Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([O:18][C:19](=[O:45])[CH:20]([NH:29][C:30]([C:32]1([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:16]([O:18][C:19](=[O:45])[CH:20]([NH:29][C:30]([C:32]1([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:24][CH:23]=1)[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.2 mL of Trifluoromethanesulfonic anhydride (7.1 mmol) is added slowly dropwise to a solution of 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-amino]-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (2.70 g, 6.4 mmol) and 0.7 mL (8.7 mmol) of pyridine in 20 mL of CH2Cl2 at 0° C., and the solution is stirred at 0° C. for 1 hour. The reaction mixture is then partitioned between water and CH2Cl2. The organic phase is separated and washed with saturated aqueous NaHCO3 solution, dried over MgSO4, filtered, and concentrated to yield 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-amino]-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic acid ethyl ester as a tan solid; 1H NMR (250 MHz, CDCl3) δ 7.25 (d, 2H), 7.17 (d, 2H), 4.80 (q, 1H), 4.75 (s, 1H), 4.10 (two quartets, 2H), 3.12 (ABX m, 2H), 2.00-2.20 (m, 2H), 1.60-2.00 (m, 6H), 1.40 (s, 9H), 1.18 (t, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH3:39])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]3[O:33][CH2:32]3)[CH:24]=2)[CH:20]=1)=[O:13]>C(Cl)Cl.CO>[CH3:39][N:8]([CH3:7])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]([OH:33])[CH2:32][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:24]=2)[CH:20]=1)=[O:13]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC2CO2)c1
Reactant: C1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(O)CN2CCCCC2)c1
Yield: 84 %

Procedure:
Piperidine (3 g) was added to a stirred solution of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-(2,3-epoxypropoxy)benzamide (0.19 g) in a mixture of methylene chloride (3 ml) and methanol (3 ml). The resultant solution was stirred at ambient temperature for 18 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.19 g); NMR Spectrum: (DMSOd6) 1.6 (m, 6H), 2.18 (s, 3H), 2.92 (m, 12H), 4.02 (m, 2H), 4.22 (m, 1H), 6.9 (m, 1H), 7.2 (m, 4H), 7.29 (t, 1H), 7.43 (t, 1H), 7.57 (m, 31H), 7.8 (d, 1H), 9.92 (br s, 1H), 10.12 (br s, 1H); Mass Spectrum: M+H+ 531.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[C:16](=[O:18])[N:23]([CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26])[C:10]2=[O:12]
Reactant: O=C(O)c1cccc(OCc2cccc(Cl)c2)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4cccc(Cl)c4)c3C2=O)C(=O)N1
Yield: 36.4 %

