Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]2[C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.C(OO)(=[O:21])C>>[CH3:1][C:2]1[N:3]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]2[C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:7]([O-:21])=[CH:6][C:5]=2[N:14]=1
Reactant: CC(=O)OO
Reactant: Cc1nc2cnc3cccnc3c2n1CC(C)C
Product: Cc1nc2c[n+]([O-])c3cccnc3c2n1CC(C)C

Procedure:
In one aspect, the invention provides a method for making 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine. The method includes: providing N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in a carrier including toluene; combining the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst and isopropanol to form a mixture; subjecting the mixture that includes the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine and the hydrogenation catalyst to a hydrogen atmosphere under conditions effective to form N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine; removing at least a portion of the hydrogenation catalyst from the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine; removing at least a portion of the isopropanol from the mixture of N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in a carrier that includes toluene and isopropanol; heating the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier to a temperature of 20° C. to 55° C.; combining the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier with p-toluenesulfonic acid to form a mixture; combining the mixture that includes the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and p-toluenesulfonic acid with a trialkyl orthoacetate at a temperature of 70° C. to 100° C.; maintaining the temperature at 70° C. to 100° C. for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine; cooling the mixture that includes 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine to a temperature of 45° C. to 55° C.; combining the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with an oxidizing agent including peracetic acid to form a mixture; maintaining the mixture that includes the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine and peracetic acid at a temperature of 45° C. to 55° C. for a time sufficient to form 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine; and isolating at least a portion of the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([O:27][CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([O:27][CH3:28])[N:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(OC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCc1nc(OC)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methoxy-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.0 g), phenylboronic acid (1.3 g), copper(II) acetate (2.0 g), pyridine (2.2 mL), triethylamine (3.7 mL), molecular sieves 4 A (2.0 g) and dichloromethane (54 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.6 g, 65%) as a colorless liquid.
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5](=[O:24])[NH:6][C:7]1[CH:8]=[C:9]([C:13]#[C:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH3:3]>CCO.[Pd]>[CH2:25]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:24])[NH:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:10]=[CH:11][CH:12]=1)[CH2:26][CH3:27]
Reactant: CCCN(CCC)C(=O)Nc1cccc(C#CCNC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: CCCN(CCC)C(=O)Nc1cccc(CCCNC(=O)OC(C)(C)C)c1

Procedure:
A solution of tert-butyl 3-(3-(3,3-dipropylureido)phenyl)prop-2-ynylcarbamate (25) (0.17 g, 0.455 mmol) in EtOH (10 mL) was degassed with vacuum/Ar. Pd/C (10%, 0.0293 g) was added and the atmosphere was purged with H2. The mixture was stirred under H2-filled balloon at room temperature for 5 hrs. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was crystallized from EtOAc/hexanes to give tert-butyl 3-(3-(3,3-dipropylureido)phenyl)propylcarbamate (26) as a pale yellow solid. Yield (0.0946 g, 55%); 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.22-7.26 (m, 2H), 7.07 (t, J=7.6 Hz, 1H), 6.82 (br.t, J=5.1 Hz, 1H), 6.70-6.74 (m, 1H), 3.21 (t, J=7.4 Hz, 4H), 2.90 (q, J=6.1 Hz, 2H), 2.45 (t, J=8.0 Hz, 2H), 1.61 (m, 2H), 1.48 (sextet, J=7.4 Hz, 4H), 1.35 (s, 9H), 0.82 (t, J=7.4 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:13][CH2:14][C:15]3[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])=[C:9]([CH3:24])[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:6]=2[N:7]=1.[CH3:33][NH2:34]>>[OH:23][C:16]1[C:15]([CH2:14][NH:13][C:11]([C:10]2[C:5]3[CH:4]=[N:3][C:2]([NH:34][CH3:33])=[N:7][C:6]=3[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:9]=2[CH3:24])=[O:12])=[C:20]([CH3:21])[CH:19]=[C:18]([CH3:22])[N:17]=1
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Reactant: CN
Product: CNc1ncc2c(C(=O)NCc3c(C)cc(C)nc3O)c(C)n([C@H](C)c3ccccc3)c2n1
Yield: 34 %

