Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:22](=[O:25])(=[O:24])[NH2:23])[C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:7]([OH:9])=[O:8])([O-])=O.[H][H].[OH-].[Na+]>O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:22](=[O:24])(=[O:25])[NH2:23])[C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15])[C:7]([OH:9])=[O:8]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1S(=O)(=O)c1ccccc1
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1S(=O)(=O)c1ccccc1

Procedure:
A suspension of 3-nitro-4-phenylsulphonyl-5-sulphamyl-benzoic acid (6 g) in water (300 ml) was hydrogenated at room temperature and 1.1 atmospheres hydrogen pressure after addition of Pd-on-carbon catalyst (0.3 g catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the reaction mixture was neutralized by addition of 2N sodium hydroxide, and the catalyst was removed from the resulting suspension by filtration. The filtrate was adjusted to a pH of 2.5 by addition of 4N hydrochloric acid, and the precipitated 3-amino-4-phenylsulphonyl-5-sulphamyl-benzoic acid was collected by suction. After recrystallization from aqueous ethanol, the acid had a melting point of 278° C (decomp.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[I-:16].[Na+]>CC(C)=O>[I:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(OCCCCCCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCCCCCI)cc1
Reaction time: 8 h

Procedure:
To a solution of 32.7 g (146 mmol) of 4-(5-chloropentoxy) benzonitrile in 350 mL acetone is added 38.3 g (150 mmol) of sodium iodide in 230 mL of acetone. The reaction is heated to reflux and stirred overnight. The acetone is removed under reduced pressure and the residue partitioned between water and ether. The ethereal layer is dried, filtered and evaporated to give 4-(5-iodopentoxy) benzonitrile, m.p. 51°-54° C.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]>>[CH2:16]([O:15][C@@H:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:20][C:21]1[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)[O:24][C:25]=1[CH3:26])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:18])[CH3:17]
Reactant: CCO[C@@H](Cc1ccc2[nH]ccc2c1)C(=O)OC
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Product: CCO[C@@H](Cc1ccc2c(ccn2Cc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1)C(=O)O
Yield: 50 %

Procedure:
Starting from (S)-2-ethoxy-3-(1H-indol-5-yl)-propionic acid methyl ester and 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole, the title compound was obtained in 50% yield as a pale yellow solid. MS: (M−H)− 471.1.
Reaction SMILES: [F:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH2:12]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH:17][C:3](=[O:5])[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[F:1])[CH3:13]
Reactant: O=C(O)C(F)c1ccccc1
Reactant: CCOC(=O)[C@H](C)N
Product: CCOC(=O)[C@H](C)NC(=O)C(F)c1ccccc1

Procedure:
Following General Procedure BF above, and using α-fluorophenyl acetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel (Rf=0.75 in 1:1 EtOAc:hexane) and purification was by chromatography on silica gel using 1:2 ethyl acetate/hexanes as the eluent.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:21]1[O:29][CH:22]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[ClH:30]>C(OCC)(=O)C.CS(C)=O>[ClH:30].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:21][CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:29])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: c1ccc(C2CO2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: OC(COC1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 5.00 g of 1-benzyl-4-hydroxypiperidine, 1.97 g of potassium tert-butoxide and 4 ml of dimethyl sulfoxide was heated to 80° C. Thereto was dropwise added 2.10 g of styrene oxide over 40 minutes. The resulting mixture was stirred for 3 hours at the same temperature. The reaction mixture was added to a mixture of 100 ml of ice water and 80 ml of ethyl acetate. The mixture was adjusted to pH 11.5 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=10/1). The resulting oily product was dissolved in 8 ml of ethanol. To the solution were added 1 ml of a 6N dry hydrogen chloride-ethanol solution and 20 ml of diethyl ether. The mixture was stirred for 30 minutes at room temperature. The resulting crystals were collected by filtration, washed with a mixture of 2 ml of ethanol and 2 ml of diethyl ether, and dried to obtain 930 mg of 2-(1-benzylpiperidin-4-yloxy)-1-phenylethanol hydrochloride (compound No. 113).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH2:15][N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[N:14]=1
Reactant: OC1CCNCC1
Reactant: O=Cc1cccc(Br)n1
Product: OC1CCN(Cc2cccc(Br)n2)CC1

