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[ CAS No. 540-37-4 ] {[proInfo.proName]}

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Chemical Structure| 540-37-4
Chemical Structure| 540-37-4
Structure of 540-37-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 540-37-4 ]

CAS No. :540-37-4 MDL No. :MFCD00007848
Formula : C6H6IN Boiling Point : -
Linear Structure Formula :- InChI Key :VLVCDUSVTXIWGW-UHFFFAOYSA-N
M.W : 219.02 Pubchem ID :10893
Synonyms :

Calculated chemistry of [ 540-37-4 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 0.0
Num. H-bond donors : 1.0
Molar Refractivity : 43.56
TPSA : 26.02 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.97 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.59
Log Po/w (XLOGP3) : 2.34
Log Po/w (WLOGP) : 1.88
Log Po/w (MLOGP) : 2.41
Log Po/w (SILICOS-IT) : 2.15
Consensus Log Po/w : 2.07

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.23
Solubility : 0.13 mg/ml ; 0.000593 mol/l
Class : Soluble
Log S (Ali) : -2.53
Solubility : 0.653 mg/ml ; 0.00298 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.0
Solubility : 0.222 mg/ml ; 0.00101 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.71

Safety of [ 540-37-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 540-37-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 540-37-4 ]
  • Downstream synthetic route of [ 540-37-4 ]

[ 540-37-4 ] Synthesis Path-Upstream   1~76

  • 1
  • [ 288-13-1 ]
  • [ 540-37-4 ]
  • [ 17635-45-9 ]
YieldReaction ConditionsOperation in experiment
57% at 125℃; for 24 h; sealed tube Following General Procedure A (125 0C, 24 hours), 1 H-pyrazole (102 mg, 1.5 mmol) is coupled with 4-iodoaniline (220 mg, 1.0 mmol). The s crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes = 50/50) to provide 90 mg (57 percent isolated yield) of the desired product as an orange solid. <n="48"/>36- 47 -IdentificationMp: 42°C.1H NMR (400 MHz, CDCI3): δ 7.70 (dd, 1H, H7), 7.59 (d, 1 H, H9), 7.34-7.38 (m, 2H1 H2l6), 6.63-6.67 (m, 2H, H3,5), 6.33-6.34 (m, 1 H, H8), 3.67 (s, 2H, Hio). 13C NMR (100 MHz, CDCI3): δ 145.33 (C4), 140.24 (C9), 132.39 (C1), 126.76 (C7), 121.11 (C2,6), 115.46 (C3|5), 106.83 (C8).IR (KBr) : v (cm-1) = 3381 , 3298, 3192, 1632, 1525, 1398, 1280, 1176, 1126, 1051 , 1033, 943, 823, 751 , 612, 521. GC/MS: rt = 19.16 min, IWZ = 159. HRMS: 160.0873 (M+H). Theoretical: 160.0875.
Reference: [1] Angewandte Chemie - International Edition, 2007, vol. 46, # 6, p. 934 - 936
[2] Patent: WO2008/4088, 2008, A2, . Location in patent: Page/Page column 46-47
[3] Tetrahedron Letters, 2009, vol. 50, # 42, p. 5868 - 5871
[4] RSC Advances, 2015, vol. 5, # 130, p. 107547 - 107556
  • 2
  • [ 3054-95-3 ]
  • [ 540-37-4 ]
  • [ 13327-31-6 ]
YieldReaction ConditionsOperation in experiment
10% With hydrogenchloride In water at 111℃; for 24 h; General procedure: A 1N HCl solution (82.5 mL) was added to the aniline (~1 mmol) in a round bottom flask. To this was added acrolein diethyl acetal (2.5 mmol). The resulting solution was refluxed at 111 °C for 24 hours. After cooling to room temperature, the solution was neutralized (pH 7−8) by addition of solid Na2CO3. The product was then extracted into dichloromethane (3 x 100 mL), and the combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude residue was then purified by column chromatography (elution mixture of hexane with ethyl acetate or 15percent ethyl acetate/cyclohexane with methanol) to give the desired quinoline product.
Reference: [1] Tetrahedron Letters, 2015, vol. 56, # 46, p. 6436 - 6439
  • 3
  • [ 540-37-4 ]
  • [ 13327-31-6 ]
Reference: [1] Chinese Chemical Letters, 2014, vol. 25, # 5, p. 779 - 782
  • 4
  • [ 109-97-7 ]
  • [ 540-37-4 ]
  • [ 52768-17-9 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 23, p. 8943 - 8946
[2] Letters in Organic Chemistry, 2010, vol. 7, # 3, p. 212 - 218
[3] Advanced Synthesis and Catalysis, 2008, vol. 350, # 9, p. 1253 - 1257
  • 5
  • [ 13331-23-2 ]
  • [ 540-37-4 ]
  • [ 59147-02-3 ]
YieldReaction ConditionsOperation in experiment
92% With C7H10N2*Pd(2+)*2Cl(1-); potassium carbonate In methanol; water for 0.166667 h; Reflux; Schlenk technique General procedure: A 20mL Schlenk tube with a magnetic stir bar was charged with aryl halide (2mmol), arylboronic acid (2.4mmol), K2CO3 (5mmol), 10mL of solvent [H2O, H2O–MeOH (1:1), H2O–EtOH (1:1), H2O–EG (1:1)] and an aliquot of 0.01M solution of palladium complexes PdCl2(L)2 or Pd[(L)4]Cl2 in MeOH (0.001–0.2molpercent) under air atmosphere. The reaction mixture was placed in a preheated oil bath: at 100°C for MeOH–H2O, at 110°C for EtOH–H2O, at 140°C for H2O and at 160°C for EG–H2O; and stirred under reflux for the given time. After this time, the mixture was cooled, acidified by 5M HCl (in the case of acids) and diluted with 10mL of H2O and 10mL of Et2O (or EtOAc). The organic phase was separated, and the aqueous layer was extracted with Et2O EtOAc) (2×10mL). The combined organic layers were washed with H2O (10mL), brine (10mL), and dried over Na2SO4. The pure products were obtained by a simple filtration of ether solution through silica gel pad and evaporation of a solvent.
