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]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>C(OCC)(=O)C>[OH:13][C:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1)([CH3:15])[CH3:16]
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(C(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(C(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.65 g), sodium hydrogen carbonate (0.95 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C. for 30 min, 4′-({1-[4-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.45 g) was added, and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.15 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then 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 (0.27 g, 54%) as a colorless solid.
Reaction SMILES: OS(O)(=O)=O.[C:6]([C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1N)([CH3:9])([CH3:8])[CH3:7].NC1C=CC=CC=1.N([O-])=[O:28].[Na+].NC(N)=O>O.CCOC(C)=O>[C:6]([C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[OH:28])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1O
Temperature: 0 °C

Procedure:
In a 250 ml round bottom flask, 20 mL concentrated H2SO4 was added to 2-tert-butyl-5-nitro-aniline (7.15 g) by adding 5 mL aliquots of acid and sonicating with occasional heating until all of the starting aniline went into solution. H2O (84 ml) was added with stirring, then the reaction was cooled to 0° C. forming a yellow-orange suspension. A solution of NaNO2 (2.792 g) in H2O (11.2 mL) was added dropwise to the suspension and stirred for 5 min. Excess NaNO2 was neutralized with urea, then the cloudy solution was transferred to 500 ml 3-necked round bottom flask then added 17 mL of 1:2H2SO4:H2O solution, and heated at reflux. Two additional 5 mL aliquots of 1:2H2SO4:H2O solution, a 7 mL aliquot of 1:2H2SO4:H2O solution and another 10 mL of 1:2H2SO4: H2O were added while heating at reflux. The mixture was cooled to RT forming a black layer floating on top of the aqueous layer. The black layer was diluted with EtOAc (300 mL) and separated. The organic layer was washed with H2O then brine, dried over Na2SO4 and concentrated in vacuo. Crude oil was purified on silica gel column with 8% EtOAc/Hexanes. Upon drying under vacuum, the 2-tert-butyl-5-nitrophenol was isolated as a brown solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.[C:13]([OH:19])(=[O:18])[CH2:14]C(O)=O.C([O-])(=O)C.[NH4+:24]>C(O)C>[NH2:24][CH:11]([C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:14][C:13]([OH:19])=[O:18]
Reactant: O=Cc1cnc2ccccc2c1
Reactant: O=C(O)CC(=O)O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1cnc2ccccc2c1
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution containing quinoline-3-carboxaldehyde 5-1 (5 g, 31.8 mmol), malonic acid (3.6 g, 35.0 mmol), and ammonium acetate (5.0 g, 63.6 mmol) in anhydrous ethanol (125 mL) was heated at reflux for 12 h. After cooling to room temperature, the resulting white solid was collected by filtration and washed with cold ethanol (150 mL) and then dried under vacuum to provide 5-2 as a white solid (3.84 g, 17.8 mmol, 56%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][C@H:8]([C:12]1[O:13][CH:14]=[C:15]([C:17](O)=[O:18])[N:16]=1)[CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:33][NH:34][CH3:35].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:33][N:34]([CH3:35])[C:17]([C:15]1[N:16]=[C:12]([C@H:8]([CH2:9][CH:10]=[CH2:11])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])[O:13][CH:14]=1)=[O:18]
Reactant: CNC
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)c1nc(C(=O)O)co1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=CC[C@H](CC(=O)OC(C)(C)C)c1nc(C(=O)N(C)C)co1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.8 %

Procedure:
A solution of 2-[(1R)-1-(2-tert-butoxy-2-oxoethyl)-3-butenyl]-1,3-oxazole-4-carboxylic acid (Preparation 116) (10.77 g, 38.3 mmol) in dichloromethane (250 ml), at 0° C., was treated with 1-hydroxybenzotriazole hydrate (5.75 g, 42.6 mmol), dimethylamine hydrochloride (3.45 g, 42.3 mmol) and N,N-diisopropylethylamine (13 ml, 75.13 mmol) and lastly 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.10 g, 42.3 mmol), allowed to warm to room temperature and stirred for 20 hours under a nitrogen atmosphere. The reaction mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, aqueous citric acid (10%), water and brine, dried over anhydrous sodium sulphate and filtered. The solvent was removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a solvent gradient of 7:3 (pentane:ethyl acetate) gradually changing to 1:1 (pentane:ethyl acetate) to afford the title compound as a colourless oil (9.9 g).
Reaction SMILES: [N:1]1([CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].[NH2:30]OS(O)(=O)=O>O>[NH2:30][N:13]1[C:14]2[C:9](=[CH:8][C:7]([CH:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:12]1=[O:17]
Reactant: O=c1ccc2cc(C(c3cccc(C(F)(F)F)c3)n3cncn3)ccc2[nH]1
Reactant: NOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)ccc2cc(C(c3cccc(C(F)(F)F)c3)n3cncn3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of compound 3 (7.3 g) and NaOH (4.12 g) in water (20 ml) was stirred at room temperature for 15 minutes. Hydroxylamine-O-sulfonic acid (6.3 g) was added portionwise and the mixture was stirred for 12 hours. The precipitate was filtered off and crystallyzed from 2-propanol, yielding 2.3 g (±)-(1-amino-6-[1H-1,2,4-triazol-1-yl-[3-(trifluoromethyl)phenyl]methyl]-2(1H)-quinolinone (compound 20; mp. 222.3° C.).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[N+:2]=[N-:3].[OH-].[Na+]>CO>[N:1]([CH2:4][CH2:5][O:6][CH2:7][C:8]([OH:10])=[O:9])=[N+:2]=[N-:3]
Reactant: CCOC(=O)COCCN=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=NCCOCC(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.3 %

Procedure:
To a solution of ethyl 2-azidoethoxyacetate (6.56 g, 37.9 mmol) in MeOH (80 ml) was added 1N aq. NaOH (80 ml) and the mixture was stirred at room temperature overnight (17 h). After removing the insoluble material, the methanol was evaporated in vacuo and this was saturated with sodium chloride and washed with ether (30 ml×3). The aqueous layer acidified with 3N HCl (30 ml) was extracted with ether (40 ml×4). The ether extracts were washed with brine, dried (MgSO4) and evaporated to yield 4.25 g (29.3 mmol, 77.3%) of 2-azidoethoxyacetic acid as a colourless oil: 1Hmr (CDCl3) δ: 3.3-4.0 (4H, m, --OCH2CH2N3), 4.22 (2H, s, --COCH2O--), 9.52 ppm (1H, s, --CO2H, exchanged with D2O); ir (neat) νmax : 2600-3300 (br,-- CO2H) 2100 (azide) and 1740 cm-1C=O--CO2H). This material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)([OH:20])[CH3:19])[N:14]3[CH3:17])=[C:10]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1)[CH3:2].CCN(CC)CC.[CH:44]1([C:47](Cl)=[O:48])[CH2:46][CH2:45]1>C(Cl)Cl>[CH:44]1([C:47]([N:24]2[CH2:25][CH2:26][CH:21]([C:18]([C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)([OH:20])[CH3:19])[CH2:22][CH2:23]2)=[O:48])[CH2:46][CH2:45]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(C)(O)C3CCNCC3)n(C)c2n1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(C)(O)C3CCN(C(=O)C4CC4)CC3)n(C)c2n1
Reaction time: 0.25 h
Yield: 44 %

Procedure:
A solution of 1-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-1-piperidin-4-ylethanol and NEt3 (74 μL, 0.53 mmol) in DCM (5 mL) was cooled to −78° before the addition of cyclopropane carbonyl chloride (18 μL, 0.20 mmol). The resulting mixture was stirred for 15 min then quenched with H2O and extracted with DCM. The combined organics were dried (phase separator) and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% NH4OH in water on a gradient acetonitrile 10-70%) affording 865 as a white solid (44 mg, 44%). LCMS (method I): RT 3.51 min, [M+H]+ 559.4. 1H NMR (CDCl3, 400 MHz): δ 8.01-8.00 (1 H, m), 7.80 (1 H, d, J=7.13 Hz), 7.33-7.28 (2 H, m), 4.71 (1 H, brd s), 4.32 (4 H, brd s), 3.98 (3 H, s), 3.87 (4 H, t, J=4.69 Hz), 3.40 (2 H, q, J=7.47 Hz), 3.14-2.98 (1 H, m), 2.60-2.43 (1 H, m), 2.20-2.09 (1 H, m), 1.86-1.65 (6 H, m), 1.62-1.36 (3 H, m), 1.47 (3 H, t, J=7.47 Hz), 1.00-0.93 (2 H, m), 0.75-0.74 (2 H, m)
