Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=[O:2].[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13]>CN(C)C1C=CN=CC=1.C(#N)C.CCOC(C)=O>[C:12]([O:16][C:17]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
5-Formylindole (1.45 g, 10.0 mmol) and 4-dimethylaminopyridine (1.47 g, 12.0 mmol) were dissolved in acetonitrile (20 mL) with stirring at ambient temperature. Once dissolution was complete, the reaction mixture was cooled to −10° C. with stirring. Di-t-butylcarbonate (2.18 g, 10.0 mmol) was added in one portion. Stirring was continued for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and the organic solution was washed successively with water (20 mL), a 1N HCl solution (10 mL), a saturated NaHCO3 solution (20 mL) and brine (20 mL). The organic solution was dried over MgSO4 and filtered. Solvent was removed in vacuo from the filtrate to provide a pale yellow oil (2.45 g, 100% yield): 1H NMR (CDCl3, 300 MHz): 10.1 (s, 1H), 8.31 (d, 1H, J=8), 8.12 (s, 1H), 7.87 (dd, 1H, J=8, 1), 7.70 (d, 1H, J=4), 6.71 (d, 1H, J=4), 1.71 (s, 9H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][CH:10]=1
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCc3ccccc3)cc1)C2
Agent: [Pd]
Solvent: CO
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(O)cc1)C2
Yield: 22 %

Procedure:
(4-Benzyloxy-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone from Example E75.1 (800 mg, 1.95 mmol) was dissolved in methanol (100 ml) and hydrogenated over 10% Pd/C catalyst (400 mg) for 7 h. The mixture was filtered through Celite® filter agent, washed with chloroform and methanol and the filtrate was concentrated in vacuo to yield the title compound (140 mg, 22%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([CH3:22])[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])C1C=CC=CC=1>C(O)C.C1CCCCC=1.[OH-].[OH-].[Pd+2]>[Si:15]([O:14][CH2:13][C@@H:12]([CH3:22])[CH2:11][CH2:10][CH2:9][OH:8])([C:18]([CH3:20])([CH3:21])[CH3:19])([CH3:17])[CH3:16]
Reactant: C[C@@H](CCCOCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: C[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 162.1 %

Procedure:
Catalytic Transfer Hydrogenolysis Protocol: 48.5 mg of Pd(OH)2 on activated charcoal (20%) (Pearlman's catalyst) is added to a solution of (S)-1-benzyloxy-5-(tert-butyldimethylsilyloxy)-4-methyl-pentane 5 (485 mg, 1.5 mmol) in 12.0 ml of absolute ethanol and 6.0 ml of cyclohexene. The mixture is heated under ref lux until the reaction is completed (tic monitoring). If starting material can still be detected after 8 h, some catalyst is added and refluxing is continued until the reaction is completed. After cooling to room temperature the catalyst is filtered off. The filtrate is concentrated in vacuo. Purification of the residue by flash column chromatography (pentane/diethyl ether 5:1) affords (S)-5-(tert-butyldimethylsilyloxy)4-methyl-pentan-1-ol 6 (565 mg, 97%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][NH:4][C:3]1=[O:10].[H][H]>CC(O)=O.[Pd]>[Cl:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][NH:4][C:3]1=[O:10]
Reactant: CC1(C)CNC(=O)C(Cl)(Cl)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CNC(=O)C(Cl)C1
Reaction time: 0.33 h

