Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:22](=[O:24])[NH2:23])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])(C)(C)C.C(OCC)C>Cl.C(OCC)(=O)C>[ClH:19].[Cl:19][C:18]([Cl:20])([Cl:21])[CH2:17][O:16][C:14](=[O:15])[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]([NH2:7])[C:22](=[O:24])[NH2:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC(Cl)(Cl)Cl)C(N)=O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: NC(=O)[C@@H](N)CCCCNC(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 181.7 %

Procedure:
[(1S)-1-carbamoyl-5-(2,2,2-trichloroethoxycarbonylamino)pentyl]carbamic acid tert butyl ester (39.5 g; 94 mmole) was dissolved in a solution of hydrogen chloride in ethyl acetate (1.5 M, 300 ml) and stirred for 30 min. Diethyl ether (300 ml) was added and the precipitate was filtered and dried to afford 30.5 g of ((5S)-5-amino-5-carbamoylpentyl)carbamic acid 2,2,2-trichloroethyl ester hydrochloride.
Reaction SMILES: [Na].C([O:4][C:5]([C:7]1[N:8]=[N:9][NH:10][N:11]=1)=[O:6])C.Br[CH2:13][C:14]1[CH:18]=[C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[O:16][N:15]=1>CN(C=O)C>[Cl:24][C:21]1[S:20][C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][N:9]3[N:10]=[N:11][C:7]([C:5]([OH:4])=[O:6])=[N:8]3)[CH:18]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1nn[nH]n1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(O)c1nnn(Cc2cc(-c3ccc(Cl)s3)on2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 100 mg 2H-Tetrazole-5-carboxylic acid ethyl ester sodium salt in 1 ml DMF, 59 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001) 460 pp. WO 0107436 A2] were added and the mixture was stirred at room temperature for 16 h. Then the reaction mixture was concentrated under reduced pressure. The residue was taken-up in 1 ml THF and after addtion of 1 ml of a 1M NaOH solution stirred for 16 h at RT. The mixture was acidified with half concentrated hydrochloric acid to pH 3 and the precipitate collected by filtration. The product was obtained as a white solid, which was dried under reduced pressure. Yield: 49 mg.
Reaction SMILES: C([O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]3[N:28]([CH3:29])[C:27](=[O:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[CH3:31])[N:20]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)(=O)C>C1COCC1.C(OCC)(=O)C.CO.[Pd]>[CH3:29][N:28]1[C:27](=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[CH3:31])[N:20]=[C:19]1[CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:33][CH:32]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)Oc1ccc(C(=O)c2ccc(C=Cc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc2nc(CCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of 2-[2-[4-(4-acetoxybenzoyl)phenyl]vinyl]-3,5-dimethyl-4(3H)-quinazolinone (631 mg) in THF-ethyl acetate-methanol (1:1:1) (50 ml) was added 10% Pd/C (50% hydrous) (126 mg) and the mixture was stirred under hydrogen at room temperature for 2 hours. The catalyst was then filtered off and the filtrate was concentrated. After the residue was suspended in ethanol (10 ml), 1N-aqueous sodium hydroxide solution (2.9 ml) was added and the mixture was stirred at room temperature for 2 hours. This reaction mixture was concentrated and the residue was suspended in water (20 ml) and neutralized with 1N-hydrochloric acid (2.9 ml). The precipitate was collected by filtration, washed with water, and dried to provide 538 mg of white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([NH:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH3:22])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[CH2:23](N(CC)CC)[CH3:24]>C(O)CC.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]>[CH:17]([NH:16][N:15]1[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([CH:23]=[CH2:24])=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=[C:14]1[CH2:20][CH2:21][CH3:22])([CH3:19])[CH3:18]
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1NC(C)C
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCCO
Product: C=Cc1ccc2c(c1)nc(N)c1nc(CCC)n(NC(C)C)c12
Temperature: 100 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
A suspension of 7-bromo-N1-isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.71 g, 4.72 mmol) in 34 mL of 1-propanol was placed under an atmosphere of nitrogen. The mixture was treated with triethylamine (1.25 mL, 9.44 mmol) and then the headspace of the flask was evacuated and back-filled with nitrogen (3×). The reaction mixture was treated with potassium vinylfluoroborate (0.695 g, 5.19 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.069 g, 0.094 mmol) and the head-space purged and backfilled as before. The reaction was heated to 100° C. After 16 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 50 mL of CHCl3 and washed with 5% Na2CO3 solution (15 mL). There was a thick emulsion that did not fully separate. The organic portion was washed with H2O (15 mL) resulting in another slowly separating emulsion. The combined aqueous washes were back extracted with CHCl3 (15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield an orange solid. The solid was purified by chromatography (SiO2, 20% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield N1-isopropyl-2-propyl-7-vinyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.92 g) as a tan solid.
Reaction SMILES: CO[C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH3:11])[N:4]=1.[CH3:12][NH2:13].C(O)(=O)C>O>[CH3:10][O:9][C:7]1[N:6]=[C:5]([CH3:11])[N:4]=[C:3]([NH:13][CH3:12])[N:8]=1
Reactant: COc1nc(C)nc(OC)n1
Reactant: CN
Solvent: CC(=O)O
Solvent: O
Product: CNc1nc(C)nc(OC)n1
Reaction time: 4 h
Yield: 93 %

