Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:13]=2)[C:3](OCC)=[O:4].[NH2:27][C:28](N)=[O:29].C[O-].[Na+].C(=O)([O-])O.[Na+].Cl>C(O)C.O>[CH2:20]([O:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:9]([CH2:8][CH:2]3[O:1][C:28](=[O:29])[NH:27][C:3]3=[O:4])[CH:10]=[N:11]2)=[CH:16][CH:15]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(O)Cc1cnc2cc(OCc3ccccc3)ccc2c1
Reactant: NC(N)=O
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Product: O=C1NC(=O)C(Cc2cnc3cc(OCc4ccccc4)ccc3c2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
In ethanol (1.5 mL) were suspended ethyl 2-hydroxy-3-(7-benzyloxy-3-quinolyl)propionate (162 mg, 0.461 mmol.), urea (48.7 mg, 0.804 mmol.) and sodium methoxide (28% methanolic solution, 0.12 mL, 0.622 mmol.). The resulting suspension was stirred for one hour at room temperature, and then heated under reflux for 4 hours. The reaction mixture was cooled, and neutralized by addition of saturated aqueous sodium hydrogen carbonate solution after addition of 1N hydrochloric acid (1.0 mL) and water (2.0 mL). Insolubles were collected, washed with ethyl acetate and ether, and dried under reduced pressure, to give 110 mg of the desired compound as white crystalline powder (yield 66%).
Reaction SMILES: O[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[F:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:18]([C:16]1[CH:17]=[C:12]([C:11]2[O:22][C:2]3[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=3[N:10]=2)[C:13]([F:21])=[CH:14][CH:15]=1)([O-:20])=[O:19]
Reactant: O=C(Nc1cc(Cl)cc(Cl)c1O)c1cc([N+](=O)[O-])ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(Cl)cc(Cl)c3o2)c1

Procedure:
Prepared by the method of Example 15b), from N-(2-hydroxy-3,5-dichlorophenyl)-2-fluoro-5-nitrobenzamide (798 g, 2.3 mmol) and p-toluenesulfonic acid monohydrate (961 g, 5.1 mmol) the subtitle compound was obtained (597 mg, 79%). 1H NMR (DMSO) δ 9.00(t, 1H), 8.78(s, 1H), 8.24(dd, 1H), 7.97(s, 1H), 7.77(s, 1H), 7.09(d, 1H), 3.46(q, 2H), 1.73(m, 2H), 1.04(t, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.Cl>>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH2:31][NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: NCCOCCO
Agent: Cl
Product: OCCOCCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 2-(2-amino-ethoxy)-ethanol and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. The product was converted to the mesylate salt analogous to example 17 being converted to the HCl salt. M.P. 111-119° C.; LC-MS: 460 (MH+); HPLC RT: 3.40 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH2:14][CH:13]3[N:10]([C:11](=[O:17])[CH:12]3[CH2:15][CH3:16])[C:9]=2[C:18]([O:20]CC2C=CC([N+]([O-])=O)=CC=2)=[O:19])=[CH:3][CH:2]=1.[H][H]>O1CCOCC1.P([O-])([O-])([O-])=O.[Pt]=O>[N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH2:14][CH:13]3[N:10]([C:11](=[O:17])[CH:12]3[CH2:15][CH3:16])[C:9]=2[C:18]([OH:20])=[O:19])=[CH:3][CH:2]=1
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccncc3)CC12
Reactant: [H][H]
Agent: O=[Pt]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCC1C(=O)N2C(C(=O)O)=C(Sc3ccncc3)CC12
Reaction time: 4 h
Yield: 56.2 %