Procedure:
A solution of (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenyl ethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (30 mg, 0.07 mmol) in methylamine (1 M in tetrahydrofuran, 3 mL) was stirred at 150° C. for 30 minutes under microwave (pressure: 17.2 bar, equipment power: 150 W). The mixture was concentrated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford (R)—N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-2-(methylamino)-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (10 mg, 34%). LRMS (M+H+) m/z: calcd 444.23. found 444. HPLC purity (214 nm): 92%. 1H NMR (300 MHz, CD3OD): δ 8.55 (s, 1H), 7.30-7.23 (m, 5H), 6.15-6.10 (m, 2H), 4.47 (s, 2H), 2.90 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H), 2.24 (s, 3H), 2.03 (d, J=7.2 Hz, 3H).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:33])[NH:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])[N:14]=2)[CH2:7]1)(=O)=O.[C:34]([O-:37])(=[S:36])[CH3:35].[K+]>CN(C)C=O>[C:34]([S:36][CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:33])[NH:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])[N:14]=2)[CH2:7]1)(=[O:37])[CH3:35]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)NCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)NCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Temperature: 80 °C
Reaction time: 7 h
Yield: 57.4 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-{4-[2-(p-nitrobenzyloxycarbonylamino)-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (607.3 mg, 1.22 mmol) (obtained as described in Reference Example 56(6)) in dimethylformamide (33 ml) was added potassium thioacetate (1.06 g, 7.35 mmol) at room temperature. The reaction mixture was stirred in an oil bath (80° C.) for 7 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed successively with 0.5M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (1:2) as the eluant to afford 3-acetylthio-1-{4-[2-(p-nitrobenzyloxycarbonylamino)-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (335.8 mg, yield 58%) as a pale brown solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][OH:6].[H-].[Na+].Cl[C:10]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([F:27])[CH:21]=2)[CH:17]=[C:16]([C:28]([F:31])([F:30])[F:29])[C:11]=1[C:12]([O:14]C)=[O:13].Cl>O1CCCC1>[F:27][C:22]1[CH:21]=[C:20]([C:18]2[CH:17]=[C:16]([C:28]([F:31])([F:29])[F:30])[C:11]([C:12]([OH:14])=[O:13])=[C:10]([O:6][CH2:5][CH:3]3[CH2:4][CH:2]3[CH3:1])[N:19]=2)[CH:25]=[CH:24][C:23]=1[CH3:26]
Reactant: COC(=O)c1c(C(F)(F)F)cc(-c2ccc(C)c(F)c2)nc1Cl
Reactant: CC1CC1CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(F)(F)F)c(C(=O)O)c(OCC3CC3C)n2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
37 mg (0.431 mmol) of (2-methylcyclopropyl)methanol and 17 mg (0.431 mmol) of sodium hydride (60% strength dispersion in mineral oil) were initially charged in 5 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 60 minutes. 100 mg (0.288 mol) of methyl 2-chloro-6-(3-fluoro-4-methylphenyl)-4-(trifluoromethyl)nicotinate (Example 2A) in 2 ml of tetrahydrofuran were then added. The mixture was stirred at reflux temperature for 3 h and then at room temperature overnight. For work-up, the reaction mixture was adjusted to pH 1 using 1N hydrochloric acid. After removal of the volatile components on a rotary evaporator, the product was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 10:90→90:10). This gave 20 mg (18% of theory) of the target compound.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[CH2:14](Br)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>>[C:17]1([C:15]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[O:3][CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Reactant: O=C(CBr)c1ccccc1
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3)co2)cc1
Yield: 20 %

