Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:15][CH2:14]4)=[CH:9][S:10][C:6]=2[C:5]([C:29]2[CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH2:33][CH:34]=2)=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:22]1([CH2:21][C:20]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([C:8]4[C:7]5[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:29]6[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=6)[C:6]=5[S:10][CH:9]=4)=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[O:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N)c3c(-c4ccc5c(c4)CCN5C(=O)Cc4ccccc4)csc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(C2=CCNCC2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
A mixture of 1,1-dimethylethyl 4-{4-amino-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-7-yl}-3,6-dihydro-1(2H)-pyridinecarboxylate (54 mg, 0.095 mmol) and TFA (1.0 mL, 12.98 mmol) in Dichloromethane (DCM) (1 mL) was stirred at room temperature under Nitrogen for 1 hr. The mixture was then concentrated in vacuo, NaHCO3 (5 mL) was added, and it was extracted with methylene chloride (3×5 mL). The extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 12 g SiO2, DCM to 90/10/1 DCM/MeOH/NH4OH gradient over 20 minutes) to give 3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]-7-(1,2,3,6-tetrahydro-4-pyridinyl)thieno[3,2-c]pyridin-4-amine (33 mg, 0.064 mmol, 66.8% yield) as a beige solid. LC/MS (ES) m/z=467 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.42 (d, J=1.77 Hz, 2H), 2.96 (t, J=5.56 Hz, 2H), 3.23 (t, J=8.34 Hz, 2H), 3.43 (d, J=3.03 Hz, 2H), 3.89 (s, 2H), 4.25 (t, J=8.46 Hz, 2H), 5.40 (br. s., 2H), 6.16 (br. s., 1H), 7.19-7.39 (m, 7H), 7.43 (s, 1H), 7.79 (s, 1H), 8.16 (d, J=8.34 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[C:26]([C:28]1[C:33](Cl)=[CH:32][CH:31]=[CH:30][N:29]=1)#[N:27]>CN(C=O)C.O>[C:26]([C:28]1[C:33]([S:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:32][CH:31]=[CH:30][N:29]=1)#[N:27]
Reactant: N#Cc1ncccc1Cl
Reactant: COc1ccc(CS)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(CSc2cccnc2C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-methoxy-α-toluenethiol (268 mg, 1.74 mmol) in DMF (1 mL) at 0° C. was added a solution of sodium bis(trimethylsilyl)amide in THF (1.3 mL, 1M, 1.3 mmol). The resulting solution was added via cannula to a solution of 2-cyano-3-chloropyridine (200 mg, 1.45 mmol) in DMF (1 mL) at 0° C. After stirring for 2 h at 0° C., the mixture was poured into water and extracted with ethyl acetate, and the organic extracts were concentrated. The crude product was purified by column chromatography on silica gel, affording 2-cyano-3-(4-methoxybenzylthio)pyridine in quantitative yield. 1H NMR (CDCl3) δ 3.80 (s, 3), 4.20 (s, 2), 6.83 (d, 2, J=10), 7.22 (d, 2, J=10), 7.34 (dd, 1, J=5, 8), 7.66 (d, 1, J=8), 8.50 (d, 1, J=5). To a solution of this compound (245 mg, 0.96 mmol) and anisole (0.52 mL, 4.8 mmol) in trifluoroacetic acid (1.5 mL) at 0° C. was added trifluoromethanesulfonic acid (0.25 mL, 2.8 mmol). The mixture was allowed to warm to room temperature, and was stirred for 1 h. The solvent was removed with a rotary evaporator, and the residue was purified by flash chromatography on silica gel, affording 117 mg (90%) of 2-cyano-3-mercaptopyridine. 1H NMR (CDCl3) δ 4.15 (s, 1), 7.39 (dd, 1, J=5, 8), 7.78 (d, 1, J=8), 8.48 (d, 1, J=5).
Reaction SMILES: [Si]([O:8][CH:9]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]3[NH:35][C:34](=[O:36])[O:33][N:32]=3)[CH:29]=2)[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10]1)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>CCO.C1COCC1>[OH:8][CH:9]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]3[NH:35][C:34](=[O:36])[O:33][N:32]=3)[CH:29]=2)[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(-c3noc(=O)[nH]3)ccc1O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)c1cc(-c3noc(=O)[nH]3)ccc1O2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 13.4 g of tert-butyl 4-([tert-butyl(dimethyl)silyl]oxy)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-spiro[chroman-2,4′-piperidine]-1′-carboxylate in 200 mL of EtOH-THF (5.5:1) at 0° C. was added 67 ml of 1M HClaq dropwise, and the reaction mixture was stirred at rt for 18 h. The reaction mixture was cooled to 0° C., and the mixture was basified with NaHCO3. The mixture was concentrated in reduced pressure, and the residue was acidified with 1M HClaq. The aqueous mixture was extracted with a mixture of CHCl3-MeOH (9:1) three times, and the combined organic layers was washed with brine, dried over Na2SO4, and concentrated in reduces pressure to give the product as a pale brown solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=O)C.[F:27][C:28]([F:40])([F:39])[O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.[F-].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.CO>[O:7]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:33]2[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:39])[F:40])=[CH:35][CH:34]=2)[CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: O[C@@H]1[C@@H](O)[C@H](Oc2cncc(-c3ccc(OC(F)(F)F)cc3)c2)SC[C@H]1O
Temperature: 110 °C
Yield: 68 %

