Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(OC(=O)[N:16](C)[C@@H:17]3[CH2:36][C:35]4=[CH:37][CH:38]=[C:32]([CH:33]=[CH:34]4)[O:31][CH2:30][CH:29]=[CH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH2:21][C@H:20]([CH:39]([CH3:41])[CH3:40])[NH:19][C:18]3=[O:42])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CO.[Pd]>[NH2:16][C@@H:17]1[CH2:36][C:35]2=[CH:34][CH:33]=[C:32]([CH:38]=[CH:37]2)[O:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH2:21][C@H:20]([CH:39]([CH3:40])[CH3:41])[NH:19][C:18]1=[O:42]
Reactant: CC(C)[C@H]1COCCCCCC=CCOc2ccc(cc2)C[C@@H](N(C)C(=O)OC2c3ccccc3-c3ccccc32)C(=O)N1
Agent: [Pd]
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)[C@H]1COCCCCCCCCOc2ccc(cc2)C[C@@H](N)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.87 (1.46 mmol) of 9H-fluoren-9-yl-methyl((13S,16R)-13-isopropyl-15-oxo-2,11-dioxa-14-azabicyclo[16.2.2]docosa-1(21),4,18(22),19-tetraen-16-yl)-carbamate and 0.16 g of 10% Pd/C in 100 ml of methanol was stirred under a hydrogen atmosphere at RT. After stirring overnight and addition of 0.5 ml of piperidine, stirring was continued for 2 h, and the mixture was filtered and freed of solvent. The residue was separated by preparative HPLC. The required fractions were combined and freeze dried. 0.18 g of the title compound was obtained as trifluoroacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:5].[CH2:34]([N:38]=[C:39]=[O:40])[CH2:35][CH2:36][CH3:37]>C(Cl)(Cl)Cl>[N+:31]([C:28]1[CH:29]=[CH:30][C:2]([NH:1][C:39]([NH:38][CH2:34][CH2:35][CH2:36][CH3:37])=[O:40])=[C:3]([CH:27]=1)[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:10][CH2:9]1)=[O:5])([O-:33])=[O:32]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCCCN=C=O
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Step 1): To a solution of 2amino-5nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (Preparation 28) (1.2 g, 2.69 mmol) in CHCl3 (15 ml) was added n-butylisocyanate (802 mg, 8.09 mmol). After the solution was refluxed for 24 hours, the solvent was evaporated. The residue was purified by column chromatography on silica gel to give 5-nitro-2-(N'-n-butylureido)-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 1.1 g (75%).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[S:22](=[O:27])(=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([CH2:28][CH2:29][CH2:30][Cl:31])[C:10]=2[CH:9]=1.Cl>C(O)C>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[S:22](=[O:26])(=[O:27])[N:23]([CH3:24])[CH3:25])[N:11]([CH2:28][CH2:29][CH2:30][Cl:31])[C:10]=2[CH:9]=1
Reactant: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(O)cc1N2CCCCl
Reactant: C1=COCCC1
Agent: Cl
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(OC3CCCCO3)cc1N2CCCCl