Procedure:
In the same manner as in Example 1, methyl 4-carbamoylbenzoate was reacted with phenacyl bromide to obtain methyl 4-(4-phenyl-2-oxazolyl)benzoate. The product was recrystallized from ethanol. Yield: 20%. Pale yellow prisms. Melting Point: 175 to 176° C.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].C[O:14][C:15](=O)[CH:16]([CH3:19])[CH2:17]O.[OH-].[Na+]>Cl>[OH:14][CH2:15][CH:16]([C:19]1[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([OH:2])=[O:12])[C:5]=2[N:11]=1)[CH3:17]
Reactant: COC(=O)C(C)CO
Reactant: COC(=O)c1cccc(N)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(CO)c1nc2c(C(=O)O)cccc2[nH]1
Temperature: 90 °C
Reaction time: 24 h
Yield: 25.8 %

Procedure:
To a solution of 2,3-diaminobenzoic acid methyl ester (2.1 g, 14.1 mmol) in 4 M HCl (90 mL) was added 2-methyl-3-hydroxypropionic acid methyl ester (5 g, 42.3 mmol). The mixture was stirred at ˜90° C. for 24 h. It was neutralized by use of aqueous sodium hydroxide solution to pH ˜3, and concentrated to dryness. The residue was suspended in methanol, and filtered through a filter paper. After the filtrate was concentrated, the remaining solid residue was dissolved in water and washed with ethyl acetate. The aqueous solution was evaporated in vacuo yielding the title intermediate as a pale yellow oil (˜800 mg). The crude product was used in the next step without further purification. (m/z): [M+H]+ calcd for C11H12N2O3 221.09. found 221.3. 1H-NMR (CD3OD) δ (ppm) 8.1 (d, 1H), 7.9 (m, 1H), 7.6 (t, 1H), 3.8 (m, 2H), 3.6 (m, 1H), 1.4 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:18][CH2:17]1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[OH:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][CH:16]2[CH2:21][CH2:20][CH:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:18][CH2:17]2)[CH:31]=[CH:32][C:33]=1[OH:34]
Reactant: OB(O)c1ccc(O)c(Cl)c1
Reactant: CCN(CC)C1CCC(Nc2c(C(C)=O)cnc3ccc(Br)cc23)CC1
Product: CCN(CC)C1CCC(Nc2c(C(C)=O)cnc3ccc(-c4ccc(O)c(Cl)c4)cc23)CC1
Yield: 58.7 %

Procedure:
Following general procedure D, 1-{6-bromo-4-[4-(diethylamino)cyclohexylamino]quinolin-3-yl}ethanone (30 mg, 0.072 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (34 mg, 0.200 mmol) to afford the desired product (19.7 mg, 59%) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 8.95 (s, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.02 (dd, J=8.7, 1.9 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.53 (dd, J=8.4, 2.3 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 4.31 (s, 1H), 3.52-3.43 (m, 1H), 3.22 (q, J=7.2 Hz, 4H), 2.70 (s, 3H), 2.46 (d, J=12.3 Hz, 2H), 2.20 (d, J=11.9 Hz, 2H), 1.88-1.65 (m, 4H), 1.41-1.30 (m, 6H); ESI MS m/z 466 [C27H32ClN3O2+H]+; HPLC 97.7% (AUC), tR=10.44 min.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([CH2:16][OH:17])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=1)=[O:4].CC([O-])(C)C.[K+]>C1COCC1>[I:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]1([CH3:15])[NH:5][C:3](=[O:4])[CH2:2][O:17][CH2:16]1
Reactant: CC(CO)(Cc1cccc(I)c1)NC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(Cc2cccc(I)c2)COCC(=O)N1
Reaction time: 0.33 h

Procedure:
A solution of rac-2-chloro-N-[1-hydroxymethyl-2-(3-iodo-phenyl)-1-methyl-ethyl]-acetamide H-7 (1.0 g, 2.7 mmol) in THF (13 mL) was added dropwise to a RT solution of KOtBu (6.8 mL, 6.8 mmol, 1M soln. in THF) under argon and the reaction mixture was stirred for 20 min. The reaction was quenched with 1M aq. HCl, diluted with water and concentrated in vacuo. The remaining aqueous phase was extracted with DCM (3×) and the combined organic extracts were dried over Na2SO4, filtered and evaporated in vacuo to give the title compound that was used further without purification. LC-MS A: tR=0.75 min; [M+H+MeCN]+=373.02.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:23])=[C:10]([C:15]3[N:16]=[C:17]([CH2:20][NH:21][CH3:22])[S:18][CH:19]=3)[C:11]=2[O:13]C)[C:6](=[O:24])[C:5]([C:25]([OH:27])=[O:26])=[CH:4]1)[CH3:2].Br>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:23])=[C:10]([C:15]3[N:16]=[C:17]([CH2:20][NH:21][CH3:22])[S:18][CH:19]=3)[C:11]=2[OH:13])[C:6](=[O:24])[C:5]([C:25]([OH:27])=[O:26])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3csc(CNC)n3)c(OC)c21
Agent: Br
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3csc(CNC)n3)c(O)c21
Temperature: 70 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To 700 mg (1.79 mmol) of the 1-ethyl-6-fluoro-1,4-dihydro-8-methoxy-7-[2-[(methylamino)methyl]-4-thiazolyl]-4-oxo-3-quinolinecarboxylic acid was added 8 ml of hydrobromic acid in acetic acid and the mixture was heated to 70° C. After four hours 8 ml more hydrobromic acid was added and the mixture stirred overnight. The solids were collected, dissolved in aqueous ammonia and concentrated to one fourth volume. Filtration gave 580 mg of 1-ethyl-6-fluoro-1,4-dihydro-8-hydroxy-7-[2-[(methylamino)methyl]-4thiazolyl]-4-oxo-3-quinolinecarboxylic acid, mp 242°-246° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][NH:14][CH3:15])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].[C:16]1([C:26](Cl)=[O:27])[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.O>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:12])[CH2:13][N:14]([CH3:15])[C:26]([C:16]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)=[O:27])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNCC(CCO)c1ccc(F)c(F)c1
Reactant: O=C(Cl)c1cccc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN(CC(CCO)c1ccc(F)c(F)c1)C(=O)c1cccc2c1CCCC2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 78.6 %