Procedure:
0.5 g (1.11 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 0.275 g (1.33 mM) of 4-(trifluoromethoxy)phenylboronic acid, 0.373 g (2.45 mM) of cesium fluoride and 0.24 g of tetrakis(triphenylphosphine)palladium catalyst grafted onto polystyrene resin are mixed in 3.5 ml of DME and 5 ml of methanol. The reaction mixture is heated at 110° C. for 20 minutes by microwaves. It is filtered and then concentrated under reduced pressure. The crude product is purified by chromatography on a silica column (eluent: dichloromethane/methanol 90/10; v/v) to give the expected product in the form of a white solid with a yield of 68%.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].C1C=CC=CC=1.CCO>CC(C)=O.CN(C=O)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1)[CH3:23]
Reactant: O=c1c2ccccc2oc2ccc(O)cc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)COc1ccc2oc3ccccc3c(=O)c2c1

Procedure:
A mixture of 2-hydroxyxanthone (4.39 g, 20.6 mmol) prepared as described above, ethyl bromoacetate (4.5 mL, 40 mmol), and anhydrous potassium carbonate (16.6 g, 0.12 mol) in acetone (200 mL) plus DMF (10 mL) was refluxed for 6 hours. The cooled reaction mixture was filtered to remove inorganic salts, washed with acetone (2×50 mL), concentrated, and placed under hexane whereupon crystals formed. Yield: 4.87 g (79%), TLC: Rf 0.81 [one spot, benzene-EtOH (20:3)], m.p. 122°-123° C.; 1H-NMR (CDCl3, 200 MHz) 8.32 (d,J=7.9 Hz, 1H), 7.63-7.75 (m, 2H), 7.33-7.50 (m, 4H), 4.74 [s, 2H, OCH2 (C=O)], 4.29 (q,J=7.1 Hz, 2H), 1.32 (t,J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[Li]CCCC.CCCCCC.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CCOCC.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:31])=[C:3]([C:9]([F:12])([F:11])[F:10])[CH:4]=1
Reactant: FC(F)(F)c1cc(Br)ccc1Br
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(c1ccccc1)c1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 90 %