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cu][C:15]#[N:16].CCCCCC.C(OCC)(=O)C>CN(C)C=O>[C:15]([C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]([CH3:12])[C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:16]
Reactant: N#C[Cu]
Reactant: COC(=O)c1c(C)ccc(F)c1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1c(C)ccc(F)c1C#N
Yield: 73 %

Procedure:
Methyl 3-fluoro-2-iodo-6-methylbenzoate (440 mg, 1.49 mmol) and copper(I) cyanide (200 mg, 2.24 mmol) were dissolved in N,N-dimethylformamide (5.5 mL) and the resulted solution was refluxed under nitrogen atmosphere for 3 hours. The solvent was removed under reduced pressure and the residue was diluted with dichloromethane and washed with 15% ammonium hydroxide. Organic phase was dried over sodium sulfate, filtered and evaporated. Column chromatography (n-hexane/ethyl acetate: 7/3) afforded title compound (210 mg, 73% yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:27][CH:28]=2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[S:27][CH:28]=[C:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=4)[N:25]=3)[CH2:30][CH2:31]2)=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4cccc(F)c4)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 42.8 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (300 mg, 1.04 mmol), 1-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperazine (250 mg, 0.949 mmol) and diisopropylethylamine (0.330 ml, 1.90 mmol) in dimethylsulfoxide (3.2 ml) was stirred at 70° C. for 4 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (163 mg, 42.7%) as a solid.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[CH:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.[BrH:27].C(Cl)Cl>>[Br:27][CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[CH:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)O
Reactant: Br
Solvent: ClCCl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)C(CBr)=CS[C@H]12
Reaction time: 0.83 h

Procedure:
A cooled solution (in ice) of benzyl ester of 3-acetoxymethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid (77 mg., 0.15 mmole) is stirred while hydrogen bromide (0.5 ml.) in methylene chloride (0.32 mmole) is added dropwise. The reaction is stopped 50 minutes later by simply bubbling off the excess hydrogen bromide with nitrogen. Removal of the solvent affords the benzyl ester of 3-bromomethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid which is employed directly in Step C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>N1C=CC=CC=1>[CH2:7]([C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nncs1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
2-Amino-1,3,4-thiadiazole (439 mg, 4.3 mmol) was suspended in pyridine (1.5 mL). p-Dodecylbenzenesulfonyl chloride (1.0 mg, 2.9 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred at this temperature for 1 h. The reaction mixture was then added to aqueous 10% HCl (15 mL) and the resulting mixture extracted with ethyl acetate (3×30 mL). The organic extracts were washed with water (3×50 mL), brine (3×50 mL), dried over anhydrous Na2SO4, filtered, and volatiles evaporated to yield a solid mass. Chromatography on silica gel (70-230 mesh) eluted with 2% MeOH in CH2Cl2 gave the product (600 mg, 1.5 mmlo, 51%). Recrystallization from hexanes:ethyl acetate (3:7) gave an analytical sample, mp 126-127° C.; 1H NMR (500 MHz, CDCl3) δ 0.87 (3, t, J=6.5 Hz), 1.20-1.36 (18, m), 1.54-1.63 (2, m), 2.62 (2, t, J=7.5 Hz), 7.25 (2, d, J=8.0 Hz), 7.83 (2, d, J=8.0 Hz), 8.28 (1, s), 12.81 (1, br s); 13C NMR (125 MHz, CDCl3) δ 14.0, 22.6, 29.2, 29.3, 29.4, 29.5, 29.6, 31.0, 31.8, 35.8, 126.4, 128.9, 138.0, 142.8, 148.5, 167.5; MS (LCQ, ESI+) Calcd for C20H32N3O2S2 410.1936. found 410.10 (M+H)+; HRMS (ESI+, m/z) Calcd C20H32N3O2S2 410.1936. found 410.1932 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:17](=[O:19])[NH:16][C:15]4[CH:20]=[C:21]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:22]=[CH:23][C:14]=4[C:13]=3[C:12]3[C:30]([CH3:42])=[N:31][N:32](CC4C=CC(OC)=CC=4)[C:11]=3[N:10]=2)=[CH:5][C:4]=1C(F)(F)F.C(OC(C)C)(C)C.[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57]>>[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:17](=[O:19])[NH:16][C:15]4[CH:20]=[C:21]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:22]=[CH:23][C:14]=4[C:13]=3[C:12]3[C:30]([CH3:42])=[N:31][NH:32][C:11]=3[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nc(C)c3c4c(c(-c5ccc(OC)c(C(F)(F)F)c5)nc32)c(=O)[nH]c2cc(N3CCNCC3)ccc24)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: COc1ccc(-c2nc3[nH]nc(C)c3c3c2c(=O)[nH]c2cc(N4CCNCC4)ccc23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3 g (4.77 mmol) of 5-(4-methoxy-3-(trifluoromethyl)phenyl)-3-(4-methoxybenzyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one dissolved in 25 ml of trifluoroacetic acid is carried at 70° C. for 4 hours and then cooled to room temperature before the addition of isopropyl ether (50 ml). The reaction medium is stirred at room temperature for 30 minutes and then the precipitate obtained is filtered to yield 5-(4-methoxyphenyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one trifluoroacetate. The solid is dissolved in 40 ml of anhydrous dichloroethane. The reaction medium is cooled to 0° C. before the slow addition of 30.3 ml (30.3 mmol) of a 1 M solution of boron tribromide in dichloromethane. The reaction medium is carried at reflux for 20 hours with the regular addition of a cold 1 M solution of boron tribromide in dichloromethane (30.3 ml, 30.3 mmol additional in total) until the reaction is quenched. Methanol (roughly 100 ml) is added and then the reaction medium is stirred for 2 hours. The solvents are concentrated. Saturated aqueous NaHCO3 solution is added and the aqueous phase is washed with ethyl acetate. The aqueous phase is evaporated and then purified by silica gel chromatography (eluent: 60:14:24:2 dichloromethane/methanol/cyclohexane/ammonium hydroxide to pure methanol) to yield 150 mg (12.5%) of 2-hydroxy-5-(1-methyl-6-oxo-9-(piperazin-1-yl)-6,7-dihydro-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-5-yl)benzoic acid hydrochloride in the form of a yellow solid.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13]N=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>>[CH2:33]([NH:35][C:36]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:11]2[CH:2]=[CH:13][C:14]([C:15](=[O:16])[C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])=[C:9]([NH2:8])[N:10]=2)[CH2:32][CH2:31]1)=[O:37])[CH3:34]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCN=C=O
Product: CCNC(=O)N1CCC(Nc2ccc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The title compound was prepared from [4-amino-2-(piperidin4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt (Example 22) and ethyl isocyanate (Aldrich 98%) using the procedure described in Example 24. HRMS, observed: 416.2097, Calcd for (M+H)+: 416.2093.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27]1([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)C(Cl)=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH:43]1([NH2:46])[CH2:45][CH2:44]1>>[CH:43]1([NH:46][C:24]([C@@H:9]2[CH2:10][C:11](=[N:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:12][N:8]2[C:6](=[O:7])[CH:33]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:26])[CH2:45][CH2:44]1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: NC1CC1
