate/hexanes to give 100 mg (76%) of the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:34]([O:33][CH2:32][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cc1cccc(Br)c1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 43.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3-bromophenyl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 244, (S)-3-(benzyloxy)-2-(2-(3-bromophenyl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (3 mg, 43.3%). MS (EI) for C30H26BrFN2O4. found 578.4 (MH+).
Reaction SMILES: [CH3:1][C:2]([OH:9])([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH:10]12[CH2:16][CH:13]([CH:14]=[CH:15]1)[CH2:12][CH:11]2[CH2:17][CH2:18][CH2:19][C:20](OC)=[O:21]>>[CH:10]12[CH2:16][CH:13]([CH:14]=[CH:15]1)[CH2:12][CH:11]2[CH2:17][CH2:18][CH2:19][C:20]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:9])([CH3:8])[CH3:1])=[O:21]
Reactant: CC(C)(O)CCCCO
Reactant: COC(=O)CCCC1CC2C=CC1C2
Product: CC(C)(O)CCCCOC(=O)CCCC1CC2C=CC1C2
Yield: 92 %

Procedure:
By following the procedure of Synthesis Example 2 except that 5-methyl-1,5-hexanediol was used instead of 4-methyl-1,4-pentanediol and methyl 4-(5-norbornen-2-yl)butyrate used instead of methyl 5-norbornene-2-carboxylate, there was obtained 5-hydroxy-5-methylhexyl 4-(5-norbornen-2-yl)butyrate. Yield 92%.
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1)=O.O.[NH2:38][NH2:39]>>[NH:38]([C:3]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:10][CH:11]=1)=[O:2])[NH2:39]
Reactant: COC(=O)Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Reactant: NN
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)NN)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 102 mg (0.21 mmol) of tert-butyl (3RS,4RS)-4-(4-methoxycarbonylmethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 0.5 ml of hydrazine hydrate was heated to 120° C. for 18 hours. For the working-up, the reaction mixture was cooled to room temperature, treated with 3 ml of ice-water and extracted twice with 5 ml of methylene chloride each time. The combined organic phases were dried over sodium sulphate and evaporated under reduced pressure. There were obtained 63 mg (63% of theory) of tert-butyl (3RS,4RS)-4-(4-hydrazinocarbonylmethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless foam; Rf : 0.22 (SiO2, methylene chloride:methanol:ammonia=95:5:0.1).
Reaction SMILES: CO.[O:3]([C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:29]#[CH:30])([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[N+:26]([O-])=O)[CH2:14][CH2:13]1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O.[Fe]>[O:3]([C:10]([N:12]1[CH2:17][CH2:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[NH2:26])([C:29]#[CH:30])[CH2:14][CH2:13]1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C(=O)Oc2ccccc2)CC1
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Product: C#CC1(Oc2ccc(F)cc2N)CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
To a stirred suspension of 735 ml of methanol and 51.7 g of 1-N-phenoxycarbonyl-4-ethynyl-4-(4-fluoro-2-nitrophenoxy)piperidine was added a solution of 51 ml of concentrated hydrochloric acid in 206 ml of water. To the stirred mixture was added, in aliquots, 80.2 g of iron (reduced, electrolytic). The mixture was stirred 2 hr, heated to 45° for 1 hr and allowed to cool to room temperature. The mixture was poured into ice/water, extracted twice with dichloromethane, washed with saturated sodium chloride solution and dried over anhydrous potassium carbonate. The mixture was filtered and the filtrate was evaporated. The residue was purified by chromatography on a Waters Prep 500 High Pressure Liquid Chromatograph (1×500 cc silica gel: eluent: 0.5 methanol/dichloromethane). Concentration of the appropriate fractions provided an oil, which crystallized on standing to provide 15.7 g (33%) of product. Recrystallization from cyclohexane/ethyl acetate provided the analytical sample, mp 125°-127°.
Reaction SMILES: [CH2:1]([N:5]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:6](=[O:29])[C:7]([CH3:28])([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:10]=1)[CH3:8])[CH:2]([CH3:4])[CH3:3]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([CH3:8])([CH3:28])[C:6]([N:5]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:1][CH:2]([CH3:4])[CH3:3])=[O:29])=[CH:10][C:11]=1[NH:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc(N)c(NCCCN2CCCCC2)c1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
N,N-diisobutyl-2-methyl-2-{4-nitro-3-[(3-piperidin-1-ylpropyl)amino]phenyl}propanamide (1.6 g) in solution in a mixture of ethyl acetate/ethanol 2:1 (100 ml) and 10% palladium on carbon (160 mg) are introduced into an autoclave. After stirring for 4 hours under a hydrogen atmosphere (3 bars) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (1.4 g, 94% yield).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11]1[CH:20]=[C:19]2[C:21]([O:23][C:24](=O)[C:17]3=[C:18]2[C:13](=[CH:14][C:15]([N+:26]([O-:28])=[O:27])=[CH:16]3)[CH:12]=1)=[O:22]>N1C=CC=CC=1>[CH2:2]([O:9][N:10]1[C:24](=[O:23])[C:17]2[CH:16]=[C:15]([N+:26]([O-:28])=[O:27])[CH:14]=[C:13]3[C:18]=2[C:19](=[CH:20][CH:11]=[CH:12]3)[C:21]1=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3cc([N+](=O)[O-])cc(c23)C(=O)N1OCc1ccccc1
Yield: 91 %

Procedure:
O-Benzyl hydroxylamine hydrochloride (0.8 g, 6.5 mmol) was added to a suspension of 3-nitro-1,8-naphthalic anhydride (1.0 g, 4.1 mmol) in pyridine (20 mL). The mixture was refluxed for 3 hours and concentrated in vacuo. The solid residue obtained was purified by column chromatography (silica gel using 2% methanol in chloroform). Fractions containing the target compound were combined, concentrated, and dried to give 1.3 g of the title compound. mp 239-241° C.;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1.[CH2:35]([S:37]([NH2:40])(=[O:39])=[O:38])[CH3:36]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:6][CH:7]=1
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)cc1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(C)cc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 15.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.17 g, 0.36 mmol) obtained in step 2 and ethanesulfonamide (0.20 g, 1.89 mmol), the title compound (0.03 g, 14%) was obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[NH2:11][CH2:12][CH:13]([OH:36])[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C>CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH:21]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH:13]([OH:36])[CH2:12][NH:11][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[NH:4][CH:5]=[N:6]4)[CH2:16][CH2:17]2)=[CH:23][CH:24]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCC(O)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Solvent: CO
Solvent: CCN(CC)CC
Product: OC(CNc1ncnc2nc[nH]c12)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 6-chloropurine (0.728 g, 4.7 mmol), 1-amino-3-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-2-propanol (1.73 g, 4.77 mmol) and triethylamine (1.36 mL, 9.5 mmol) in MeOH (20 mL) was heated to reflux for 7 days and the solvent was removed in vacuo. The residue was dissolved in CHC3 and the extracted with aqueous sodium bicarbonate (2×100 mL); the organic phase was dried over sodium sulfate and evaporated to give a solid which was purified by flash chromatography on silica gel with 5% MeOH in CHCl3. The product was a colorless solid which was triturated with ether, 1.5 g (70%), mp 140°-170° C.; IR (KBr) 3000 cm-1 ; 300 MHz 1H NMR (CDCl3); δ 8.17 (s, 1H), 8.11 (s, 1H), 7.5-7.0 (m, 8H), 4.90 (br s, 1H), 4.34 (s, 1H), 3.87 (br s, 1H), 3.7-2.0 (m, 12H); MS 480 (MH+)