Procedure:
15.7 g.) is prepared by reacting dihydropyran (102 g.) with 2-hydroxy-6-dimethylsulphamoyl-10-(3-chloropropyl)-phenothiazine (17.2 g.) in the presence of an 8N solution of hydrogen chloride in ethanol (0.1 cc.).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
To a solution of 4-phenyl phenol (5.00 g, 29.38 mmol) in acetone (100 mL) was added at room temperature, methyl bromoacetate (2.92 mL, 30.84 mmol) and cesium carbonate (14.36 g, 44.06 mmol). The mixture was stirred at room temperature for 5 h. The white precipitate was filtered and the filtrate was concentrated to dryness. Purification by flash chromatography (Hex:EtOAc/7:3) gave 6.76 g of (biphenyl-4-yloxy)-acetic acid methyl ester as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH2:22][C:23]3([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:26][CH2:25][CH2:24]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=2)=[N:5][CH:4]=1.[C:34](O)(=[O:37])[CH2:35][OH:36].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(OCC)(=O)C.CN(C=O)C>[F:33][C:32]1[C:27]([C:23]2([CH2:22][N:14]([C:11]3[N:12]=[N:13][C:8]([C:6]4[S:7][C:3]([CH2:2][NH:1][C:35](=[O:36])[CH2:34][OH:37])=[CH:4][N:5]=4)=[CH:9][CH:10]=3)[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:26][CH2:25][CH2:24]2)=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)CO
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CN)s2)nn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CNC(=O)CO)s2)nn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
t-butyl 6-(5-(aminomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (4.8 g, 10 mmol), glycolic acid (0.9 g, 12 mmol), HOBt (1.6 g, 12 mmol), EDC (2.3 g, 12 mmol), DMF (50 mL), and TEA (5.9 mL) were added to a 250 mL round bottom flask and the reaction was heated to 60° C. and stirred for 1 h. The reaction was poured into ethyl acetate (400 mL), washed with water (3×100 mL), and the combined organic layers were separated, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (EtOAC/hexanes) to afford 3.9 g of t-butyl (1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-((2-hydroxyacetamido)methyl)thiazol-2-yl)pyridazin-3-yl)carbamate as a white solid. This compound was dissolved in 30% TFA/CH2Cl2 (30 mL) and stirred for 1 h. The reaction was concentrated, dissolved in EtOAc (200 mL), washed with potassium carbonate (3×30 mL), concentrated, and then recrystallized with ethanol to give a white solid that was further purified with reverse phase chromatography to give 305 mg of N-((2-(6((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)methyl)-2-hydroxyacetamide as a white solid (M+H=429.1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[O:52][CH2:53][CH2:54][O:55][CH2:56][CH3:57].C(=O)([O-])[O-].[K+].[K+]>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.O>[CH2:56]([O:55][CH2:54][CH2:53][O:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[CH:21][CH:22]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1)[CH3:57]
Reactant: CCOCCOc1ccccc1OB([O-])[O-]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOCCOc1ccccc1-c1ccc2c(c1)C=C(C(=O)Nc1ccc(CN(C)C3CCOCC3)cc1)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 2-(2-ethoxyethoxy)phenyl borate (145 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 10 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[2-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 118) (245 mg).
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)OCC(C)C.C(N(CC)CC)C.[BH4-].[Na+].Cl>O1CCCC1>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCc1ccc(C2CCCCC2)cc1
Yield: 87.8 %

Procedure:
Under a nitrogen stream, tetrahydrofuran (1.2 L, 15.0 v/w) was added to 4-cyclohexylbenzoic acid (80.0 g, 0.382 mol) and then isobutyl chlorocarbonate (52.0 ml, 0.401 mol) was added. Triethylamine (56.0 ml, 0.401 mol) was added to the reaction mixture with stirring under ice-cooling and the mixture was stirred at the same temperature for 30 min. The resulting precipitate was collected by filtration. To a suspension of sodium borohydride (58.0 g, 1.53 mol) in tetrahydrofuran (160 ml, 2.0 v/w) prepared in a different reaction vessel was carefully added the above-mentioned filtrate with stirring under ice-cooling under a nitrogen stream. After stirring at room temperature for 1.5 hr, distilled water (160 ml, 2.0 v/w) was added with stirring under ice-cooling. After stirring under ice-cooling for 20 min, 2N-hydrochloric acid (825 ml, 4.3 eq) was added. After stirring at room temperature for 30 min, the mixture was extracted with ethyl acetate (400 ml) and the organic layer was washed successively with distilled water (100 ml), 2N-aqueous sodium hydroxide solution (100 ml), distilled water (100 ml) and saturated brine (100 ml), and dried over magnesium sulfate (70 g). After filtration and solvent evaporation, the residue was dried in vacuo to give the title compound (63.8 g, yield 87.8%) as a white solid.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:16][C:17]1[N:18]([CH2:25][C@:26]2([CH3:29])[CH2:28][O:27]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1.CN(C=O)C>O>[Cl:16][C:17]1[N:18]([CH2:25][C@@:26]([CH3:29])([OH:27])[CH2:28][N:11]2[CH2:10][CH:9]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CC=C(c2ccccc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 57 %