Reference: [1] Catalysis Communications, 2016, vol. 79, p. 17 - 20
  • 6
  • [ 540-37-4 ]
  • [ 59147-02-3 ]
Reference: [1] European Journal of Organic Chemistry, 2013, # 13, p. 2545 - 2554
  • 7
  • [ 540-37-4 ]
  • [ 18471-73-3 ]
Reference: [1] Tetrahedron Letters, 2009, vol. 50, # 50, p. 6985 - 6988
[2] Tetrahedron, 2010, vol. 66, # 17, p. 3135 - 3146
  • 8
  • [ 109-04-6 ]
  • [ 540-37-4 ]
  • [ 18471-73-3 ]
Reference: [1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 2, p. 286 - 297
  • 9
  • [ 540-37-4 ]
  • [ 882521-96-2 ]
  • [ 18471-73-3 ]
Reference: [1] Tetrahedron Letters, 2004, vol. 45, # 4, p. 685 - 687
  • 10
  • [ 93830-58-1 ]
  • [ 540-37-4 ]
  • [ 13296-04-3 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 11, p. 4755 - 4763
  • 11
  • [ 3034-53-5 ]
  • [ 540-37-4 ]
  • [ 193017-26-4 ]
Reference: [1] Synthesis, 2001, # 1, p. 128 - 134
  • 12
  • [ 333-20-0 ]
  • [ 540-37-4 ]
  • [ 16582-58-4 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: at 20℃; Cooling with ice
Stage #2: With ammonium hydroxide In water
General procedure: A mixture of 0.1 mol of 4-substituted aniline and 0.1 mol of Potassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH) was cooled in an ice bath and stirred for 10-20 min, and then 0.1 mol bromine in glacial acetic acid was added dropwise at such a rate to keep the temperature below 10 °C throughout the addition. The reaction mixture was stirred at room temperature for 2-4 h, the hydrobromide (HBr) salt thus separated out was filtered, washed with acetic acid, dried, dissolved in hot water and basified to pH 11.0 with ammonia solution (NH4OH) and the resulting precipitate was filtered, washed with water and dried to get the desired product 3a-k. The progress of the reaction was monitored by Thin Layer Chromatography using toluene: acetone (8:2) solvent system.
Reference: [1] European Journal of Medicinal Chemistry, 2012, vol. 53, p. 41 - 51
[2] Heteroatom Chemistry, 2012, vol. 23, # 4, p. 399 - 410
[3] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 24 - 30
[4] Medicinal Chemistry, 2013, vol. 9, # 4, p. 596 - 607
[5] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
  • 13
  • [ 1147550-11-5 ]
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Reference: [1] European Journal of Organic Chemistry, 2011, # 31, p. 6206 - 6217
  • 14
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Reference: [1] Medicinal Chemistry Research, 2013, vol. 22, # 1, p. 195 - 210
[2] Journal of Chemical Research, 2014, vol. 38, # 10, p. 611 - 616
[3] Patent: US2016/2600, 2016, A1,
  • 15
  • [ 540-72-7 ]
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  • [ 16582-58-4 ]
Reference: [1] Die Pharmazie, 1967, vol. 22, # 6, p. 229 - 233
  • 16
  • [ 15192-76-4 ]
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  • [ 16582-58-4 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1956, p. 1701
  • 17
  • [ 540-37-4 ]
  • [ 20780-76-1 ]
Reference: [1] European Journal of Pharmacology, 2007, vol. 556, # 1-3, p. 200 - 206
[2] Tetrahedron, 2005, vol. 61, # 25, p. 6082 - 6087
[3] Chemische Berichte, 1924, vol. 57, p. 1773
[4] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 292 - 302
[5] Medicinal Chemistry, 2016, vol. 12, # 5, p. 489 - 498
  • 18
  • [ 302-17-0 ]
  • [ 540-37-4 ]
  • [ 20780-76-1 ]
Reference: [1] Pharmazie, 1980, vol. 35, # 1, p. 14 - 16
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 8, p. 1882 - 1885
  • 19
  • [ 92-87-5 ]
  • [ 540-37-4 ]
  • [ 51751-44-1 ]
Reference: [1] Patent: US2015/364695, 2015, A1,
  • 20
  • [ 540-37-4 ]
  • [ 40107-07-1 ]
Reference: [1] Patent: US2012/41024, 2012, A1,
[2] Patent: EP2566477, 2015, B1,
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 10, p. 4867 - 4880
  • 21
  • [ 288-88-0 ]
  • [ 540-37-4 ]
  • [ 6523-49-5 ]
Reference: [1] RSC Advances, 2014, vol. 4, # 83, p. 44105 - 44116
  • 22
  • [ 540-37-4 ]
  • [ 51207-86-4 ]
Reference: [1] Tetrahedron Letters, 2015, vol. 56, # 8, p. 1004 - 1006
  • 23
  • [ 288-32-4 ]
  • [ 540-37-4 ]
  • [ 2221-00-3 ]
YieldReaction ConditionsOperation in experiment
75% With copper(l) chloride; sodium hydroxide; 3-(diphenylphosphino)propionic acid In dimethyl sulfoxide at 120℃; for 14 h; Inert atmosphere; Sealed tube General procedure: NH-containing heterocycle (1.4 mmol) and DMF (2.0 mL) were added to a mixture of CuCl (15.0 molpercent) and ligand 1 (20.0 molpercent) in DMF (2.0 mL), aryl iodide (1.0 mmol), NaOH (2.0 mmol). The mixture was vigorously stirred at 120 °C for 14 h under a dry nitrogen atmosphere. After completion of the reaction (as monitored by TLC), H2O was added and the organic layer was extracted with EtOAc, washed with brine and dried over MgSO4. The solution was filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography. The purity of the compounds was checked by 1H NMR and yields are based on aryl iodide. All the products are known and the spectroscopic data (FT‑IR and NMR) and melting points were consistent with those reported in the literature.