Procedure:
10] To 4-hydroxypiperidine (143 mg, 1.41 mmol) was added a solution of 6-bromo-2-pyridine-carboxaldehyde (200 mg, 1.08 mmol) to give 2-bromo-6-[(4-hydroxypiperidyl)methyl]-pyridine as a white -solid. MS m/z: 271.0 (M+H). Calc'd for C11H15BrN2O—271.15.
Reaction SMILES: [Mg].[C:2]([O:8][CH:9]([CH3:11])[CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[C:12](Cl)(=[O:14])[CH3:13].S(=O)(=O)(O)O>C(O)C.ClC(Cl)(Cl)Cl>[C:4]([CH:3]([C:12]([CH3:13])=[O:14])[C:2]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])(=[O:5])[CH3:6]
Reactant: CC(=O)CC(=O)OC(C)C
Reactant: CC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CC(=O)C(C(C)=O)C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 103.3 %

Procedure:
5 ml of tetrachloromethane are added to 23.3 g (1 mol) of magnesium turnings in 50 ml of dry ethanol under nitrogen and in the absence of moisture. After the beginning of gas evolution, a solution of 147.1 g (1 mol) of isopropyl acetoacetate in 100 ml of dry ethanol was slowly added dropwise, the reaction mixture being kept at the reflux temperature. Stirring was carried out for a further 4 hours at this temperature, after which the mixture was cooled. 78.5 g (1 mol) of acetyl chloride was slowly added dropwise at 10° C. Stirring was continued for a further 4 hours at room temperature and hydrolysis was then effected with a mixture of 450 ml of ice water and 25 ml of concentrated sulfuric acid. The organic phase was separated off, dried, and evaporated down under reduced pressure. 192.3 g of >96% pure isopropyl 2-acetylacetoacetate were obtained.
Reaction SMILES: [CH2:1]([CH:8]([NH2:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37](O)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23]>>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37]([NH:21][CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23]
Reactant: NC(Cc1ccccc1)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Product: CCOC(=O)c1ccc(CC(=O)NC(Cc2ccccc2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared analogously to Example 19 from α-benzyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11](O)[C:10]=2[CH:21]=1)(=[O:5])=[O:4].O1CCOCC1.[ClH:29]>CCOCC>[Cl:29][CH:11]1[C:10]2[CH:21]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:22])[CH3:1])[CH:7]=[CH:8][C:9]=2[CH:15]=[CH:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=2
Reactant: Cl
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)C(O)c1ccccc1C=C2
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(Cl)c1ccccc1C=C2
Reaction time: 5 h

Procedure:
A solution of 1.0 g. (0.00317 mole) of 3-dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten-5-ol in a mixture of 2 ml. of dry dioxane and 2 ml. of absolute ether is cooled in ice and saturated with dry hydrogen chloride. The mixture is allowed to stand at room temperature for 5 hours and then is refrigerated overnight. The white crystalline product is collected, washed with petroleum ether, and dried in a vacuum desiccator over calcium chloride. The yield of 5-chloro-3-dimethylsulfamoyl-5H-dibenzo[a,d]cycloheptene is 600 mg., m.p. 139.5°-143.5° C. Dilution of the mother liquor with petroleum ether gives a second crop which is recrystallized from a mixture of ether and a petroleum ether affording 250 mg., m.p. 138.5°-142.5° C.
Reaction SMILES: [CH:1]1([CH2:4][C:5](Cl)=[O:6])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH3:21])[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:11][CH:10]=1>ClC1C=CC=CC=1.C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].[Zn]>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]([CH3:21])[C:17]([C:5](=[O:6])[CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:18][C:19]=2[CH3:20])=[CH:13][CH:14]=1
Reactant: O=C(Cl)CC1CC1
Reactant: Cc1ccn(C)c1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: Cc1cc(C(=O)CC2CC2)n(C)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.1 %