Procedure:
4-Phenyl-1,2,3,6-tetrahydropyridine hydrochloride (0.495 g, 2.53 mmol) was added to a sodium hydroxide solution, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To the residue, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.5 g, 2.29 mmol) and DMF (5 ml) were added followed by stirring at 70° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)propan-2-ol (0.492 g, yield 57%) as a yellow oil.
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18]CC)=[O:17])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: O=C(O)CC1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 8 parts of ethyl 1-(phenylmethyl)-4-piperidineacetate hydrochloride and 80 parts of a dilute hydrochloric acid solution was stirred and refluxed for 4 hours. After cooling, the reaction mixture was evaporated. The residue was washed with 2-propanone and the solvent was evaporated again. The solid residue was washed with 2-propanone, filtered off and dried, yielding 6 parts of 1-(phenylmethyl)-4-piperidineacetic acid hydrochloride; mp. 137°-145° C. (2)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[Br:14][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cc(CO)ccc1Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(CBr)ccc1Cl
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of (4-chloro-3-nitrophenyl)methanol (5.0 g, 26.6 mmol) in toluene (100 mL) was added phosphorus tribromide (0.879 mL, 9.32 mmol) at 40° C. The reaction mixture was stirred at 100° C. for 15 mins and partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound.
Reaction SMILES: O1CCC[CH2:2]1.[Br:6][C:7]1[CH:8]=[C:9]([CH:16]=[O:17])[C:10]2[O:14][CH2:13][O:12][C:11]=2[CH:15]=1.C[Mg]Br>C(OCCCC)CCC>[Br:6][C:7]1[CH:8]=[C:9]([CH:16]([OH:17])[CH3:2])[C:10]2[O:14][CH2:13][O:12][C:11]=2[CH:15]=1
Reactant: O=Cc1cc(Br)cc2c1OCO2
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCCCOCCCC
Product: CC(O)c1cc(Br)cc2c1OCO2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65.4 %

Procedure:
To 150 mL tetrahydrofuran, was added 6-bromo-benzo[1,3]dioxole-4-carbaldehyde (15 g, 65.4 mmol). To the solution was added a solution of methyl magnesium bromide (1.0 M) in di-n butyl ether (72 mL) followed by exotherm and solid formation. The mixture was stirred at 25° C. for 2.5 hours and evaporated in vacuo to a solid. The mixture was suspended in ethyl acetate washed with 1N citric acid, brine, and dried over anhydrous magnesium sulfate. The mixture was filtered and evaporated to an oil. The oil was induced to crystallize from ethyl acetate and hexane giving a white solid which was filtered and dried in vacuo giving a solid, 10.48 g, 65.4% yield. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH:49]1[CH2:54][CH2:53][CH2:52][C@@H:51]([C:55]([OH:58])([CH3:57])[CH3:56])[CH2:50]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([C:14]([N:49]3[CH2:54][CH2:53][CH2:52][C@@H:51]([C:55]([OH:58])([CH3:57])[CH3:56])[CH2:50]3)=[O:16])=[CH:12][O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(O)[C@@H]1CCCNC1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC[C@@H](C(C)(C)O)C2)cc1
Yield: 77.4 %

