Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]1([CH2:18][O:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([N:26]3[C:31](=[O:32])[C:30]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]5[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=5)=[CH:36][CH:35]=4)=[C:29]([CH2:48][CH2:49][CH3:50])[N:28]4[N:51]=[CH:52][N:53]=[C:27]34)[CH2:22][CH2:21]2)[CH2:17][CH2:16][CH2:15]1>O.C(OCC)(=O)C>[OH:13][C:14]1([CH2:18][O:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([N:26]3[C:31](=[O:32])[C:30]([CH2:33][C:34]4[CH:35]=[CH:36][C:37]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[C:46]5[NH:3][C:4](=[O:7])[O:5][N:47]=5)=[CH:38][CH:39]=4)=[C:29]([CH2:48][CH2:49][CH3:50])[N:28]4[N:51]=[CH:52][N:53]=[C:27]34)[CH2:24][CH2:25]2)[CH2:17][CH2:16][CH2:15]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O)CCC3)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O)CCC3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.18 g), sodium hydrogen carbonate (0.29 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C. for 30 min, 4′-[(4-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.095 g) was added, and the mixture was stirred at 90° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.034 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.031 mL) were added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, adjusted to pH 4 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.048 g, 46%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C@@H:9]([C:23]([OH:25])=O)[CH2:10][CH2:11][C@@H:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[F:22])[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:12]1[CH2:13][NH:14][C:23](=[O:25])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](CN)c1cccc(F)c1F)C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Reaction time: 1 h

Procedure:
To a solution (5S)—N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine from Step D (22.0 g, 48.0 mmol) in CH2Cl2 (700 mL) were added EDC (11.0 g, 57.6 mmol) and HOAT (3.27 g, 24.0 mmol) followed by triethylamine (10.0 mL, 72.0 mmol). After 1 h, aqueous NaHCO3 was added, the layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with CH2Cl2:MeOH—90:10, to give the title compound. MS: m/z=341 (M+1).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[O:13]1[CH2:19][CH:18](O)[CH2:17][O:16][CH2:15][CH2:14]1.[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:16]1[CH2:17][CH:18]([N:32]([N:23]2[C:22](=[O:21])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:31])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:19][O:13][CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O
Reactant: OC1COCCOC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C1COCCOC1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.1 h
Yield: 92.1 %

