Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].[H-].[Na+].[CH2:19](I)[CH2:20][CH3:21]>CN(C=O)C.CCCCCC>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[O:16][CH2:19][CH2:20][CH3:21]
Reactant: CCCI
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A solution of 2-bromo-4,6-di-tert-butyl-phenol (18.58 g, 65 mmol) in DMF (200 mL) was added to a stirred slurry of sodium hydride in anhydrous DMF (500 mL) precooled to −7° C. over 15 min. The resulting reaction mixture was stirred at <0° C. for 0.5 h. n-Propyl iodide was added and stirring of the olive green reaction mixture was continued for 18 h. after removal of the ice bath. The reaction was quenched with de-ionized water (2.5 L), 1 M HCl (250 mL) and 5% LiCl solution (250 mL). The resulting mixture was extracted with ethyl acetate (2×250 mL). Sodium chloride (q.s. to saturation) was added to facilitate the separation. The aqueous layer was extracted with hexane (200 mL). The combined organic layers were washed with 5% LiCl (2×200 mL) dried (MgSO4) and filtered. The solvent was removed under vacuum to give a viscous oil which was a 2:1 ration of product to DMF. The residue was dissolved in hexane (100 mL) and the solution was washed with 5% LiCl solution (3×30 mL). The hexane solution was dried (MgSO4), filtered, and the hexane was removed under vacuum to give a light brown oil which crystallized on standing to give a tan solid (21.23 g, 99%). The product may be purified by sublimation at 150° C. at 0.5 torr to give a light yellow solid. NMR (250 Mz, CDCl3): δ 7.32 (d, 1H, J=2.4 Hz), 7.20 (d, 1H, J=2.4), 3.92 (t, 2H, J=6.8), 1.82 (sex, 2H), 1.00 (t, 3H, J=7.4). MS [EI+] 326, 328 (M+H)+.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:14])=O>>[CH3:11][C:12](=[N:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:14]
Reactant: CC(C)=O
Reactant: NNC(=O)c1ccncc1
Product: CC(C)=NNC(=O)c1ccncc1
Temperature: 20 °C

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 68.5 g (0.5 mol) of isonicotinohydrazide and 500 ml of acetone and then heated under reflux for 24 hours. The reaction liquid was cooled down to 20° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby the intended compound (white crystal) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH2:17][OH:18])[CH2:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:15][O:18][CH2:17]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(CO)CO)CC1
Agent: Cc1ccccc1S(=O)(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C2COC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of 4-(2-hydroxy-1-(hydroxymethyl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (7.62 g, 0.029 mol) in anhydrous THF (100 mL) at 0° C., a solution of n-BuLi (1.6 M in hexanes, 18.4 mL, 0.029 mol) was added dropwise. The resulting mixture was stirred at 0° C. for 30 min, then a solution of toluenesulfonyl chloride (5.26 g, 0.028 mol) in anhydrous THF (50 mL) was added by canula. The thick reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. A solution of n-BuLi (1.6 M in hexanes, 18.4 mL, 0.029 mol) was added dropwise and the reaction mixture heated at 60° C. for 2 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, pentane:EtOAc; gradient from 100:0 to 20:80) to afford 4-oxetan-3-ylpiperidine-1-carboxylic acid tert-butyl ester as a white solid (5.33 g, 75%). TFA (10 mL) was added to a solution of 4-oxetan-3-yl-piperidine-1-carboxylic acid tert-butyl ester (7.1 g, 0.029 mol) in DCM (100 mL) and the mixture stirred at ambient temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (50 g), the cartridge was washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 95:5 to 90:10 to 85:15 to 80:20) to afford 4-Oxetan-3-ylpiperidine as a colourless oil which solidified on standing (2.05 g, 49%). 1H NMR (CDCl3, 300 MHz) δ 4.75 (dd, J=7.9, 6.0 Hz, 2H); 4.52-4.42 (m, 2H); 3.14-3.04 (m, 2H); 2.81-2.67 (m, 1H); 2.61 (td, J=12.2, 2.6 Hz, 2H); 1.85-1.68 (m, 1H); 1.60 (m, 2H) and 1.02 (qd, J=12.2, 4.0 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.C(N([CH2:15][CH3:16])CC)C.[C:17]([O:20][CH2:21][CH3:22])(=O)[CH3:18]>C(OC(C)COC)(=O)C>[CH:16]1([CH2:18][CH2:17][O:20][CH:21]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=2)[CH3:22])[CH2:15][CH2:4][CH2:3][CH2:2][CH2:9]1.[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CCOC(C)=O