80 %Chromat. With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h; General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.
Reference: [1] Green Chemistry, 2013, vol. 15, # 2, p. 336 - 340
[2] Journal of the Chinese Chemical Society, 2013, vol. 60, # 8, p. 1007 - 1013
[3] RSC Advances, 2014, vol. 4, # 14, p. 7321 - 7329
[4] New Journal of Chemistry, 2015, vol. 39, # 4, p. 2901 - 2907
[5] Chemistry - An Asian Journal, 2014, vol. 9, # 12, p. 3418 - 3430
[6] Journal of Chemical Research, 2014, vol. 38, # 2, p. 128 - 129
[7] Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 2200 - 2202
[8] RSC Advances, 2015, vol. 5, # 2, p. 1522 - 1528
[9] Tetrahedron, 2006, vol. 62, # 18, p. 4435 - 4443
[10] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2136 - 2145
[11] RSC Advances, 2014, vol. 4, # 29, p. 15122 - 15130
[12] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
  • 24
  • [ 540-37-4 ]
  • [ 13939-06-5 ]
  • [ 71-36-3 ]
  • [ 94-25-7 ]
YieldReaction ConditionsOperation in experiment
90% With C35H20F34NO3(1-)*Pd(2+)*Cl(1-); N-ethyl-N,N-diisopropylamine In neat (no solvent) at 130℃; for 0.2 h; Microwave irradiation General procedure: A mixture of the aryl halide (1.0 mmol), alcohol (5.0 equiv), Mo(CO)6 (0.5 equiv), DIPEA (1.5 equiv) and palladacycle 1 (1 mol percent Pd) was heated in a pressure tube at 130 °C under microwave irradiation. The reaction was monitored by TLC. When the reaction has completed, the reaction mixture was cooled to room temperature and the alcohol was removed. The crude mixture was subjected to F-SPE to remove palladacycle 1 (see general procedure for the recycling of palladacycle 1) and the solution of crude product was concentrated, diluted with EtOAc (20 mL) and washed successively with 2 M HCl (210 mL) and water (10 mL). The organic layer was driedover anhydrous MgSO4, filtered and concentrated to give pure 6.
Reference: [1] Tetrahedron, 2014, vol. 70, # 45, p. 8545 - 8558
  • 25
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  • [ 35418-07-6 ]
Reference: [1] MedChemComm, 2013, vol. 4, # 12, p. 1562 - 1570
  • 26
  • [ 616-38-6 ]
  • [ 540-37-4 ]
  • [ 60577-34-6 ]
YieldReaction ConditionsOperation in experiment
76% With 1,8-diazabicyclo[5.4.0]undec-7-ene In 1-methyl-pyrrolidin-2-one at 250℃; for 0.2 h; Flow reactor General procedure: Selective N-monomethlyation reactions were performed in a Vapourtec E-series continuous flow system equipped with a high temperature tube reactor (10 mL, stainless steel, 0.03'' i.d., Fig. 2 ) and a membrane back pressure regulator (Zaiput). Stock solutions of aniline (20 mmol, 1.0 equiv, 2 M), DMC (5.05 mL, 60 mmol, 3.0 equiv, 6 M), and DBU (4.47 mL, 30 mmol, 1.5 equiv, 3 M) were prepared in oven-dried 10 mL volumetric flasks using NMP as the solvent. The solutions were transferred to screw-thread vials with septum caps and reagents were pumped directly from the vials. After the high temperature coiled tube reactor was heated to 250 °C, peristaltic pumps (Vapourtec V-3) were used to pump the reactant solutions into the system (0.277 mL/min each for a 12 min residence time). The solutions were mixed with a cross-mixer (0.4″ i.d.), passed though the high temperature coiled tube reactor. Upon exiting the reactor, the reaction stream was passed through a short segment of stainless steel tubing to enable the reaction to cool and then exited the system by passage through the back pressure regulator (Note: PFA fittings should not be used at the exit of the reactor as they will deform due to the high temperature of the reaction stream and cause leaks in the system. Stainless steel connectors and tubing (12'') were used in our system.). After the flow system was equilibrated for 18 min, the product stream was collected for 5 min (2.77 mmol of aniline). The crude mixture was dissolved in ethyl acetate and washed with brine. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 25 g Ultra-sil, 3–15percent ethyl acetate in hexanes) to afford the desired product.
Reference: [1] Tetrahedron, 2018, vol. 74, # 25, p. 3124 - 3128
  • 27
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Reference: [1] ACS Catalysis, 2015, vol. 5, # 7, p. 4082 - 4088
[2] Organic Letters, 2018, vol. 20, # 19, p. 5985 - 5990
[3] RSC Advances, 2012, vol. 2, # 23, p. 8645 - 8652
[4] Journal of Catalysis, 2017, vol. 347, p. 57 - 62
  • 28
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Reference: [1] Organic Letters, 2009, vol. 11, # 6, p. 1225 - 1228
  • 29
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  • [ 698-70-4 ]
Reference: [1] Chemical Communications, 2010, vol. 46, # 20, p. 3538 - 3540
  • 30
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Reference: [1] Chemical Communications, 2014, vol. 50, # 49, p. 6523 - 6525
  • 31
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  • [ 540-37-4 ]
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Reference: [1] Patent: US2003/65187, 2003, A1,
  • 32
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  • 34
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  • [ 14235-81-5 ]
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  • 36
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  • 38
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  • [ 74-88-4 ]
  • [ 698-70-4 ]
YieldReaction ConditionsOperation in experiment
34% With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 48 h; 4-Iodobenzenamine (1327 mg, 6.06 mmol), NaHCO3 (1140 mg, 13.57 mmol), and DMF (4 mL) were added into the 25 mL flask, the resulting mixture was stirred at rt, iodomethane (2415 mg, 17.00 mmol) was added dropwise via a dropping funnel. After the complete conversion of the starting material as monitored by TLC (eluent: petroleum ether/ethyl acetate = 2/1), the mixture was poured into cold water (10 mL), the organic layer was separated, the aqueous phase was extracted with ethyl acetate (10 mL × 3), the organic phase was combined and washed with a saturated aqueous solution of NaCl, and dried over anhydrous MgSO4. The solvent was evaporated. Flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10/1) afforded 4-iodo-N,N-dimethylbenzenamine as a pale yellow solid (508 mg, 34percent).
