Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.[OH:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)\[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[C:32]1(/[C:22](=[N:21]/[O:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:2][C:3]3[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[O:5][N:4]=3)=[CH:39][CH:38]=2)/[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Reactant: ClCc1noc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2noc(-c3ccccc3)n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
A mixture of 3-chloromethyl-5-phenyl-1,2,4-oxadiazole (362 mg), ethyl E-6-(4hydroxybenzyloxyimino)-6-phenylhexanoate (600 mg), potassium carbonate (467 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-6-phenyl-6-[4-(5-phenyl-1,2,4-oxadiazol-3-ylmethoxy)benzyloxyimino]hexanoate (649 mg, yield 75%) as a colorless oil from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: Cl[CH:2]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:3]1[S:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[N:24][CH:25]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH:13]1([CH:2]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[N:24][CH:25]=2)[C:3]2[S:4][C:5]3[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1c(C(Cl)C2CCCCC2)sc2ccccc12
Reactant: COC(=O)c1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCCC2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a mixture of 2-[chloro(cyclohexyl)methyl]-3-methyl-1-benzothiophene (664 mg) synthesized in Example A10(2), methyl 5-aminopyridine-2-carboxylate (362 mg), sodium iodide (714 mg) and N,N-dimethylformamide (10 mL) was added sodium carbonate (505 mg), and the mixture was stirred at 80° C. overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (460 mg, 49%) as a pale-yellow solid.
Reaction SMILES: [CH:1]1[C:4]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]4[CH:26]=[CH:25][C:22]5[CH:23]=[CH:24][C:21]=5[CH:20]=4)[C:11]=3[C:12]#[N:13])=[CH:8][C:3]=2[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:23]1[C:22]2[CH:25]=[CH:26][C:19]([O:18][C:14]3[CH:15]=[CH:16][CH:17]=[C:10]([O:9][C:7]4[CH:6]=[CH:5][C:4]5[CH:1]=[CH:2][C:3]=5[CH:8]=4)[C:11]=3[CH2:12][NH2:13])=[CH:20][C:21]=2[CH:24]=1
Reactant: N#Cc1c(Oc2ccc3c(c2)C=C3)cccc1Oc1ccc2c(c1)C=C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1c(Oc2ccc3c(c2)C=C3)cccc1Oc1ccc2c(c1)C=C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 500 ml, 4-necked round-bottomed flask equipped with an overhead mechanical stirrer, a thermometer/adaptor, a reflux condensor and a funnel was added 2,6-di-(4-benzocyclobutenoxy)benzonitrile followed by 260 ml of anhydrous diethyl ether. The resultant mixture was placed in an ice bath and stirred under anitrogen atmosphere. When the internal temperature reached 0° C., lithium aluminum hydride was added through the attached funnel in 3 portions (0.69 g, 0.96 g, 0.50 g), each addition followed by washing the funnel with about 10 ml Et2O, over a period of 15 minutes. The resulting mixture was stirred at 0° C. for 20 minutes, then the ice bath was removed and the mixture was allowed to warm to room temperature. The reaction mixture was then refluxed gently for 17 hours.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([O:11][C:12]([C:14]1[C:18]([CH3:19])=[C:17]([C:20]2[Se:21][CH:22]=[CH:23][CH:24]=2)[N:16]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:15]=1)=[O:13])[CH3:10]>C(#N)C>[CH2:9]([O:11][C:12]([C:14]1[C:18]([CH3:19])=[C:17]([C:20]2[Se:21][C:22]([Br:8])=[CH:23][CH:24]=2)[N:16]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:15]=1)=[O:13])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc[se]2)c1C
Solvent: CC#N
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Br)[se]2)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.9 %