Product: O=C(NC1CC1)[C@@H]1CC(=NOCc2ccc(Cl)c(Cl)c2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and cyclopropylamine the title compound was obtained in 49% purity by LC/MS. MS(ESI+): m/z=536.6.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]=[CH2:18])=[CH:12][CH:11]=1)[CH3:2].C1C=CC=CC=1.[CH3:25][SiH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29].C(O)C>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C1COCC1>[CH3:25][Si:26]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])[CH2:18][CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:15][CH:14]=1
Reactant: C=CCc1ccc(OCCOCCOCC)cc1
Reactant: CCO[SiH](C)OCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: c1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOCCOCCOc1ccc(CCC[Si](C)(OCC)OCC)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
This compound was made by first heating a mixture of 2.8 g (0.011 mol) of 3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-1 -propene (prepared as in Example 1), 5 g of benzene and 1.1 equivalent of methyldiethoxysilane under an argon atmosphere at 85° C. for one hour. After one hour, a trace amount (0.01 μL) of 1 part chloroplatinic acid in 1 part ethanol and 98 parts THF was added and the mixture was heated overnight at 85° C. The product was isolated by distillation to give 4.2 g (97%) of methyl diethoxy 3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propysilane, bp 135° C./0.08mm; NMR (δ): 0.20(3H,s), 0.65(2H,m), 1.05(9H,t), 1.50(2H,m), 2.70(2H,t), 3.90(12H,m), 7.0(2H,d), 7.15(2H,d).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([CH3:13])[C:5]([O:14][CH2:15][C:16]#[N:17])=[CH:4][CH:3]=1.Cl.[NH:19]1CCN=[C:20]1[CH2:24]OC1C=C(NS(C)(=O)=O)C=CC=1.NC1C=C(C=CC=1)OCC#N>>[ClH:1].[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:6]([CH3:13])[C:5]([O:14][CH2:15][C:16]2[NH:19][CH2:20][CH2:24][N:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(OCC#N)ccc(Cl)c1NS(C)(=O)=O
Reactant: CS(=O)(=O)Nc1cccc(OCC2=NCCN2)c1
Agent: Cl
Agent: N#CCOc1cccc(N)c1
Product: Cc1c(OCC2=NCCN2)ccc(Cl)c1NS(C)(=O)=O

Procedure:
N-[6-chloro-3-(4,5-dihydro-1H-imidazol-2-ylmethoxy)-2-methylphenyl]-methanesulfonamide hydrochloride was prepared from N-(6-chloro-3-cyanomethoxy-2-methylphenyl)-methanesulfonamide in a manner similar to that described in Example 1 for the preparation of N-[3-(4,5-dihydro-1H-imidazol-2-ylmethoxy)phenyl] methanesulfonamide hydrochloride from (3-aminophenoxy)acetonitrile.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][C:10]([F:16])([F:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: FC1(F)CCNCC1
Solvent: O
Product: FC1(F)CCN(c2ccc(Br)cn2)CC1
Reaction time: 8 h
Yield: 46 %

Procedure:
2,5-Dibromopyridine (1.30 g) was heated with 4,4-difluoropiperidine (2 g) in diaethylacetamide (4 ml) at 120° C. for 24 h, then at 150° C. for 8 h. The solution was allowed to cool, then poured into water (30 ml). The aqueous phase was extracted with ether (×3) and the combined extracts washed with water, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography gave the product as, a colourless oil (0.70 g).