Procedure:
5000 g of a 40% by weight strength methanolic solution of 2,4-dimethoxy-6-methyl-1,3,5-triazine are initially charged and then, at from 5 to 10° C., admixed with a 40% by weight strength aqueous methylamine solution to neutralize the acetic acid, establishing a pH of from 7.2 to 7.5 (glass electrode). At from 13 to 15° C., 1500 g of a 40% by weight strength aqueous methylamine solution are then introduced over a period of 8 hours. After the addition of the methylamine solution has ended, stirring is continued at 14° C. for another 4 hours and then with water-cooling for 12 hours. The reaction product is subsequently filtered off with suction using a nutsch filter and washed with 5×900 ml of a 2% by weight strength methylamine solution and finally with 4×900 ml of water. The yield of 2-methoxy-4-methyl-6-methylamino-1,3,5-triazine, based on the dried product, is 1850 g (yield: about 93%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH2:8][CH3:9].[Br:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([I:19])[N:13]=1.O>CN(C)C=O>[Br:11][C:12]1[C:17]([O:18][CH2:7][CH2:8][CH3:9])=[CH:16][CH:15]=[C:14]([I:19])[N:13]=1
Reactant: Oc1ccc(I)nc1Br
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(I)nc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (1.38 g) and n-propyl iodide (1.13 g) were added to a solution of 2-bromo-6-iodopyridin-3-ol (1.0 g, described in WO 2007088996) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure to give 2-bromo-6-iodo-3-propoxypyridine as a crude product.
Reaction SMILES: [O:1]([NH2:3])[CH3:2].[C:4]1([CH3:14])[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.O>N1C=CC=CC=1>[CH3:2][O:1][NH:3][S:10]([C:7]1[CH:8]=[CH:9][C:4]([CH3:14])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: CON
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CONS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
Methoxylamine (9.00 g (108 mmol) was suspended in pyridine (30.0 ml). To this, under cooling with ice and with stirring, p-toluenesulfonyl chloride (19.07 g (100 mmol)) was added and the mixture was stirred under cooling with ice for 30 minutes and at room temperature for 2 hours. Water (200.0 ml) was added to the reaction mixture to bring about separation of crystals. After 30 minutes' stirring, the crystals were filtered and washed to give 20.26 g (99%) of N-methoxy-p-toluenesulfonamide as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].Cl.I[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[C:27]([CH3:39])[CH:26]=1.C(NC(C)C)(C)C>C1COCC1.[Cu](I)I>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[C:10][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[C:27]([CH3:39])[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(I)cc34)cc2C)cn1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: I[Cu]I
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCNC(=O)OC(C)(C)C)cc34)cc2C)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.9 %

Procedure:
A mixture of prop-2-ynyl-carbamic acid tert-butyl ester (2.65 g, 17.08 mmol) and (6-Iodo-quinazolin-4-yl)-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine hydrochloride (8.2 g, 16.27 mmol), dichlorobis(triphenylphosphine) palladium (II) (570 mg, 0.81 mmol), copper iodide (154 mg, 0.81 mmol), and diisopropylamine (4.78 mL, 34.16 mmol) in anhydrous THF (80 mL) was stirred at room temperature for 5 hours. After concentration, the residue was dissolved in CH2Cl2 (100 mL), washed with aqueous NH4Cl and brine, dried over sodium sulfate, and concentrated to give the crude product (7.89 g, 98%) as a light yellow solid which was then used without further purification.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:17][CH2:18][S:19][CH3:20])[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])(=[O:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:29])C=1>ClCCl>[C:1]([O:4][CH:5]([CH2:17][CH2:18][S:19]([CH3:20])=[O:29])[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCCNC(=O)C(CCSC)OC(C)=O
Solvent: ClCCl
Product: CCCCCCCCNC(=O)C(CCS(C)=O)OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a solution of 4-(methylthio)-1-(octylamino)-1-oxobutan-2-yl acetate (6.33 g, 20.86 mmol) in dichloromethane (200 mL) at 0° C. was added mCPBA (77%, 4.67 g, 20.86 mmol). The resulting mixture was allowed to warm to room temperature with stirring overnight. The reaction was washed with saturated sodium bicarbonate (3×100 mL), 1N HCl (1×100 mL), and brine (1×100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give a yellow oil (6.7 g, 100%). m/z 320 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[C:12]4[C:25]5([CH2:29][O:28][C:27]([NH2:30])=[N:26]5)[C:21]5([CH2:24][O:23][CH2:22]5)[C:17]5([CH2:20][CH2:19][CH2:18]5)[O:16][C:13]4=[CH:14][CH:15]=3)=[CH:6][N:5]2[CH:31]=1.C(O)(=O)C.[H][H]>CCO.O=[Pt]=O>[CH3:1][C:2]1[N:3]=[C:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:11]=[C:12]4[C:25]5([CH2:29][O:28][C:27]([NH2:30])=[N:26]5)[C:21]5([CH2:24][O:23][CH2:22]5)[C:17]5([CH2:18][CH2:19][CH2:20]5)[O:16][C:13]4=[CH:14][CH:15]=3)[CH2:6][N:5]2[CH:31]=1
Reactant: [H][H]
Reactant: Cc1cn2cc(-c3ccc4c(c3)C3(COC(N)=N3)C3(COC3)C3(CCC3)O4)ccc2n1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cn2c(n1)CCC(c1ccc3c(c1)C1(COC(N)=N1)C1(COC1)C1(CCC1)O3)C2
Temperature: 25 °C
Reaction time: 38 h
Yield: 83.2 %

Procedure:
A suspension of 6′-(2-methylimidazo[1,2-a]pyridin-6-yl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (66 mg, 0.16 mmol), acetic acid (27 μl, 0.06 mmol) and PtO2 (13 mg) in EtOH (3.3 ml) was stirred at room temperature under the hydrogen atmosphere at 3 atm for 8 hours. To the mixture was added acetic acid (63 μl), and the mixture was stirred at room temperature under hydrogen atmosphere at 3 atm for 38 hours. The mixture was filtrated through celite pad. And then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silicagel column chromatography (28% NH4OH/EtOH/CHCl3=2:20:80) followed by trituration in iPr2O and filtration to give 6′-(2-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (56 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.[NH2:37][CH:38]1[CH:43]2[CH2:44][CH2:45][N:40]([CH2:41][CH2:42]2)[CH2:39]1.C(N(CC)CC)C>C(#N)C.CN(C1C=CN=CC=1)C>[N:40]12[CH2:45][CH2:44][CH:43]([CH2:42][CH2:41]1)[CH:38]([NH:37][C:17]([C:16]1[C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH:13]=[CH:14][CH:15]=1)=[O:19])[CH2:39]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1cccc2nc(-c3ccc(F)cc3)oc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NC1CN2CCC1CC2)c1cccc2nc(-c3ccc(F)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A solution of 2-(4-fluorophenyl)benzoxazole-7-carboxylic acid (0.100 g, 0.39 mmol) in acetonitrile (10 mL) was treated with DCC (0.089 g, 0.43 mmol) and the mixture stirred at room temperature for 1 h. After this time a thick granular precipitate had formed. 3-Aminoquinuclidine dihydrochloride (0.086 g, 0.43 mmol) and DMAP (0.010 g, 0.08 mmol) were then added to the reaction followed by the dropwise addition of triethylamine (0.101 g, 1.00 mmol) over 15 min. The reaction was then stirred at room temperature overnight. Subsequent concentration of the reaction mixture and purification of the resulting solid residue by column chromatography afforded 0.100 g (70% yield) of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-fluorophenyl)benzoxazole-7-carboxamide as a white solid: mp 185-187° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.46 (d, J=6.7 Hz, 1H), 8.24 (m, 2H), 7.95 (m, 1H), 7.70 (m, 1H), 7.51 (m, 3H), 4.06 (m, 1H), 3.21 (m, 1H), 2.92 (m, 1H), 2.74 (m, 4H), 1.96 (m, 2H), 1.64 (m, 2H), 1.44 (m, 1H); MS (ESI) m/z 366 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[C@@H:9]([CH3:11])[OH:10])=[O:6])[CH3:3].[H-].[Na+].F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26]>CN(C)C=O>[CH3:15][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[C@@H:9]([CH3:11])[O:10][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])=[O:6])[CH3:3]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1ccccc1[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C

Procedure:
A solution of N-[(1,1-dimethylethoxy)-carbonyl]-L-threonine (5.02 g., 22.9 mmol.) in dry dimethylformamide (10 ml.) was added dropwise over a period of 30 minutes to a cooled (0° C.) suspension of 60% sodium hydride (1.93 g., 48.25 mmol., 2.11 eq.) in dry dimethylformamide (40 ml.). The reaction was stirred at 0° C. until the frothing subsided (about 3.5 hours). The reaction mixture was treated dropwise with 1-fluoro-2-nitrobenzene (2.67 ml., 25.2 mmol., 1.1 eq.) over a period of 20 minutes and stirred at 0° C. under argon for 2 hours. The reaction mixture was then placed in the cold room (5° C.) and stirred overnight. The reaction mixture was poured into ice-water (500 ml.) and extracted with ethyl ether (2×200 ml.). The aqueous phase was brought to pH 1.0 with 6N hydrochloric acid (200 ml.) and extracted with ethyl acetate (3×300 ml.). The combined ethyl acetate extracts were washed with water (2×300 ml.), and brine (300 ml.), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuo. The crude residue was loaded onto celite and purified by chromatography on a 10×20 cm. silica gel column. Elution with methylene chloride (31.), 99:1 methylene chloride:methanol (21.), 95:5 methylene chloride:methanol, and 100:5:0.5 methylene chloride:methanol:acetic acid (5 1.) gave 6.07 g. of title compound. TLC (methylene chloride:methanol:acetic acid, 100:5;0.5) Rf =0.16.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][CH:17]([CH3:28])[CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)[CH3:15]>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH:17]([O:16][CH2:14][CH3:15])[CH3:28])=[CH:27][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)COc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Solvent: CN(C)C=O
Product: CCOC(C)COc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 3 h
Yield: 37.6 %

Procedure:
In 15 ml of N,N-dimethylformamide were dissolved 1.5 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 2.2 g of 4-(2-ethoxypropoxy)-benzyl bromide, and the resulting solution was heated under stirring on an oil bath at 80° to 90° C. for 3 hours. Then, similarly to the procedures in Preparation Example 2, 1.1 g of the aimed product was obtained as an oil.
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].COC(OC)[N:13]([CH3:15])C.O.[NH2:19]N>C(O)C>[CH2:8]([C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:15][NH:13][N:19]=1)[CH3:9]
Reactant: NN
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)CC(=O)OC
Solvent: CCO
Solvent: O
Product: CCc1n[nH]cc1C(=O)OC
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 3-oxopentanoate (2.6 g) and dimethylformamide dimethylacetal (2.8 mL) was stirred at 100° C. for 12 hr, and allowed to cool. Ethanol (50 mL) and hydrazine monohydrate (1.1 mL) were added to the reaction mixture, and the mixture was treated in the same manner as in Example 1(3) to give a crude product of methyl 3-ethyl-1H-pyrazole-4-carboxylate. This was dissolved in dimethylformamide (30 ml), potassium carbonate (4.2 g) and 2-chloro-5-trifluoromethylpyridine (3.6 g) were added, and the mixture was stirred at 100° C. for 2 hr. In the same manner as in Example 1(4), the title object compound (4.7 g, 79%) was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1([CH3:27])[C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:17]=2[NH:16][C:15](=[O:26])[O:14]1>>[CH3:12][C:13]1([CH3:27])[O:14][C:15](=[O:26])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=3)=[CH:19][C:18]1=2
Reactant: N#CCc1ccc(Br)cc1F
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(CC#N)c(F)c3)cc21