Procedure:
To a solution of 1,4-dibromo-2-(trifluoromethyl)benzene (300 mg, 0.987 mmol) in 2 mL of Et2O (C=0.5M) was added dropwise a 1.6M solution of BuLi in hexane (650 μL, 1.05 eq) at −78° C. After 25 min of stirring, benzaldehyde (120 μL, 1.2 eq) was slowly added. The mixture was stirred for 2 h at −78° C. and was allowed to warm to r.t. overnight. Then, the reaction mixture was hydrolyzed with water and with a 1M HCl solution to acidify. The layers were separated. The aqueous layer was extracted with DCM (3×10 mL). The combined organics were washed with brine, dried over MgSO4, filtered and solvents were removed in vacuo. The crude residue was purified by silica gel flash chromatography (cyclohexane/AcOEt 95:5) to afford the desired product in 90% yield (295 mg) as uncoloured oil. 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=2.1 Hz, 1H), 7.67 (dd, J=8.4, 2.1 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.39-7.27 (m, 5H), 6.24 (s, 1H), 2.44 (s, OH); 13C NMR (75 MHz, CDCl3) δ 142.3 (C), 141.4 (q, J=1.4 Hz, C), 135.5 (CH), 131.5 (CH), 129.3 (q, J=30.9 Hz, C), 128.8 (q, J=6.1 Hz, CH), 128.7 (CH), 128.0 (CH), 126.5 (CH), 123.5 (q, J=274.6 Hz, C), 121.7 (C), 70.6 (q, J=2.1 Hz, CH); MS (ESI) m/z: 375.0, 377.0 [M−H+HCO2H, 79Br, 81Br]−; 705.2, 707.2 [2M−2H+HCO2H, 79Br, 81Br]−.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([CH:20]=[O:21])[C:9]([N:12]3[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:30][C:31]1[CH:35]=[C:34]([CH3:36])[NH:33][N:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.CCOC(C)=O.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]>[CH3:19][C@H:14]1[O:15][C@@H:16]([CH3:18])[CH2:17][N:12]([C:9]2[C:8]([CH:20]=[O:21])=[CH:7][C:6]3[C:2]([N:32]4[C:31]([CH3:30])=[CH:35][C:34]([CH3:36])=[N:33]4)=[N:3][O:4][C:5]=3[C:10]=2[F:11])[CH2:13]1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@H](C)O1
Reactant: Cc1cc(C)[nH]n1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(C)n(-c2noc3c(F)c(N4C[C@@H](C)O[C@@H](C)C4)c(C=O)cc23)n1
Temperature: 150 °C

Procedure:
To a stirred and degassed solution of 3-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde (Intermediate 534, 0.15 g, 0.48 mmol) in toluene was added K3PO4 (0.51 g, 2.40 mmol), 3,5-dimethyl-1H-pyrazole (92 mg, 0.96 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-phos) (4 mg, 0.009 mmol) and tris(dibenzylideneacetone)dipalladium(0) (8 mg, 0.009 mmol), sequentially and the reaction mixture was heated to 150° C. for 2 h in microwave reactor. The reaction mixture was diluted with EtOAc (15 mL). The organic layer was washed successively with water (2×10 mL), brine (2×10 mL), dried over anhydrous Na2SO4 and, after filtration, concentrated. The residue was purified over silica gel column using a gradient of ethylacetate in pet.ether to give product title compound as solid. Yield: 100 mg (56%).
Reaction SMILES: O.[OH-].[Na+].C([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=2)[C:13]=1[CH3:14])=[O:8])C.Cl>C(O)C>[Cl:21][C:20]1[C:15]([N:12]2[C:13]([CH3:14])=[C:9]([C:7]([OH:8])=[O:6])[CH:10]=[N:11]2)=[N:16][CH:17]=[C:18]([CH3:22])[CH:19]=1
Reactant: CCOC(=O)c1cnn(-c2ncc(C)cc2Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cnc(-n2ncc(C(=O)O)c2C)c(Cl)c1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 70.6 %

Procedure:
Water (9 ml) and 4N aqueous solution of sodium hydroxide (9 ml) were added to a solution of 1-(3-chloro-5-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.03 g) in ethanol (18 ml) at room temperature, and the mixture was stirred at 80° C. for 3.5 hours. After completion of the reaction, the reaction solution was cooled to 0° C. and 1N hydrochloric acid aqueous solution (38 ml) was added. The precipitated solid was collected by filtration to give the titled compound (654 mg) as a light brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]([CH3:11])[C:7](=[O:12])[CH:6]=1)=O.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][N:8]1[CH:9]=[CH:10][C:5]([C:3]([NH:14][NH2:15])=[O:2])=[CH:6][C:7]1=[O:12]
Reactant: NN
Reactant: COC(=O)c1ccn(C)c(=O)c1
Solvent: CCO
Solvent: O
Product: Cn1ccc(C(=O)NN)cc1=O
Temperature: 78 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
The title compound of example 24 (4.0 g, 23.9 mmol) was dissolved in ethanol (50 mL). Hydrazine hydrate (5.8 mL, 119 mmol) was added and the reaction was stirred at 78° C. for 3 hours. The reaction mixture was then cooled to room temperature and the product was filtered off to give 3.13 g (78% yield) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18](Br)[CH:17]=3)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:31]1(B(O)O)[CH2:33][CH2:32]1.[F-].[K+]>C1COCC1.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].C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([CH:31]2[CH2:33][CH2:32]2)[CH:17]=3)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(Br)cc3n2C2CCC2)cc1
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(C4CC4)cc3n2C2CCC2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A mixture of [4-(6-bromo-3-cyano-1-cyclobutyl-1H-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester (0.17 g, 0.4 mmol), cyclopropylboronic acid (0.047 g, 0.55 mmol), (tert-butyl)3PHBF4 (0.014 g, 0.048 mmol), KF (0.093 g, 1.6 mmol), and Pd2(dba)3-CHCl3, 0.021 g, 0.02 mmol) in THF (2.0 mL) was stirred at 60° C. overnight. The mixture was concentrated, taken up in CH2Cl2 and filtered through Celite. The solid was washed with CH2Cl2 and the filtrate was purified on silica gel (CH2Cl2) to provide [4-(3-cyano-1-cyclobutyl-6-cyclopropyl-1H-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester as a solid (0.10 g, 59%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:16])[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[CH3:16][N:8]([C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:10])[C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CN(C(=O)c1cccs1)c1ccc(O)cc1
Product: CN(C(=O)Oc1ccc(N(C)C(=O)c2cccs2)cc1)c1ccccc1