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  • [ 698-70-4 ]
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  • 41
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  • [ 29632-73-3 ]
YieldReaction ConditionsOperation in experiment
44% at 20℃; To a solution of 4-iodo aniline (1.1 g, 5.0 mmol), in 6 mL of HO Ac, was added a solution of Br2 (250 μ., 4.8 mmol) and the mixture stirred overnight at room temperature. The reaction mixture was washed with brine, saturated aqueous NaHC03 and extracted with Et20, dried (Na2S04), filtered and concentrated. Purification by column chromatography (Hexane:EtOAc = 9: 1, 4: 1, 2: 1) provided the title compound as a brown oil (570 mg, 1.9 mmol, 44 percent) Rf: 0.46 (Hexane:EtOAc, 4: 1). 1H NMR (400 MHz; CDC13): δ 6.54 (1H, d, J = 8.2 Hz, ArCH), 7.37 (1H, d, J = 8.4 Hz, ArCH), 7.70 (1H, s, ArCH). 13C NMR (100 MHz; CDC13): δ 110.0, 117.3, 131.1, 134.4, 136.9, 139.9, 143.8.
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[2] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 8, p. 774 - 779
[3] Patent: WO2018/148721, 2018, A1, . Location in patent: Page/Page column 83
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[2] Journal of Organic Chemistry, 2015, vol. 80, # 2, p. 882 - 896
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  • 49
  • [ 683-60-3 ]
  • [ 540-37-4 ]
  • [ 7664-66-6 ]
YieldReaction ConditionsOperation in experiment
74% With hemicucurbituril supported [Bmim]Cl In toluene for 10 h; Reflux General procedure: A mixture of aryl halide (1 mmol) and sodium alkoxide(3.0 mmol) was refluxed in the presence of 200 mg ofHmCucSILP catalyst in toluene (5 mL) for an appropriatetime as indicated in Table 2. After completion of thereaction, the reaction mixture was filtered and solvent wasevaporated in vacuo to give the crude product, which waspurified by column chromatography over silica gel usinghexane/EtOAc as the eluent.
Reference: [1] Catalysis Letters, 2016, vol. 146, # 12, p. 2485 - 2494
  • 50
  • [ 109-86-4 ]
  • [ 540-37-4 ]
  • [ 33311-29-4 ]
YieldReaction ConditionsOperation in experiment
5.3% With caesium carbonate In toluene at 110℃; EXAMPLE 40; 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid [4-(2-methoxy-ethoxy)-phenyl]-amide; a. 4-(2-Methoxy-ethoxy)-phenylamine; A mixture of 4-iodoaniline (219 mg, 1.0 mmol), 2-methoxyethanol (152 mg, 2.0 mmol), copper iodide (19.0 mg, 0.1 mmol), cesium carbonate (554 mg, 1.7 mmol) and 1,10-phenanthroline (36.0 mg, 0.2 mmol) was stirred in toluene (0.5 mL) at 110° C. overnight. The reaction was then cooled to RT and filtered through silica gel and washed with diethyl ether. The ether was removed in vacuo to obtain a crude solid. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a solid (8.9 mg, 5.3percent). 1H NMR (300 MHz, CDCl3) δ 6.82-6.72 (m, 4H), 4.06 (t, 2H), 3.72 (t, 2H), 3.45 (s, 3H).
Reference: [1] Patent: US2006/281772, 2006, A1, . Location in patent: Page/Page column 72
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  • [ 540-37-4 ]
  • [ 6331-71-1 ]
Reference: [1] Tetrahedron Letters, 2015, vol. 56, # 8, p. 1004 - 1006
  • 52
  • [ 140-88-5 ]
  • [ 540-37-4 ]
  • [ 5048-82-8 ]
YieldReaction ConditionsOperation in experiment
89% With palladium diacetate; triethylamine In neat (no solvent) at 100℃; for 4 h; Sealed tube General procedure: In a typical reaction, aryl halide (1.0 mmol), olefin (1.5 mmol),Et3N (2 mmol), Pd(OAc)2 (0.01 mmol) and [HQ-PEG1000-DIL][BF4](0.1 mmol) were added to a tube and sealed. The reaction mixture was stirred at 100 C for a certain time. At the end of the reaction, the final mixture was cooled to room temperature and extracted with diethyl ether. The combined organic extracts were dried over anhydrous MgSO4 and concentrated to give the crude product, which was purified by column chromatography on silica gel (200-300 mesh) using ethyl acetate/petroleum ether as eluent to afford the desired product in high purity. Only the trans-products were selectively obtained and characterized by comparison of 1H NMR data in the literature. The catalyst left in the reaction vessel was dried in vacuo for 2 h.The residue was subjected to a second run by charging the reaction tube with fresh starting materials without further addition of Pd(OAc)2 and [HQ-PEG1000-DIL][BF4].
75% With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 6 h; Inert atmosphere General procedure: A mixture of 4-iodotoluene (5 g, 22.93 mmol), ethyl acrylate (4.587 g, 45.87 mmol) and potassium carbonate (6.330 g, 45.87 mmol) was taken in DMF (15 ml) and then added SS-Pd (10.27 g, 2 molpercent Pd). The reaction mixture was heated at 100 oC for 6 h under nitrogen atmosphere. After cooling the reaction mixture was diluted with 15ml of ethyl acetate and washed with cold water. The organic layer was finally washed with brine and dried over anhydrous Na2SO4. The crude mixture was purified by column chromatography (EtOAc:Hexane, 1:99), afforded (E)-ethyl 3-p-tolylacrylate 1 as colourless liquid (4.051g, 93percent yield)
60% With potassium phosphate In N,N-dimethyl-formamide at 100℃; for 5 h; General procedure: A mixture of aryl halide (1 mmol), ethylacrylate (1 mmol), K3PO4 (1 mmol), nano-Pd/Fe3O4/ZnO (0.003 g), and DMF (1.0 mL) was put into a preheated oil bath at 100 °C foran appropriate period of time. Then, the reaction mixture was diluted with EtOAc and the catalyst was removed by a magnet. The filtrate was extracted with water and the organic layer dried over CaCl2 and evaporated under reduced pressure. Resulting products were purified by column chromatography over silica gel using n-hexane/ethylacetate (5:1) as eluent to give the desired pure product with excellent yield.
Reference: [1] Journal of Organometallic Chemistry, 2013, vol. 739, p. 1 - 5
[2] Tetrahedron Letters, 2012, vol. 53, # 52, p. 7044 - 7051
[3] Advanced Synthesis and Catalysis, 2016, vol. 358, # 23, p. 3736 - 3742
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[5] Synlett, 2011, # 3, p. 369 - 372
[6] Organic and Biomolecular Chemistry, 2004, vol. 2, # 15, p. 2249 - 2252
[7] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2008, vol. 47, # 10, p. 1549 - 1554
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Reference: [1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
  • 54
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Reference: [1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
  • 55
  • [ 5720-06-9 ]
  • [ 540-37-4 ]
  • [ 263901-48-0 ]
Reference: [1] European Journal of Organic Chemistry, 2007, # 32, p. 5364 - 5375
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 15, p. 3057 - 3061
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2648 - 2659
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Reference: [1] European Journal of Organic Chemistry, 2013, # 13, p. 2545 - 2554
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Reference: [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 5, p. 1706 - 1712
[2] Advanced Synthesis and Catalysis, 2014, vol. 356, # 7, p. 1571 - 1576
  • 58
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  • [ 540-37-4 ]
  • [ 75-65-0 ]
  • [ 120363-13-5 ]
Reference: [1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 32, p. 6715 - 6719
  • 59
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  • [ 134856-58-9 ]
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[3] Journal of Organic Chemistry, 2003, vol. 68, # 6, p. 2167 - 2174
[4] Chemistry - A European Journal, 2001, vol. 7, # 21, p. 4706 - 4714
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  • 60
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  • [ 540-37-4 ]
  • [ 95331-56-9 ]
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Reference: [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 10, p. 2048 - 2056
[2] Patent: WO2012/37108, 2012, A1,
[3] Organic Process Research and Development, 2017, vol. 21, # 7, p. 1003 - 1011
  • 63
  • [ 887144-94-7 ]
  • [ 540-37-4 ]
  • [ 97760-97-9 ]
YieldReaction ConditionsOperation in experiment
61% With potassium carbonate; nickel(II) hydroxide In dimethyl sulfoxide at 35℃; for 2 h; In the preparation method of the trifluoromethyl aromatic amine of the present embodiment, the aromatic amine is p-iodoaniline, and other reactions and post-treatment processes are the same as in the embodiment 28.
The preparation method of the trifluoromethyl aromatic amine of the present embodiment, the aromatic amine is aniline, and the nickel compound is nickel hydroxide.The base is potassium carbonate, and the reaction process parameters are: 1-trifluoromethyl-1,2-phenyliodo-3(H)-one (0.5 mmol, 1.0 eq).Aromatic amine (1.5 mmol, 3.0 eq), nickel hydroxide 10 molpercent, potassium carbonate (1.5 mmol, 3.0 eq),DMSO (2 mL) was reacted at 35 ° C for 2 h, and the other reactions and workup procedures were the same as in Example 1.
60% With tris[2-phenylpyridinato-C2,N]iridium(III) In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Irradiation Under nitrogen or argon, 4-iodoaniline 0.4 mmol,0.2mmol, Ir (ppy) 3(2mg) and DMF1 ml was added to the reaction flask, followed by blueLED lights (7W) irradiation until complete conversion of trivalent iodine reagentcompletion of the reaction at room temperature. Add 10 ml of saturated Na 2CO3 Aqueoussolution, and extracted with ethyl acetate three times, the organic layer was washedwith water and once with saturated brine, dried over anhydrous Na 2SO 4The organic layerwas dried. Column chromatography (eluent: petroleum ether 60-90: ethyl acetate = 20: 1-10: 1) to give the product in 60percent yield.
