Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([CH3:9])[CH2:3]1.[H-].[Na+].[CH2:12](Br)[CH:13]=C.[CH3:16]N(C=O)C>>[CH2:9]([C:4]1([CH3:16])[C:5](=[O:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)[CH:12]=[CH2:13]
Reactant: C=CCBr
Reactant: CN(C)C=O
Reactant: CC1CN(C)CCC1=O
Agent: [H-]
Agent: [Na+]
Product: C=CCC1(C)CN(C)CCC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,3-Dimethyl-piperidin-4-one (6 g, 47.24 mmol) was dissolved in 20 mL DMF and sodium hydride (2.07 g, 51.95 mmol) was added portionwise at 0° C. under nitrogen atmosphere. This was followed by dropwise addition of allyl bromide (5.71 g, 47.19 mmol) in 4 mL DMF at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at RT for 15 min, quenched with ice-water and extracted with EtOAc (3×100 mL). The organic layer was washed with water (3×100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh) eluting with 7% EtOAc in hexane to obtain 3.2 g of 3-allyl-1,3-dimethyl-piperidin-4-one.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=[CH:3]1.[CH:11]1(I)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[CH:11]1([O:9][C:8]([C:5]2[CH:4]=[CH:3][C:2](=[O:1])[N:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[N:6]=2)=[O:10])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: IC1CCCC1
Reactant: O=C(O)c1ccc(=O)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OC1CCCC1)c1ccc(=O)n(C2CCCC2)n1

Procedure:
6-Oxo-1,6-dihydropyridazine-3-carboxylic acid (1 g, 7.14 mmol) was stirred with cyclopentyl iodide (2.05 ml, 17.8 mmol) and potassium carbonate (3 g, 21.4 mmol) in 15 ml DMF for 14 h at room temperature. 50 ml CH2Cl2 was added and the reaction mixture was filtered. The filtrate was concentrated and the title compound was purified by prep HPLC. Yield: 20 mg (0.072 mmol, 1%, MS m/z: 277(100%, M+1)).
Reaction SMILES: C(=O)([O-])[O-].[Cs+2].[CH3:6][O:7][N:8]([CH3:17])[C:9]([C:11]1[N:12]=[C:13](Br)[S:14][CH:15]=1)=[O:10].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>CN(C=O)C.CCOC(C)=O>[CH3:6][O:7][N:8]([CH3:17])[C:9]([C:11]1[N:12]=[C:13]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[S:14][CH:15]=1)=[O:10]
Reactant: c1c[nH]cn1
Reactant: CON(C)C(=O)c1csc(Br)n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1csc(-n2ccnc2)n1
Temperature: 120 °C
Yield: 91.7 %

Procedure:
Cesium(II)carbonate (1.36 g, 4.18 mmol) was added to a solution of 2-bromo-thiazole-4-carboxylic acid methoxy-methyl-amide (500 mg, 1.99 mmol) and imidazole (135 mg, 1.99 mmol) in DMF (5 mL) under a nitrogen atmosphere at r.t. prior to heating at 120° C. for 40 minutes in the microwave reactor. The reaction was then cooled to r.t., diluted with EtOAc (100 mL), washed with 1M NaOH (75 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated to a white solid. Purification was achieved using column chromatography (CH2Cl2 to 9:1 CH2Cl2/MeOH) to afford 435 mg (92%) of 2-imidazol-1-yl-thiazole-4-carboxylic acid methoxy-methyl-amide as a white solid. [M+H]+ 239.02.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:28][OH:29].O>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([NH:28][OH:29])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(CC(=O)NO)N2Cc3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A mixture of 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (15.0 g, 42.7 mmol) and N,N′-carbonyldiimidazole (7.27 g, 44.8 mmol) in tetrahydrofuran (50 mL) under nitrogen was stirred at room temperature for 2 hours. To the resulting solution was added hydroxylamine hydrochloride (3.86 g, 55.5 mmol). The resulting suspension was stirred for 18 hours. To the suspension was added water (150 mL) and stirring was continued for 1 hour. The suspension was filtered, the solid was washed with water (5×30 mL) and ether (2×20 mL), and then was dried in a vacuum oven overnight (60° C., <1 torr) to give 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide as a white solid (13.0 g, 82% yield): mp, 167-168° C.; 1H NMR (DMSO-d6) δ1.29 (t, J=6.9 Hz, 3H, CH3) 2.81-2.86 (m, 2H, CH2), 3.72 (s, 3H, CH3), 3.96-4.04 (m, 2H, CH2), 4.13 (d, J=17.5 Hz, 1H, CHH), 4.54 (d, J=17.5 Hz, 1H, NCHH), 5.73 (t, J=7.9 Hz, 1H, NCH), 6.84-6.92 (m, 3H, Ar), 7.43-7.68 (m, 4H, Ar), 8.83 (br.s, 1H, OH), 10.61 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 14.68, 35.04, 46.22, 51.20, 55.44, 63.73, 111.85, 112.19, 119.21, 122.78, 123.43, 127.83, 131.29, 131.85, 132.27, 141.67, 147.85, 148.42, 165.99, 166.82. Anal. Calcd for C20H22N2O5: C, 64.85; H, 5.99; N, 7.56. Found: C, 64.73; H, 6.17; N, 7.36.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][N:14]4[C:18](=[O:24])[CH2:19][NH:20][C:21](=O)[CH:22]=[C:13]4[C:12]=3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.ClCCCl.[CH:29]([C:32]1[N:33]=[CH:34][NH:35][CH:36]=1)([CH3:31])[CH3:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][N:14]4[C:18](=[O:24])[CH2:19][N:20]=[C:21]([N:35]5[CH:36]=[C:32]([CH:29]([CH3:31])[CH3:30])[N:33]=[CH:34]5)[CH:22]=[C:13]4[C:12]=3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1c[nH]cn1
Reactant: O=C1C=C2c3nccc(-c4ccc(F)nc4)c3CCN2C(=O)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)c1cn(C2=NCC(=O)N3CCc4c(-c5ccc(F)nc5)ccnc4C3=C2)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
EXAMPLE 94. To a stirred solution of 4-(6-fluoropyridin-3-yl)-5,6,9,10-tetrahydro-[1,4]diazepino[1,7-h][1,7]naphthyridine-8,11-dione (31 mg, 0.096 mmol) in 1,2-dichloroethane (2 mL) POCl3 (29.3 mg, 0.19 mmol) was added and the resulting suspension was stirred at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. For complete removal of POCl3 the residue was taken up in toluene and evaporated twice again and dried under high vacuo. The resulting crude chloro compound was dissolved in 1,2-dichloroethane (5 mL), 4-isopropyl-1H-imidazole (53 mg, 0.48 mmol) was added and the mixture was stirred at 100° C. for 1 h. The reaction mixture was allowed to warm to rt and diluted with DCM. Saturated aqueous NaHCO3 solution was added and the mixture was extracted twice with DCM. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by SFC (column: DEAP 5 μm, 250×30 mm, 60A, Princeton; eluent: from 6% MeOH/CO2 to 11% MeOH/CO2 in 11 min; flow 100 mL/min; UV detection at 220 nm) and yielded the title compound as beige powder (11 mg). UPLC-MS: MS 417.2 (M+H+); UPLC rt 0.87 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17-1.34 (m, 6 H), 2.81-2.98 (m, 3 H), 4.05 (br. s., 2 H), 4.40 (s, 2 H), 7.09 (dd, J=8.3, 2.8 Hz, 1 H), 7.22-7.36 (m, 2 H), 7.77 (td, J=7.9, 2.1 Hz, 1 H), 7.96 (s, 1 H), 8.03 (s, 1 H), 8.23 (d, J=1.5 Hz, 1 H), 8.68 (d, J=4.8 Hz, 1 H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:40](Br)[CH3:41].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][N:30]5[CH2:35][CH2:34][N:33]([CH2:40][CH3:41])[CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)NN2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1
Temperature: 40 °C
Yield: 67.1 %

Procedure:
4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperazin-1-yl)benzamide (108 mg, 0.2 mmols), ethyl bromide (33 mg, 0.3 mmols) and N,N-diisopropyl ethylamine (106 μL, 0.3 mmols) were mixed in a screw cap vial (5 mL) in DMF (2 mL) heated at 40° C. for 5-8 hrs, then purified to provide the title compound (76.9 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (t, J=7.1 Hz, 3 H) 1.14-1.89 (m, 10 H) 2.33 (q, J=6.99 Hz, 2 H) 2.48 (m, 4 H) 2.93 (t, J=4.55 Hz, 4 H) 3.31 (s, 3 H) 3.93 (s, 3 H) 4.06 (t, J=13.22 Hz, 2 H) 4.45 (m, 1 H). 7.41 (d, J=8.0 Hz, 1 H) 7.43 (s, 1 H) 7.90 (s, 1 H) 8.20 (s, 1 H) 8.26 (d, J=8.08 Hz, 1 H) 9.38 (s, 1 H) [M+H] calculated for C28H38F2N8O3, 572; found 572.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][C:20]([C:22]3[N:23](C(OC(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=3)=O)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:34]C(OC(C)(C)C)=O)=O)(C)(C)C.[OH:42][CH:43]1[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C.O>[F:17][C:13]1[C:12]2[C:11]3[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:34])[C:10]=3[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=[CH:19][C:18]=2[N:45]1[CH2:46][CH2:47][CH2:48][CH:43]([OH:42])[CH2:44]1
Reactant: OC1CCCNC1
Reactant: CC(C)(C)OC(=O)Oc1cc2c(C#CC(=O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(F)c3c(N4CCCC(O)C4)cc(-c4ccc[nH]4)c1c23
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 4 above) (230 mg, 0.40 mmol) and 3-hydroxy-piperidine (Aldrich, 1.23 g, 12.13 mmol) in DMF (15 ml) was heated to 120° C. for 1.5 hours. The mixture was cooled and NaH (Aldrich, 140 mg, 5.83 mmol) was added in small portions with stirring. After 30 minutes at room temperature and then 20 hours at 120° C. the mixture was cooled and poured into a mixture of ethyl acetate and water. The aqueous layer was extracted few more times with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 60% ethyl acetate in hexanes) and further purified by HPLC (silica gel, 35% ethyl acetate in hexanes) and a precipitation out of THF with excess of pentane to give 6-fluoro-5-(3-hydroxy-piperidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 45 mg, 31%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12]Br)[C:5]([O:7][CH3:8])=[O:6].[C:14]([O-:17])(=[O:16])[CH3:15].[K+].O.C(OCC)(=O)C>CN(C)C=O>[C:14]([O:17][CH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Br:1])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccc(CBr)c(Br)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COC(C)=O)c(Br)c1
Reaction time: 17.5 h
Yield: 63.6 %

Procedure:
10.85 g of methyl 3-bromo-4-(bromomethyl)benzoate was dissolved in 108 mL of N,N-dimethylformamide, to which 3.46 g of potassium acetate was added at room temperature, and this solution was stirred for 17.5 hours at the same temperature. The reaction mixture was added to a mixture of water and ethyl acetate, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to yield 6.43 g of methyl 4-[(acetyloxy)methyl]-3-bromobenzoate as white solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Cl:12])=[C:6]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH:5]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][C:6]=1[O:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23]
Reactant: COC(=O)c1cc(OC)c(Cl)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(=O)O)cc(OCCc2ccc(Cl)cc2Cl)c1Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.51 g (1.31 mmol) of 4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-methoxy-benzoic acid methyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1-2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19](COC(=O)C(C)(C)C)[C:18](=[O:36])[N:17]([CH2:37][CH2:38][O:39][CH2:40][CH3:41])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:36])[N:17]([CH2:37][CH2:38][O:39][CH2:40][CH3:41])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2CCOCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2CCOCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[7-(2-Butynyl)-1-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (50 mg) and potassium carbonate (15 mg) were dissolved in N,N-dimethylformamide (1.2 ml), and 2-bromoethylethyl ether (12 μl) was added to the solution. The mixture was stirred at 60° C. for 2 hours, diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After the organic layer was concentrated by distillation, the residue was purified by silica gel column chromatography to give 4-[7-(2-butynyl)-1-(2,2-dimethylpropionyloxymethyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester from the elution fraction of hexane-ethyl acetate (2:1). The obtained 4-[7-(2-butynyl)-1-(2,2-dimethylpropionyloxymethyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in a solvent mixture of tetrahydrofuran (1.0 ml) and methanol (0.5 ml), sodium hydride (5 mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation to give 