Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][N:11]([CH2:46][CH:47](OCC)OCC)[C:12]([CH:14]([NH:27][C:28](=[O:45])[CH2:29][CH:30]([NH:34][C:35]([NH:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:31][CH:32]=[CH2:33])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C(C)(C)C)=[CH:18][CH:17]=3)=[O:13])[C:4]=2[N:3]=[CH:2]1>C(O)=O>[CH2:38]([NH:37][C:35]([N:34]1[CH:30]([CH2:31][CH:32]=[CH2:33])[CH2:29][C:28](=[O:45])[N:27]2[CH:14]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[C:12](=[O:13])[N:11]([CH2:10][C:9]3[C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=[CH:7][CH:8]=3)[CH2:46][CH:47]12)=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2scnc12)CC(OCC)OCC)NC(=O)NCc1ccccc1
Solvent: O=CO
Product: C=CCC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3cccc4scnc34)CC2N1C(=O)NCc1ccccc1
Yield: 40.7 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-hex-5-enoic acid [1-[benzothiazol-4-ylmethyl-(2,2-diethoxy-ethyl)-carbamoyl]-2-(4-tert-butoxy-phenyl)-ethyl]-amide (3.67 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and hexane to give 2-Allyl-8-benzothiazol-4-ylmethyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic acid benzylamide (1.2 g, 3 step yield: 35%). 1H NMR (CDCl3, 300 MHz) δ 9.20 (5, 1H), 7.4˜7.26 (m, 3H), 7.2 (d, J=7.01, 2H), 6.98 (t, J=8.0, 1H), 6.80 (m, 3H), 6.75 (t, J=7.0, 1H), 6.5 (d, J=8.76, 2H), 5.6 (m, 1H), 5.25 (t, J=1H), 5.05 (d, J=10.75, 1H), 5.0 (d, J=18.54, 1H), 4.87 (d, J=14.51, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H), 3.5˜3.3 (m, 2H), 3.25˜3.1 (m, 2H), 2.6-2.4 (m, 2H), 2.2 (t, J=7.2, 2H) MS ESI 596 (M+H), 618 (M+Na).
Reaction SMILES: O1CCCC1[C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)[CH2:9][CH:10]1[C:17]2[CH:16]=[C:15]([C:18]([O:20]C)=[O:19])[NH:14][C:13]=2[CH2:12][CH2:11]1.[OH-].[Li+].[CH2:27]1[CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:31][CH2:27][CH:28]([C:6]2[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=2)[CH2:9][CH:10]2[C:17]3[CH:16]=[C:15]([C:18]([OH:20])=[O:19])[NH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:29]1
Reactant: C1CCOC1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(C2CCCO2)c1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(C2CCOC2)c1

Procedure:
The title compound was synthesized from methyl 4-(3-(tetrahydrofuran-2-yl)benzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.028 g, 0.086 mmol) and lithium hydroxide (0.036 g, 0.86 mmol in 0.75 mL water), according to General Procedure 7. THF (0.75 mL) was used to solubilize the starting material. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound: 11 mg, 41% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.71-1.83 (m, 1H), 1.96-2.06 (m, 2H), 2.07-2.14 (m, 1H), 2.27-2.36 (m, 1H), 2.49-2.63 (m, 3H), 2.69-2.83 (m, 2H), 3.21-3.28 (m, 1H), 3.87-3.93 (q, 1H), 4.04-4.09 (q, 1H), 4.82-4.83 (m, 1H), 6.26-6.36 (d, 1H), 7.09-7.11 (m, 2H), 7.14-7.18 (m, 1H), 7.21-7.26 (m, 1H); LCMS-MS (ESI−) 310.2 (M−H); HPLC (UV=98.99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][CH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: COc1cc(C=O)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(Oc1c(Cl)cc(CO)cc1OC)c1ccccc1
Yield: 63.9 %