Procedure:
NBS (1.6 g, 9.34 mmol) was added in several small portions to a magnetically stirred solution of 1-(2,4-dichloro-phenyl)-4-methyl-5-selenophen-2-yl-1H-pyrazole-3-carboxylic acid ethyl ester (2.0 g, 4.67 mmol) in acetonitrile at 0° C. The resulting mixture was stirred at room temperature for 48 h. The precipitate was filtered out, washed with saturated aqueous sodium sulfite and cold water, and then dried under vacuum to give the desired compound (2.2 g, 92%) as a white solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]2[CH2:19][CH2:18][CH:17]([C:20](N)=[O:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.[OH-:23].[K+].O.Cl>C(O)CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:21])=[O:23])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: [OH-]
Reactant: NC(=O)C1CCC([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: O=C(O)[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Temperature: 180 °C

Procedure:
42 g of crude 4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]-cyclohexyl]cyclohexanecarboxamide were suspended in 500 ml of ethylene glycol while gassing with argon and then treated with 19 g of solid potassium hydroxide. The mixture was heated to 180° C. (bath temperature) for 5 hours while stirring. After cooling the reaction mixture was poured into 500 ml of water, acidified to pH about 3 with 10 percent hydrochloric acid and extracted three times with 300 ml of methylene chloride each time. The combined organic phases were washed once with 500 ml of 1 percent hydrochloric acid and twice with 500 ml of water each time, dried over magnesium sulfate, filtered and evaporated. The dark brown crude product (41 g) was purified by chromatography on silica gel with ethyl acetate. Crystallization of the product obtained (36 g) from acetone gave 13.8 g of pure trans-4-[trans-4-(2-(1,3-dioxolan-2-yl) ethyl]cyclohexyl]cyclohexanecarboxylic acid. Working-up of the mother liquor gave a further 2.5 g of pure product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[NH2:7])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.O>[C:20]([NH:7][C:6]1[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(NC(=O)c2ccccc2)cc(C(C)=O)c1
Reaction time: 1 h

Procedure:
Compound 26, FIG. 7E.26: A solution of 3,5-diacetylaniline (0.885 g) in tetrahydrofuran (10 mL) containing 0.45 mL pyridine was treated with 0.65 mL benzoyl chloride. The mixture was stirred 1 hr, then treated with 1 mL water and stirred 15 min. The mixture was then diluted with 40 mL water and stirred 30 min. Filtration and washing with water and isopropanol gave colorless needles of N-benzoyl-3,5-diacetylaniline, 1.36 g, mp 188°-189° C. A suspension of N-benzoyl-3,5-diacetylaniline (0.844 g) in aq. 87.5% ethanol (8 mL) containing 0.73 g aminoguanidine hydrochloride and a trace of HCl was heated at reflux for 18 hr. Cooling and filtration gave 1.357 g of N-benzoyl-3,5-diacetyl bis(amidinohydrazone) dihydrochloride (Compound 26), mp 268°-72° C.
Reaction SMILES: CO[C:3](=[O:22])[CH:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH3:14])[N:13]=1)=[S:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][C:12]1[N:13]=[C:9]([N:8]2[C:3](=[O:22])[CH:4]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:5][C:6]2=[S:7])[S:10][CH:11]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=S)Nc1nc(C)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1csc(N2C(=O)C(Cc3ccccc3)NC2=S)n1
Temperature: 25 °C
Yield: 25.4 %

Procedure:
A solution of N-[[(4-methyl-2-thiazolyl)amino]thioxomethyl]-DL-phenylalanine methyl ester (0.94 g, 2.80 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 24 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl acetate-hexanes to provide 216.1 mg (25%) of the titled product:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[I:14]I.Cl>CCCCCC.C1(C)C=CC=CC=1.CCOCC>[I:14][C:8]1[CH:9]=[CH:10][C:5]([C:4]([F:12])([F:13])[F:3])=[CH:6][C:7]=1[OH:11]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: II
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Oc1cc(C(F)(F)F)ccc1I
Reaction time: 8 h
Yield: 102.1 %