Procedure:
To 40.8 g (0.21 mol) of 3,3-dichloro-5,5-dimethyl-2-piperidone dissolved in 410 mL of AcOH was added 10% Pd/C (50% wet, 6.2 g) and NaOAc-3H2O (62.4 g, 0.46 mol) and the mixture was hydrogenated at 300 kPa for 20 min. The pressure of hydrogen was adjusted at 300 kPa every 5 min. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. CHCl3 (400 mL) and water (300 mL) were added to the residue and the aqueous layer was neutralized with 4 mol/L NaOH. The mixture was separated and the aqueous layer was extracted with CHCl3 (5×300 mL) and the organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica-gel column chromatography, and then the column was eluted with hexane-AcOEt (1:1). The titled compound was obtained as a white solid (20.4 g, 59.9%). (J. Med. Chem., 20, 1176 (1977))
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13]CC3C=CC=CC=3)[CH:11]=2)[N:6]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:5]=1)(=[O:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[N:6]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cn1nc(C(C)=O)c2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)Cn1nc(C(C)=O)c2cc(O)ccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To methyl 2-(3-acetyl-5-(benzyloxy)-1H-indazol-1-yl)acetate (3.70 g, 10.9 mmol) in THF (80 mL) was added Pd/C (10%, 400 mg). The reaction mixture was stirred at 50° C. overnight under a H2 atmosphere. The reaction mixture was filtered over a pad of Celite and washed with CH2Cl2, then volatiles were evaporated to give the title compound. MS (LC/MS): 248.9 [M+H]+, 271.0 [M+Na]+; tR (HPLC conditions c): 3.36 min.
Reaction SMILES: C([O:4][C:5]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:6]=1[O:7][CH2:8][CH:9]([OH:23])[CH2:10][N:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C=C.O.C(N(CC)CC)C>C(O)C.[Cl-].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.[Rh+3].[Cl-].[Cl-]>[CH2:12]([N:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10][CH:9]([OH:23])[CH2:8][O:7][C:6]1[CH:24]=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:5]=1[OH:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CCOc1c(OCC(O)CN(Cc2ccccc2)C(C)(C)C)cccc1[N+](=O)[O-]
Agent: [Rh+3]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CC(C)(C)N(Cc1ccccc1)CC(O)COc1cccc([N+](=O)[O-])c1O

Procedure:
A solution of 19.4 g of 1-(2-allyloxy-3-nitro-phenoxy)-3-(N-benzyl-tert.-butylamino)-2-propanol in a mixture of 350 ml of ethanol, 35 ml of water and 5 ml of triethylamine, with the addition of 1 g of rhodium tris-(triphenylphosphine)-chloride, is stirred under reflux for 45 minutes. After filtering and evaporating the filtrate, crude 1-(N-benzyl-tert.-butylamino)-3-(2-hydroxy-3-nitro-phenoxy)-2-propanol is obtained in the form of a dark red oil, which is used further without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:10].CO.[BH4-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[OH:10]
Reactant: O=C(c1ccc(F)cc1)c1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(c1ccc(F)cc1)c1ccc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
To a stirred and cooled (10°-15° C.) mixture of 25 parts of (2,4-dichlorophenyl)(4-fluorophenyl)methanone and 80 parts of methanol are added portionwise 4.9 parts of sodium borohydride at about 10° C. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is diluted with water and the solvent is evaporated. The residue is taken up in water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated, yielding 22 parts of 2,4-dichloro-α-(4-fluorophenyl)benzenemethanol as a residue.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:4]=[CH:5][C:6]=1[C:7](OCC)=[O:8].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][C:2]1[N:3]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:13])=[O:14])[CH:4]=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1ccn(S(=O)(=O)c2ccccc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1c(CO)ccn1S(=O)(=O)c1ccccc1

Procedure:
By a similar operation as in Reference Example 13 and using ethyl 2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (8.05 g) and 1.5 mol/L diisobutylaluminum hydride toluene solution (55 mL), the title compound was obtained as white crystals (yield 6.61 g, 96%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[CH2:3]([O:10][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccncc2)cc1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A flask is charged with NaH (60% dispersion in mineral oil, 0.72 g, 18.0 mmol) then suspended in DMF (30 mL) and cooled to 5° C. To this mixture is added benzyl alcohol (1.04 mL, 10.0 mmol) drop-wise. The mixture is stirred for 15 minutes then 4-chloropyridine-HCl (1.00 g, 6.67 mmol) is added in three portions over 5 min. The resulting mixture is stirred at 5° C. for 10 min then warmed to 60° C. and stirred for 1.5 h. The mixture is then cooled to 23° C., treated with water, and extracted with EtOAc. The combined organics are dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, 5% EtOAc in hexanes to 50% EtOAc in hexanes) gives the title intermediate (1.10 g, 89%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1>>[CH3:20][C:21]1[CH:22]=[C:23]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Cc1cccc(S)c1
Product: Cc1cccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)c1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3-methyl-thiophenol.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[C:22](=[O:29])[NH:23][NH:24][C:25]=2[CH:26]([CH3:28])[CH3:27])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]([O:33][CH2:34][C@H:35]1[O:40][C@H:39](Br)[C@H:38]([O:42][C:43]([CH3:45])=[O:44])[C@@H:37]([O:46][C:47]([CH3:49])=[O:48])[C@H:36]1[O:50][C:51]([CH3:53])=[O:52])=[O:32].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[C:43]([O:42][C@@H:38]1[C@@H:37]([O:46][C:47](=[O:48])[CH3:49])[C@@H:36]([O:50][C:51](=[O:52])[CH3:53])[C@@H:35]([CH2:34][O:33][C:31](=[O:32])[CH3:30])[O:40][C@H:39]1[O:29][C:22]1[C:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[CH:19][CH:18]=2)=[C:25]([CH:26]([CH3:27])[CH3:28])[NH:24][N:23]=1)(=[O:44])[CH3:45]
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(OCCC(=O)OCc2ccccc2)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)OCc3ccccc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 12 using 4-({4-[2-(benzyl-oxycarbonyl)ethoxy]phenyl}methyl)-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-galactose instead of 4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[N+]([O-])([O-])=O.[Ag+:14].[Br-].[K+]>O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Ag:14]
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: [Ag]
Temperature: 50 °C
Reaction time: 0.03 h