Reference: [1] Organic Letters, 2018, vol. 20, # 13, p. 3732 - 3735
[2] Patent: CN108503552, 2018, A, . Location in patent: Paragraph 0240-0244
[3] Patent: CN103553857, 2016, B, . Location in patent: Paragraph 0021-0022
[4] Organic Letters, 2014, vol. 16, # 6, p. 1768 - 1771
  • 64
  • [ 2314-97-8 ]
  • [ 540-37-4 ]
  • [ 97760-97-9 ]
YieldReaction ConditionsOperation in experiment
90% With fac-tris(2-phenylpyridinato-N,C2')iridium(III); potassium carbonate In 1,2-dichloro-ethane at 20℃; for 24 h; Inert atmosphere; Schlenk technique; Irradiation General procedure: A 25 mL of Schlenk tube equipped with a magnetic stir bar were charged with aniline (1.2 mmol, 3.0 equiv) or heterocycles (0.8 mmol, 2.0 equiv), K2CO3 (0.8 mmol, 2.0 equiv) and fac-Ir(ppy)3 (2.6 mg, 0.004 mmol, 1 mol percent), under air. The vessel was evacuated and backfilled with Ar (3 times), CF3I stock solution (0.56 mL, 0.71 mmol/mL in 1,2-chloroethane or 0.36 mL, 1.11 mmol/mL in DMSO, 1.0 equiv), anhydrous 1,2-dichloroethane (3 mL) were then added. The tube was screw capped and stirred at room temperature under irradiation of blue LEDs (12 W) for 24 hours. The reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (3×5 mL). The filtrate was concentrated. The residue was subjected to column chromatography on silica gel to afford the pure product.
Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 41, p. 3939 - 3941
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  • [ 342617-07-6 ]
Reference: [1] Patent: US2012/41024, 2012, A1,
[2] Patent: EP2566477, 2015, B1,
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 10, p. 4867 - 4880
  • 66
  • [ 24424-99-5 ]
  • [ 540-37-4 ]
  • [ 159217-89-7 ]
YieldReaction ConditionsOperation in experiment
98% at 80℃; for 0.166667 h; Green chemistry General procedure: The reactions were carried out in a 50 mL RB flask under reduced pressure for 10 min at 80°C unless reported differently. In a typical experiment, 5 mmol of amine was added to 5 mmol of BOC anhydride, and the reaction was allowed to proceed for 10 min. The desired product was obtained in a rotary evaporator under vacuum conditions.
87% With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 3 h; A mixture of 4-iodoaniline 2 (9.39 g, 42.8 mmol) and Boc2O (8.78 g, 47.1 mmol) in DMF [(25] mL) and DIEA (5 mL) was stirred at RT for 3 hr, diluted with AcOEt (300 mL), and washed with [H20] (2x, each 150 mL). The organic layer was dried (MgSO4) and evaporated to give compound 3 (11.89 g, [87percent, 1H-NMR).]
73% for 16 h; Heating / reflux To a solution of 4-iodoaniline (10 g) in tetrahydrofuran (200 mL) was added di-tert-butyl dicarbonate (11 g), and the reaction mixture was heated under reflux for 16 hrs. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography, and tert-butyl 4-iodophenylcarbamate was obtained as crystals from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). Recrystallization from ethyl acetate-hexane gave colorless prism crystals (10.7 g, yield 73percent). melting point: 148-149°C.
70%
Stage #1: With lithium bis(trimethylsilyl)amide In tetrahydrofuran at 0 - 20℃;
Stage #2: at 20℃; for 2 h;
4-IODOANILINE (3.28 g, 15 mmol) was dissolved in anhydrous THF (70 ml), cooled to 0°C and treated with lithium hexamethyldisilazide (1M in THF, 30ML, 30 mmol). After warming to room temperature di-tert-butyl dicarbonate (3.27 g, 15 mmol) in anhydrous THF (30 ml) was added dropwise and the mixture stirred for 2 h. The reaction was quenched by the addition of sat. NH4C1 solution, the organic phase was separated and washed with water. After concentration the crude product was purified by flash column chromatography (ethyl acetate/heptane 4: 1) yielding (4-iodo-phenyl) -carbamic acid tert-butyl ester as a tan solid (3.37 g, 70 percent ;-10 percent contamination with di-tert-butyl ester) MS: M = 318.0 (ESI-) 'H-NMR (400 MHz, [D6]-DMSO) : 1.47 (s, 9H), 7.29 (d, 2H), 7.57 (d, 2H), 9.46 (s, br, NH)
70% With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 2 h; 4-Iodoaniline (3.28 g, 15 mmol) is dissolved in anhydrous THF (70 ml), cooled to 0° C. and treated with lithium hexamethyldisilazide (1M in THF, 30 ml, 30 mmol). After warming to room temperature di-tert-butyl dicarbonate (3.27 g, 15 mmol) in anhydrous THF (30 ml) is added dropwise and the mixture stirred for 2 h. The reaction is quenched by the addition of sat. NH4Cl solution, the organic phase is separated and washed with water. After concentration the crude product is purified by flash column chromatography (ethyl acetate/heptane 4:1) yielding (4-iodo-phenyl)-carbamic acid tert-butyl ester as a tan solid (3.37 g, 70percent; 10percent contamination with di-tert-butyl ester). MS: M=318.0 (ESI-) 1H-NMR (400 MHz, [D6]-DMSO): δ=1.47 (s, 9H), 7.29 (d, 2H), 7.57 (d, 2H), 9.46 (s, br, NH)
58.2% With dmap; triethylamine In methanol at 50℃; To a solution of V-1 (10 g, 45.66 mmol), TEA (9.22 g, 91.23 mmol) and DMAP (50 mg) in MeOH (100 mL) was added di-tert-butyl dicarbonate (19.8 g, 50.2 mmol). The mixture was heated to 50° C. overnight. After completion of the reaction, the mixture was concentrated, the residue was purified by column chromatography (PE/EA=10/1) to afford V-2 (8.47 g, yield 58.2percent).
48% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 14 h; Cooling with ice The 4-iodo aniline (5.0 g, 22 . 83 mmol) dissolved in DMF (50 ml) in. To the obtained by adding in a mixture of diisopropylethylamine (2.5 ml). Furthermore, under the ice, a mixture of to the resulting dropping (Boc)2O (11.0 g, 50 . 04 mmol). After the completion of the dropping, the resulting reaction mixture at room temperature for 14 hours. Then ice water into the mixture in (250 ml). The resulting mixture is extracted with methylene chloride. The resulting organic phase is concentrated to obtain crude product under reduced pressure. Under heating, the resulting crude product using normal hexane beating. The slurry is cooling, filtering to obtain 3.5 g of white solid (yield: 48.0percent).