Procedure:
To a round bottom flask under N2 was added 14.2 g (0.296 mole) of sodium hydride, 50% in oil. The NaH was washed twice with hexane, and 33.15 g (0.205 mole) of m-trifluoromethylphenol in 1 liter of toluene was added. After five minutes 51.9 g (0.205 mole) of iodine was added all at once, and the solution allowed to stir overnight. The reaction was poured into 3N HCl, ether added, and the separated organic layer washed with water, brine and dried with MgSo4. The solvent was evaporated in vacuo to give 60.3 g (100% yield) of 2-iodo-5-trifluoromethylphenol, mp 36°-38° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9]([NH2:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C.Cl[Cu]>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=NN(c2ccccc2)CC1
Agent: Cl[Cu]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccn(-c2ccccc2)n1
Reaction time: 5 h
Yield: 30.4 %

Procedure:
Using the same apparatus as in Example 1 and following the same modalites, 5 g (0.031 mole) of 1-phenyl-3-amino-2-pyrazoline were dissolved in 15 ml of acetic acid with addition of 0.2 g (0.00201 mole) of CuCl, under an oxygen head. Oxidation was completed after about 5 hours. Acetic acid was neutralized with sodium bicarbonate, it was filtered and the precipitate was extracted with ether. By evaporating the ethereal solution, 1.5 g of 1-phenyl-3-aminopyrazole were obtained.
Reaction SMILES: [CH:1]([N:4]1[C:11]2[C@@H:10]3[CH2:12][C@@H:9]3[CH2:8][C:7]=2[C:6]([C:13]([OH:15])=O)=[N:5]1)([CH3:3])[CH3:2].[C:16]1([C:22]([NH2:25])([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:23][C:22]([NH:25][C:13]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:12][C@H:10]3[C:11]=2[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=1)=[O:15])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:24]
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)n1nc(C(=O)O)c2c1[C@@H]1C[C@@H]1C2
Product: CC(C)n1nc(C(=O)NC(C)(C)c2ccccc2)c2c1[C@@H]1C[C@@H]1C2

Procedure:
The title compound was prepared in a manner similar to that described in Method G, using (1aR,5aR)-2-Isopropyl-1a,2,5,5a-tetrahydro-1H-2,3-diazacyclopropa[a]pentalene-4-carboxylic acid and 2-phenylpropan-2-amine. LCMS m/z=324.6 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:3]>CO.Cl.O1CCOCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:6]2[CH:7]=[C:8]3[C:12](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)[NH:11][CH:10]=[C:9]3[CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(F)cc4)cc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)c1cc(-c2ccc(F)cc2)cc2c(C3CCNCC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinecarboxylate (92.9 g, 0.205 mmol) in methanol (10 mL), HCl in dioxane (4M, 2.01 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the resulting residue was partitioned between ethyl acetate (50 mL) and 5% of aqueous NaOH (50 mL). The aqueous layer washed with ethyl acetate (2×50 mL) and the combined organic phases were dried and concentrated under reduced pressure to give desired product (55.9 mg, 78%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:10][C:11]2[N:12]([C:14]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[N:15][N:16]=2)[N:13]=1.Cl>C(Cl)Cl.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)=[CH:10][C:11]2[N:12]([C:14]([CH2:17][CH:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[N:15][N:16]=2)[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Clc1ccc(-c2cc3nnc(CC4CCNCC4)n3nc2-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 170.8 %

Procedure:
To a solution of tert-butyl 4-((6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)piperidine-1-carboxylate (Example 19) (0.6 g, 1.11 mmol) in CH2Cl2 (15 mL) was added 2 M HCl in diethyl ether (5 mL. The resulting mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. The obtained residue was evaporated with CH2Cl2 three times, dried in high vacuum overnight to afford 450 mg (85%) of the title compound as an off-white powder. HPLC/MS (method A): retention time=3.01 min, (M+H)+=438.2.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].I[C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1>O1CCOCC1.CO>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=2)=[CH:18][CH:17]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Oc1ccc(I)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Oc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 110 °C
Reaction time: 19 h