Procedure:
2-cyclopropylacetyl chloride (11.83 g, 100.00 mmol) solution in chlorobenzene (60 ml) was added to the stirred solution of 2-(4-chlorophenyl)-1,3-dimethyl-1H-pyrrole (prepared according to the procedure given in Kazuhiko Taguchi et al., Tetrahedron Letters, 2005, 46, 4539-4542) (17.10 g, 83.00 mmol) and Zinc (10.87 g, 166.00 mmol) in toluene (100 ml) at 25° C. The reaction mixture was stirred at 25° C. for 3 h. The progress of the reaction was monitored by TLC. The mixture was diluted with a saturated solution of sodium bicarbonate (100 ml) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic layer was washed with water (1×50 ml) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using 5-10% ethyl acetate in hexanes as an eluent to obtain the title compound 3(7.20 g, 30.1%). MS: m/z 288 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][C:10]2([CH2:13][CH:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][C:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:26][C:27]1([NH:31][C:20]([CH:17]2[CH2:16][CH2:15][N:14]([CH:12]3[CH2:13][C:10]4([CH2:23][CH2:24][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]4)[CH2:11]3)[CH2:19][CH2:18]2)=[O:22])[CH2:30][CH2:29][CH2:28]1
Reactant: CC1(N)CCC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(N3CCC(C(=O)O)CC3)C2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NC(=O)C2CCN(C3CC4(CCN(C(=O)OC(C)(C)C)C4)C3)CC2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
1-[6-(tert-Butoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine-4-carboxylic acid was dissolved in DMF (5 mL) and (1-methylcyclobutyl)amine hydrochloride (0.37 g, 3.03 mmol), HATU (0.844 g, 2.22 mmol) and DIPEA (1.305 g, 10.1 mmol) were added. The reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 μm, 60 A, 50 mL per min, gradient 0% to 10% MeOH in DCM]) to give tert-butyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.627 g, 76.7%) as a white foam.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[S:36])=[C:30]([CH:38]([CH3:40])[CH3:39])[CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:2]([NH:1][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[N:15]=[CH:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=4)[N:12]=3)[CH:6]=2)=[O:3])=[S:36])=[C:30]([CH:38]([CH3:40])[CH3:39])[CH:29]=1
Reactant: CC(C)c1cc(F)ccc1NC(N)=S
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: CC(C)c1cc(F)ccc1NC(=S)NC(=O)NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(4-fluoro-2-isopropylphenyl)thiourea and isolated as an off-white solid (0.242 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CC#N.CCOC(C)=O>[C:20]([O:19][C@@H:18]1[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[O:29][C@H:17]1[N:6]1[C:5]2[CH:7]=[C:8]([Cl:12])[CH:9]=[C:10]([Cl:11])[C:4]=2[N:3]=[C:2]1[Cl:1])(=[O:22])[CH3:21]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Clc1cc(Cl)c2[nH]c(Cl)nc2c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3c(Cl)cc(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
To a suspension of 1.362 g (6.15 mmol) of 2,4,6-trichlorobenzimidazole in 31 mL of MeCN, was added 1.52 mL (6.15 mmol) of BSA. The reaction mixture was stirred at 80° C. for 15 min to give a clear solution. This solution was treated with 2.153 g (6.675 mmol) of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose and 1.426 mL (7.380 mmol) of TMSOTf at 80° C. for 1 h. The reaction mixture was cooled and diluted with EtOAc (150 mL). The EtOAc solution was washed with sat. NaHCO3 solution (150 mL×2), sat. NaCl solution (150 mL), dried (Na2SO4), and evaporated. The residue was coevaporated with MeOH and then suspended in 50 mL of hot MeOH. The suspension was cooled, filtered, and the solid product was washed with MeOH to give 2.103 g of 80 as white crystals (This product showed one spot on TLC). The mother liquor was evaporated and the residue was chromatographed on a silica column (2.5×20 cm, eluted with CHCl3 and 0.5% MeOH/CHCl3). Evaporation of fractions 20-24 (20 mL per fraction) and recrystallization from MeOH gave an additional 0.258 g of 80 as white crystals. The total yield of 80 was 2.361 g (80%). MP: 198°-200° C. MS: (El) m/e 480.0069 (4%, for C18H1735ClN237ClN2O7 : M+ =480.0072). 1 H NMR (DMSO-d6): δ7.89 (d, 1, 7-H, J7-5 =2.0 Hz), 7.58 (d, 1, 5-H), 6.26 (d, 1, 1'-H, J1'-2' =7.0 Hz), 5.54 (t, 1, 2'-H, J2'-3' =7.0 Hz), 5.44 (dd, 1, 3'-H, J3'-4' =4.5 Hz), 4.48, 4.38 (2×m, 3, 4'-H and 5'-H), 2.14, 2.02 (2×s, 9, 3×Ac). 13H NMR (DMSO-d6): δ169.84, 169.37, 169.09 (3×COCH3), 140.91 (C2), 137.39 (C3a), 134.14 (C7a), 128.47 (C6), 123.66 (C4), 123.25 (C5), 111.06 (C7), 86.91 (C1'), 79.58 (C4'), 70.54 (C2'), 68.55 (C3'), 62.47 (C5'), 20.48, 20.19, 19.90 (3×COCH3). Anal. Calcd. for C18H17Cl3N2O7 : C, 45.07; H, 3.57; N, 5.84. Found: C, 45.08; H, 3.62; N, 5.87.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20]2=[O:25])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[Cl:26][C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][C:37]=1F)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([C:30](=[O:31])[N:32]([CH3:33])[CH3:34])[CH:35]=[CH:36][C:37]=1[O:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20]2=[O:25])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6]
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Reactant: CN(C)C(=O)c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N(C)C)cc3Cl)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Yield: 31 %

