Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:14][CH2:15][C:16]#[N:17].Cl>C(OCC)C>[ClH:14].[Cl:14][CH2:15][C:16]1[N:17]=[C:4]([OH:6])[C:3]2[C:2](=[CH:11][C:10]([O:12][CH3:13])=[CH:9][CH:8]=2)[N:1]=1
Reactant: N#CCCl
Reactant: COC(=O)c1ccc(OC)cc1N
Agent: Cl
Solvent: CCOCC
Product: COc1ccc2c(O)nc(CCl)nc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 127.7 %

Procedure:
To a mixture of methyl 2-amino-4-methoxybenzoate (5.4 g, 30.0 mmol) and chloroacetonitrile (2.8 mL, 45.0 mmol) was added anhydrous hydrogen chloride (4M solution in 1,4-dioxane, 20.0 mL, 80 mmol) and the reaction mixture was stirred at 50° C. for 30 minutes. After cooling it to room temperature the resulting slurry was diluted with diethyl ether (100 mL) and the stirring was continued for an additional 30 minutes. The off-white precipitate was collected by filtration, washed with diethyl ether and dried in vacuo to provide 2-(chloromethyl)-7-(methyloxy)quinazolin-4-ol hydrochloride (7.5 g, 96%). MS (EI) for C10H9ClN2O2: 225 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][NH2:28]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH3:29])[CH3:22]
Reactant: CN(C)CCCCN
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)CCCCN/C=C1\C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and N1,N1-dimethylbutane-1,4-diamine (29.1 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a light salmon solid, 65.5 mg, (73% yield) MS (ES+): 366.2, (M+H).
Reaction SMILES: [Li][CH2:2]CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[C:9]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:8]=1.CI.[ClH:32].C(OC(=O)C)C.Cl>C1COCC1.C(OCC)(=O)C.O>[ClH:32].[ClH:32].[C:26]([C:9]1[CH:8]=[C:7]([CH3:2])[CH:12]=[CH:11][C:10]=1[N:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)([CH3:27])([CH3:28])[CH3:29]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2C(C)(C)C)CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(N2CCNCC2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of n-BuLi (1.6 M in n-hexane, 5.7 mL, 9.1 mmol) in THF (30 mL) was added a solution of tert-butyl 4-(4-bromo-2-tert-butylphenyl)piperazine-1-carboxylate (Example 85, 3.0 g, 7.55 mmol) in THF (10 mL) at −80° C. After stirred for 30 minutes at that temperature, it was added methyl iodide (1.61 g, 11.3 mmol) and allowed to be warmed to room temperature. After 16 h, it was added water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over MgSO4, and the solvent was evaporated under reduced pressure to get crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=97:3 to 90:10) to provide a white solid. It was added 4 M hydrochloric acid in ethyl acetate solution (7.5 mL). After 16 h, it was concentrated under reduced pressure to give a pale yellow powder, which was re-crystallized from methanol, ethyl acetate and hexane to provide a white powder. It was subjected to purification by high performance liquid chromatography [Column: Gilson, Ltd. High throughput purification system, YMC Combiprep ODS-A, S-5 μm, 50 mm×20 mm; Gradient cycle: H2O (contains 0.1% CF3COOH)-acetonitrile (contains 0.1% CF3COOH), 90:10 (0 min)-90:10 (1 min)-10:90 (4.2 min)-10:90 (5.4 min)-90:10 (5.5 min)-90:10 (5.6 min); Flow rate: 25 mL/min; detection wavelength: UV 220 nm] to give a white solid. It was added 4 M hydrochloric acid ethyl acetate solution (7.5 mL). The solvent was removed under reduced pressure to give 1-(2-tert-butyl-4-methylphenyl)piperazine dihydrochloride (1.08 g, 47%) as a white powder.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@@:9]1(C)[C:28]([O-:30])=[O:29])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-]>CO.O>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[CH2:10][C@H:9]1[C:28]([OH:30])=[O:29])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@@H]2CN(C(=O)OC(C)(C)C)[C@](C)(C(=O)[O-])C2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
To a solution of 1-BOC 2-methyl (2S,4S)-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]pyrrolidine-2-carboxylate (1.02 g, 2.32 mmol) prepared in Step B in methanol (7 ml) and water (7 ml) was added LiOH (0.15 g, 6.99 mmol). The reaction mixture was stirred at rt for 3 h, concentrated in vacuo, and extracted with EtOAC. The organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (0.93 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:26])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:25])[CH2:16][O:17]CC2C=CC=CC=2)=[CH:10][CH:9]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:26])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:25])[CH2:16][OH:17])=[CH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)COC(=O)c1ccc(NC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)COC(=O)c1ccc(NC(=O)CO)cc1
Reaction time: 5 h

Procedure:
4-(2-Benzyloxy-acetylamino)-benzoic acid methoxycarbonylmethyl ester 7 (10 grams, 28.98 mmol) is dissolved in methanol (100 mL) in a pressure vessel. Pd/C (10%, 3 grams) is added, and the mixture is stirred under an atmosphere of hydrogen (4 Kg) for 5 hours. The catalyst is removed by filtration, and the methanol is distilled off. The crude 8 can be purified in a suitable solvent.
Reaction SMILES: [C:1]([N:3]=[C:4]1[N:19]([CH3:20])[C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13](B(O)O)=[CH:14][C:15]=3[C:6]=2[N:5]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])=[CH:23][CH:22]=1)#[N:2].Br[C:33]1[CH:34]=[C:35]([NH:41][S:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)(=[O:44])=[O:43])[C:36]([O:39][CH3:40])=[N:37][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:1]([N:3]=[C:4]1[N:19]([CH3:20])[C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([C:33]4[CH:34]=[C:35]([NH:41][S:42]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)(=[O:44])=[O:43])[C:36]([O:39][CH3:40])=[N:37][CH:38]=4)=[CH:14][C:15]=3[C:6]=2[N:5]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])=[CH:23][CH:22]=1)#[N:2]
Reactant: COc1ncc(Br)cc1NS(=O)(=O)c1ccccc1
Reactant: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(B(O)O)ccc3ncc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2ccc(C(C)(C)C#N)cc2)c(=NC#N)n4C)cc1NS(=O)(=O)c1ccccc1
Temperature: 111 °C

Procedure:
To the stirred solution (2-(cyanoimino)-1-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)boronic acid (0.390 mmol) in dry DMF (5 ml) was added N-(5-bromo-2-methoxypyridin-3-yl)benzenesulfonamide (0.39 mmol) followed by catalyst palladium dichlorobis triphenylphosphine (0.039 mmol). Saturated solution of sodium carbonate (0.780 mmol) was added to it and the resulting solution was heated at 111° C. for 8 minutes in microwave. Solvent was removed and the crude material was extracted with EtOAc, washed with brine several times and dried over anhydrous Na2SO4. The solvent was evaporated and the crude solid was purified (silica gel column, CHCl3/MeOH as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.01 (s, 1H), 9.23 (s, 1H), 8.20 (d, J=8.7 Hz, 1H), 7.88 (s, 4H), 7.84 (m, 1H), 7.70 (m, 4H), 7.56 (m, 3H), 6.83 (s, 1H), 3.92 (s, 3H), 3.58 (s, 3H), 1.81 (s, 6H); MS (m/z): 629 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21]([C:23]1[O:24][C:25]3[CH:31]=[C:30](Br)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2.[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21]([C:23]1[O:24][C:25]3[CH:31]=[C:30]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2o1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc3c2)cc1
Temperature: 82.5 °C

Procedure:
A mixture of 130 mg (0.86 mmol) of 4-methoxyphenylboronic acid, 200 mg (0.57 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamide (Example 2A), 1.72 ml (1.72 mmol) of 1N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 ml of DMF is heated at 80-85° C. for 18 h. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane/methanol 20:1, dichloromethane/methanol-/ammonia 80:20:2). The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 160 mg (68% of theory) of the title compound are isolated.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[CH:14][N:4]2[N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>COCCO>[N:20]1([CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][N:13]=[CH:14][N:4]3[N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCCCN1CCCC1
Reactant: Clc1nn2cnnc2c2c1CCCC2
Solvent: COCCO
Product: c1nnc2c3c(c(NCCCCN4CCCC4)nn12)CCCC3
Temperature: 0 °C

Procedure:
A solution of 9.1 g of 6-chloro-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine and 17.7 g of 1-(4-aminobutyl)pyrrolidine in 50 ml of 2-methoxyethanol was heated at reflux for 16 hours. The reaction mixture was then poured into ice water and the tan solid which formed was separated by filtration and recrystallized from toluene to give 6-[4-(1-pyrrolidinyl)butylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine melting at about 158.5°-160° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][C:26]([NH2:28])=[O:27])[C:14]([Cl:29])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[C:30](OC(=O)C)(=[O:32])[CH3:31].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:30]([NH:1][CH:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][C:26]([NH2:28])=[O:27])[C:14]([Cl:29])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3])(=[O:32])[CH3:31]
Reactant: CC(N)c1cccc(Nc2ncc(Cl)c(CCc3ccccc3CC(N)=O)n2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NC(C)c1cccc(Nc2ncc(Cl)c(CCc3ccccc3CC(N)=O)n2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 70.4 %