Procedure:
The title product was prepared from thiophene-2-carboxylic acid (4-hydroxy-phenyl)-methyl-amide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (16%, oil). HPLC-MS: m/z=367.2 (M+1); Rt: 3.97 min.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][C:12](=[O:17])[N:13]([CH3:16])[C:14](=[O:15])[C:9]2=[N:8][C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3C=CC=CC=3)[CH:19]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4].[CH3:31][O:32]C1C=C(C=CC=1OC)C=O>>[CH2:1]([N:5]1[C:10]2=[N:11][C:12](=[O:17])[N:13]([CH3:16])[C:14](=[O:15])[C:9]2=[N:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:32][CH3:31])=[C:20]([O:24][CH3:25])[CH:19]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCCCn1nc(-c2cccc(Oc3ccccc3)c2)nc2c(=O)n(C)c(=O)nc1-2
Product: CCCCn1nc(-c2ccc(OC)c(OC)c2)nc2c(=O)n(C)c(=O)nc1-2

Procedure:
Compound 21 is prepared, as described in 4, by reacting the hydrazine 20 (176 mg, 0.54 mmol) with 3,4-dimethoxybenzaldehyde (88 mg, 0.54 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][NH2:15])[CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.CN(C1C=CC=CN=1)C.[C:25](OC([O-])=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].O>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][NH:15][C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NCc1cccc(-c2ccc(Br)cn2)c1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(Br)cn2)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
1.07 g (4 mmol, 1 eq) of [3-(5-bromopyrid-2-yl)phenyl]methylamine are dissolved in 10 mL of dichloromethane in the presence of 1 mL of triethylamine and 200 mg of dimethylaminopyridine. 1.7 g (8 mmol, 2 eq) of tert-butyl dicarbonate are added and the reaction mixture is stirred overnight at 40° C. The reaction is stopped by adding 30 ml of water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 1.18 g of tert-butyl [3-(5-bromopyrid-2-yl)phenyl}methylcarbamate are obtained. Yield=81%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N#N.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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]>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Product: COc1ccc(-c2cc(NC(C)=O)cc([N+](=O)[O-])c2)cc1
Yield: 73 %

Procedure:
A solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (1 g, 3.8 mmol) in 1,2-dimethoxyethane (20 ml) was degassed by N2 bubbling for 5 min. 4-Methoxyphenylboronic acid (0.69 g, 4.4 mmol, 1.1 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (0.31 g, 0.38 mmol, 0.1 eq.) and aqueous sodium carbonate (1 g, 9.5 mmol, 2.5 eq.) were added and the procedure of Example 1(d) was followed. The crude residue of the product was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 73% yield (0.8 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[CH2:6]([C:8]([CH2:10][CH3:11])=[O:9])[CH3:7]>>[CH3:1][Si:2]([CH3:5])([CH3:4])[O:9][C:8]([CH2:10][CH3:11])=[CH:6][CH3:7]
Reactant: CCC(=O)CC
Reactant: C[Si](C)(C)Cl
Product: CC=C(CC)O[Si](C)(C)C

Procedure:
From reaction between diethylketone and trimethylchiorosilane to form 3-trimethylsilyloxy-2-pentene (1.2.4.17). This product was reacted with 1-fluoropyridinium triflate (1.2.4.5) to obtain 2-fluoro-3-pentanone (1.2.4.9). After bromination with pyridinium bromide followed by reduction using diborane 2-fluoro-4-bromopentane-3-ol (1.2.4.18) was obtained. Reaction of this product with sodium methylate yielded the title compound (1.2.4.16). This compound was made also by reacting 2-(1-bromoethyl)-3-methyl oxirane (1.2.4.13) with HF/Py (70%) followed by treatment of the resulting 2-bromo-4-fluoropentan-3-ol (1.2.4.18) with K2CO3 /MeOH.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(S[C:16]1[N:17]=[C:18]([OH:25])[C:19]2[S:24][CH2:23][CH2:22][C:20]=2[N:21]=1)C.O>C(O)(=O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:16]3[N:17]=[C:18]([OH:25])[C:19]4[S:24][CH2:23][CH2:22][C:20]=4[N:21]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCSc1nc(O)c2c(n1)CCS2
Solvent: O
Solvent: CC(=O)O
Product: Oc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Temperature: 125 °C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
6.4 g (39 mmol) of N-phenylpiperazine (III) is placed in 2.2 mL of glacial acetic acid, heated to 125° C., then 3.2 g (15 mmol) of 2-ethylsulfanyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (II) is added, and the mixture is heated to 175° C. After 1.5 hours, the resulting solid is stirred with water, suction filtered, washed with ethanol, and dried. 4.3 g product (91%) is obtained as a powder.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22]C)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:24][CH3:25])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C(S)CC.O>CN(C=O)C.C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[OH:22])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:24][CH3:25])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(-c3ccccc3OC)nc(=O)c1-2
Agent: CCCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccccc3O)nc(=O)c1-2
Reaction time: 0.33 h
Yield: 57.5 %

Procedure:
To a solution of 1-cyclopentyl-3-ethyl-6-(2-methoxyphenyl)-pyrazolo[3,4-d]pyrimidin-4-one (0.5 g, 1.5 mmol) in DMF (10 ml) was added NaH (0.15 g, 3.75 mmol, 60% NaH in mineral oil). The reaction mixture was stirred for 20 minutes, then propanethiol (0.228 g, 3.0 mmol) was added and the mixture was stirred at room temperature for 4 hours, then at 110° C. for 9 hours. The reaction mixture was stripped to dryness and then water (15 ml) followed by acetic acid (1 ml) were added. A precipitate formed which was collected by filtration, washed with water and recrystallized by DARCO® treatment from ethyl acetate to afford 0.28 g (58%) of 1-cyclopentyl-3-ethyl-6-(2-hydroxyphenyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 272°-273° C., as white fibrous needles.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1)[O:8][C:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:6]([CH3:22])[C:5]2=[O:23].C([O-])(=O)C.[Na+].[H][H]>[C].[Pd].C(O)(C)C>[CH3:22][C:6]1[C:5](=[O:23])[C:4]2[C:9](=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=[CH:2][CH:3]=2)[O:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(Cl)cc2c(=O)c(C)c(-c3ccccc3)oc12
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)c1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Reaction time: 6 h
Yield: 81.9 %

Procedure:
Into a pressure reactor were placed 1.5 g (4.57 m mole) of methyl 6-chloro-3-methylflavone-8-carboxylate, 1.8 g (14.2 m mole) of sodium acetate, 150 ml of isopropanol and 0.075 g of 5% palladium-carbon. After the atmosphere was replaced with hydrogen gas, reaction was conducted at 70° C. under a pressure of 5.0 kg/cm2G for 6 hours. Thereafter the contents were withdrawn from the reactor and were subjected to filtration while being hot to remove the catalyst. The solvent was recovered from the filtrate to provide 1.1 g (82.1%) of white needle-like crystals which melt at 162.2° to 164.8° C. The crystals were recrystallized from alcohol to obtain a product having a melting point of 166.4° to 168.2° C. The product was found identical in melting point with the compound prepared by the conventional method. When the product of this example and the compound prepared by the conventional method were melted together, the melting point was not lower than that of the product of this example.