Procedure:
A mixture of 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 18) (206 mg, 0.6 mmol), 3-chloro-4-fluoro-N,N-dimethyl-benzamide (CAS no. 871657-07-7) (192 mg, 0.9 mmol) and potassium carbonate (166 mg, 1.2 mmol) in N,N-dimethylacetamide (5 mL) was stirred at 160° C. for 6 hours. The solution was evaporated under reduced pressure, the residue dissolved in ethyl acetate (40 mL), washed with water (2×20 mL) and brine (10 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica eluting with 0-4% methanol in DCM to afford the product (98 mg, 31%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.27 (m, 1H), 2.54-2.67 (m, 1H), 2.55 (s, 3H), 2.93 (s, 3H), 2.98-3.19 (m, 6H), 3.34-3.57 (m, 2H), 4.92 (t, 1H), 6.86 (s, 1H), 7.06 (d, 1H), 7.16 (s, 1H), 7.33 (d, 1H), 7.40 (s, 1H), 7.57 (s, 1H), 8.13 (s, 1H), 8.53 (s, 1H), 9.51 (s, 1H); m/z 524 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1B(O)O.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][CH:32]=[N:33]3)=[CH:28][CH:27]=2)[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][CH:32]=[N:33]3)=[CH:28][CH:27]=2)[CH:20]=1
Reactant: Clc1cc(Oc2ccc3cccnc3c2)ncn1
Reactant: COCOc1cc(C(F)(F)F)ccc1B(O)O
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: Cc1ccccc1
Solvent: CCO
Product: COCOc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Temperature: 140 °C