Procedure:
A mixture of 0.50 g (2.65 mmol) of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde, 0.668 g (2.92 mmol) of methyl 2-bromophenylacetate and K2CO3 (0.73 g, 5.3 mmol) in acetone (8 mL) was refluxed for 14 h. The mixture was cooled, filtered and evaporated in vacuo, and the residue was purified by flash chromatography on a silica gel column using 5% ethylacetate in hexane to afford 0.570 g (64%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:5][CH2:4][CH2:3]1.CN(C=O)C.S(Cl)([Cl:32])=O>C(Cl)Cl>[Cl:32][CH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[C:7]([C:6]2[C:2]([CH3:24])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCC2(C)C)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2=CCCC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound T1.7 (1.10 g, 3.37 mmol) and a catalytic amount of DMF (0.10 mL) in DCM (12.0 mL), was slowly added thionyl chloride (0.802 g, 6.74 mmol) at 0° C. After addition, the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting residue was purified by CombiFlash® chromatography (silica gel column eluted with hexane/EtOAc, 100/0 to 95/5) to give the title compound T1 (1.15 g). 1H NMR (400 MHz, CDCl3) δ ppm. 7.32-7.39 (m, 2H), 7.28-7.29 (m, 1H), 6.88 (t, 1H), 6.80-6.82 (m, 2H), 5.56 (s, 1H), 4.66 (s, 2H), 3.78 (s, 3H), 2.27-2.29 (m, 2H), 1.69 (t, 2H), 0.89 (s, 6H).
Reaction SMILES: [CH2:1]([CH:3]([NH2:6])[CH2:4][CH3:5])[CH3:2].N1C=CC=CC=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].O>O1CCCC1.CCCCCC>[CH2:1]([CH:3]([NH:6][C:14](=[O:15])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(N)CC
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: O
Product: CCC(CC)NC(=O)Oc1ccccc1
Yield: 147 %