Procedure:
In 1,000 ml of water were dissolved 10 g of gelatin and 6.5 g of benzotriazole and then the solution was stirred at 50° C. A solution of 8.5 g of silver nitrate dissolved in 100 ml of water was added to the foregoing solution over a period of 2 minutes and further a solution of 1.2 g of potassium bromide dissolved in 50 ml of water was added thereto over a period of 2 minutes. By adjsuting the pH of the emulsion thus prepared, excessive salts were precipitated and after removing the salts thus precipitated, the pH of the emulsion was adjusted to 6.0 to provide 200 g of a silver benzotriazole emulsion containing silver bromide.
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][C:7]([NH:11]C(=O)C)([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2>C(O)C.[Pd]>[NH2:11][C:7]12[CH2:10][C:3]([CH2:2][OH:1])([CH2:9][CH2:8]1)[CH2:4][CH2:5][CH2:6]2
Reactant: CC(=O)NC12CCCC(CO)(CC1)C2
Agent: [Pd]
Solvent: CCO
Product: NC12CCCC(CO)(CC1)C2
Yield: 94.6 %

Procedure:
To a solution of N-(5-(hydroxymethyl)bicyclo[3.2.1]octan-1-yl)acetamide (3.70 g, 12.8 mmol) in ethanol (30 mL) was added Pd/C (371 mg) and the reaction mixture was hydrogenated at room temperature (1 atm) overnight. The catalyst was then removed by filtration and the filtrate was concentrated under reduced pressure to afford 1.88 g (95%) of the title compound, (5-aminobicyclo[3.2.1]octan-1-yl)methanol as a brown oil. ESI-MS m/z: 156 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[S:9])[NH:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1.[CH3:20]I>C(O)C>[CH3:1][N:2]1[C:8]([S:9][CH3:20])=[N:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1
Reactant: CN1Cc2ccccc2C(c2ccccc2)NC1=S
Reactant: CI
Solvent: CCO
Product: CSC1=NC(c2ccccc2)c2ccccc2CN1C
Yield: 61.4 %

Procedure:
A solution of 8 g (30 mmol) of the thione of Example 152 and 2.7 mL (44 mmol) of methyl iodide in 100 mL of ethanol was refluxed two hours, cooled, and the hydriodide of the product filtered off. The salt was partitioned between methylene chloride and aqueous sodium bicarbonate, the organic layer dried over magnesium sulfate, and stripped. The residue was dissolved in ethanol and 2.7 g of methanesulfonic acid was added followed by ether. The resulting precipitate was filtered off and recrystallized from ethanol to yield 5.2 g of product as the methanesulfonate salt, mp 195-196.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:28])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.[F:45][C:46]([F:52])([F:51])[S:47]([OH:50])(=[O:49])=[O:48]>C1(OC)C=CC=CC=1>[F:45][C:46]([F:52])([F:51])[S:47]([OH:50])(=[O:49])=[O:48].[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
305 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-(4-methyl-1-piperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 1) were suspended in 627 μl of anisole, and then the suspension was placed over an ice bath. 3.14 ml of trifluoroacetic acid and 56 μl of trifluoromethanesulfonic acid were then added to the suspension, and the resulting mixture was stirred for 1 hour at room temperature. At the end of this time, the solvent was removed by distillation under reduced pressure. The residue was washed with diethyl ether by repeated decantation, after which it was dried under reduced pressure to obtain 318 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C:21]([OH:26])([CH3:25])[C:22](O)=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:45])([C:41]([F:44])([F:43])[F:42])[CH2:38][CH2:39][NH2:40]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C:21]([OH:26])([CH3:25])[C:22]([NH:40][CH2:39][CH2:38][C:37]([F:45])([F:36])[C:41]([F:44])([F:43])[F:42])=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCC(F)(F)C(F)(F)F
Reactant: CC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: CC(O)(C(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-hydroxy-2-methyl-malonamic acid and 3,3,4,4,4-pentafluorobutylamine, the title compound was prepared in the same manner as described for example 1c. Light yellow, viscous oil (88%). MS: m/e=620(M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[CH2:14][CH2:15][CH2:16][C:6]=3[C:5]=2[CH:4]=1.[Mg]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c(=O)c3c(c2c1)CCC3
Agent: [Mg]
Product: COc1ccc2c(c1)C1CCCC1C(=O)N2
Yield: 10.2 %