Procedure:
To a stirred cooled (0° C.) mixture of 3-(3,4-difluorophenyl)-N-methyl-4-amino-1-butanol (0.917 g, 4.26 mmol) in DCM (35 mL) and 1N NaOH (10 mL) was added dropwise a solution of 5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride (0.829 g, 4.26 mmol) in DCM (20 mL). The mixture was stirred at 0° C. for 2.5 h, additional H2O and DCM were added and the mixture was extracted with DCM (2×20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification by chromatography (0%, 50%, 100% EtOAc in Et2O) provided the title compound (1.25 g, 79%) as a solid. MS m/z 374 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[CH:22][NH:21][C:20]=1[CH:33]=O>C(O)C.N1CCCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10](=[CH:33][C:20]1[NH:21][CH:22]=[C:23]([C:24]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[O:25])[C:19]=1[CH3:18])[C:11](=[O:17])[NH:12]2
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccccc3F)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 36 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(2-fluoro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (40 mg, 36%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[CH2:16]([C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][N:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=3)[CH2:31][CH2:30]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15])[CH3:17]
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: COc1cccc(N2CCNCC2)c1
Product: CCC1(CCCCN2CCN(c3cccc(OC)c3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(3-methoxyphenyl)-piperazine.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]([F:23])([F:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:7][O:6]1)=[O:4].[OH-].[Na+:25]>C(O)C.O>[Na+:25].[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:5]2([C:3]([O-:4])=[O:2])[CH2:7][O:6]2)([F:22])[F:23])=[CH:16][CH:17]=1
Reactant: COC(=O)C1(C(F)(F)CCCCCOc2ccc(Cl)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])C1(C(F)(F)CCCCCOc2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A solution of 348 mg (1 mmol) of 2-[6-(4-chlorophenoxy)-1,1-difluorohexyl]-2-oxiranecarboxylic acid methyl ester of Example 7 in 10 ml of 95% ethanol is treated with a solution of 40 mg (1 mmol) of sodium hydroxide in 5 ml of water. The solution is stirred at room temperature for 3 hours and is then rotoevaporated. The obtained solid is triturated two times with ethyl ether and the solvent is removed to give 289 mg (77.1%) of the title compound: m.p. 140°-153° C.; IR (KBr) 1645, 1618 cm-1 ; NMR (d6 -DMSO) δ 1.46 (4H, m), 1.73 (2H, p, J=7 Hz), 2.42 (2H, m), 2.70 (1H, d, J=7 Hz), 2.76 (1H, d, J=7 Hz), 3.98 (2H, t, J=7 Hz), 7.00 (2H, d, J=10 Hz) and 7.36 (2H, d, J=10 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[Br:37][CH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCc1cc(CO)ccc1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cc(CBr)ccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of (2-ethyl-biphenyl-4-yl)-methanol (780 mg, 3.67 mmol) and PPh3 (1.44 g, 5.5 mmol) in DCM (15 mL) at 0° C. is added CBr4 (1.82 g, 5.5 mmol) in DCM (2 mL). The reaction is stirred at 0° C. for 1 h followed by concentration. The residue obtained is purified by silica gel chromatography (5% EtOAc in hexanes) to give 4-bromomethyl-2-ethyl-biphenyl as a colorless oil.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:30])[NH:10][C:11]([CH2:15][NH:16][CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[N:12]2)=[CH:7][CH:6]=1)=[O:4].Cl.O1CCOCC1>C(Cl)Cl>[OH:1][NH:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:30])[NH:10][C:11]([CH2:15][NH:16][CH:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[N:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2nc3cc(C(=O)NO)ccc3c(=O)[nH]2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(NO)c1ccc2c(=O)[nH]c(CNC3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[({7-[(hydroxyamino)carbonyl]-4-oxo-3,4-dihydroquinazolin-2-yl}methyl)amino]piperidine-1-carboxylate, 1-56 (98 mg, 0.23 mmol) in methylene chloride (3.2 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (3.2 mL, 12.8 mmol). The reaction mixture was stirred at rt for 2 h. The solid was filtered and washed with DCM to afford N-hydroxy-4-oxo-2-[(piperidin-4-ylamino)methyl]-3,4-dihydroquinazoline-7-carboxamide.2[HCl] (44 mg, 48%). LC-MS: (FA) ES+ 318; 1H NMR (300 MHz, DMSO) δ 12.80 (s, 1H), 11.63 (s, 1H), 10.04 (s, 1H), 9.48-9.28 (m, 1H), 9.07 (s, 1H), 8.18 (d, J=8.3 Hz, 1H), 8.07 (d, J=1.2 Hz, 1H), 7.88 (dd, J=8.3, 1.5 Hz, 1H), 4.28 (s, 2H), 3.45-3.26 (m, 3H), 3.02-2.84 (m, 2H), 2.34-2.20 (m, 2H), 2.11-1.88 (m, 2H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:19]=[CH:18][C:13]([CH:14]=[CH:15][CH2:16]Cl)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CN(C)C=O.O>[Cl:9][C:10]1[CH:19]=[CH:18][C:13]([CH:14]=[CH:15][CH2:16][NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH2:8])=[CH:12][CH:11]=1
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1NCC=Cc1ccc(Cl)cc1
Yield: 82.2 %

Procedure:
19.6 g of 1,2-phenylenediamine was dissolved in 300 ml of dimethylformamide, to the solution were added 11.3 g of the above-prepared 4-chlorocinnamyl chloride crystals and 12.5 g of potassium carbonate at a room temperature with stirring, and the mixture was stirred for 48 hours under the same condition. After adding water and sodium chloride, the reaction mixture was extracted twice with 1000 ml of chloroform, and the extract was dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure. Resulting residue was applied to a silica gel column and eluted with hexane/ethyl acetate (3:1), to obtain 12.85 g of the title compound as colorless crystals.