Procedure:
1-Ethylpropylamine (11.6 ml, 100 mmol) was dissolved in tetrahydrofuran (400 ml); pyridine (8.9 ml, 110 mmol) was added thereto at room temperature; and the reaction mixture was stirred. The reaction mixture was cooled with ice bath; phenyl chloroformate (13.8 ml, 110 mmol) was added dropwise; and the reaction mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture; the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with diethyl ether:hexane=1:5 to yield the title compound as crystals (22.3 g, 147 mmol, 59.1%).
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:25]([CH2:27][C@@H:28](O)[CH2:29]C(OCC)=O)#N.Cl>O1CCCC1.O1CCCC1.CCCCCCC>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH2:9][CH2:25][CH2:27][CH2:28][CH3:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)N(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C[C@H](O)CC#N
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCCCCC(=O)N(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred -10° C. solution of N,N-diphenylacetamide (211 g, 1.0 mol) in tetrahydrofuran (1.0 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.5 L of 2M) while maintaining the temperature between -10° C. to -5° C. The mixture is stirred at -0° C. to 20° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (40 g, 0.25 mol) as a solution in 200 mL of tetrahydrofuran is added to the previously prepared anion. The reaction mixture is stirred for 30 minutes at -5° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (1 L). The aqueous layer is extracted with 500 mL of ethyl acetate, the aqueous layer is separated and reextracted with 100 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (R)-6 -cyano-5-hydroxy-3-oxo. N,N-diphenylhexanamide which is not isolated. A small sample is purified by column chromatography on flash silica gel (60:40 hexane:ethyl acetate) as an oil. Proton nuclear magnetic resonance spectroscopy (1H-NMR): (Acetone-d6) δ2.02 (m, 2H), 2.73 (m, 2H), 4.1 (m, 2H), 4.52 (m, 1H), 4.74 (s, 1H), 7.2-7.4 (m, 10H).
Reaction SMILES: [Na].[F:2][C:3]1[CH:19]=[CH:18][C:6]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1.[CH:23](I)([CH3:25])[CH3:24].[OH-].[Na+]>CN(C=O)C>[F:2][C:3]1[CH:19]=[CH:18][C:6]([N:7]([CH:23]([CH3:25])[CH3:24])[S:8]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2[N+](=O)[O-])cc1
Reactant: CC(C)I
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(c2ccc(F)cc2[N+](=O)[O-])C(C)C)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
4′-Fluoro-2′-nitro-p-toluenesulfonanilide sodium salt (66.46 g (200 mmol)) was dissolved in DMF (66 ml). To this, under heating in an oil bath kept at 120° C., isopropyl iodide (102.0 g (600 mmol)) was added over a period of 20 minutes. The resulting mixture was left to cool to room temperature, mixed with 1% aqueous sodium hydroxide solution and stirred. The resulting crystals were filtered, washed with water and ethanol, successively. The crude crystals thus obtained were recrystallized from ethyl acetate to give 30.58 g (43%) of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[O:13][C:12]([C:14](=[O:31])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:19][CH:18]=3)=[N:11][CH:10]=2)[N:4]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CC(O)C.O.[Br-].[Zn+2].[Br-]>[NH:32]1[C:1]([C:3]2[N:4]=[C:5]([C:9]3[O:13][C:12]([C:14](=[O:31])[CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:19][CH:18]=4)=[N:11][CH:10]=3)[CH:6]=[CH:7][CH:8]=2)=[N:2][N:34]=[N:33]1
Reactant: N#Cc1cccc(-c2cnc(C(=O)CCc3ccc(COc4ccccc4)cc3)o2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CC(C)O
Solvent: O
Product: O=C(CCc1ccc(COc2ccccc2)cc1)c1ncc(-c2cccc(-c3nnn[nH]3)n2)o1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
2-Cyano-6-(2-(3-(4-(phenoxymethyl)phenyl)propanoyl)oxazol-5-yl)pyridine (98 mg, 0.24 mmol), sodium azide (31 mg, 0.48 mmol), and zinc bromide (27 mg, 0.12 mmol) were dissolved in i-PrOH/H2O (1:2, 2.1 mL) and warmed at reflux for 24 h. The reaction solution was allowed to cool to ambient temperature and was quenched with aqueous 1 N HCl. The solution was diluted with EtOAc and the organic phase was washed with saturated aqueous NaCl, dried over Na2SO4, and the solvent was removed in vacuo. The crude product was purified by tritration in 3% CH2Cl2/ether to provide 1-(5-(6-(1H-tetrazol-5-yl)pyridin-2-yl)oxazol-2-yl)-3-(4-(phenoxymethyl)phenyl)propan-1-one as a pale yellow solid (60 mg, 55%): NMR (DMSO-d6, 600 MHz) δ 8.25-8.24 (m, 3H), 8.08-8.05 (m, 1H), 7.38 (d, 2H, J=8.0 Hz), 7.31-7.27 (m, 4H), 6.99 (d, 2H, J=8.7 Hz), 6.92 (t, 1H, J=7.3 Hz), 3.47 (t, 2H, J=7.5 Hz), 3.02 (t, 2H, J=7.5 Hz); 13C NMR (DMSO-d6, 150 MHz) δ 207.8, 188.3, 159.7, 158.7, 153.0, 147.3, 141.6, 141.2, 136.2, 130.8, 129.7, 129.6, 129.2, 124.1, 123.3, 122.0, 116.1, 70.2, 32.0, 30.0; HR ESI-TOF m/z 453.1681 (M+H+, C25H20N6O3, requires 453.1670).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH2:19][C:18]2[C:13](=[N:14][C:15](S(C)(=O)=O)=[N:16][CH:17]=2)[N:12]([CH3:24])[C:11]1=[O:25].[CH2:26]([N:28]([CH2:39][CH3:40])[CH2:29][CH2:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:27]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH2:19][C:18]2[C:13](=[N:14][C:15]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:28]([CH2:39][CH3:40])[CH2:26][CH3:27])=[CH:38][CH:37]=3)=[N:16][CH:17]=2)[N:12]([CH3:24])[C:11]1=[O:25]
Reactant: CN1C(=O)N(c2c(Cl)cc(Cl)cc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2c(Cl)cc(Cl)cc2Cl)C3)cc1
Temperature: 180 °C
Yield: 17 %