Procedure:
Prepared according to procedure B from 4-bromo-2-fluorophenylacetonitrile (T. Alessi A. H. P. U.S. Pat. No. 4,895,862) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. A grey solid; mp 253-256° C. 1H-NMR(DMSO-d6) δ10.35 (s, 1H) 7.67-7.49 (m, 5H), 6.97 (d, 1H; J=8.6 Hz) 4.09 (s, 2H) 1.67 (s, 6H); MS [M−H]− m/z 309. Anal. Calc. For C18H15N2FO2.0.15H2O: C, 69.07; H, 4.93; N, 8.95. Found C, 69.27; H, 5.05; N, 8.50
Reaction SMILES: [NH2:1][C:2]1[N:21]=[C:5]2[NH:6][C:7]([CH3:20])=[C:8]([C:18]#[N:19])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C(N(CC)CC)C>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([CH:9]2[N:4]3[N:3]=[C:2]([N:1]4[C:25](=[O:26])[C:24]5[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:22]4=[O:27])[N:21]=[C:5]3[NH:6][C:7]([CH3:20])=[C:8]2[C:18]#[N:19])=[CH:15][CH:14]=1)#[N:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(N)nc2N1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(N3C(=O)c4ccccc4C3=O)nc2N1
Reaction time: 1 h

Procedure:
Under argon, (rac)-2-amino-7-(4-cyanophenyl)-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (15 g, 54.1 mmol) together with phthalic anhydride (11.22 g, 75.7 mmol, 1.4 eq.) was suspended in a mixture of toluene (500 ml) and pyridine (600 ml), triethylamine (1.51 ml, 10.8 mmol, 0.2 eq.) was added and the mixture was heated under reflux overnight. More pyridine (200 ml), phthalic anhydride (8 g, 54.0 mmol, 1.0 eq.) and triethylamine (1.51 ml, 10.8 mmol, 0.2 eq.) were then added, and the mixture was heated under reflux for another 12 h. The reaction mixture was then concentrated under reduced pressure and the residue was dried under high vacuum (12 h). Three times, the crude product was suspended in ethanol (100 ml), stirred for 1 h, filtered off, washed with pentane and dried under high vacuum. The product obtained was a light-beige solid (20 g), which was recrystallised from DMF/methanol. To this end, the solid was initially dissolved in hot DMF (250 ml, 150° C.) and the cold DMF solution was then slowly, with stirring, poured into methanol (1.3 liters), whereupon the product precipitated out. The precipitate was filtered off and dried under high vacuum. Reprecipitation from DMF/methanol gave 15.91 g (99% pure, 71.5% of theory) of the title compound.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[C:12]([OH:14])=[O:13]>C(Cl)Cl.CO>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[C:12]([O:14][CH3:1])=[O:13]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 0.17 h

Procedure:
Trimethylsilyldiazomethane (2M/ether, 3.5 mL) was added slowly to a solution of 3,5-dichlorobenzoic acid (2-C) (955 mg, 5.0 mmol) in methylene chloride (5.0 mL) and methanol (2.0 mL) until the yellow color persisted. After stirring for 10 min, the mixture was evaporated in vacuo to give methyl 3,5-dichlorobenzoate (2-D).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9](=[O:11])(=[O:10])[NH2:12])(=[O:23])=[O:22]
Reactant: Nc1ccc(F)cc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)c1cccc(F)c1F
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cc(F)ccc1NS(=O)(=O)c1cccc(F)c1F
Reaction time: 8 h
Yield: 45.5 %

Procedure:
2-Amino-5-fluorobenzenesulfonamide (29 mg, 0.15 mmol) was dissolved in pyridine (1 ml) and 2,3-difluorophenylsulfonyl chloride (19 μl, 0.15 mmol) was added and the reaction stirred overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (25 mg, 46%).