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 22, p. 5864 - 5869
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[6] Chemistry - An Asian Journal, 2013, vol. 8, # 1, p. 113 - 120
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[10] Angewandte Chemie - International Edition, 2014, vol. 53, # 41, p. 11046 - 11050[11] Angew. Chem., 2014, vol. 126, # 41, p. 11226 - 11230,5
[12] Patent: US2014/200215, 2014, A1, . Location in patent: Paragraph 0965; 0966
[13] Patent: CN105384739, 2016, A, . Location in patent: Paragraph 0242; 0243; 0244
[14] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 6, p. 1203 - 1212
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Reference: [1] Patent: US6251919, 2001, B1,
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  • [ 170911-92-9 ]
YieldReaction ConditionsOperation in experiment
43% With potassium phosphate; copper(l) iodide In ethylene glycol; isopropyl alcohol at 80℃; for 30 h; A mixture of 4-iodoaniline (0.654 g, 3 mmol), piperazine-1-carboxylic acid tert-bvyl ester (0.67 g, 3.6 mmol), potassium phosphate (1.272 g, 6 mmol), ethylene glycol (0.33 ml) and copper iodide (0.03 g, 0.15 mmol) in 2-propanol (3 ml) was placed under argon in a sealed-tube and heated to 8O0C for 30 hours. After being cooled to room temperature, the medium was washed with water (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane: acetone, 70:30) to yield 43a (0.36 g, 1.3 mmol, 43percent) as a yellow powder.
Reference: [1] Patent: WO2006/124118, 2006, A1, . Location in patent: Page/Page column 59
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 7, p. 2779 - 2796
  • 72
  • [ 142-08-5 ]
  • [ 540-37-4 ]
  • [ 13143-47-0 ]
YieldReaction ConditionsOperation in experiment
95% With 8-quinolinol; potassium carbonate In N,N-dimethyl-formamideInert atmosphere; Reflux; Large scale In a 3000L reactor, iodoaniline 438kg, 2-hydroxypyridine 190kg, 8-hydroxyquinoline 58kg, potassium carbonate 207kg, N,N-dimethylformamide (DMF) 1500kg, nitrogen protection, stirring is turned on. The mixture was warmed to reflux and reacted overnight. Chromatography was followed up to the end of the reaction. The potassium iodide was removed by filtration. Part of the DMF was recovered under reduced pressure, cooled to 50° C., and filtered to give crude 1-(4-aminophenyl)-1H-pyridin-2-one. The crude product was added with 740 kg of ethanol, heated and dissolved, and 55 kg of activated carbon was added for decoloration. The solution was filtered while hot, and the filtrate was cooled and crystallized. The product was filtered, dried and packaged to give 1-(4-aminophenyl)-1H-pyridin-2-one with a yield of 95. percent,The purity is 99percent.
70% With copper(l) iodide; 8-quinolinol; caesium carbonate In 1,4-dioxane; dimethyl sulfoxide at 120℃; for 15 h; Sealed tube 11128] In a similar manner as described in Example 114,(R)-5-(3-(4-methoxybenzamido)piperidin- 1 -yl)-3-(4-(2-ox-opyridin- 1 (2H)-yl)phenylamino)pyrazine-2-carboxamide(154) was prepared using 1 -(4-aminophenyl)pyridin-2(1H)-one. MS found for C29H29N704 as (M+H) 540.1, (M—H)538.3. UV: X=260, 285, 308, 346, 369 nm Synthesis of i-(4-aminophenyl)pyridin-2(1H)-one: The mixture of 4-iodoa-niline (1.00 g, 4.56 mmol), 2-hydroxypyridine (650 mg, 6.84mmol), fine powder Cs2CO3 (2.97 g, 9.12 mmol), fine powderCul (180mg, 0.92 mmol), 8-hydroxyquinoline (140mg, 0.92mmol) in 6 mE DMSO and 10 mE dioxane was stirred in asealed tube at 120° C. for 15 h. The mixture was diluted with300 mE EtOAc, filtered through celite, washed with brine,dried, concentrated and subjected to flash column with 0 to7percent MeOR in dichioromethane to isolate this compound (590mg, yield 70percent).
53.45% With copper(l) iodide; 8-quinolinol; potassium carbonate In dimethyl sulfoxide at 130℃; for 12 h; Inert atmosphere General procedure: Compound 1 (5g, 22.83mmol) was dissolved in DMSO (120mL), followed by the addition of 2-Piperidinone (4.53g, 45.66mmol), CuI (0.43g, 2.28mmol), 8-hydroxy-quinoline (0.66g, 4.57mmol) and K2CO3 (9.46g, 68.49mmol). The mixture was heated to 130°C under N2 for 12h, cooled, and quenched with water (120mL). The organics were extracted with ethyl acetate (2×150mL) and dried (Na2SO4). Purification by silica gel column chromatography (n-hexane/ethyl acetate, 5/1 to 3/1, as eluent) afforded compound 2 as faint yellow (2.80g, 64.47percent).
39.8% With copper(l) iodide; 8-quinolinol; caesium carbonate In dimethyl sulfoxide at 120℃; A mixture of pyridin-2-ol (2.00 g, 21.0 mmol), 4-iodoaniline (4.61 g, 21.0 mmol), 8-quinolinol (0.61 g, 4.2 mmol), Cul (0.80 g, 4.2 mmol) and Cs2C03 (10.26 g, 31.5 mmol) in DMSO (50 mL) was stirred at 120°C for overnight. After filtration, the filtrate was partitioned between EA and water and the aqueous layer was further extracted with EA. The combined organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as a green solid (1.56 g, 39.8 percent yield). MS (m/z): 186.9 (M+H)+.