Procedure:
Under an N2 atmosphere 21.7 mL 2 M Na2CO3 solution and 250 mg (0.22 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 8.0 g (21.7 mmol) 5-iodo-pyridin-2-ol and 3.81 g (23.9 mmol) 4-chlorophenyl-boric acid in 120 mL 1,4-dioxane and 30 mL dry MeOH and the reaction mixture is stirred for 19 h at 110° C. The mixture is evaporated down i. vac., the residue is combined with water, the precipitate is filtered off, washed with water and dried at 40° C. in the circulating air dryer until a constant weight is obtained.
Reaction SMILES: [NH2:1][C:2](=[N:31]O)[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:7].CCO.[ClH:36]>[Pd].O>[ClH:36].[NH2:31][C:2](=[NH:1])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:7]
Reactant: CC(C)c1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2cccc(C(N)=NO)c2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2cccc(C(=N)N)c2)cc1
Reaction time: 14 h
Yield: 61.6 %

Procedure:
A mixture of N1-[3-(amino(hydroxyimino)methyl)benzoyl]-N2-(4-isopropylbenzoyl)-4-hydroxy-1,2-benzenediamine (209 mg, 0.48 mmol), EtOH (5 mL), H2O (2.5 mL), 1N HCl (0.5 mL, 0.5 mmol), and 10% Pd/C (217 mg) was hydrogenated at 1 atm. for 14 h. The reaction was filtered through diatomaceous earth with hot methanolic washes. The filtrate was concentrated and the residue was resubjected to the hydrogenation conditions using 10% Pd/C (189 mg). After 6 h, the reaction mixture was filtered through diatomaceous earth with hot methanolic washes. The filtrate was concentrated to give the title compound as a solid (134 mg, 62%); NMR(300 MHz, DMSO-d6): δ10.27 (s, 1H), 9.89 (s, 1H), 9.45 (s, 2H), 9.14 (s, 2H), 8.42 (s, 1H), 8.23 (d, J=7.5, 1H), 7.94 (d, J=7.2, 1H), 7.86 (d, J=8.1, 2H), 7.73 (t, J=7.8, 1H), 7.28 (m, 4H), 6.65 (d, J=8.7, 1H), 2.90 (m, 1H), 1.19 (s, 3H), 1.17 (s, 3H); MS(FD): 399.2 (M−OH).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1(O)[CH2:14][CH2:13][CH2:12]1.S(=O)(=O)(O)O.[H][H]>C(O)C.[Pd]>[CH:11]1([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C:2]([F:17])([F:1])[F:16])[CH2:12][CH2:13][CH2:14]1
Reactant: OC1(c2cnccc2OCC(F)(F)F)CCC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: FC(F)(F)COc1ccncc1C1CCC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a solution of 1-[4-(2,2,2-Trifluoro-ethoxy)-pyridin-3-yl]-cyclobutanol (Example 108b, 3.88 g, 15.7 mmol) in ethanol (50 ml) under argon atmosphere was added sulfuric acid 97% (4.62 g, 2.51 ml, 47.1 mmol) and palladium(0) on charcoal 10% (384 mg, 3.61 mmol). The reaction vessel was pressurized with hydrogen to 2.5 bar and stirred at 50° C. for 18 hours. The reaction mixture was cooled down to room temperature, filtered through a pad of Celite and the filter cake was washed twice with ethanol. The filtrate was evaporated down to dryness, the residue was dissolved in ethylacetate and extracted with an 2.0M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. The organic phases were combined, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (3.05 g, 84%) as yellow oil. MS (ESI, m/z): 232.6 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:3]=1[C:4]([NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])=O.S(Cl)(Cl)=O>ClCCl>[CH3:10][C:7]1([CH3:11])[CH2:8][O:9][C:4]([C:3]2[C:2]([F:1])=[CH:15][C:14]([F:16])=[CH:13][C:12]=2[F:17])=[N:6]1
Reactant: CC(C)(CO)NC(=O)c1c(F)cc(F)cc1F
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2c(F)cc(F)cc2F)=N1
Temperature: 25 °C