Procedure:
A mixture of 3-(3-chloro-benzyloxy)-phthalic acid (1.6 g, 5.1 mmol), alpha-amino-glutarimide hydrochloride (0.87 g, 5.3 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(3-chloro-benzyloxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (0.74 g, 37% yield); HPLC: Waters Symmetry C18, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 6.44 min (99.8%); mp, 249-251° C.; 1H NMR (DMSO-d6) □ δ 2.02-2.07 (m, 1H, CHH), 2.54-2.62 (m, 2H, CH2), 2.83-2.91 (m, 1H, CHH), 5.12 (dd, J=6, 12 Hz, 1H, CH), 5.39 (s, 2H, CH2), 7.40-7.87 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.92, 48.77, 69.05, 115.72, 116.69, 120.10, 125.65, 126.85, 127.84, 130.42, 133.18, 133.26, 137.07, 138.76, 155.19, 165.32, 166.74, 169.89, 172.75. Anal Calcd For C20H15N2O5Cl+0.1H2O: C, 59.96; H, 3.82; N, 6.99; Cl, 8.85. Found: C, 59.93; H, 3.54; N, 6.91; Cl, 9.00.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH:11]=O.[CH2:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.O>[CH2:13]([NH:20][CH2:11][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: CCCCCCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCCNCc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a solution of 1-methylindole-2-carbaldehyde (1.59 g, 10.0 mmol) and heptylamine (1.49 mL, 10.0 mmol) in ethanol (50 mL) were added acetic acid (2.3 mL, 40 mmol) and sodium cyanoborohydride (0.75 g, 12.0 mmol) and the reaction mixture was stirred at room temperature overnight. Water (5 mL) was added and the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (75 mL) and aqueous 1 M KOH (75 mL) and the phases were separated. The aqueous layer was extracted with ethyl acetate (2×75 mL) and the combined organic phase was washed with brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a column of silica gel (130 g) with ethyl acetate (17-33% gradient) in heptane as the eluent yielded 1.57 g (61%) of a yellow oil, which solidified upon standing.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH3:16])[C@H:14](OC(OCC2C=CC=CC=2)=O)[C@@H:13]([NH:28]C(OC(C)(C)C)=O)[C@:12]1(C)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:44](=O)=O.[OH-:47].[Na+]>CCOC(C)=O>[NH2:28][C@H:13]1[C@@H:14]([CH2:44][OH:47])[C@@H:15]([CH3:16])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:12]1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: [OH-]
Reactant: C[C@@H]1[C@H](OC(=O)OCc2ccccc2)[C@@H](NC(=O)OC(C)(C)C)[C@](C)(c2ccccc2)N1C(=O)OCc1ccccc1
Reactant: O=C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H](CO)[C@H](N)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a stirred solution of (2S*,3S*,4R*,5R*)-1-benzyloxycarb-onyl-4-(benzyloxycarbonyloxy)-methyl-3-[N-(t-butoxycarbonyl)-amino]-5-methyl-2-phenylpyrrolidine (0.80 g, 1,82 mmol) in AcOEt (15 ml) was added conc. HCl aq. (8.0 ml) at room temperature; on the addition evolution of CO2 gas took place. After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated in vacuo to give a syrupy residue. This was basified to pH 10-11 with 20% NaOH aq. solution, and then extracted with AcOEt. The combined AcOEt extracts were washed with sat. NaCl aq. solution (×1), dried (K2CO3), and concentrated in vacuo to give title compound (0.61 g, 98%): IRmax (film): 3380(m), 1700(s), 1682(s), 1605(m), 1585(m), 1110(s), 750(m), 700(s) cm-1 ; 1H-NMR δ: 7.52-7.13(m, 9H), 6.99(br.s, 1H), 5.05(br.s, 3H), 4.92(d, J=8.1 Hz, 1H), 3.89(dd, J=10.4, 2.9 Hz, 1H), 3.76(dd, J=10.4, 10.4 Hz, 1H), 3.60-3.45 (m, 1H), 3.50(dd, J=11.2, 8.1 Hz, 1H), 2.10-1.70(m, 3H), 1.61(br.d, J=4.3 Hz, 3H) ppm. This was employed in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1([CH3:27])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17]CC3C=CC=CC=3)=[C:13]([O:25][CH3:26])[CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1>[Pd].C(OCC)(=O)C>[OH:1][C:2]1([CH3:27])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:25][CH3:26])[CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: COc1cc(CCC2CC(C)(O)CC(=O)O2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CCC2CC(C)(O)CC(=O)O2)ccc1O

Procedure:
Using 140 mg of 3hydroxy-3-methyl-7-(p-benzyloxy-m-methoxyphenyl)-5-heptanolide, 140 mg of 5% palladium-charcoal and 14 ml of ethyl acetate, the reaction and the purification of the product were carried out according to the method described in Example 27 affording 75 mg of the desired compound melting at 162°-164° C.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=1.[C:14]1([O:22][CH3:23])[C:15](=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:16][CH3:17]>C1(C)C=CC=CC=1>[OH:13][CH:12]([C:9]1[CH:10]=[CH:11][N:6]=[CH:7][CH:8]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[C:15]([O:16][CH3:17])[C:14]=1[O:22][CH3:23]
Reactant: COc1ccccc1OC
Reactant: O=Cc1ccncc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COc1cccc(C(O)c2ccncc2)c1OC
Temperature: 5 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
In a 2 L flask, 48 g of veratrole was dissolved in 200 g of toluene and 138 g of butyl lithium solution (15% in hexane) were added at temperatures from 4° C. to 6° C. The mixture was stirred for one hour at about 5° C. and 3 hours at ambient temperature. Then 26.7 g of 4-pyridinecarboxaldehyde (9) in 120 g of toluene was added at around ambient temperature. The reaction mixture was stirred for about 4.5 hours. The mixture was then cooled to around 5° C. and quenched with 133 mL of water. The mixture was then heated to around 80° C. The organic layer was separated, washed with 67 mL of water and separated. The residual water was removed by azeotropic distillation. The solution was then cooled to −15° C. to −5° C. The product was collected by filtration and washed with 27 g of cold toluene. The yield was 50 g of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10) (81% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6](=[C:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[CH3:43][O:44][C:45](=[O:89])[NH:46][CH:47]([C:51]([N:53]1[CH2:57][CH2:56][CH2:55][CH:54]1[C:58]1[NH:59][C:60]([C:63]2[CH:72]=[CH:71][C:70]3[C:65](=[CH:66][CH:67]=[C:68]([C:73]4[CH:78]=[CH:77][C:76]([C:79]5[NH:80][C:81]([CH:84]6[CH2:88][CH2:87][CH2:86][NH:85]6)=[N:82][CH:83]=5)=[CH:75][CH:74]=4)[CH:69]=3)[CH:64]=2)=[CH:61][N:62]=1)=[O:52])[CH:48]([CH3:50])[CH3:49].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:43][O:44][C:45](=[O:89])[NH:46][CH:47]([C:51]([N:53]1[CH2:57][CH2:56][CH2:55][CH:54]1[C:58]1[NH:59][C:60]([C:63]2[CH:72]=[CH:71][C:70]3[C:65](=[CH:66][CH:67]=[C:68]([C:73]4[CH:78]=[CH:77][C:76]([C:79]5[NH:80][C:81]([CH:84]6[CH2:88][CH2:87][CH2:86][N:85]6[C:7](=[O:9])[C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[C:10]6[CH2:15][CH2:14][O:13][CH2:12][CH2:11]6)=[N:82][CH:83]=5)=[CH:75][CH:74]=4)[CH:69]=3)[CH:64]=2)=[CH:61][N:62]=1)=[O:52])[CH:48]([CH3:50])[CH3:49]
Reactant: COC(=O)NC(C(=O)O)=C1CCOCC1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)=C1CCOCC1
Reaction time: 0.08 h
Yield: 49.7 %