Procedure:
54 mg of p-nitrobenzyl 3-(4-pyridylthio)-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate obtained in Example 17 was dissolved in a mixture of 2 ml of dioxane and 2 ml of a 0.1 M phosphate buffer (pH 7.0). Then, 54 mg of platinum oxide was added, and the reaction was performed at room temperature for 4 hours in a Paar reducing apparatus (hydrogen pressure 4 kg/cm2). The catalyst was removed by filtration. The filtrate and the wash liquid were combined and concentrated under reduced pressure to about 2/3 of the original amount. To the resulting solution was added 2.5 g of sodium chloride, and further water was added to make the total amount 50 ml. The solution was charged on a column of Diaion HP-20AG (1.1×20 cm), and eluted with 300 ml in total of an aqueous solution of acetone having a concentration gradually varying from 0 to 30% by a concentration gradient method. The eluate was fractionated into 5 g fractions. The fractions were screened by high-velocity liquid chromatography, and fractions having an ultraviolet absorption at λmax 303 nm were collected, and lyophilized to afford 20.7 mg (yield 56.8%) of the captioned product.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10]Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[K].[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[CH2:15].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[N:1]1([C:7]([O:9][CH2:10][O:18][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C=C(C)C(=O)O
Reactant: O=C(OCCl)N1CCOCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCOC(=O)N1CCOCC1
Reaction time: 0.25 h

Procedure:
Chloromethyl morpholine-4-carboxylate (1 equiv.) is added to a 0.1M solution of the potassium salt of methacrylic acid (1.1 equiv.) and 18-crown-6 (2/100 equiv.) in DMF at 0° C. After 15 min at 0° C. and a suitable time at elevated temperature the reaction mixture is filtered and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography giving the wanted methacryloyloxymethyl morpholine-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([OH:16])=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:4]=2[CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:4]=2[CH:3]=1
Reactant: OC1=Cc2ccccc2C=Cc2cc(Br)ccc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1Cc2ccccc2C=Cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.3 %

Procedure:
To a solution of 2-bromo-5-hydroxy-dibenzo[a,e]cyclooctene (2.3 g) in dry dichloromethane (100 ml) was added pyridinium dichromate (5.75 g) and crushed 4 A molecular sieves (3 g). After stirring at room temperature for 14 h, diethyl ether (200 ml) was added and the reaction mixture was filtered through a plug of celite. The solvent was removed in vacuo and the residue purified by chromotagraphy on flash silica with 5% ethyl acetate in hexane as eluent to give as a colourless solid. the title compound (2.1 g, m.p. 121°-123° C.). δ (360 MHz, CDCl3) 4.03 (2H, s, CH2), 6.92 (1H, d, J=12.8 Hz, CHA =CHB), 7.09 (1H, d, J=12.8 Hz, CHa =CHB), 7.20-7.56 (6H, m, ArH), 8.08 (1H, d, J=8.5 Hz, BrC=CH--CH= C--C=O). m/e 300 and 298 (M+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:24][C:25]1[CH:26]=[C:27]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[CH:29][C:30]=1[C:31]([F:32])([F:33])[F:34]
Reactant: OB(O)c1ccc(C(F)(F)F)c(Cl)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4ccc(C(F)(F)F)c(Cl)c4)c(C(=O)O)s3)c2cc1OC
Yield: 15.9 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-chloro-4-trifluoromethylphenylboronic acid (33.7 mg, 0.15 mmol) gave 4-(3-Chloro-4-trifluoromethyl-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (7.7 mg, 16%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.91 (br.s., 1 H); 8.85 (s, 1 H); 8.48 (d, 1 H); 8.31 (dd, 1 H); 7.89 (d, 1 H); 7.84 (s, 1 H); 7.39 (s, 1 H); 3.86 (s, 3 H), 3.85 (s, 3H). MS 484 m/z (M+1).
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(C)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([O-:34])=[O:33]
Reactant: O=C(O)/C=C/C(=O)O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC(C)O
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 80 °C
Reaction time: 21 h

Procedure:
Sitagliptin (4 g) and isopropanol (60 mL) are charged into a round-bottom flask and the mixture is heated to about 80° C. for about 30 minutes to obtain a clear dissolution. Fumaric acid (1.14 g) is added and the reaction mixture is refluxed for about 2 hours. The reaction mixture is cooled to about 30° C. and stirred for about 21 hours. The separated solid is filtered, washed with isopropanol (4 mL), and dried under reduced pressure at about 45° C. for about 2 hours to afford the title compound. (Yield: 4.0 g; MC: 1.05% w/w; HPLC purity: 99.47%)
Reaction SMILES: COC1C=C(C(O)C)ON=1.[Br:11][C:12]1[CH:16]=[C:15]([CH:17]([OH:20])[CH2:18]C)[O:14][N:13]=1.BrC1C=C(C(O)CCC)ON=1>>[Br:11][C:12]1[CH:16]=[C:15]([C:17](=[O:20])[CH3:18])[O:14][N:13]=1
Reactant: CCC(O)c1cc(Br)no1
Agent: CCCC(O)c1cc(Br)no1
Agent: COc1cc(C(C)O)on1
Product: CC(=O)c1cc(Br)no1