Procedure:
8-Methoxy-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one (0.78 g, 3.6 mmol) and magnesium (2.5 g, 103 mmol) are reacted to form 80 mg (10%) of product analogously to Example 7.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[C:3](=[O:11])[N:4]([CH3:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cnc(O)c(F)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc([N+](=O)[O-])cc(F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a stirred suspension of 3-fluoro-2-hydroxy-5-nitropyridine (2.03 g, 12.84 mmol) and K2CO3 (3.55 g, 25.7 mmol) in DMF (20 mL) under Ar was added MeI (1.20 mL, 19.26 mmol). The reaction mixture was stirred for 1 hr at rt, concentrated, diluted with water (100 mL), and extracted with CH2Cl2. (2×150 mL) The combined organic layers were washed with water, dried over Na2SO4 and evaporated to afford the crude title product (2.06 g, 11.97 mmol, 93% yield) as a yellow solid. tR: 2.22 min (HPLC 1); tR: 0.49 min (LC-MS 2); ESI-MS: 173 [M+H]+ (LC-MS 2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[C:11]3[N:15]=[C:16](SC)[N:17]=[C:10]23)=[CH:4][CH:3]=1.[ClH:20]>>[Cl:20][C:16]1[N:17]=[C:10]2[N:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:14]=[CH:13][CH:12]=[C:11]2[N:15]=1
Reactant: Cl
Reactant: CSc1nc2cccn(Cc3ccc(Cl)nc3)c-2n1
Product: Clc1ccc(Cn2cccc3nc(Cl)nc2-3)cn1
Temperature: -10 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
A solution of 4-[(6-chloro-3-pyridyl)methyl]-2-methylsulfanyl-imidazo[4,5-b]pyridine (2.22 g, 7.63 mmol) in 25 mL concentrated aqueous hydrochloric acid was cooled to −10° C. and gaseous Cl2 was bubbled through the solution for 1 h. The mixture was stirred at −10° C. for additional 2 h and for 12 h at room temperature. Afterwards the reaction mixture was poured into ice-water, basified to pH 4-5 with NaOH solution (15% in H2O) and extracted three times with CH2Cl2. The combined organic extracts were washed with water, dried with Na2SO4 and the solvent was removed under reduced pressure. Purification by flash column chromatography (SiO2, gradient of MeOH/CH2C12) yielded 1.23 g (4.43 mmol, 58%) of compound E1.8.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=[C:20]([C:30](O)=[O:31])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:34]([NH2:36])[CH3:35]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=[C:20]([C:30]([NH:36][O:34][CH3:35])=[O:31])[CH:19]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(N4CCNCC4)n3)CC2)c(Cl)c1Cl
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(N2CCNCC2)n1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-piperazin-1-ylpyrimidine-4-carboxylic acid (Example 194) and methoxylamine hydrochloride.
Reaction SMILES: [CH2:1]([C:3]1([O:35][C:36](=[O:45])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH2:26][CH2:27][CH2:28][OH:29])([CH3:25])[CH3:24])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)[CH3:2].[O:46]1[C:50]([C:51](Cl)=[O:52])=[CH:49][CH:48]=[N:47]1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:38]([O:37][C:36]([O:35][C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH2:26][CH2:27][CH2:28][O:29][C:51]([C:50]2[O:46][N:47]=[CH:48][CH:49]=2)=[O:52])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)=[O:45])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO
Reactant: O=C(Cl)c1ccno1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)c1ccno1
Temperature: 21 °C
Reaction time: 5 h

Procedure:
A mixture of Compound 53 (70 mg, 0.11 mmol), 4-dimethylaminopyridine (30 mg, 0.25 mg), and isoxazole-5-carbonyl chloride (35 μL, 0.22 mmol) in 3.0 mL of dichloromethane was stirred at 21° C. for 5 hours. The reaction was quenched with saturated sodium bicarbonate solution, and aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to afford a crude product, which was chromatographed to give the desired product.