Procedure:
DEAD (2.2 M in toluen, 1.55 mL) was added dropwise to a solution of 1,4-dioxepan-6-ol (265 mg), t-butyl (1,3-dioxoisoindolin-2-yl)carbamate (560 mg) obtained in preparation example 14-(1) and triphenylphosphine (840 mg) in THF (10 mL) under ice-cooling over 3 minutes. The reaction mixture was stirred at 0° C. for 6 minutes, and further stirred at room temperature overnight The reaction mixture was concentrated under reduced pressure. After toluene (2.5 mL) was added to the resulting residue, the precipitated solid was removed by filtration. The filtrate was purified by silica gel column chromatography (ethyl acetate/n-heptane, 20%) to give the title compound (713 mg).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31]([N:33]1[CH2:39][CH2:38][CH:37]([OH:40])[CH:36]([NH:41][C:42](=[O:44])[CH3:43])[CH2:35][CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:23]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37](=[O:40])[CH:36]([NH:41][C:42](=[O:44])[CH3:43])[CH2:35][CH2:34]1)=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(=O)NC1CCN(C(=O)OCc2ccccc2)CCC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)NC1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
11 g Dess Martin Periodane was added to 6.2 g 4-acetylamino-5-hydroxy-azepane-1-carboxylic acid benzyl ester in 100 mL dichloromethane and stirred for 1 h at RT. The mixture was diluted with dichloromethane and washed with 2 mol/L sodium hydroxide solution. The organic layere was washed with brine, dried and concentrated. The residue was purified by chromatographie on silica gel (EtOAc) to yield 5.5 g of the desired product. (M+H)+: 305
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=2)[CH2:3][CH2:2]1.[C:13](=O)([O-])[O-].[K+].[K+].CI.C(OCC)C>CC(C)=O>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=2)[CH3:13])[CH2:3][CH2:2]1
Reactant: Ic1cccc(CNC2CC2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CI
Product: CN(Cc1cccc(I)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A solution of cyclopropyl-(3-iodo-benzyl)-amine (Intermediate 88, 4.1 g, 15 mmol) in acetone (20 mL) was treated with potassium carbonate (2.07 g, 15 mmol) and methyl iodide (1.4 mL, 22.5 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1 h. Diethyl ether was added, the solids were filtered off and filtrate was evaporated to a residue that was subjected to flash column chromatography over silica gel (230–400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound (3.3 g, 77%).
Reaction SMILES: [Hg:1](OC(C)=O)OC(C)=O.[CH2:10]([O:17][CH2:18][C@@H:19]([OH:42])[C@@H:20]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:21]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:22]([OH:25])[CH:23]=[CH2:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-:43].[K+]>C1COCC1.O.CCOC(C)=O>[CH2:27]([O:26][C@H:21]1[C@H:20]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C@@H:19]([CH2:18][O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:42][C@H:23]([CH2:24][Hg:1][Cl:43])[C@@H:22]1[OH:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(=O)O[Hg]OC(C)=O
Reactant: C=C[C@H](O)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1C[Hg]Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a suspension of Hg(OAc)2 (12.4 g, 38.8 mmol, 1.0 equiv) in dry THF (174 mL), under nitrogen, was added a solution of (2R,3R,4R,5S)-1,3,4-tris(benzyloxy)hept-6-ene-2,5-diol (17.4 g, 38.8 mmol, 1.0 equiv) in dry THF (87 mL). The reaction mixture was stirred at room temperature for 16 hours and then a solution of KCl (4.3 g, 58.2 mmol, 1.5 equiv) in water (20 mL) was added. After 30 minutes, the reaction mixture was diluted with EtOAc (150 mL) and then washed with water (2×100 mL). The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with 20% EtOAc in hexane, to give (((2S,3R,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-hydroxytetrahydro-2H-pyran-2-yl)methyl)mercury(II) chloride as a pale yellow oil (22.6 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.37-7.29 (m, 11H), 7.27-7.24 (m, 2H), 7.23-7.19 (m, 2H), 4.62-4.48 (m, 6H), 4.37 (dd, J=7.1, 3.7 Hz, 1H), 4.15 (dt, J=6.3, 4.1 Hz, 1H), 3.82 (dd, J=10.1, 6.7 Hz, 1H), 3.72 (q, J=2.8, 1.9 Hz, 1H), 3.65-3.59 (m, 2H), 3.53-3.47 (m, 2H), 2.06-2.00 (m, 1H), 1.77 (dd, J=12.1, 3.8 Hz, 1H). ESI (M+1-Cl) 647.1; calc for C28H31ClHgO5 684.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([NH:18][C:19]2[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=2)[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][S:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[CH:3]=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[N:7]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(CSc2nc(Cl)cc(Nc3cc(C)n[nH]3)n2)cc1
Reactant: CN1CCNCC1
Product: COc1ccc(CSc2nc(Nc3cc(C)n[nH]3)cc(N3CCN(C)CC3)n2)cc1

Procedure:
The above-prepared [6-chloro-2-(4-methoxy-benzylsulfanyl)-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (500 mg, 1.38 mmol) in 1-methylpiperazine (10 mL) is heated at 130° C. for 15 hours. The solvent is then removed in vacuo and the residue is purified by flash chromatography (SiO2, dichloromethane/MeOH gradient) to give the desired product (2-(4-methoxy-benzylsulfanyl)-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH:8]=1)[OH:7].O1CCOCC1.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>P(Cl)(Cl)(Cl)=O.O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([C:18]2[C:17]([CH:16]=[O:23])=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([CH:8]=1)[OH:7]
Reactant: O=Cc1ccccc1
Reactant: Cc1cc(O)cc(O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(O)c(-c2ccccc2C=O)c(O)c1

Procedure:
To a solution of 621 g. of 5-methylresorcinol in 1 l. of dioxane were added 530 g. of benzaldehyde and 30 g. of phosphorus oxychloride as a catalyst. The resulting mixture was reacted at room temperature for 24 hours and then poured into 5 l. of a cold water. There was obtained a pale brown powdery resin.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:31][OH:32])([N:7]1[CH:11]=[C:10]([C:12]2[C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:16]=3[CH:15]=[C:14]([CH3:30])[CH:13]=2)[CH:9]=[N:8]1)[C:4](O)=[O:5].C(O)C.O.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:5][CH2:4][C:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([OH:29])([C:25]([F:28])([F:26])[F:27])[C:16]=3[CH:15]=[C:14]([CH3:30])[CH:13]=2)[CH:9]=[N:8]1)([CH2:31][OH:32])[CH2:2][OH:1]
Reactant: Cc1cc(-c2cnn(C(CO)(CO)C(=O)O)c2)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(-c2cnn(C(CO)(CO)CO)c2)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Reaction time: 5 h
Yield: 83.9 %

Procedure:
To a solution of an optically active form (15.5 g) of 3-hydroxy-2-hydroxymethyl-2-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid in tetrahydrofuran (31 ml) was added dropwise at room temperature a 1.09M solution (127 ml) of borane-tetrahydrofuran complex in tetrahydrofuran, and the mixture was stirred for 5 hr. To the reaction mixture was added dropwise ethanol (15 ml) at room temperature and the mixture was stirred at 75° C. for 1 hr. To this mixture were added water (90 ml) and saturated aqueous sodium hydrogen carbonate (150 ml), and the mixture was extracted twice with ethyl acetate (150 ml, 75 ml). The combined organic layer was successively washed once with saturated aqueous sodium hydrogen carbonate (75 ml), twice with water (75 ml) and once with saturated brine (75 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the obtained residue in ethanol (45 ml) was added sodium borohydride (1.3 g) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture was added 1N hydrochloric acid (150 ml), and the mixture was extracted with ethyl acetate (150 ml). The separated aqueous layer was extracted again with ethyl acetate (75 ml). The combined organic layer was successively washed with water (75 ml), saturated aqueous sodium hydrogen carbonate (75 ml), water (75 ml) and saturated brine (75 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 10/1) to give the title compound (12.6 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:12])=[N:5][C:6]([CH3:11])=[C:7]([CH2:9]Cl)[CH:8]=1.[C-:13]#[N:14].[K+].C[N:17]([CH3:20])C=O>O>[C:13]([CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][C:20]#[N:17])[C:6]([CH3:11])=[N:5][C:4]=1[CH3:12])#[N:14]
Reactant: CN(C)C=O
Reactant: [C-]#N
Reactant: Cc1nc(C)c(CCl)cc1CCl
Agent: [K+]
Solvent: O
Product: Cc1nc(C)c(CC#N)cc1CC#N
Reaction time: 4 h

Procedure:
A solution of 3,5-bis-chloromethyl-2,6-dimethyl-pyridine (18.0 g, 88.2 mmol) in dimethylformamide (110 mL, 0.8 M) is cooled to 0° C. and treated with a solution of potassium cyanide (12.4 g, 190 mmol) in water (35 mL). The cooling bath is removed, and after 4 h, ice-cooled H2O (600 mL) is added. The resulting solids are filtered, washed with ice-cooled water (100 mL) and recrystallized from H2O to provide 5-cyanomethyl-2,6-dimethyl-pyridin-3-yl-acetonitrile as light brown flakes (10.9 g, 67%): mp 65-67° C.; Rf 0.23 (20% n-heptane in ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 7.61 (s, 1 H), 3.69 (s, 4 H), 2.56 (s, 6 H); ESI-LCMS m/z calcd for C11H11N3: 185.1; found 186.0 (M+1)+. Anal. Calcd for C11H11N3.0.15H2O: C, 70.30; H, 6.06; N, 22.36. Found: C, 70.44; H, 6.01; N, 22.13.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1>>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[N:8][O:9][C:10]=3[C:11]([F:14])([F:12])[F:13])[N:3]=[CH:2]2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 12 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (70 mg, 0.25 mmol) was converted, using 4-fluoronitrobenzene instead of 4-fluoroacetophenone, to the title compound (12 mg, 12%) which was obtained as a yellow solid. MS: m/e=401.0 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:21]=[CH:20][C:14]3[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=3[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:21]=[CH:20][C:14]3[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=3[CH:12]=2)[C:8]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)c1ccc2c(c1)CCS2(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)c2ccc3c(c2)CCS3(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
A solution of 3-cyclopentyl-2-(1,1-dioxo-2,3-dihydro-benzo[b]thiophen-5-yl)-propionic acid (114 mg, 0.37 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 212 μL, 0.43 mmol) which produced gas evolution and it was stirred at 0° C. for 15 min and it was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to ˜1.5 mL. In a separate flask, a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 63 mg, 0.41 mmol), 2,6-lutidine (61 μL, 0.55 mmol) and methylene chloride (5 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride, diluted with another portion of methylene chloride (1 mL), dropwise. After addition was complete the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction mixture was diluted with methylene chloride (10 mL) and washed with a saturated aqueous sodium bicarbonate solution (15 mL). The aqueous layer was then extracted with methylene chloride (2×10 mL). The organic layers were then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification using reverse phase HPLC afforded 3-cyclopentyl-2-(1,1-dioxo-2,3-dihydro-benzo[b]thiophen-5-yl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (103 mg, 63%) as a white foam (as a racemic mixture): ES-HRMS m/e calcd for C23H31N3O4S (M+H)+ 446.2108, observed 446.2109; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3 H, CH3), 1.10 (m, 2H, CH2), 1.38-1.79 (m, 8H, 4×CH2), 2.07 (m, 1H, CH), 3.33 (t, J=6.8 Hz, 2H, ArCH2), 3.56 (t, J=6.8 Hz, 2H, SO2CH2), 3.86 (s, 2 H, NCH2), 3.91 (m, 1 H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.51 (m, 3H, Ar), 7.69 (d, Jo=8.5 Hz, 1H, Ar), 10.75 (s, 1H, NH).
Reaction SMILES: O[CH:2]1[O:6][C:5](=O)[CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.O.[NH2:17][NH2:18]>C(O)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:2]=[N:18][NH:17][C:5](=[O:6])[CH:4]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C2=CC(=O)OC2O)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cn[nH]c(=O)c2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A suspension of 5-hydroxy-4-(4-methoxyphenyl)-5H-furan-2-one (2.00 g, 9.7 mmol) in 15 mL of ethanol was stirred as hydrazine hydrate (0.97 g, 2.0 eq) was added in dropwise. The reaction was stirred at 85° C. overnight, and then the solvent was reduced. The solid was collected and washed with cold EtOH to give 1.7 g (87%) of 5-(4-methoxy-phenyl)-2H-pyridazin-3-one: MS m/z 203 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:36]=[CH:37][C:38]([O:40]CC=C)=[O:39])=[CH:6][CH:5]=1.C1COCC1.N1CCOCC1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:44])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:36]=[CH:37][C:38]([OH:40])=[O:39])=[CH:8][CH:9]=1
Reactant: C=CCOC(=O)C=Cc1c(CCOc2ccc(C(=O)OC)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: COC(=O)c1ccc(OCCc2c(C=CC(=O)O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
6.12 g of 4-{2-[2-(2-Allyloxycarbonyl-vinyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (0.098M, 1 eq.) and 1.12 g of tetrakis(triphenylphosphine) palladium (0) (0.001M, 0.1 eq.) were added to 75 mL of THF. To the reaction 8.60 ml of morpholine (0.098M, 1 eq.) was added drop-wise over 20 min. After addition was complete the reaction was stirred at room temperature for 4 hours. The reaction was poured into 250 mL of ethyl acetate and the organic solution was extracted with 1N NaOH (2×75 mL). The aqueous layers were combined and acidified with 1N HCl, the acidic solution was extracted with ethyl acetate (3×75 mL). The organic layers were combined and washed with brine (1×50 mL), dried over magnesium sulfate, filtered and evaporated to yield 4-{2-[1-Benzhydryl-2-(2-carboxy-vinyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester as a yellow oil (5.40 g, 97% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)=[O:8].Cl[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.[OH-].[Na+].O>CS(C)=O>[F:1][C:2]([F:16])([F:17])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1)=[O:8]
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=C(CCCCC(F)(F)F)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(CCCCC(F)(F)F)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A mixture of 3-(6,6,6-trifluorohexanoyl)phenol (6.8 g, 27 mmol) and 2-chloromethylquinoline (4.4 g, 25 mmol) in DMSO (75 ml) containing 2N NaOH solution (14 ml) was stirred at room temperature overnight (13 hrs.). The dark reaction mixture was poured into water (200 ml) and the aqueous solution was extracted with ethyl acetate (4×30 ml). The organic extract was washed with 1N NaOH solution, water and brine and then dried over MgSO4. After removal of all volatiles, a dark liquid was obtained which solidified on standing (7.2 g). This solid was chromatographed (3% ethanol in toluene on silica gel) to obtain a beige color solid (4.5 g; mp 83°-4° C.), which was chromatographed again (15% acetone in hexanes on silica gel) to get a white solid (3.1 g; mp 86°-87° C.). This pure material was recrystallized from hexanes-acetone (trace) to leave the desired compound as a colorless, crystalline solid (2.4 g), mp 88°-88.5° C. (first crop; second crop mp 87°-88° C.).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C1C=CC2N(O)N=NC=2C=1.[C:16]([N:23]1[CH2:31][CH2:30][CH:26]([C:27]([OH:29])=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[C:19]([O:18][C:16]([N:23]1[CH2:24][CH2:25][CH:26]([C:27]([N:3]([CH3:2])[O:4][CH3:5])=[O:29])[CH2:30][CH2:31]1)=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 18 °C
Reaction time: 12 h

Procedure:
A 100 L round-bottomed-flask equipped with a mechanical stirrer, thermocouple and nitrogen inlet was charged with DMF (51 L), N,O-dimethylhydroxyamine hydrochloride (2.62 Kg, 26.55 mol), HOBT (1.2 Kg, 8.85 mol), and N-Boc isonipecotic acid (4.10 Kg, 17.70 mol). The mixture warmed to 18 ° C. as the diisopropylethylamine (4.60 Kg, 6.2 L, 35.41 mol) was added over 15 min. The EDC.HCl (5.09 Kg, 26.55 mol) was added in three portions over 3 h maintaining an internal temperature of 18° C. with gentle cooling. The reaction mixture was held at 18° C. for 12 h. HPLC analysis shows no remaining 1. The reaction mixture was pumped into an extractor containing 74 L of water at 5° C. The resulting solution (39.3 g/L of 2) was extracted with ethyl acetate (4×37 L).