Agent: C=Cc1ccc(O)cc1
Solvent: COCC(C)OC(C)=O
Product: C=Cc1ccc(OC(C)OCCC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
p-Hydroxystyrene (VP-8000, produced by Nippon Soda Co., Ltd.) in an amount of 70 g was dissolved in 320 g of propylene glycol monomethyl ether acetate (PGMEA) with heating, dehydrated by vacuum distillation, and then cooled to 25° C. To this solution, 0.35 g of pyridinium p-toluenesulfonate and 22.4 g of cyclohexane ethanol were added, and further 17.5 g of t-butyl vinyl ether was added at a slow speed. In the resulting mixture, reaction was run for 5 hours at 20° C. Thereafter, the reaction solution was admixed with 0.28 g of triethylamine and 320 ml of ethyl acetate, and washed with 150 ml each of distilled water for three times. Therefrom, the solvent was distilled away, and the residue was concentrated. The thus obtained oil was dissolved in 100 ml of acetone, and poured slowly into 2 liter of distilled water. As a result, a powdery matter separated out. This powdery matter was filtered off and dried to yield 54 g of the desired resin.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O(CCCNC(C)(C)CC1C=CC([O:47][CH3:48])=CC=1)C1C=CC=CC=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:47][CH3:48])[CH:23]=[C:22]([Cl:1])[CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cc(Cl)cc(OC)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 378 (M-15,.1), 275 (5), 274 (34), 273 (16), 272 (100), 163 (5), 121 (17), 114 (8).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:7]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(C)(C)C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1cc(C(C)(C)C)nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.7 %

Procedure:
To a mixture of tert-butyl (3-tert-butyl-1H-pyrazol-5-yl)methylcarbamate (501 mg, 1.98 mmol, 1 equiv.), 4-fluorophenylboronic acid (554 mg, 3.96 mmol, 2 equiv.) and copper acetate (541 mg, 2.97 mmol, 1.5 equiv.) in dichloromethane (30 mL) was added pyridine (315 mg, 0.315 mL, 3.96 mmol, 2 equiv) and the mixture was stirred in the presence of air for 2 d at room temperature. The reaction mixture was filtered over silica gel, the filter cake was washed with dichloromethane (250 mL) and the solvent of the filtrate was evaporated to give tert-butyl (3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methylcarbamate (232 mg, 34%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:21]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:20]3[C:11]([C:12]4[CH:13]=[CH:14][C:15]([C:27]([O:29]C)=[O:28])=[N:16][C:17]=4[CH2:18][CH2:19]3)=[N:10]2)=[CH:5][C:4]=1[CH3:31])#[N:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:21]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:20]3[C:11]([C:12]4[CH:13]=[CH:14][C:15]([C:27]([OH:29])=[O:28])=[N:16][C:17]=4[CH2:18][CH2:19]3)=[N:10]2)=[CH:5][C:4]=1[CH3:31])#[N:2]
Reactant: COC(=O)c1ccc2c(n1)CCC1C2=NN(c2ccc(C#N)c(C)c2)C1C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)ccc1C#N
Temperature: 25 °C
Reaction time: 6 h
Yield: 36 %

Procedure:
In a dried reaction flask, the crude methyl 2-(4-cyano-3-methylphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylate (0.682 g, about 1.5 mmol) and 10% aqueous NaOH solution (1.97 mL, 4.925 mmol) were dissolved in methanol (3 mL) and tetrahydrofuran (8 mL). The reaction solution was stirred at room temperature for 6 hr. The reaction solution was concentrated at a reduced pressure to reduce the volume to half. The residue was adjusted with 1 M HCl under an ice bath to a pH value of 5-6, and filtered to obtain a crude brick red solid, which was then washed with methanol, ethanol and ethyl acetate to produce a solid (0.216 g) in 36.0% yield.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[CH:9][CH:8]=1.O>CN(C)C=O>[C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([C:18]3[NH:19][N:3]=[N:2][N:1]=3)[CH:20]=[CH:21][CH:22]=2)=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(COc3cccc(-c4nnn[nH]4)c3)cc2)cc1
Temperature: 125 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
To a mixture of sodium azide (2.37 g, 36.45 mmol) and ammonium chloride (1.95 g, 36.45 mmol) in dry N,N-dimethylformamide (100 mL) under an atmosphere of nitrogen, 3-(biphenyl-4-ylmethoxy)benzonitrile (8.0 g, 28.04 mmol) was added and the reaction mixture was stirred at 125° C. for 18 hours. To the cooled reaction mixture water (100 mL) was added and the reaction mixture stirred for 0.75 hour. The precipitate was filtered off and washed with water, 96% ethanol (2×50 mL), and dried in vacuo at 50° C. for 18 hours affording 5.13 g (56%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:4]=2[CH:3]=1.[CH3:13][S:14][CH2:15][S:16]([CH3:18])=[O:17]>>[NH2:12][C:11]([C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([CH3:1])=[CH:3][C:4]=2[CH:10]=1)=[C:15]([S:16]([CH3:18])=[O:17])[S:14][CH3:13]
Reactant: Cc1cc2cc(C#N)ccc2o1
Reactant: CSCS(C)=O
Product: CSC(=C(N)c1ccc2oc(C)cc2c1)S(C)=O

Procedure:
2-Methyl-5-cyanobenzo(b)furan (17.25 g., 0.11 mole) was treated with methyl methylthiomethyl sulphoxide as described in Example 8, Part B, to yield 1-amino-1-[2-methyl-5-benzo(b)furanyl]-2-methylsulphinyl-2-methylthioethylene (12.4 g.), m.p. 185°-186° C.
Reaction SMILES: [F:1][C:2]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH:30][C:11](=[O:13])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[CH:19]=[CH:20][CH:21]=[C:22]([OH:23])[C:2]=3[F:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:26]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(O)c2F)=CC1=O
Reactant: Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C)n1)N1CC(Oc2cccc(O)c2F)=CC1=O
Temperature: 0 °C
Yield: 40.8 %

Procedure:
To a solution of (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 126, 0.226 g, 0.70 mmol) in N,N-dimethylformamide (4 mL) was added 1-methyl-1H-pyrazol-3-ylamine (0.340 g, 3.50 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.340 g, 0.77 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.108 g, 0.84 mmol) was added. The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was extracted with ethyl acetate and washed with a citric acid solution. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 10% to 100% (9:1 dichloromethane:methanol)/hexanes) which afforded (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (0.115 g, 41%) as a white solid: HR-ES-MS m/z calculated for C20H23FN4O4 [M+Na]+ 425.1595, observed 425.1597, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.45 (m, 1H), 1.53-1.63 (m, 1H), 1.67-1.79 (m, 1H), 3.73 (s, 3H), 4.20 (d, J=18.5 Hz, 1H), 4.57 (d, J=18.5 Hz, 1H), 4.84-4.92 (m, 2H), 6.40 (d, J=1.7 Hz, 1H), 6.85 (t, J=7.8 Hz, 1H), 6.91 (t, J=7.8 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), H), 7.54 (d, J=1.7 Hz, 1H), 10.35 (br. s., 1H), 10.72 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[NH:5][C:4](=[O:28])[CH2:3]1.C([O-])(=O)C.[K+].Br[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.ClCCl>CN(C=O)C>[F:41][C:37]1[CH:36]=[C:35]([N:5]2[C:4](=[O:28])[CH2:3][C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]2=3)[CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)Nc3ccccc32)C(C)C)cc1