Procedure:
In a similar manner 3-methoxy-5-(1-hydroxyethyl)-isoxazole, 3-bromo-5-(1-hydroxypropyl)-isoxazole and 3-bromo-5-(1-hydroxybutyl)-isoxazole were oxidized to afford
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[Br:16]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C>[Br:16][C:8]1[CH:7]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[NH:2][CH3:1]
Reactant: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CNc1c(Br)cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
To a mixture of methyl-(2-nitro-4-trifluoromethyl-phenyl)-amine (16 g) and acetonitrile (200 ml) was added N-bromosuccinimide (15 g) while ice-cooling. The reaction mixture was stirred at room temperature for 5 hours. To the resulting reaction mixture was poured saturated aqueous sodium hydrogen carbonate solution, and then the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give (2-bromo-6-nitro-4-trifluoromethyl-phenyl)-methyl-amine (15 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:16][C:17]([CH3:32])([CH3:31])[CH2:18][CH2:19][O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[C@@H:10]([OH:15])[CH2:11][CH2:12][CH:13]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:35](OC)([CH3:37])[CH3:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH2:16][C:17]([CH3:31])([CH3:32])[CH2:18][CH2:19][O:20][Si:21]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:23])[CH3:24])[CH:28]([CH3:30])[CH3:29])[C@H:10]([CH2:11][CH2:12][CH:13]=[CH2:14])[O:15][C:35]1([CH3:37])[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(C)(C)OC
Reactant: C=CCC[C@H](O)[C@H](CC(C)(C)CCO[Si](C(C)C)(C(C)C)C(C)C)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: C=CCC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCO[Si](C(C)C)(C(C)C)C(C)C

Procedure:
1.80 g of 6(S)-tert-butoxycarbonylamino-8,8-dimethyl-5(S)-hydroxy-10-triisopropylsilyloxydec1-ene are stirred in 10 ml each of methylene chloride and dimethoxypropane with 50 mg of p-toluenesulfonic acid hydrate at room temperature for 2 h. After the mixture has been concentrated, the residue is purified over 250 g of silica gel with a 1:20 mixture of ethyl acetate and hexane as the mobile phase: Rf (1:20 mixture of ethyl acetate and hexane)=0.40.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.N#N.C(N(CC)CC)C.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.[Cu]I>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:32]#[C:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nccn2c(C3CCC3)nc(C#Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.4 %

Procedure:
A solution of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine (50 mg, 0.159 mmol) in N,N-dimethylformamide (6 mL) and evacuated and charged with N2 three times, then treated with triethylamine (0.044 mL, 0.318 mmol), phenylacetylene (0.175 mL, 1.59 mmol), and copper (I) iodide (3.0 mg, 0.0159 mmol). The mixture re-evacuated and charged with N2 twice more, then charged with tetrakis(triphenylphoshine)palladium (0) (20.2 mg, 0.0175 mmol) and evacuated and charged with N2 a final two times. The reaction mixture was stirred at rt for 16 h, then concentrated in vacuo, dissolved in MeOH/CH3CN (1:1)(4 mL) and was filtered through a 0.45 fritted μM autovial prior to purification via mass directed preparative HPLC that afforded 13 mg of the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 1.87-1.99 (m, 1H), 2.01-2.15 (m, 1H), 2.32-2.47 (m, 4H), 3.87-3.99 (m, 1H), 6.66 (brs, 2H), 7.08 (brs, 1H), 7.40-7.51 (m, 4H), 7.59-7.67 (m, 2H); MS (ES+): m/z 289.13 [MH+].
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:23]=[CH:22][C:13]3[N:14]([CH2:19][C:20]#[N:21])[C:15](=[O:18])[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24](N)[CH2:25][NH2:26]>C(Cl)(Cl)Cl.C(O)C>[C:1]1([S:7]([C:10]2[CH:23]=[CH:22][C:13]3[N:14]([CH2:19][C:20]4[NH:26][CH2:25][CH2:24][N:21]=4)[C:15](=[O:18])[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCN
Reactant: N#CCN1C(=O)COc2cc(S(=O)(=O)c3ccccc3)ccc21
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C1COc2cc(S(=O)(=O)c3ccccc3)ccc2N1CC1=NCCN1
Temperature: -15 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
To a solution of (7-benzenesulfonyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-acetonitrile (0.156 g., 0.475 mmol) in 10 mL anhydrous chloroform was added ethanol (0.029 mL, 0.5 mmol), and the resulting solution was cooled in a water ice/acetone bath to −15° C. Hydrogen chloride gas was bubbled through the solution for 10 minutes, and the flask was sealed and kept at −15° C. for 18 hours. The reaction mixture was concentrated in vacuo and 0.5 Torr vacuum was applied to the residue for 2 hours. The crude imidate was dissolved in 5 mL anhydrous chloroform, and to this solution was added ethylene diamine (0.033 mL, 0.5 mmol) in 4 mL anhydrous chloroform and 5 mL ethanol. The resulting solution was stirred at room temperature for 3 hours, and was then concentrated in vacuo. The residue was purified by flash chromatography (30% “magic base” (6:1:0.1 methylene chloride:methanol:ammonia) in dichlormethane) to give 0.130 g (0.35 mmol, 74%) of 7-benzenesulfonyl-4-(4,5-dihydro-1H-imidazol-2-ylmethyl)-4H-benzo[1,4]oxazin-3-one as a clear oil. MS: 372 (M+H)+, mp: 113.7-116.0° C. (HCl salt).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][C:3](=[O:11])[NH:4][C:5]=2[CH:10]=1)=[O:19]
Reactant: O=C(Cl)CCCCCBr
Reactant: O=C1COc2ccccc2N1
Product: O=C1COc2ccc(C(=O)CCCCCBr)cc2N1

Procedure:
Using 2H-1,4-benzoxazin-3(4H)-one (15.0 g) and 6-bromohexanoyl chloride (2.5.8 g) according to the same method as that of Reference Example 1, the title compound (14.8 g) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].O[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[O:5][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13](=[O:14])[CH:12]=1
Reactant: O=C(CO)c1ccccc1
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1-c1cc(=O)c2ccccc2o1

Procedure:
7 is prepared from 2-methylbenzoyl chloride (8) and 2-hydroxyacetophenone by the procedure of Example 1. The material is purified by vacuum column (eluting with 10% ethyl acetate in hexane), yielding 7 with a melting point of 45.5°-47.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34]([C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=1)([CH3:36])[CH3:35].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:34]([C:37]1[CH:44]=[CH:43][C:40]([CH2:41][N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[CH:39][CH:38]=1)([CH3:36])[CH3:35]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(CN2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)cc1