Procedure:
To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid methyl ester (141 mg, 0.62 mmol) in methanol (1.8 mL) was added an aqueous LiOH solution (1 M, 1.8 mL, 1.8 mmol). The resulting solution was stirred at room temperature for 16 hours and then washed with ethyl acetate. The ethyl acetate washing was discarded and the aqueous layer was acidified with concentrated HCl. The acidified aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO4), and concentrated to give methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid. To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid (23 mg, 0.11 mmol) in dimethylformamide (0.6 mL) was added HATU (41 mg, 0.11 mmol). After stirring for 5 minutes, a solution of {2-methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester trihydrochloride (50 mg, 0.068 mmol) in dimethylformamide (0.6 mL) was added to the reaction, followed immediately by diisopropylethylamine (85 μL, 0.49 mmol). The reaction was stirred for 1 hour at room temperature then diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous NaHCO3 solution, water and brine, dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield {1-[2-(5-{6-[4-(2-{1-[2-methoxycarbonylamino-2-(tetrahydropyran-4-ylidene)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (28 mg, 50%).
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[C:10]([C:14]1[CH:15]=[C:16]([NH2:36])[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:20]=2)[N:18]=1)([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](=[O:6])[NH:36][C:16]1[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([CH:27]([CH3:29])[CH3:28])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:31])[CH3:32])[CH:20]=2)[N:18]=[C:14]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:15]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)[Si](Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1)(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
2,2,2-Trichloroethylchloroformate (1.09 mL, 7.92 mmol) was added to a solution of Intermediate 22a (1.53 g, 3.96 mmol) and DIPEA (2.75 mL, 15.8 mmol) in THF (40 mL) at 0° C. The reaction was stirred at RT for 3 h then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (2.22 g, 99%). LCMS (Method 4): Rt 5.55 min, m/z 560, 562 [MH+].
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](=NO)[C:3]1=[O:15].[H][H].C([OH:20])C>[Pd].Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([OH:20])[C:3]1=[O:15]
Reactant: CN1C(=O)C(=NO)C(=O)c2ccccc21
Reactant: [H][H]
Reactant: CCO
Agent: [Pd]
Agent: Cl
Product: Cn1c(=O)c(O)c(O)c2ccccc21

Procedure:
A suspension of 1-methyl-3-oximino-quinolin-2,4(1H)-dione (1.7 gm, Formula 1.02, Example 1) and 10% palladium on charcoal (0.5 gm) in a mixture of ethanol (90 ml) and 2N hydrochloric acid (40 ml) was hydrogenated at atmospheric conditions. After 2.5 hrs no further uptake of hydrogen (510 ml) was observed. The reaction mixture was filtered and the solid cake was extracted with hot glacial acetic acid (2×100 ml). The combined filtrates were evaporated under reduced pressure and the produce was crystallized from acetic acid/water to give the title compound (1.6 gm). That the expected product was obtained was confirmed by the spectral data: MS (FAB): m/e 192 (M.+ +1); NMR (DMSO): δ3.66 (s, 3H, CH3 --N), 8.79 (s, 1H, OH), 10.16 (s, 1H, OH) ppm.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:20]([C:19]2[CH:18]=[N:17][C:16]([Cl:15])=[CH:24][CH:23]=2)=[O:21])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2ccc(Cl)nc2)C1

