4-(4-Ethyl-1-piperazinyl)benzenamine

General procedure: The nitrophenyl analogue 7a–7e (7.5 mmol) was dissolved in ethanol (50 mL), and to this solution was added 10percent Pd/C (0.2 g). The reaction mixture was stirred at room temperature under an atmosphere of HGeneral procedure: Concisely, 1-(4-Nitro phenyl)-4-substitued piperazine derivatives (1-18) were refluxed for 3-4 h in chloroform (20 ml) with theSn/HCl solution. The solution was prepared before by dissolving tin (15mM) in30ml Con. HCl. The reaction mixture was cooled under tap water and neutralizedwith 15percent NaOH solution. The resulting compound was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulphate andevaporated under reduced pressure to afford of 4-(4-substitutedpiperazin-1-yl)-phenylamine derivatives (19-36)as solid compounds.(5-Chloro-1-methyl-1H-pyrrolo[2, 3-c]pyridin-2-yl)(2, 6-difluoro-3, 5-dimethoxyphenyl)methanol (1000 mg, 2.8 mmol), (5-Chloro-1H-pyrrolo[2, 3-c]pyridin-2-yl)(2, 6-difluoro-3, 5-dimethoxyphenyl)methanol (1100 mg, 3.0 mmol ), (5-Chlorothieno[2, 3-c]pyridin-2-yl)(2, 6-difluoro-3, 5-dimethoxyphenyl)methanol (730 mg, 1.96 mmol), 4 -(4-ethylpiperazin-1-yl)aniline (590 mg, 2.36 mmol), Pd2 (dba) 3 (360 mg, 0.393 mmol), XantpHos (454 mg, 0·785 mmol), Cs2CO3 (1.28 g, 3.93 mmol) It was mixed with toluene (10 ml) and stirred at 110 C under Ar protection overnight. The reaction solution was directly dried by column chromatography (dichloromethane:methanol = 95:5) to give compound (2, 6-difluoro-3, 5-dimethoxyphenyl) (5-((4-(4-) Ethyl piperazin-1-yl)phenyl)amino)thieno[2, 3-c]pyridine-2-yl)methanone 1 g, purity 80%, yield 86.8%.(5-Chlorofuro[2, 3-c]pyridin-2-yl)(2, 6-difluoro-3, 5-dimethoxyphenyl)methanone (2 g, 5.65 mmol), 4-( 4-ethylpiperazin-1-yl)aniline (1.36 g, 6.78 mmol), cesium carbonate (2.76 g, 5.65 mmol), XantpHOS (1.3 g, 2.26 mmol) and Pd2dba3 (1 g, 1.1 mmol) were added to 30 ml in order. In toluene.Argon was replaced 3-5 times and heated to 110 C (oil bath) for overnight reaction.The reaction was complete by TLC.The mixture was cooled to rt, filtered, and the filter cake was washed with EA, and the filtrate was evaporated to dryness and purified by column (MeOH: DCM = 0-100: 1-70:1) to give solid (2, 6-difluoro-3, 5-dimethyl Oxyphenyl)(5-((4-(4-ethylpiperazin-1-yl)-2-nitrophenyl)amino)furo[2, 3-c]pyridin-2-yl)methanone (2.5g, 79%).General procedure: S8 (0.5 g, 0.72 mmol), 4-morpholinoaniline (0.26 g, 1.44 mmol), PXantPhos-Pd-G2 (0.064 g, 0.072 mmol), NaO-tBu(0.2 g, 2.16 mmol), and 12 mL of toluene were added to a microwavetube and sealed. The mixture was heated at 145 C for 1 h in an oilbath. After cooling, the solution was filtered using diatomite andconcentrated under vacuum, and the residue was diluted withbrine and extracted with ethyl acetate three times. The combinedorganic layers were dried with anhydrous sodium sulfate andfiltered. The solvent was removed under reduced pressure and theresidue was purified by silica flash chromatography to yield anintermediate product. Then, the intermediate product was dissolvedin 8mL of dichloromethane and 8mL TFA, and stirred for4 h at room temperature. The solution was concentrated undervacuum and dissolved in 10 mL of ethyl alcohol and 5 drops ofwater. K2CO3 (0.5 g, 3.6 mmol) was added and the reaction wasstirred for 1 h. The reaction mixture was filtered and concentratedunder vacuum. The residue was purified by silica flash chromatographyto yield a deprotected amino compound (0.107 g, 21%).Then, the deprotected compound (0.107 g, 0.21 mmol) was dissolvedin 5mL of THF and stirred at 0 C. Five drops of water andN, N-diisopropyl-ethylamine (0.1 mL, 0.63 mmol) were added to thereaction, followed by acryloyl chloride (16 mL, 0.2 mmol). The reactionwasstirred at 0 C for 10 min. The solutionwas concentratedunder vacuum and the residue was purified by silica flash chromatographyto yield compound 9 (0.013 g, 3% for the last threesteps).According to scheme I, to a 250-mL flash were added Compound Ia-1, i.e. 2, 6-dichloro-3, 5-dimethoxyaniline (10mmol) and AcOH (24ml), and added dropwisely under an ice-bath a solution of sodium nitrite (15mmol) in sulphuric acid (5.8ml) . The mixture was stirred at 25C until the solution became clear. The resulting dark yellow solution was poured into 150ml of an ice-water, and urea (6mmol) was added. The mixture was stirred and filtered. An aqueous solution of potassium iodide (15mmol) was added to the above dark-yellow solution. The mixture was heated at 85C for 2 hours, and cooled to room temperature. NaHSO3 (3.4 mmol) was added, and the mixture was stirred