Procedure:
1-[1-(4-Isopropyl-benzyl)-piperidin-4-yl]-4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 4-isopropylbenzaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.18 (d, 6H, J=6.6 Hz), 1.94-1.99 (m, 2H), 2.15-2.24 (m, 4H), 2.85-2.90 (m, 1H), 2.95-2.99 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.60 (s, 2H), 4.74-4.80 (m, 1H), 7.20-7.27 (m, 4H), 7.62-7.64 (m, 2H), 8.04-8.06 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=506.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:27]3[CH:28]=[CH:29][C:24]([CH2:23][O:22][CH3:21])=[CH:25][CH:26]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COCc1ccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Yield: 96 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (3.0 g, 10.1 mmol, 1 eq.) in 1,2 dimethoxyethane (6 mL). Add 4-methoxymethyl-benzene boronic acid (2.01 g, 12.12 mmol, 1.2 eq.). Add tetrakis(triphenylphosphine)-palladium (1.17 g, 1.01 mmol, 0.1 eq.) followed by potassium carbonate (3.77 g, 27.3 mmol, 2.7 eq.). Heat the reaction mixture at 100° C. for 17 hr. Partition the reaction mixture between EtOAc and water. Separate layers. Extract the aqueous layer with dichloromethane. Combine organic layers, dry over anhydrous Na2SO4, filter and concentrate. Purify by normal phase chromatography with 10-30% EtOAc/hexane to afford the title preparation (3.7 g, 96% yield). LC MS (ES): m/z=385.3 [M+H].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20](=O)[NH:21][CH:22]=[N:23]3)=[C:18]([O:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:17]=2)[CH2:9][CH2:8]1.C(N(C(C)C)CC)(C)C.C(#N)CCC.[Cl:48][C:49]1[C:54]([NH2:55])=[C:53]2[O:56][CH2:57][O:58][C:52]2=[CH:51][CH:50]=1>O>[Cl:48][C:49]1[C:54]([NH:55][C:20]2[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:14][CH2:13][N:10]4[CH2:9][CH2:8][N:7]([CH3:6])[CH2:12][CH2:11]4)=[CH:17][C:18]=3[O:27][CH:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:23]=[CH:22][N:21]=2)=[C:53]2[O:56][CH2:57][O:58][C:52]2=[CH:51][CH:50]=1
Reactant: CN1CCN(CCOc2cc(OC3CCOCC3)c3c(=O)[nH]cnc3c2)CC1
Reactant: Nc1c(Cl)ccc2c1OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCC#N
Product: CN1CCN(CCOc2cc(OC3CCOCC3)c3c(Nc4c(Cl)ccc5c4OCO5)ncnc3c2)CC1
Temperature: 96 °C

Procedure:
Under an atmosphere of nitrogen gas, phosphoryl chloride (0.07 ml) was added to a stirred mixture of 7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (0.2 g), diisopropylethylamine (0.22 ml) and butyronitrile (2 ml) that had been heated to 96° C. and the resultant mixture was heated to 96° C. for 4 hours. A second portion (0.12 ml) of phosphoryl chloride was added and the resultant mixture was heated to 96° C. for 1.7 hours. 6-Chloro-2,3-methylenedioxyaniline (0.098 g) was added and the resultant mixture was heated to 96° C. for 2 hours. The mixture was allowed to cool to ambient temperature. Water (2 ml) was added and the organic layer was separated. The aqueous layer was washed with butyronitrile (1 ml). The aqueous layer was basified to pH9 by the addition of concentrated aqueous sodium hydroxide solution (47% w/w) and extracted with n-butanol (2×2 ml). The resultant organic layers were combined and evaporated. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.094 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]21[C:10]1[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][C:9]=1S[CH2:7][CH2:6]2.C([O-])(=O)C.[Na+].O[O:24][S:25]([O-:27])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].Cl>O.CO>[O:1]1[CH2:5][CH2:4][O:3][C:2]21[C:10]1[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][C:9]=1[S:25](=[O:27])(=[O:24])[CH2:7][CH2:6]2
Reactant: O=C(O)c1ccc2c(c1)C1(CCS2)OCCO1
Reactant: O=S([O-])OO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=S(=O)([O-])O[O-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)C1(CCS2(=O)=O)OCCO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
8.5 g (0.034 mol) of the title compound of Step D and 41.5 g (0.51 mol) of sodium acetate were added to 160 mL of methanol. The suspension was cooled to about 0° C., and a solution of 35.2 g (0.057 mol) of OXONE® (potassium peroxymonosulfate, purchased from Aldrich Chemical Company) in 160 mL of water was added dropwise while keeping the temperature below 6° C. The mixture was warmed to room temperature and stirred under nitrogen overnight. The mixture was diluted with 100 mL of water, cooled to about 0° C., acidified to pH 2 with concentrated hydrochloric acid, and extracted with chloroform (3×200 mL). The combined organic layers were dried (MgSO4), filtered, and evaporated to dryness. The crude product was triturated with a hexane:diethyl ether mixture (9:1) to yield 6.98 g of the title compound of Step E as a solid melting at 208° C. (dec). 1H NMR (Me2SO-d6): δ2.6 (m,2H), 3.7 (m,2H), 4.1-4.2 (m,4H), 7.9-8.15 (3H), 13.6 (br s,1H).