Procedure:
63.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 6-chloro-nicotinic acid to give (R)-3-{[(6-chloro-pyridine-3-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Yellow oil. MS 340.1 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25](=[O:30])[CH2:24]4)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: O=C(O)C(=O)N1CCC(Oc2ccc(F)cc2)CC1
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(Oc4ccc(F)cc4)CC3)ccc2N1

Procedure:
The title compound is prepared from [4-(4-fluoro-phenoxy)-piperidin-1-yl]-oxo-acetic acid and 5-amino-1,3-dihydro-indol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 209-211° C. (diethyl ether)
Reaction SMILES: C[O:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([C:9]2[O:10][C:11]3[C:16]([C:17](=[N:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])=[CH:5][CH:4]=1.[S-]CC.[Na+]>CN(C)C=O.O.ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[O:10][C:11]3[C:16]([C:17](=[N:19][S:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)(=[O:22])=[O:21])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)c2cc(=NS(=O)(=O)c3ccccc3)c3ccccc3o2)cc1
Agent: CC[S-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(O)cc1)c1cc(=NS(=O)(=O)c2ccccc2)c2ccccc2o1
Reaction time: 48 h

Procedure:
Combine 2-(4-methoxybenzoyl)-4-benzenesulfonylimino-4H-chromene (1 mmol) and sodium thioethoxide (2 mmol) in dimethylformamide (5 mL). Stir for 48 hours. Dilute the reaction mixture with water and dichloromethane. Separate the organic layer, dry over MgSO4, filter, and evaporate in vacuo. Chromatograph on silica gel to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:7]
Reactant: CCOC(=O)c1cccc(CCNC)c1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Product: CCOC(=O)c1cccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1f with 2e produced 3z. MS found M+H=467. The oxalate salt of 3z was recrystallized from ethyl acetate; mp 128-129° C.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[N:7][NH:6][C:5](=[O:9])[CH:4]=1.[H-].[Na+].[CH3:18][O:19][C:20](=[O:29])[CH:21](Br)[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1>[CH3:18][O:19][C:20](=[O:29])[CH:21]([N:6]1[C:5](=[O:9])[CH:4]=[C:3]([N:2]([CH3:1])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[N:7]1)[CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CN(c1ccccc1)c1cn[nH]c(=O)c1
Reactant: COC(=O)C(Br)CC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(N(C)c2ccccc2)cc1=O
Temperature: 50 °C
Yield: 52.7 %

Procedure:
A solution of 5-(methyl-phenyl-amino)-2H-pyridazin-3-one (74.3 mg, 0.36 mmol) in tetrahydrofuran (1.8 mL) cooled to 0° C. was treated with a 60% suspension of sodium hydride in mineral oil (19.7 mg, 0.49 mmol). Upon complete addition of the sodium hydride, the cooling bath was removed and additional tetrahydrofuran (1.8 mL) was added to facilitate stirring. The reaction was stirred at 25° C. for 2.25 h. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 0.11 g, 0.46 mmol). The reaction was then warmed to 50° C., where it stirred overnight. After this time, the reaction was cooled to 25° C. and stirred overnight. At this point, the reaction was partitioned between water (25 mL) and methylene chloride (3×25 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix 8 g, 15-35% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[4-(methyl-phenyl-amino)-6-oxo-6H-pyridazin-1-yl]-propionic acid methyl ester (67.4 mg, 51%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:18][CH2:19][CH3:20])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:4][CH:3]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH3:42][N:43]1[CH2:48][CH2:47][CH:46]([CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:45][CH2:44]1>O.CN(C)C=O>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:18][CH2:19][CH3:20])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([N:53]2[CH2:52][CH2:51][N:50]([CH2:49][CH:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)[CH2:55][CH2:54]2)=[O:17])=[CH:6][CH:7]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: CCCc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(-c2ccc(Cl)cc2)c(CCC(=O)N2CCN(CC3CCN(C)CC3)CC2)o1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of 3-[4-(4-chlorophenyl)-2-propyl-5-oxazolyl]propionic acid (41.7 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (41 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (46 mg), 4-[(1-methyl-4-piperidinyl)methyl]piperazine (60 mg) and N,N-dimethylformamide (0.5 ml) was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated, introduced into preparative HPLC and purified. To the obtained oil was added ethyl acetate, and the mixture was washed with saturated aqueous sodium hydrogen carbonate. A 4N hydrochloric acid ethyl acetate solution was added to the ethyl acetate layer and the mixture was concentrated to give 1-{3-[4-(4-chlorophenyl)-2-propyl-5-oxazolyl]propanoyl}-4-[(1-methyl-4-piperidinyl)methyl]piperazine dihydrochloride (25.0 mg, yield 32%). Recrystallization from ethanol-isopropyl ether gave colorless prism crystals. melting point: 218° c (dec.).