Procedure:
A solution of 2-(2-(2-(2-((3-(1-aminoethyl)phenyl)amino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide (38) (0.045 g, 0.11 mmol) in pyridine (3 mL) containing acetic anhydride (62 μL, 0.66 mmol) and 4-dimethylaminopyridine (2.6 mg, 0.022 mmol) was stirred at room temperature for 22 hours under a nitrogen atmosphere. The mixture was acidified with 1 M hydrochloric acid (30 mL) and extracted with DCM (3×20 mL). The combined organic phases were washed with water, brine, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was adsorbed onto silica gel and the product was purified by column chromatography (CombiFlash Rf, 4 g SiO2 Cartridge, 0-10% MeOH in DCM) to yield the title compound (39) as a white solid (0.035 g, 70%). LCMS-B: rt 6.20 min; m/z 452 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>N1C=CC=CC=1>[CH2:24]([NH:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1)=[O:28])[CH3:25]
Reactant: CCN=C=O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Solvent: c1ccncc1
Product: CCNC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.2 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (160 mg, 0.517 mmol) in pyridine (4.0 mL) was added ethyl isocyanate (409 μL, 5.17 mmol), and the mixture was stirred at room temperature for 24 hr. The solvent was evaporated under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the residue, and the aqueous layer was extracted three times with ethyl acetate. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was filtrated, and washed with ethyl acetate/hexane to give the title compound (136 mg, 69%) as a white powder.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@@H:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][N:5]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])(=[O:3])[CH3:2].C1C=C[NH+]=CC=1.[Br:33][Br-]Br.O.C(OCC)(=O)C>O1CCCC1>[Br:33][CH2:2][C:1]([C@@H:4]1[CH2:8][C@@H:7]([O:9][S:10]([CH3:13])(=[O:11])=[O:12])[CH2:6][N:5]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)=[O:15])=[O:3]
Reactant: CC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)CBr)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of (2S,4R)-2-acetyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.5 g) in tetrahydrofuran (80 ml) was added pyridinium bromide perbromide (2.59 g) at 5°-10° C. After stirring at room temperature for 3 hours, the mixture was poured into water (80 ml) and ethyl acetate (160 ml). The separated organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was subjected to a column chromatography on silica gel (60 g) eluting with a mixture of acetone and dichloromethane (1:20 V/V) to give (2S,4R)-2-bromoacetyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.98 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Yield: 10 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3,4-dichlorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (18 mg, 10%) which was obtained as a white solid. MS (ESI): m/e=369.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[N:14]=1.C(#N)C>O>[O:23]([C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:9]([C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:11])=[N:14]2)=[CH:19][CH:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(C(=O)O)cn1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4ccccc4)nc3n2)cn1
Temperature: 20 °C
Yield: 61.2 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 6-methoxypyridine-3-carboxylic acid (4.7 g), N,N'-carbonyldiimidazole (4.9 g) and 2-amino-7-phenoxy-1,8-naphthyridine (9.1 g). The product produced by precipitation in water (11 g; m.p. 115° C.) is dissolved in boiling acetonitrile (50 cc). After 10 hours' cooling at 20° C., the crystallised solid is separated by filtration, washed with diisopropyl ether (3×10 cc) and dried at 30° C. under reduced pressure (0.067 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-6-methoxypyridine-3-carboxamide (7 g) is produced, m.p. 115°-120° C.
Reaction SMILES: [Li+].[OH-].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]=1[CH2:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]2[NH:25][CH:24]([CH2:26][C:27]([O:29]C)=[O:28])[C:23](=[O:31])[N:22]([CH3:32])[CH2:21][C:20]=2[CH:33]=1)=[O:15].CC#N.O>C1COCC1.O>[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]=1[CH2:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]2[NH:25][CH:24]([CH2:26][C:27]([OH:29])=[O:28])[C:23](=[O:31])[N:22]([CH3:32])[CH2:21][C:20]=2[CH:33]=1)=[O:15]
Reactant: COC(=O)CC1Nc2ccc(C(=O)NCc3nc4ccccc4[nH]3)cc2CN(C)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: CN1Cc2cc(C(=O)NCc3nc4ccccc4[nH]3)ccc2NC(CC(=O)O)C1=O
Reaction time: 21.5 h

Procedure:
1.0 N LiOH (0.57 mL, 0.57 mmol) was added dropwise at RT to a mixture of methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.11 g, 0.26 mmol) in THF (4 mL) and H2O (5 mL). The resulting light brownish-yellow solution was stirred for 21.5 h, then was concentrated on the rotavap. The resulting residue was lyophilized to give the crude product (0.11 g, 100%) as a yellowish powder. Preparative HPLC. (PRP-1® column, step gradient, 10-20% CH3CN/H2O-0.1% TFA) afforded the title compound: 1H NMR (250 MHz, DMSO-d6) δ 6.45-9.06 (m, 9H), 5.53 (d, J=16 Hz, 1H), 5.13 (m, 1H), 4.86 (d, J=5 Hz, 2H), 3.87 (d, J=17 Hz, 1H), 2.95 (s, 3H), 2.80 (dd, J=17, 9 Hz, 1H), 2.57 (dd, J=17, 5 Hz, 1H); MS (ES) m/e 408.2 (M+H)+. Anal. Calcd for C21H21N5O4.4/3 CF3CO2H.H2O: C, 49.22; H, 4.25; N, 12.13. Found: C, 49.24; H, 4.22; N, 12.11.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.Cl[CH2:13][C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl.N12CCCN=C1CCCCC2>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:13]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[C:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: CON(C)C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CON(C)C(=O)c1oc2ccc(F)cc2c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
To a mixture of 1-(5-fluoro-2-hydroxyphenyl)ethanone (10.0 g), 2-chloro-N-methoxy-N-methylacetamide (9.82 g), sodium iodide (19.5 g) and N,N-dimethylformamide (200 mL) was added potassium carbonate (18.0 g), and the mixture was stirred at 80° C. overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a brown solid. To a solution (200 mL) of the obtained solid in N,N-dimethylformamide was added 1,8-diazabicyclo[5.4.0]undec-7-ene (9.71 mL), and the mixture was stirred at 120° C. for 4 hr. 1N Hydrochloric acid was added to quench the reaction, and the 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 (ethyl acetate:hexane=1:3, volume ratio) to give the title object compound (4.37 g, 28%) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([N:25]2[CH2:24][CH2:23][N:22]([C:20](=[O:21])[CH2:19][N:5]3[C:6]([CH3:7])=[C:2]([Br:1])[C:3]([C:8]([F:9])([F:11])[F:10])=[N:4]3)[CH2:27][CH2:26]2)=[CH:33][CH:32]=1
Reactant: Cc1[nH]nc(C(F)(F)F)c1Br
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Br)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
Protocol T was followed using 4-Bromo-5-methyl-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 6.96–7.1 (m, 2H), 6.84–6.89 (m, 2H), 5.2(s, 2H), 3.6.2–3.8 (m, 4H), 3.0–3.16 (m, 4H), 2.32 (s, 3H). 13C NMR (400 MHz, CDCl3): 162, 146.4, 142.2, 118.5, 116.2, 52, 50.4, 46.2, 42.2, 15.2.
Reaction SMILES: [Na].F[C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[NH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1>C(O)C1C=CC=CC=1>[CH2:7]([O:13][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[NH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[C:6]1[CH:11]=[CH:12][CH:3]=[CH:4][CH:5]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: [Na]
Solvent: OCc1ccccc1
Product: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 118.4 %

Procedure:
Sodium metal (4.4 g, 19 mmol) was added to benzyl alcohol (100 ml) at ambient temperature and the mixture stirred for 30 minutes then heated at 80° C. for 1 hour. The mixture was then cooled to 40° C. and 7-fluoro-3,4-dihydroquinazolin-4-one (7.8 g, 47 mmol) was added. The reaction mixture was stirred at 130° C. for 4 hours and allowed to cool to ambient temperature and stirred for 18 hours. The solution was quenched with water (800 ml) and acidified to pH3 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and ether and dried for 4 hours at 60° C. under high vacuum to give 7-benzyloxy-3,4-dihydroquinazolin-4-one (7.02 g, 63%). 7-Benzyloxy-3,4-dihydroquinazolin-4-one (7.0 g, 27 mmol) was suspended in dry DMF (50 ml) and sodium hydride was added (1.22 g of a 60% suspension in mineral oil, 30 mmol). The reaction mixture was allowed to return to ambient temperarture, chloromethyl pivalate (4.75 g, 31.5 mmol) was added over 10 minutes and the mixture was stirred for 1 hour. The reaction mixture was quenched into water (250 ml), the aqueous phase adjusted to pH5 with 2M hydrochloric acid and extracted with ether (3×300 ml). The combined ether phases were washed with brine, dried (MgSO4) and the volatiles were removed by evaporation. The solid residue was triturated with isohexane, collected by filtration and dried under vacuum to give 7-benzyloxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (9.1 g, 90%). 7-Benzyloxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (8.0 g, 22 mmol) was dissolved in TFA (40 ml) and the mixture was heated at reflux for 3 hours then allowed to cool to ambient temperature and stirred for 18 hours. The TFA was removed by evaporation and the residue resuspended in a mixture of ether and aqueous sodium hydrogen carbonate solution. The solid was collected by filtration, washed with water and ether and dried at 40° C. for 3 hours under high vacuum to give 7-hydroxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (5.42 g, 90%).