39.8% With copper(l) iodide; 8-quinolinol; caesium carbonate In dimethyl sulfoxide at 120℃; A mixture of pyridin-2-ol (2.00 g, 21.0 mmol), 4-iodoaniline (4.61 g, 21.0 mmol), 8-quinolinol (0.61 g, 4.2 mmol), Cul (0.80 g, 4.2 mmol) and Cs2C03 (10.26 g, 31.5 mmol) in DMSO (50 mL) was stirred at 120°C for overnight. After filtration, the filtrate was partitioned between EA and water and the aqueous layer was further extracted with EA. The combined organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as a green solid (1.56 g, 39.8 percent yield). MS (m/z): 186.9 (M+H)+.

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YieldReaction ConditionsOperation in experiment
81%
Stage #1: With triethylamine In tetrahydrofuran at 0 - 20℃;
Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃;
Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 ml, 470.7 mmol) were dissolved into THF (800 mL) and cooled to 0° C. 5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL) was added dropwise to the reaction. The reaction was warmed to room temperature and stirred overnight. Reaction was cooled to 0° C. and potassium tert-butoxide (70.43 g, 627.6 mmol) was slowly added. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and then re-dissolved in ethyl acetate (500 mL) and 3N HCl (500 mL), extracted with ethyl acetate (2.x.250 mL), washed with 1N HCl (3.x.250 mL), washed with brine (1.x.250 mL), and dried (Na2SO4). Purification by silica gel chromatography using 0percent-100percentethyl acetate/hexane gradient as eluent to afford 51.03 g (81percent): 1H NMR (CDCl3) δ 7.70 (d, j=8.4 Hz, 2H), 7.03 (d, j=8.8 Hz, 2H), 3.62 (t, j=5.9 Hz, 2H), 2.56 (t, j=5.7 Hz, 2H), 2.50-1.88 (m, 4H) ppm.
81%
Stage #1: With triethylamine In tetrahydrofuran at 0 - 20℃;
Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃;
Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 mL, 470.7 mmol) were dissolved into THF (800 mL) and cooled to 0° C. 5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL) was added dropwise to the reaction. The reaction was warmed to rt and stirred overnight. Reaction was cooled to 0° C. and potassium tert-butoxide (70.43 g, 627.6 mmol) was slowly added. The reaction was warmed to rt and stirred overnight. The reaction was concentrated and then redissolved in ethyl acetate (500 mL) and 3N HCl (500 mL), extracted with ethyl acetate (2×250 mL), washed with 1N HCl (3×250 mL), washed with brine (1×250 mL), and dried (Na2SO4). Purification by silica gel chromatography using 0percent-100percent ethyl acetate/hexane gradient as eluent to afford 51.03 g (81percent): 1H NMR (CDCl3)□ δ 7.70 (d,j=8.4 Hz, 2H), 7.03 (d,j=8.8 Hz, 2H), 3.62 (t,j=5.9 Hz, 2H), 2.56 (t,j=5.7 Hz, 2H), 2.50-1.88 (m, 4H) ppm.
48.5%
Stage #1: With triethylamine In tetrahydrofuran at 0 - 20℃; for 16.5 h;
Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃;
Stage #3: With hydrogenchloride; water In tetrahydrofuran
EXAMPLE 1; l-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxo-l-piperidinyl)phenyl)-4,5,6,7- tetrahydro-lH-pyrazole- [3,4-c] pyridine-3-carboxamide; l-(4-Iodophenyl) piperidin-2-one:; Triethylamine (31.10 g, 307.38 mmol) was added to a solution of 4-iodoaniline (30.0 g, 136.98 mmol) in tetrahydrofuran (80OmL). After cooling the mixture to about 0 0C, a solution of 5- bromo-pentanoyl chloride (32.7g, 163.90 mmol) in tetrahydrofuran (20OmL) was slowly added to the mixture over a period of about 30 minutes. The mixture was stirred at ambient temperature for about 16 hours. The mixture was then cooled to about 0 0C, and potassium tert-butoxide (46.0 g, 410 mmol) was slowly added. The mixture was stirred at ambient temperature for about 18 hours. Evaporation of the solvent in vacuo afforded a thick oily mass which was acidified to a pH of about 2.0 by adding a 3 N hydrochloric acid solution. Following standard extractive workup with ethyl acetate (3 x 500 mL), the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane, 0percent-100percent) to give the title product as an off-white solid (20.0 g, yield = 48.5percent). mp: 108-1100C. 1H NMR (400 MHz, CDCl3) δ 1.93-1.95 (m, 4H), 2.55 (t, J=6.2 Hz, 2H), 3.62 (t, J=5.2 Hz, 2H), 7.02 (d, J= 8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H); IR (KBr) υ 3256, 3049, 2936, 2864, 1634, 1576, 1482, 1434, 1164, 1000, 819, 709 cm"1; MS 302 (M + 1).
Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 22, p. 5339 - 5356
[2] Patent: US2003/232804, 2003, A1, . Location in patent: Page 94
[3] Patent: US2017/50964, 2017, A1, . Location in patent: Paragraph 0699
[4] Patent: WO2010/30983, 2010, A2, . Location in patent: Page/Page column 28
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 4141 - 4147
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 21, p. 5584 - 5589
[3] Patent: WO2015/177801, 2015, A1,
[4] Patent: US2015/353541, 2015, A1,
[5] Patent: CN104513239, 2017, B,
[6] Patent: US2017/313695, 2017, A1,
[7] Patent: WO2017/187245, 2017, A1,
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Reference: [1] Patent: WO2015/177801, 2015, A1,
[2] Patent: WO2015/177801, 2015, A1,
[3] Patent: US2015/353541, 2015, A1,
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Reference: [1] Patent: WO2011/131741, 2011, A1,
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