Procedure:
To a solution of 2,4,6-trifluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide (43.8 g, 177.1 mmol) in dry dichloromethane (400 mL) was added thionyl chloride (58.9 ml, 415 mmol) via slow drop-wise addition over 25 minutes (reaction flask was immersed in an ice bath part way through the addition to control the temperature). After complete addition the material was stirred at ambient temperature over night. The volume was reduced to 30% by concentration under vacuum. To that was added ether (200 ml) and a solid precipitate (39.94 g off-white solid) was collected by filtration. The ether filtrate was set aside and the solid material was taken up in water (120 ml) and treated with an aqueous solution of sodium hydroxide (2N, 55 ml). Ethyl acetate (120 ml) was added and the mixture was transferred to a separatory funnel and shaken. The organic phase was collected and washed with an equal volume of water. The ethyl acetate phase was collected and the aqueous phases were back extracted with ethyl acetate (2×100 ml). The combined organic phases were dried (magnesium sulfate), filtered and concentrated in vacuo to provide the desired as a pure off-white solid (33.98 g). (M+H)+=230 m/e.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][C:17]2([O:24][CH2:23][CH2:22][O:21]2)[C:16]1([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([OH:30])[CH3:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.CCOCC.[O-2].[O-2].[O-2].[Cr+6]>[CH2:7]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][C:17]2([O:21][CH2:22][CH2:23][O:24]2)[C:16]1([CH3:31])[CH2:25][CH2:26][CH2:27][C:28](=[O:30])[CH3:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(O)CCCC1(C)C(OCc2ccccc2)CCCC12OCCO2
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)CCCC1(C)C(OCc2ccccc2)CCCC12OCCO2
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
A solution of pyridine (70.3 g, 0.89 mol) and chromium trioxide (44.5 g, 0.445 mol) in methylene chloride (1.8 l) in a nitrogen atmosphere is stirred for 45 minutes. Celite (180 g) is added followed by (2S*, 3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-hydroxypentyl)-cyclohexane (25.8 g, 0.074 mol) in methylene chloride (100 ml). The mixture is stirred for 90 minutes at 23° C. The mixture is then filtered and the celite cake is washed with methylene chloride (10×200 ml). The filtrate and washings are combined and the solvents are removed under reduced pressure to give a dark oil, which is diluted with ether (750 ml) and filtered. The ether phase is dried (MgSO4) and the solvents are removed at reduced pressure. The crude product (21 g) is chromatographed on SilicAR CC-7 (300 g, Mallinckrodt) in hexane. Elution with 6% ethyl acetate/hexane gives (2S*, 3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxopentyl)-cyclohexane as a clear colorless oil (15.7 g, 61%): ir (neat) 1712 cm-1 (CO); nmr (CDCl3)δ 1.06 (s, 3H, --CH3), 2.04 (s, 3H, ##STR50## 2.30 (m, 2H, --CH2 --CO), 3.50 (m, 1H, ##STR51## 3.98 (s, 4H, ketal), 4.55 (d of d, J=10 Hz, 2H, --O--CH2Ph), 7.20 (s, 5H, aromatic).
Reaction SMILES: C(N=S(C1C=CC(CN2C(=O)C3C(=CC=CC=3)C2=O)=CC=1)(C)=[O:5])#N.[C:25]([N:27]=[S:28]([C:30]1[CH:31]=[CH:32][C:33]([N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])=[N:34][CH:35]=1)[CH3:29])#[N:26]>>[C:25]([N:27]=[S:28]([C:30]1[CH:31]=[CH:32][C:33]([N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])=[N:34][CH:35]=1)([CH3:29])=[O:5])#[N:26]
Reactant: CS(=NC#N)c1ccc(N2C(=O)c3ccccc3C2=O)nc1
Reactant: CS(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Product: CS(=O)(=NC#N)c1ccc(N2C(=O)c3ccccc3C2=O)nc1

Procedure:
The title compound is prepared in analogy to preparation 6c, substituting 2-(4-(N-cyano-S-methylsulfinimidoyl)benzyl)isoindoline-1,3-dione with 2-(5-(N-cyano-S-methylsulfinimidoyl)pyridin-2-yl)-isoindole-1,3-dione (preparation 16c). ESI mass spectrum: [M+H]+=341; r.t. HPLC: 0.88 min (Z018_S04).