Reactant: Fc1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccc(F)c3)c3ccccc32)C(C)C)cc1
Temperature: 100 °C
Yield: 80.4 %

Procedure:
To a stirring solution of 500 mg (1.3 mmol) 2-(2,4-Dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide in 5 mL DMF is added 248 mg (3.9 mmol, 3 equiv) of Cu powder, 255 mg (2.6 mmol, 2 equiv) of potassium acetate, and 289 μL (2.6 mmol, 2 equiv) of 1-bromo-3-fluorobenzene. The reaction is heated to 100° C., and after 3 h an additional 289 μL (2.6 mmol, 2 equiv) of 1-bromo-3-fluorobenzene and 248 mg (3.9 mmol, 3 equiv) of Cu powder were added. The reaction is heated at 100° C. for 20 h then is poured onto ice. Dichloromethane is added, and the mixture is filtered through celite. The filtrate is poured into a separatory funnel, and the layers separated. 2 mL of a 30% solution of NH4OH were added to the aqueous layer, and the resulting blue solution is extracted with dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography (gradient 2:1-1:1 hexanes:ethyl acetate) to afford 497 mg of 2-[5-(3-Fluoro-phenyl)-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ7.45-7.25 (m, 4H), 7.18-6.93 (m, 8H), 5.04 (m, 1H), 4.35 (d, 1H, J=16.3), 4.17 (d, 1H, J=16.1), 3.88 (s, 3H), 3.56 (dd, 2H, J=12.0, 29.8), 1.12 (d, 6H, J=6.8); low resolution MS (FAB)m/e 476 (MH+).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][OH:16].O>N1C=CC=CC=1>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH:12]=[N:15][OH:16])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=Cc1coc(-c2ccccc2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: ON=Cc1coc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a solution of 2-phenyloxazole-4-carboxaldehyde (2.18 g, 12.5 mmol) in pyridine (25 ml) was added hydroxylamine hydrochloride (0.96 g, 13.8 mmol) under stirring at room temperature. After 1 hour the mixture was poured into water (200 ml) and the resulting solids were collected, washed with water and dried under vacuum. 2.02 g (10.8 mmol) of the titled compound was obtained: mp 145°-147° C.; IR (KBr) 3195, 3075, 3035, 2850, 1646, 1555, 1486, 1445, 1431 cm-1 ; 1H NMR (270 MHz, CDCl3) d 8.87 (brs,1H), 8.51 (s,1H), 8.09-8.05 (m,2H), 7.68 (sy,1H), 7.52-7.47 (m,3H).
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([OH:15])(=[O:14])[CH:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10].CI>CCCCCC>[CH3:1][C:7]([CH2:11][CH2:12][CH3:13])([CH2:8][CH2:9][CH3:10])[C:6]([OH:15])=[O:14]
Reactant: CCCC(CCC)C(=O)O
Reactant: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Product: CCCC(C)(CCC)C(=O)O

Procedure:
The alkylation of the carboxylic acids at position 2 using alkyl halides is very generally possible with the aid of n-butyllithium at elevated temperature (Pfeffer et al., Alpha-anions of carboxylic acids. II. The formation and alkylation of alpha-metalated aliphatic acids. Journal of Organic Chemistry 37, 451-458 (1972). The methylation of the tertiary carbon atom of valproic acid is possible, for example, by deprotonation of the α-hydrogen atom at C-2 using n-butyllithium in hexane at 50° C. and subsequent methylation with methyl iodide at room temperature in a yield of 32%. The other 2-alkylated carboxylic acids can also be prepared in accordance with this method.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[F:14][C:15]1[CH:16]=[C:17]([CH:23]2[NH:28][C:27]([O:29][CH3:30])=[N:26][C:25]([CH3:31])=[C:24]2[C:32](=[O:34])[CH3:33])[CH:18]=[C:19]([F:22])[C:20]=1[F:21].N1C=CC=CC=1>C(Cl)Cl>[F:14][C:15]1[CH:16]=[C:17]([CH:23]2[N:28]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[C:27]([O:29][CH3:30])=[N:26][C:25]([CH3:31])=[C:24]2[C:32](=[O:34])[CH3:33])[CH:18]=[C:19]([F:22])[C:20]=1[F:21]