4-[7-(2-butynyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. A quarter of the obtained 4-[7-(2-butynyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in trifluoroacetic acid (0.5 ml), and the solution was stirred at room temperature for 30 minutes. After the solvent was removed by distillation, a half of the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as elution solvent to give 3.2 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C@H:8]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=3)[CH2:9][N:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:11][C@@H:6]2[CH:5]=[CH:4][CH2:3]1.[H][H]>CO.[Pt]=O>[O:1]=[C:2]1[N:7]2[C@H:8]([C:16]3[CH:17]=[C:18]([F:24])[C:19]([F:23])=[C:20]([F:22])[CH:21]=3)[CH2:9][N:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:11][C@@H:6]2[CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: COC(=O)N1C[C@@H]2C=CCC(=O)N2[C@H](c2cc(F)c(F)c(F)c2)C1
Agent: O=[Pt]
Solvent: CO
Product: COC(=O)N1C[C@@H]2CCCC(=O)N2[C@H](c2cc(F)c(F)c(F)c2)C1

Procedure:
Platinum oxide (10 mg) was added to a solution of methyl (4R*,9aS*)-6-oxo-4-(3,4,5-trifluorophenyl)-1,3,4,6,7,9a-hexahydropyrido[1,2-a]pyrazine-2-carboxylate obtained by performing the above method again (292 mg) in methanol (5 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for three hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 255 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].[Cl-].[NH4+].C(O)C.CO>[Fe].O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[NH2:8]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2F)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCc2ccccc2F)c(Cl)c1
Temperature: 68 °C

Procedure:
In a glass flask provided with a condenser, thermometer, mechanical stirrer and nitrogen inlet, —under nitrogen flow—25.0 g of 2-Chloro-[(2-fluorobenzyl)oxy]-4-nitrobenzene of formula (V), 14.9 g of powder iron (MW: 55.85, 3.0 mol. equiv.), 42.7 g of ammonium chloride (MW: 53.49, 9.0 mol. equiv.), 350 mL of Ethanol denatured with Methanol and 85 mL of purified water were introduced. The reaction mixture was stirred at reflux temperature (68° C.) for 2 hours.
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH2:8][CH2:9][C:10]4[CH2:11][C:12](=[O:19])[CH2:13][CH2:14][C:15]=43)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.N1C=CC=CC=1.C1C=C[NH+]=CC=1.Br[Br-]Br.C1(O)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C@:2]12[CH2:18][CH2:17][C:16]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C:15]=3[CH2:14][CH2:13][C:12](=[O:19])[CH:11]=4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=C(CCC(=O)C3)[C@H]1CC2
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: Oc1ccccc1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CCC3=C1CC2
Reaction time: 0.02 h
Yield: 30.8 %

Procedure:
Estra-5(10),16-dien-3-one (3) (0.38 g, 1.5 mmole), in pyridine (5.0 mL, 62 mmol) was cooled in an ice-salt bath to -13° C. and pyridinium bromide perbromide (1.58 g, 4.94 mmole) was added in small portions so that T<-4° C. After swirling 1 min. phenol (0.25 g, 2.7 mmole) was added and reaction continued 24 h at room temperature. Ethyl acetate (50 ml) was added and the reaction mixture was washed with 25 ml of 1N HCI, two 25 ml portions of saturated copper sulfate, 25 ml of 5% sodium hydroxide, and 25 ml of brine. After drying over magnesium sulfate, filtration, and concentration under reduced pressure the residue was taken up in 10 mL of abs. ethanol, granular zinc (0.33 g, 5.0 mg-atom) was added, and the mixture was refluxed 1/2 h. The supernatant was removed, the residue was washed with 10 mL of abs. ethanol, and the combined supernatants were concentrated under reduced pressure. The resulting resin was flash chromatographed on silica gel using 15% ethyl acetate/hexane as eluent. Appropriate fractions were pooled, concentrated, and then recrystallized from hexane to give solid product (117.5 mg, 0.4619 mmol, 31%), m.p. 87-92° C.
Reaction SMILES: [C:1]1([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=O)[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2>>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([N:18]=[C:10]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:8]3=[O:9])=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C1C(=O)N(c2ccccc2)c2ccccc21
Reactant: Nc1ccc2[nH]ccc2c1
Product: O=C1C(=Nc2ccc3[nH]ccc3c2)c2ccccc2N1c1ccccc1
Temperature: 140 °C
Yield: 13.9 %

Procedure:
1-phenylisatin (51.8 mg, 0.23 mmol) and 5-aminoindole (31 mg, 0.23 mmol) were mixed and heated at 140° C. for 2 h. The resulting crude product was purified by preparative TLC using ethyl acetate/hexane (6:4) as the eluent, giving the desired product as a yellow solid (10.8 mg, 14%). 1H NMR (400 MHz): δ 8.28 (s, 1H), 7.57 (t, J=7.7, 2H), 7.49-7.40 (m, 6H), 7.29-7.23 (m, 1H), 7.03 (dd, J=8.5, 1.7, 1H), 6.98 (d, J=7.6, 1H), 6.83 (d, J=8.0, 1H), 6.74, J=7.6, 1H), 6.59 (s, 1H); ESI-MS m/z found 338 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[C:14]([NH2:41])=[N:15][CH:16]=[N:17][C:18]=2[N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[N:26]([CH2:38][CH2:39][OH:40])[CH:27]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[CH:31]=4)[N:29]=3)[CH2:21][CH2:20]2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>C1COCC1>[NH2:41][C:14]1[C:13]([C:11]2[CH:10]=[N:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:12]=2)=[C:18]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[N:26]([CH2:38][CH2:39][O:40][S:52]([CH3:51])(=[O:54])=[O:53])[CH:27]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[CH:31]=4)[N:29]=3)[CH2:21][CH2:20]2)[N:17]=[CH:16][N:15]=1
Reactant: Cc1cc(-c2cn(CCO)c(C3CCN(c4ncnc(N)c4-c4cnn(C(=O)OC(C)(C)C)c4)CC3)n2)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(-c2cn(CCOS(C)(=O)=O)c(C3CCN(c4ncnc(N)c4-c4cnn(C(=O)OC(C)(C)C)c4)CC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 4-(4-amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-pyrazole-1-carboxylic acid tert-butyl ester (350.00 mg; 0.62 mmol; 1.00 eq.) in THF 5 ml added ethyl-diisopropyl-amine (0.28 ml; 1.56 mmol; 2.50 eq.), then added drop wised methanesulfonyl chloride (0.10 ml; 1.24 mmol; 2.00 eq.) at 0° C., the reaction mixture was stirred at RT for 1 hr, LC-MS showed desired as major, and starting material disappeared, removed off solvent, directly carried the crude product for next step reaction.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:23]1([CH:22]=[C:21]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=2)[C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 98.4 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (536 mg, 1 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 2 mL, 2 mmol) was stirred at room temperature for 12 h. The mixture was then diluted with ethyl acetate (150 mL), and washed with a saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (390 mg, 98.5%) as a white solid: LC/MS m/e calcd for C22H24N2O3S [M+H]+ 397.51, observed 397.2.