Procedure:
To a suspension of 2-methoxymethoxy-4-trifluoromethylphenyl-boronic acid, (Example 135(b)), (220 mg, 0.87 mmol) and 7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example 102(a)), (150 mg, 0.58 mmol) in toluene/EtOH (1:4, 3.8 mL) was added 2 M K2CO3 (1.2 mL, 2.3 mmol) and Pd(PPh3)4 (34 mg, 0.030 mmol, Strem). The reaction mixture was stirred and heated by microwave synthesizer at 140° C. for 10 min. The mixture was partitioned between CH2Cl2 and 1 N NaOH. The organic phase was separated, and the aqueous phase was extracted with CH2Cl2. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (MeOH/CH2Cl2 1:125 and then 1:100) afforded a light-yellow gum. The title compound was obtained as a white solid after recrystallization from MeOH. MP: 98.8-99.4° C. MS (ESI, pos. ion) m/z: 428 (M+1). Anal. Calcd for C22H16F3N3O3: C, 61.83; H, 3.77; N, 9.83. Found: C, 62.13; H, 3.87; N, 9.52.
Reaction SMILES: [OH:1]O.[Se](=O)=O.[CH2:6]([O:8][C:9]([C:11]1[N:12]([CH3:28])[C:13]([CH2:26][CH3:27])=[C:14]([C:24]#[N:25])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=1)=[O:10])[CH3:7].Cl>>[CH2:6]([O:8][C:9]([C:11]1[N:12]([CH3:28])[C:13]([CH2:26][CH3:27])=[C:14]([C:24]#[N:25])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:1])=[O:23])=[CH:18][CH:17]=1)=[O:10])[CH3:7]
Reactant: OO
Reactant: CCOC(=O)c1c(-c2ccc(C=O)cc2)c(C#N)c(CC)n1C
Agent: Cl
Agent: O=[Se]=O
Product: CCOC(=O)c1c(-c2ccc(C(=O)O)cc2)c(C#N)c(CC)n1C
Reaction time: 18 h

Procedure:
Add 30% hydrogen peroxide (0.66 mL, 5.8 mmol) and selenium dioxide (0.016 g, 0.15 mmol) to 4-cyano-5-ethyl-3-(4-formyl-phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-152), and heat to reflux with stirring. After 18 hours, cool the reaction mixture and pour into 1N HCl. Extract the quenched reaction with methylene chloride. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Recrystallize the residue from ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 325.1 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].C(N(CC)CC)C.[C:31]([O:34][CH2:35][C:36](Cl)=[O:37])(=[O:33])[CH3:32]>O1CCCC1>[F:20][C:8]1[C:9]([F:19])=[C:10]([C:15]([F:17])([F:18])[F:16])[C:11]([F:14])=[C:12]([F:13])[C:7]=1[N:6]1[C:2]([NH:1][C:36]([CH2:35][O:34][C:31]([CH3:32])=[O:33])=[O:37])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]1
Reactant: Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Yield: 12.4 %

Procedure:
To a stirred solution of 0.68 gram (0.0020 mole) of 5-amino-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-4-nitropyrazole and 0.42 gram (0.0042 mole) of triethylamine in 20 mL of tetrahydrofuran was added dropwise a solution of 0.55 gram (0.0040 mole) of acetoxyacetyl chloride in 8 mL of tetrahydrofuran. The reaction mixture was heated at reflux for two hours. An additional 0.43 gram of acetoxyacetyl chloride and 0.22 gram of triethylamine were added, and the mixture was heated at reflux for 20 minutes. The mixture was cooled and filtered,, and the filtrate was evaporated under reduced pressure, leaving an oil. This oil was purified by column chromatography on silica gel, eluted with ethyl acetate/n-hexane (50:50) to yield 0.11 gram of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonyloxymethylcarbonylamino-4-nitropyrazole as a waxy solid, Compound 14 of Table 1. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:20]=[C:19](F)[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[N:6][C:7]=1[NH:8][CH3:9].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:20]=[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[N:6][C:7]=1[NH:8][CH3:9]
Reactant: C1CNCCN1
Reactant: CNc1ncc(Oc2cc(F)ccc2C(=O)OC)cc1Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CNc1ncc(Oc2cc(N3CCNCC3)ccc2C(=O)OC)cc1Cl

Procedure:
A solution of EXAMPLE 377E (0.230 g) and piperazine (0.255 g) in dimethylsulfoxide (3 mL) was heated to 85° C. for 1 hour. The reaction was cooled and diluted with ethyl acetate (75 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated to give the title compound.