Procedure:
A mixture of 200 mg (0.48 mmol) of 3-(2,4,6-trichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 300 mg (1.4 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 30 minutes. The mixture was cooled and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to afford 45 mg (17%) of 3-(2,4,6-trichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 142° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[S:9][CH:10]=1)=[O:5])[CH3:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCOC(=O)c1csc(-c2ccc(OC)cc2)n1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
2-Bromo-thiazole-4-carboxylic acid ethyl ester (1.00 mmol, 236 mg), 4-methoxyphenylboronic acid (1.50 mmol, 228 mg), Pd2(DBA)3 (0.020 mmol, 18 mg), S-Phos (0.060 mmol, 25 mg) and potassium phosphate tribasic monohydrate (1.5 mmol, 0.35 g) were loaded into a Schlenk tube containing a stir bar. The Schlenk tube was capped with a rubber septum, evacuated and refilled with nitrogen. Toluene (2 mL) was added through the septum via a syringe and the Schlenk tube was sealed with a Teflon screw cap under a flow of nitrogen, and put into an oil bath at 100° C. The reaction was allowed to stir at 100° C. for 15 hours, then the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo and the resultant crude residue was purified using column chromatography on silica gel (eluent: Hexane/EtOAc (4:1)) to provide 2-(4-Methoxy-phenyl)-thiazole-4-carboxylic acid ethyl ester as a yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[O:33]([CH2:40][C:41](Cl)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:41](=[O:42])[CH2:40][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:20][CH2:19]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(N2CCN(C(=O)COc3ccccc3)CC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.1 %

Procedure:
To a solution of 5-amino-2-(4-fluorophenyl)-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) in DMF (2 ml) was added diisopropylethylamine (0.33 mmol, 55 μL) followed by phenoxyacetyl chloride (0.17 mmol). The reaction was stirred at room temperature for 4 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 0.5% CH3OH in CH2Cl2), yielding the pure title compound (30 mg) which was characterized by its mass spectrum: MS m/z (%): 465 ([M+H]+, 100).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:28]I>C1COCC1>[CH3:28][CH:9]([CH2:8][CH2:7][N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=1)=[O:11]
Reactant: CI
Reactant: O=C(CCCN1CCOCC1)c1cccc(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CCN1CCOCC1)C(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of 4-(4-morpholinyl)-1-{3-[(phenylmethyl)oxy]phenyl}-1-butanone (88 mg, 0.26 mmol) in THF (3 mL), was added NaH (23 mg, 60% suspension, 0.57 mmol). This suspension was stirred at rt for 30 min, then MeI (25 μl, 0.39 mmol) was added. The reaction mixture was stirred at rt for 3 h, then quenched with water. The reaction mixture was added EtOAC (100 ml), washed with brine, dried over Na2SO4, filtered and concentrated. The residue was then purified with flash chromatography (hexanes/ethyl acetate 1:2), to afford the title compound as a colorless oil (74 mg, 81%). MS (ES+) m/e 354 [M+H]+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12]#[N:13]>CN(C)C=O>[C:1]([O:9][CH2:11][C:12]#[N:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: N#CCBr
Solvent: CN(C)C=O
Product: N#CCOC(=O)c1ccccc1
Temperature: 0 °C
Yield: 94.7 %

Procedure:
To a suspension of 50.0 g (0.41 mol) benzoic acid in 150 mL N,N-dimethylformamide 70.0 g (0.50 mol) potassium carbonate was added and the mixture was stirred until the evolution of gas has ceased. The reaction mixture was cooled to 0° C. and a solution of 29.0 mL (0.41 mol) bromoacetonitrile in 50 mL N,N-dimethylformamide was added dropwise. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in 500 mL ethyl acetate. It was washed with water (3×150 mL), saturated aqueous sodium hydrogencarbonate (150 mL) and brine. The organic layer was separated and dried over anhydrous sodium sulfate. The drying agent was filtered off and the solvent was evaporated. The resulting crude product was purified by column chromatography (hexane-ethyl acetate 9:1 to 4:1) to yield cyanomethyl benzoate 62.6 g (95%). 1H-NMR (400 MHz; DMSO-d6): 7.98 (m, 2H), 7.69 (m, 1H), 7.54 (m, 2H), 5.20 (s, 2H); GCMS for C9H7NO2: 161 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=[CH:3]1.C([Li])CCC.CN([CH:27]=[O:28])C>C1COCC1>[CH:27]([C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:4]=1)=[O:28]
Reactant: CN(C)C=O
Reactant: Cn1cnc(-c2ccccc2)c1-c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C=O)nc(-c2ccccc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-methyl-4-phenyl-5-[4-pyridinyl]imidazole (0.275 g, 1.17 mmol) in THF at -78° C. was added n-butyllithium (0.56 mL of 2.5M solution, 1.40 mmol). The resulting red-orange solution was allowed to stir at -78° C. for 0.5 h when DMF (0.18 mL, 2.34 mmol) was added. The mixture was allowed to warm to rt and stir for 4 h, then quenched with ice water and partitioned between CH2Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with 50:1 CH2Cl2 /MeOH. The title compound was obtained as a white solid (0.187 g, 61%): mp 167°-168° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][C:11]#[N:12])=[N:8][O:9][C:5]=2[CH:4]=1.[ClH:15].[NH2:16][OH:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[ClH:15].[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][C:11](=[N:16][OH:17])[NH2:12])=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(CC#N)noc2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(CC(N)=NO)noc2c1
Reaction time: 8 h
Yield: 58.4 %

Procedure:
In ethanol (30 ml) was dissolved 6-methoxy-1,2-benzisoxazole-3-acetonitrile (1 g) and thereto was added a solution of hydroxylamine hydrochloride (0.7 g) and sodium carbonate (0.8 g) in water (5 ml) under stirring. After stirring for 4 hours, the mixture was allowed to stand at room temperature overnight. The precipitated crystallines were separated by filtration and added to ethanol containing 20 % of hydrochloric acid. The mixture was stirred for 2 hours and thereto was added ether. The precipitated crystallines were separated by filtration and recrystallized from ethanol-ether to give the desired compound (0.8 g). m.p. 185° to 187°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21](=[O:23])[CH3:22])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>>[CH3:26][N:27]([CH3:29])/[CH:28]=[CH:22]/[C:21]([C:20]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][N:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=12)=[O:23]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Product: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 25 °C

Procedure:
A mixture of 1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (11.85 g), 36.77 mmol) and N,N-dimethylformamide dimethyl acetal (100 mL) was stirred at reflux for 17 hours. The mixture was cooled to room temperature and then to 0° C. The resulting orange precipitate was collected by filtration, washed with cold hexanes, and dried under vacuum to afford the title compound as an orange solid, 10.17 g (73%). 1H NMR (DMSO-d6): δ 9.44 (s, 1H), 8.22 (d, 1H, J=9.4 Hz), 7.75 (m, 2H), 7.65 (d, 1H, J=9.5 Hz), 7.56 (d, 1H, J=12.4 Hz), 7.35 (m, 2H), 5.05 (d, 1H, J=12.3 Hz), 3.04 (s, 3H), 2.56 (s, 3H). MS (+ve ion electrospray) 377 (80), (M+).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][OH:8])=[CH:5][CH:4]=[C:3]([OH:9])[CH:2]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[OH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2][CH:1]=1
Reactant: CCOC(=O)CBr
Reactant: OCc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.8 %

Procedure:
To a mixture of 2.00 g of p-hydroxybenzyl alcohol, 3.23 g of ethyl bromoacetate, 2.45 g of anhydrous potassium carbonate and 15 ml of N,N-dimethylformamide was added tetra-n-butylammonium bromide in a catalytic amount. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and insoluble matters were filtered off. The filtrate was washed with an aqueous sodium hydroxide solution and water, in this sequence. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was applied to silica gel column chromatography. Elution with a solvent mixture of hexane-ethyl acetate (3:2) gave 2.16 g of oily ethyl [p-(hydroxymethyl)phenoxy]acetate.