Procedure:
A solution of 3-(4-methoxyphenyl)-isoxazole-4-carboxylic acid (7 mg, 0.03 mmol), N-ethyl-N-isopropylpropan-2-amine (16 μL, 0.09 mmol, 3 equ.) and TBTU (12 mg, 0.036 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 2-[(3R)-piperidin-3-yl]propan-2-ol hydrochloride (5 mg, 0.03 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z: calcd for C19H24N2O4: 344.1736, found 344.1737.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([N:8]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][O:17][C:11]=3[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>>[C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([C:26](=[O:34])[C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:24][CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][O:17][C:11]=3[CH:10]=2)=[O:7])=[CH:35][CH:36]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc3c(c2)OCO3)cc1
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc3c(c2)OCO3)cc1
Yield: 79 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3,4-methylenedioxyphenyl)benzamide (245.0 mg, 0.501 mmol) and acetic anhydride (0.057 ml, 0.60 mmol), the procedure of Inventive Example 94 was repeated to obtain 210.3 mg (79.0%) of the title compound in a colorless amorphous form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:13][CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:13][CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(CCC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(CCC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
In a mixed solvent of 2 ml of ethanol and 2 ml of tetrahydrofuran was dissolved 21.8 mg of ethyl 4-[3-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)propyl]phenoxyacetate, followed by addition of 0.25 ml of aqueous 2N sodium hydroxide solution, and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, which was then neutralized with 2N hydrogen chloride. The crystalline deposited was filtered and washed in water followed by drying, to obtain 4.0 mg of 4-[3-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)propyl]phenoxyacetic acid. The spectrometric data thereof supports the structure of [39] as follows.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([CH2:17]O)[CH:14]=[C:13]2[C:19]#[N:20])=[CH:8][CH:7]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(OCC)C>ClCCl.CCCCCC>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]2[C:19]#[N:20])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(CO)cc2C#N)cc1
Agent: CC[SiH](CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(-n2cc(C)cc2C#N)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
To a solution of 1-(4-ethoxycarbonylphenyl)-4-hydroxymethylpyrrole-2-carbonitrile (500 mg) in dichloromethane (5.5 ml) was added trifluoroacetic acid (2.8 ml) and triethylsilane (652 μl) in that order at 5° C. under nitrogen. The mixture was stirred at 5° C. for one and half hours and at ambient temperature for one hour and then poured into a mixture of diethyl ether and n-hexane (1:1). The mixture was washed with saturated sodium bicarbonate solution and brine, dried, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution by ethyl acetate/n-hexane=1/10) to yield 1-(4-ethoxycarbonylphenyl)-4-methylpyrrole-2-carbonitrile (163 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7]1.Cl[C:21]1[N:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][N:22]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][NH:15][C:21]2[N:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][N:26]=2)[CH2:8][CH2:7]1
Reactant: Clc1ncc(-c2ccccc2)cn1
Reactant: NCCNC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: Cc1ccccc1
Product: Clc1ccc(CN2CCC(NCCNc3ncc(-c4ccccc4)cn3)CC2)cc1Cl

Procedure:
The title compound (20 mg) was prepared by heating at reflux N1-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-1,2-ethanediamine (100 mg) and 2-chloro-5-phenypyrimidine (100 mg) and Hunigs' base (100 mg) in toluene for 8 hours. The mixture was purified by chromatography on silica, with ethyl acetate methanol (9:1) as eluant to give the title compound as a yellow oil. MS [M+h]+ (ES+) 456/8 1H NMR: (CDCl3) δ 1.51 (2H, m), 1.75 (2H, m), 2.15 (2H, td), 2.9 (2H, m), 3.05 (1H, m), 3.15 (2H, m), 3.44 (2H, m), 3.8 (2H, m), 6.65 (1H, m), 7.0-7.4 (8H, m), 8.5 (2H, m).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH:25]([CH3:31])[CH2:26][C:27]#[C:28][CH2:29][CH3:30])/[CH:5]=[CH:6]/[C@H:7]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][C@H:12]2[C@@H:8]1[CH2:9][C:10](=[O:24])[O:11]2>CO.CCOCC>[OH:3][C@@H:4]([CH:25]([CH3:31])[CH2:26][C:27]#[C:28][CH2:29][CH3:30])/[CH:5]=[CH:6]/[C@H:7]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][C@H:12]2[C@@H:8]1[CH2:9][C:10](=[O:24])[O:11]2
Reactant: CCC#CCC(C)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCC#CCC(C)[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
3.4 of sodium borohydride is added batchwise to a solution of 6 g of the ketone prepared in example (6e) in 200 ml of methanol, at -40° C., and the mixture is stirred for 1 h at -40° C. under argon. Next it is diluted with ether, washed with water until neutral, dried over magnesium sulfate and vacuum evaporated. By means of column chromatography on silcia gel using ether/hexane (8/2), first 2.6 g of the title compound (3-alpha-hydroxy) is elutriated, next, as the more polar component, 1.9 g of the corresponding isomeric 3 beta-hydroxy compound.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:15]=1[CH:16]=[O:17].[Cl-].[NH4+]>O1CCCC1>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:15]=1[CH:16]([OH:17])[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C#CC(=O)OC
Reactant: COc1ccc(OC)c(C=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1cc(OC)ccc1OC
Reaction time: 0.17 h

Procedure:
A solution of 8.36 ml (0.1 mol) of methyl propiolate in 100 ml of tetrahydrofuran was treated at -78° under argon with 68.8 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 16.6 g (0.1 mol) of 2.5-dimethoxybenzaldehyde in 120 ml of tetrahydrofuran was added within 40 minutes. The reaction mixture was stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 150 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-(2.5-dimethoxyphenyl)-4-hydroxy-2- butynoate as a yellow oil.