Reactant: COC1=NC(C)=C(C(C)=O)C(c2cc(F)c(F)c(F)c2)N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1=NC(C)=C(C(C)=O)C(c2cc(F)c(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
4-Nitrophenyl chloroformate (1.89 g, 9.38 mmol) was added to a solution of 6-(3,4,5-trifluorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-meth-ylpyrimidine (2.80 g, 9.38 mmol) and pyridine (10 mL) in CH2Cl2 (200 mL) at 0-5° C., and the resulting mixture was allowed to warm to room temperature. After 12 h, the solvent was evaporated and the residue was purified by flash chromatography (dichloro-methane/EtOAc, 1/9 to 3/20), giving the desired product as a white powder (4.00 g, 92%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C(=O)([O-])[O-:34].[K+].[K+].OO>CS(C)=O>[CH2:1]([O:3][C:4](=[O:32])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:34])[NH2:31])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(C#N)cc3)oc2C)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(C(N)=O)cc3)oc2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
2-(4-{2-[2-(4-Cyanophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (60 mg, 0.14 mmol) and potassium carbonate (30 mg, excess) were dissolved in dimethylsulfoxide (1 mL). After cooling to 0° C., the mixture was treated with hydrogen peroxide (120 •L of a 30% aqueous solution) and then warmed to ambient temperature. After stirring for 1 h, the mixture was partitioned between EtOAc (15 mL) and H2O. The aqueous phase was extracted with EtOAc (3×), and then the combined organic phases were dried (MgSO4), filtered and concentrated to provide the product as a white solid (58 mg, 93%): mp 112° C.; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 6.81-6.77 (m, 4H), 6.12 (br s, 1H), 5.66 (br s, 1H), 4.22 (q, J=6.8 Hz, 2H), 4.18 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.38 (s, 3H), 1.52 (s, 6H), 1.27 (t, J=7.2 Hz, 3H); MS (EI) 475.2 (M+Na)+, 453.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.I[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:17][CH2:16][CH2:15][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][CH2:10]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCN1CCN(c2ccccc2F)CC1
Yield: 65.9 %

Procedure:
A mixture of 1-(2-fluorophenyl)piperazine (0.50 g), 2-iodoethanol (0.48 g), and potassium carbonate (1.5 g) in dimethylformamide (7 mL) was heated at reflux for three hours. The solvent was removed in vacuo and the residue was purified by preparative thin-layer chomatography (silica gel, eluting with chloroform/methanol, 9:1), giving the title compound as a yellow oil (0.41 g, 65%). 1H NMR (300 MHz, CDCl3) δ7.09-6.90 (m, 4H), 3.67 (t, 2H, J=5.4 Hz), 3.13 (t, 4H, J=4.7 Hz), 2.76 (br s, 1H), 2.71 (t, 4H, J=4.8 Hz), 2.63 (t, 4H, J=5.4 Hz). 13C NMR (75 MHz, CDCl3) δ156.3 (d, J=244.1 Hz), 140.6 (d, J=8.8 Hz), 125.1 (d, J=3.4 Hz), 123.2 (d, J=8.1 Hz), 119.5 (d, J=2.9 Hz), 116.7 (d, J=20.6 Hz), 60.1, 58.4, 53.6 (2C), 51.2 (d, 2C, J=3.0 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[F:13][CH:14]([F:23])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[F:13][CH:14]([F:23])[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:20][CH:21]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nc(Nc2ccc(OC(F)F)cc2)c2ccccc2n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A mixture of 4-chloro-2-methyl-quinazoline (450 mg, 2.52 mmol), 4-difluoromethoxy-phenylamine (0.32 ml, 2.52 mmol) and sodium acetate (248.07 mg, 3.02 mmol) in 6 mL of solvent (THF:water=1:1) was stirred at 70° C. for 1 h. The reaction mixture was diluted with 30 mL of ethyl acetate. It was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica gel with acetate and hexane (1:5) as eluent, yielding 713 mg of title compound (94%). 1H NMR (CDCl3): 7.87-7.76 (m, 5H), 7.51 (t, J=8.4 Hz, 1H)), 7.40 (brs, 1H), 7.19 (d, J=8.7 Hz, 2H), 6.76-6.27 (three single peaks, 1H), 2.71 (s, 3H).