for 10 minutes. The resulting yellow solid was filtered, dried, and separated by column chromatography to produce Compound Ib-1 (8mmol). Compound Ib-1 (4 mmol), and Compound A-1, i.e. 4-piperidinone ethylene ketal (6 mmol) were dissolved in 50ml toluene, and palladium acetate (0.4 mmol), BINAP (0.48 mmol), and cesium carbonate (18 mmol) were added. The mixture was refluxed under the nitrogen protection for 3 days, and separated by column chromatography to produce Compound Ic-1. Compound Ic-1 (2.5 mmol) was dissolved in 10ml THF, and 10% aqueous H2SO4 solution (10ml) was added. The mixture was heated at 60C overnight, and separated by column chromatography to produce Compound Id-1. Compound Id-1 (1.0 mmol) was dissolved in 10ml dioxane, and DMF.DMA (6.0 mmol) and triethylamine (1.0 mmol) were added. The mixture was refluxed under the nitrogen protection for 2 days, and separated by thin layer chromatography to produce Compound Ie-1. Compound B-1, i.e., 1-fluoro-4-nitrobenzene (10 mmol) was dissolved in 20ml DMF, and C-1, i.e., N-ethylpiperazine (11 mmol), and potassium carbonate (30 mmol) were added. The mixture was reacted at 70C overnight. After cooling, the mixture was poured into ice-water, and filtered to produce Compound If-1. Compound If-1 (10 mmol) was dissolved in 20ml methanol or ethanol, and palladium/carbon (1mmol) was added. The mixture was hydrogenated at room temperature for 7 hours. The mixture was separated by column chromatography to produce Compound Ig-1. Compound Ig-1 (2.6 mmol) was dissolved in 10ml dioxane, and cyanoamine (2.73 mmol), and concentrated hydrochloric acid (3.9 mmol) were added. The mixture was stirred under reflux overnight to produce Compound Ih-1. Compound Ie-1 (1mmol) and Compound Ih-1 (1.05mmol) were dissolved in 8ml ethanol, and sodium acetate (2mmol) and triethylamine (1.05mmol) were added. The mixture was stirred under flux for 7 hours, ethanol concentrated, and water and dichloromethane were added. The organic phase was separated, dried over anhydrous sodium sulphate, and separated by thin layer chromatography to produce Compound I-1 (0.1mmol) in a yield of 10%.H1-NMR(deuterated MeOH) : delta8.11(s, 1H), delta7.56(d, 2H), delta6.99(d, 2H), delta6.72(s, 1H), delta4.25(s, 2H), delta3.93(s, 6H), delta3.56(t, 2H), delta3.23(m, 4H), delta2.92(t, 2H), delta2.8(m, 4H), delta2.64(m, 3H), delta1.2(t, 3H). ESI(+)m/z: 543General procedure: The reaction vessel was charged with 5-((3-fluorophenyl)sulfonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid(29 mg, 0.16 mmol), diisopropylethylamine (0.035 mL, 0.2 mmol), 1-hydroxybenzotriazole monohydrate (19 mg, 0.12 mmol) and dichloromethane (2 mL) were added and stirred. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI ?? HCl, 23 mg, 0.12 mmol) was added thereto and stirred at room temperature. The reaction mixture was diluted with dichloromethane (10 mL), water (10 mL) was added, and the mixture was stirred. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane: methanol = 30: 1) to obtain the desired compound (50 mg, 90% yield).General procedure: To a stirred solution of compound 7, 8, or 9 (1 equiv) in 1-butanol was added compounds 12(1.1 equiv) and p-toluenesulfonic acid (1 equiv). The mixture was placed in a pressure flask, and heated to 100C for 15h. The reaction mixture was quenched by saturated Na2CO3 aqueous solution, and then was extracted with DCM and the organic phase was washed with water, dried over anhydrous Na2SO4. The combined organic layer was concentrated under reduced pressure and was further purified by flash column chromatography using dichloromethane/methanol as eluent to afford product H1-H14, Y1-Y14, or L1-L14 as a pale yellow solid.General procedure: To a stirred solution of compound 7, 8, or 9 (1 equiv) in 1-butanol was added compounds 12(1.1 equiv) and p-toluenesulfonic acid (1 equiv). The mixture was placed in a pressure flask, and heated to 100C for 15h. The reaction mixture was quenched by saturated Na2CO3 aqueous solution, and then was extracted with DCM and the organic phase was washed with water, dried over anhydrous Na2SO4. The combined organic layer was concentrated under reduced pressure and was further purified by flash column chromatography using dichloromethane/methanol as eluent to afford product H1-H14, Y1-Y14, or L1-L14 as a pale yellow solid.

Molecular Weight:205.30
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:205.157897619
Monoisotopic Mass:205.157897619
Topological Polar Surface Area:32.5
Heavy Atom Count:15
Complexity:179
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes