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[ CAS No. 1195995-72-2 ] {[proInfo.proName]}

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Chemical Structure| 1195995-72-2
Chemical Structure| 1195995-72-2
Structure of 1195995-72-2 * Storage: {[proInfo.prStorage]}
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Product Details of [ 1195995-72-2 ]

CAS No. :1195995-72-2 MDL No. :MFCD09607735
Formula : C11H17BN2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :DCYKWKYBNWRLLZ-UHFFFAOYSA-N
M.W : 220.08 Pubchem ID :45785707
Synonyms :

Safety of [ 1195995-72-2 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P301+P310-P305+P351+P338 UN#:2811
Hazard Statements:H301-H319 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1195995-72-2 ]

* 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.

  • Downstream synthetic route of [ 1195995-72-2 ]

[ 1195995-72-2 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 1195995-72-2 ]
  • [ 1111638-68-6 ]
  • [ 1111637-57-0 ]
YieldReaction ConditionsOperation in experiment
12% With sodium carbonate In 1,2-dimethoxyethane; water at 80℃; for 19h; Microwave irradiation; H-1 Preparation of 4-(1 -isopropyl-3-(1 H-pyrrolo[2,3-b]pyridin-5-yl)-1 H-pyrazol-4-yl)pyridin-2-amine (H-1 -A mixture of the pyrazole H-1-9 (400mg, 1.31mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridin-2-amine (375mg, 1.70mmol), and 1 N sodium carbonate (4ml, 4mmol) in 5 mL of DME was flushed with nitrogen for 5 min. 1 ,1'-Bis(diphenylphospino)ferrocene palladium (II) chloride (96mg, 0.131 mmol) was then added and the mixture was heated in an oil bath. Reaction turned dark within 5min. Heating at 8O0C was continued for an additional 18 hours at which time 150mg more of 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-amine and 25mg more 1 ,1'-bis(diphenylphospino)ferrocene palladium (II) chloride were added. After degassing, the reaction was sealed and placed in microwave for 60 min at 8O0C. The mixture was filtered and the solids rinsed with water and MeOH. The filtrate was partitioned between ethyl acetate and saturated aqueous NaCI. The aqueous layer was extracted with ethyl acetate (2x). The combined organics were washed with water, saturated aqueous NaCI, and dried over MgSO4, and concentrated under vacuum to a crude brown oil (570mg) which was purified by reverse phase HPLC to give 51 mg (12% yield) of H-1 -10 as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J=6.57 Hz, 6 H) 4.45 - 4.65 (s, 1 H) 5.79 (s, 2 H) 6.25 - 6.38 (m, 2 H) 6.45 (dd, J=3.41 , 1.89 Hz, 1 H) 7.40 - 7.55 (m, 1 H) 7.71 - 7.86 (m, 1 H) 7.95 (d, J=2.02 Hz, 1 H) 8.09 (s, 1 H) 8.22 (d, J=1.77 Hz, 1 H) 11.68 (br. s., 1 H).
  • 2
  • [ 1195995-72-2 ]
  • [ 1244027-58-4 ]
  • [ 1244026-80-9 ]
YieldReaction ConditionsOperation in experiment
11% With sodium carbonate In 1,4-dioxane at 140℃; for 1h; Microwave irradiation; 85 A mixture of 6-bromo-2, 2-dimethyl-2, 3- dihydrothieno[3,2-d]pyrimidin-4 (lH)-one (0.039 g, 0.15 mmol), 4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyridin-2- amine (0.022 g, 0.10 mmol), 2 M sodium carbonate (0.075 mL, 0.15 mmol) and 1, 1' -bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (0.024 g, 0.030 mmol) in 1,4-dioxane (0.5 mL) was microwave-irradiated at 1400C for 1 h. Reactions were repeated on 0.10 mmol and 0.20 mmol scales (based on the boronic ester) . The reaction mixtures were combined, and concentrated with silica gel (10 mL) , and the residue was purified by flash chromatography (silica gel, ethyl acetate to 90:10 ethyl acetate/methanol) to give a crude product as a yellow solid, which was further purified by preparative HPLC. Preparative HPLC was carried out on a Varian Prostar 210 HPLC system using a Phenomenex Luna C18(2) column with UV detection at 254 nm and a solvent gradient of 95:5 solvent A/solvent B to 5:95 solvent A/solvent B (solvent A = water with 0.1% v/v trifluoroacetic acid; solvent B = acetonitrile with 0.1% v/v trifluoroacetic acid) . Upon concentration, a TFA salt was obtained, which was dissolved in methanol (10 mL) , and the solution was concentrated with NaHCO3 (0.2 g) and silica gel (1 mL) . Flash chromatography (silica gel, dichloromethane to 85:15 dichloromethane/methanol) gave the title compound (0.012 g, 11%) as a yellow solid:1H NMR (500 MHz, DMSO-d6) δ 1.41 (6H, s) , 6.07 (2H, s) , 6.62 (IH, d, J = 1.0 Hz), 6.72 (IH, dd, J = 5.0, 1.5 Hz), 6.92 (IH, s), 7.07 (IH, s), 7.58 (IH, s) , 7.93 (IH, d, J = 5.5 Hz) .
  • 3
  • [ 1195995-72-2 ]
  • [ 1285513-32-7 ]
  • [ 1285515-55-0 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In 1,4-dioxane at 120℃; for 0.5h; microwave irradiation; Sealed vial; 122 To a microwave vial was added 5-bromo-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzarnide (may be prepared as described in example 2; 200 mg, 0.52 mmol), 1 ,4-dioxane (2 ml), 4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-pyridinamine (201 mg, 0.78 mmol), 1 sodium carbonate (1.04 ml, 1.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (36.2 mg, 0.03 mmol). The vial was sealed and heated to 100°C for 30 minutes under microwave conditions. The mixture was evaporated in vacuo and the residue was purified using the MDAP to yield the title compound. 41 mg.MS (electrospray): m/z [M+H]+ = 3821H NMR (400 MHz, CHLOROFORM-cO 6 ppm 5.32 (2 H, s) 7.23 (1 H, d, J=4.82 Hz) 7.25 - 7.32 (1 H, m) 7.51 - 7.61 (7 H, m) 7.85 (1 H, dd, J=8.55, 2.41 Hz) 7.99 (1 H, d, J=2.63 Hz) 8.12 - 8.19 (1 H, m) 8.29 (1 H, dd, J=4.71 , 1.43 Hz) 8.64 - 8.73 (3 H, m) 10.04 (1 H, s)
  • 4
  • [ 84249-14-9 ]
  • [ 73183-34-3 ]
  • 4-(4,4,5 ,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)pyridin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate; In 1,4-dioxane; at 80℃;Inert atmosphere; equipped with a mechanical stirring three 500mL flask, 30g2--amino-4-bromo-pyridine, 52.8 g as an associated boronic acid pinacol ester, 300mL1,4- dioxane, 4.2gPd (dppf)2Cl2, 59.3g of anhydrous potassium acetate, purged with nitrogen three times, heated to about 80 open overnight.TLC the reaction was complete, cooling, filtration, the filter cake washed twice with 30mL dichloromethane and the filtrate was concentrated to dryness, 200mL of methanol and 20g active carbon was stirred at room temperature overnight, filtration.Concentrated to dryness to give an oil, and petroleum ether was added 15mL 200mL MTBE beating overnight, filtered to give 35g2--aminopyridine-4-boronic acid pinacol ester in 91percent yield.
With potassium acetate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 110℃; for 4h;Inert atmosphere; Example 206 : 1 -(3 -(2- Aminopyridin-4-yl)benzyl)-N-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H- pyrazo lo [3 ,4-d]pyrimidin-6-amineStep (i)<strong>[84249-14-9]2-amino-4-bromopyridine</strong> (0.50g, 2.9mmol), bis(pinacolato)diboron (l . lg, 1.5eq), tris(dibenzylideneacetone)dipalladium (0) (0.13g, 0.05eq), X-phos (0.14g, 0.1 eq) and potassium acetate (0.57mg, 2eq) were mixed in dioxane (2.5ml) under nitrogen before being heated at 110°C for 4h. After cooling to rt, the reaction mixture was diluted with methanol, passed through a thiol cartridge and evaporated to afford 4-(4,4,5,5-tetramethyl-1,3 ,2- dioxaborolan-2-yl)pyridin-2-amine which was used without further purification.
With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 110℃; for 4h;Inert atmosphere; A solution of <strong>[84249-14-9]2-amino-4-bromopyridine</strong> (1.16 mmol, 1.0 equiv), bispinacolata diborane (1.21 mmol, 1.05 equiv), Pd2dba3 (0.035 mmol, 3 mol percent), Xphos (0.185 mmol, 16 mol percent), and KOAc (2.77 mmol, 2.4 mmol) in dioxane, placed in a resealable pressure vessel was degassed through bubbling nitrogen for 40 min then heated at 110 °C for 4 h. A TLC check revealed that all the bromopyridine had been converted to the boronic ester. The reaction was allowed to cool to room temperature, and K3P04 (2.89 mmol, 2.5 equiv), a solution of 23 (0.1 mmol, 0.87 equiv) in dioxanes, an additional 3 mol percent of Pd2dba3 and H20 (1 mL) were added to the reaction. The mixture was degassed for 30 min and heated for 18 h at 1 10 °C. The reaction was cooled to room temperature and extracted with EtOAC (3x30 mL). The combined organic layers were dried over MgS04> filtered through Celite and the solvent was removed in vacuo. Two purifications of the residue by flash chromatography through an ISCO column using CHC13/ MeOH (10:1) provided 60 mg (21percent) of 39 as a colorless oil. 1H NMR (300 MHz, CDC13) delta 1.51-1.71 (m, 5H), 1.90-1.97 (m, 1H), 2.36 (br s, 1H), 2.80-2.85 (dd, J = 3.8, 5.0 Hz, 1H), 3.61 (s, 1H), 3.81 (d, J = 2.7 Hz, 1H), 4.66 (br s, 2H), 6.72 (s, 1H), 6.84 (d, J = 5.3 Hz, 1H), 8.02 (dd, J = 2.3, 9.5 Hz, 1H), 8.11 (s, 1H), 8.13 (d, J = 5.7 Hz,lH); 13CNMR (CDC13) delta 30.2, 31.4, 40.5, 44.3, 56.5, 62.9, 108.1, 113.9, 139.4, 140.6, 143.7, 145.9, 148.5, 157.4, 158.8, 160.6; MS (ESI) m/z 285.5 (M+H)+.
With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; XPhos; In 1,4-dioxane; at 110℃; for 4h;Inert atmosphere; A solution mixture of <strong>[84249-14-9]4-bromopyridin-2-amine</strong> (1 .0 g, 5.78 mmol), bis(pinacolato)diboron (1.6 g, 6.299 mmol) and potassium acetate (1.12 g, 11.42 mmol) in 1,4-dioxane (15 mL) was degassed with argon gas for 15 mi Pd2(dba)3 (265.9 mg, 0.290 mmol) and X-phos (277 mg, 0.580 mmol) were added. The resulting reaction mixture was stirred at 110 °C for 4 h, cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to obtain 500 mg of 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yI)pyridin-2-amine 108-1 as a brown color solid. The crude product was used as such in next step without further purification

  • 5
  • [ 1195995-72-2 ]
  • [ 766515-81-5 ]
  • [ 2650175-54-3 ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate In water at 118℃; for 18h; Inert atmosphere; 4 A solution of 2-amino-4-bromopyridine (1.16 mmol, 1.0 equiv), bispinacolata diborane (1.21 mmol, 1.05 equiv), Pd2dba3 (0.035 mmol, 3 mol %), Xphos (0.185 mmol, 16 mol %), and KOAc (2.77 mmol, 2.4 mmol) in dioxane, placed in a resealable pressure vessel was degassed through bubbling nitrogen for 40 min then heated at 110 °C for 4 h. A TLC check revealed that all the bromopyridine had been converted to the boronic ester. The reaction was allowed to cool to room temperature, and K3P04 (2.89 mmol, 2.5 equiv), a solution of 23 (0.1 mmol, 0.87 equiv) in dioxanes, an additional 3 mol % of Pd2dba3 and H20 (1 mL) were added to the reaction. The mixture was degassed for 30 min and heated for 18 h at 1 10 °C. The reaction was cooled to room temperature and extracted with EtOAC (3x30 mL). The combined organic layers were dried over MgS04> filtered through Celite and the solvent was removed in vacuo. Two purifications of the residue by flash chromatography through an ISCO column using CHC13/ MeOH (10:1) provided 60 mg (21%) of 39 as a colorless oil. 1H NMR (300 MHz, CDC13) δ 1.51-1.71 (m, 5H), 1.90-1.97 (m, 1H), 2.36 (br s, 1H), 2.80-2.85 (dd, J = 3.8, 5.0 Hz, 1H), 3.61 (s, 1H), 3.81 (d, J = 2.7 Hz, 1H), 4.66 (br s, 2H), 6.72 (s, 1H), 6.84 (d, J = 5.3 Hz, 1H), 8.02 (dd, J = 2.3, 9.5 Hz, 1H), 8.11 (s, 1H), 8.13 (d, J = 5.7 Hz,lH); 13CNMR (CDC13) δ 30.2, 31.4, 40.5, 44.3, 56.5, 62.9, 108.1, 113.9, 139.4, 140.6, 143.7, 145.9, 148.5, 157.4, 158.8, 160.6; MS (ESI) m/z 285.5 (M+H)+.
  • 6
  • 4-(4,4,5 ,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)pyridin-2-amine [ No CAS ]
  • [ 24424-99-5 ]
  • [ 1095708-32-9 ]
YieldReaction ConditionsOperation in experiment
98% In tert-butyl alcohol; at 35.0℃; for 18h;Inert atmosphere; 2-Ammopyndmc-4-boromc acid pinacol cstcr (2 0 g 9 1 rnmol) was siirrcd as asuspension in ret t-hutanol 30 mL) undei an aigon atinosphete The Boc anhydride (2 20g, 10.0 mmol) in tert-butanoi (20 mL) was added slowly, and the reaction stirred at 35 Cfor 18 hours. Analysis by H N MR showed the pinacol ester starting material had beenconsumed. The reaction mixture was concentrated under reduced pressure, and the crudematerial stirred in water fur 5 minutes. The solid was collected by filtration and dried in vacuo at 50 C. to afford tert-hutyl 4-(4,4,5,5-tetramethy1- i ,3,2-dioxaborolan-2- yi)pyridin-2-yl)carbamate (31) as a white solid (2.9 g, 98%); mp 172- 178.0C.(Lit. 188193 C). 1H NMR (200 MHz, DMSO-d6) 8 9.75 (hr s, lEO, 8.26 (di 1 H, J 0.9, 4.8 Hz),808(ni lH).,7 l8dd 111 J07 4 8Hz), 147(s 911) 131 (s 1211)
  • 7
  • [ 1195995-72-2 ]
  • [ 1809780-10-6 ]
  • [ 1809779-78-9 ]
YieldReaction ConditionsOperation in experiment
46% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide at 95℃; for 7h; 53 Example 53 N-[5-(2-aminopyridin-4-yl)pyrazin-2-yl]-3-[(4-methylpiperazin-1-yl)acetyl]amino}-4- (trifluoromethoxy)benzamide 80 mg (0.15 mmol) of N-(5-bromopyrazin-2-yI)-3-[(4-methylpiperazin-1-yI)acetyl]amino}-4-(trifluoromethoxy)benzamide (intermediate 57), 51.1 mg (0.23 mmo) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine, 42.8 mg (0.31 mmol) of potassium carbonate and 6.3 mg(7.71 imol) of 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane- complex in 0.13 mL of DMF, 0.53 mL of water and 0.73 mL of DME were stirred for 5 h at 95 °C. 51 mg (0.23 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine were added it was stirred for 2 h at 95 °C. The reaction mixture was allowed to reach rt and concentrated. The residue was purified by HPLC (method 5) to obtain 38 mg (46%) of the title compound.‘H-NMR (400MHz, DMSO-d6): 6 [ppm] = 2.19 (s, 3H), 2.40 (br. s, 4H), 2.60 (br. s, 4H), 3.22 (s, 2H), 6.10 (s, 2H), 7.17 - 7.21 (m, 2H), 7.61 - 7.65 (m, 1H), 7.93 (dd, 1H), 8.04 - 8.06 (m, 1H), 8.94 (d, 1H), 9.03 (d, 1H), 9.50 (d, 1H), 9.95 (s, 1H), 11.48 (s, 1H).LC-MS (Method 3): R = 1.05 mm; MS (ESIpos): m/z = 531 [M+H].
  • 8
  • [ 1195995-72-2 ]
  • [ 1827659-91-5 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
1: 46% 2: 14% With chloro(1,5-cyclooctadiene)rhodium(I) dimer; potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxane; water at 100℃; for 1h; Microwave irradiation; 1.6 Step 6. Preparation of Compound 107 and Compound 115 A mixture I-5 (500 mg, 1.76 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (581 mg, 2.64 mmol), 2,2-bis(diphenylphosphino)-1,1-binapthalene (110 mg, 0.176 mmol), chloro(1,5-cyclooctadiene)rhodium(I) dimer (43 mg, 0.088 mol) and potassium carbonate (121 mg, 0.88 mmol) in dioxane (10 mL) and water (2 mL) was heated in the microwave at 100° C. for 1 h. LCMS shows two peaks with mass M+1, 378, 380; one minor and major. The crude reaction was filtered and the crude compound was purified by HPLC (10 to 70% 0.05% TFA in acetonitrile). The fractions containing the second peak to elute were concentrated under reduced pressure. The resulting residue was taken up in ethyl acetate, washed with 10% aq. sodium bicarbonate, water and brine, dried (Na2SO4), filtered, and concentrated. The resulting residue was taken up in 1:1 water/acetonitrile and was lyophilized to afford Compound 107 (324 mg, 46%) as a white solid. The same was process was performed for the first peak to elute off the HPLC to afford Compound 115 (95 mg, 14%). (0390) Compound 107: LCMS m/z (M+H, 378.1); 1H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.79 (d, J=5.2 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.44 (dd, J=8.9, 2.4 Hz, 1H), 6.39 (dd, J=5.2, 1.5 Hz, 1H), 6.33 (d, J=1.4 Hz, 1H), 5.85 (s, 2H), 4.86 (t, J=5.1 Hz, 1H), 4.54 (d, J=4.6 Hz, 1H), 3.17 (d, J=5.1 Hz, 1H), 2.99 (td, J=5.2, 1.5 Hz, 1H), 1.78-1.46 (m, 4H). (0391) Compound 115 LCMS (M+H, 378.0); 1H NMR (400 MHz, DMSO) δ 9.51 (s, 1H), 7.50 (d, J=5.3 Hz, 1H), 7.45 (d, J=2.3 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.00 (dd, J=8.8, 2.4 Hz, 1H), 6.32 (d, J=5.5 Hz, 2H), 5.56 (s, 2H), 4.78 (d, J=3.5 Hz, 1H), 4.38 (d, J=3.9 Hz, 1H), 3.14 (d, J=9.8 Hz, 1H), 3.05 (d, J=9.6 Hz, 1H), 1.57 (ddq, J=17.7, 6.8, 4.1, 3.1 Hz, 4H).
  • 9
  • [ 1195995-72-2 ]
  • [ 1052715-02-2 ]
  • [ 76-05-1 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
60% Stage #1: 4-(4,4,5 ,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)pyridin-2-amine; 3-amino-N-(4-chloropyridin-3-yl)-6-(2,6-difluorophenyl)picolinamide With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,4-dioxane at 120℃; for 0.166667h; Microwave irradiation; Stage #2: trifluoroacetic acid In water; dimethyl sulfoxide; acetonitrile for 0.166667h; Synthesis of 3-amino-N-(2'-amino-[4,4'-bipyridin]-3-yl)-6-(2,6-difluorophenyl)picolinamide (2g) A solution of 3-amino-N-(4-chloropyridin-3-yl)-6-(2,6-difluorophenyl)picolinamide (1.0 equiv.), Pd(dppf)Cl2-DCM (0.10 equiv.), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (3.0 equiv.) indioxane/2M Na2CO3 (3:1, 0.19 M) was stirred in the microwave for 10 min at 120 °C. The organic phase was separated, dried with sodium sulfate, filtered, and concentrated under vacuo. The crude material was dissolved in DMSO and purified via prep-HPLC (reverse phase) and the pure fractions were lyophilized to give 3-amino-N-(2'-amino-[4,4'-bipyridin]-3-yl)-6-(2,6-difluorophenyl)picolinamide(2g) as the corresponding TFA salt in 60% yield. LCMS (m/z): 419.1 (M+); LC Rt = 2.09 min.
  • 10
  • 4-(4,4,5 ,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)pyridin-2-amine [ No CAS ]
  • [ 207799-10-8 ]
  • tert-butyl (2'-amino-[4,4'-bipyridin]-2-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 110℃; for 2h;Inert atmosphere; Sealed tube; Step a. A mixture of <strong>[207799-10-8]tert-butyl (4-bromopyridin-2-yl)carbamate</strong> (0.19 g, 0.68 mmol) in 1,4- dioxane : water (8:2) (10 ml) was prepared in a glass vial. The reaction mixture was degassed for 15 min. 2-Aminopyridine-4-boronic acid pinacol ester (0.15 g, 0.68 mmol) and K3PO4 (0.43 g, 2.04 mmol) were added to the reaction mixture at rt. The reaction mixture was degassed again for 15 min. Pd(dppf)Ci2 (0.024 g, 0.034 mmol). The glass vial was sealed and subjected to heating at 110C (external temperature) for 2 h. The resulting reaction mixture was combined with one other batch on the same scale prepared by an identical method, poured into water (50 ml) and extracted with EtOAc (2 x 30 ml). The combined organic phase was washed with brine (20 ml), dried over Na2SC>4, filtered and concentrated under reduced pressure yielding tert-butyl (2'-amino-[4,4'-bipyridin]-2-yl)carbamate (0.50 g, quantitative). LCMS: Method A, 1.71 min, MS: ES+ 287.48.
  • 11
  • [ 1195995-72-2 ]
  • [ 1636895-41-4 ]
  • [ 1636900-00-9 ]
YieldReaction ConditionsOperation in experiment
40% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In water; N,N-dimethyl-formamide at 90℃; for 2h; Inert atmosphere; O 4-([4-(2-acetamidopyridin-4-yl)pyridin-2-yl](pyrazin-2-yl)amino}methyl)-N-hydroxybenzamide To a suspension of (4) (200mg, 0.50mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2-amine (132.3mg, 0.6mmol) and Cs2C03 (326mg, lOmmol) in DMF (4m L) and H20 (1 mL) was added Pd(PPh3)4 (58mg, 0.05mmol). The mixture was flushed with N2(g) then it was heated up to 90°C for 2h. Once cooled down, H20 (20ml_) was added and a precipitate was left to settle at rt for 3h. After filtration, washings with H20 (2ml_) and drying, a pale orange solid was obtained, which was purified by flash column chromatography with heptane/EtOAc (4: 1-0: 1) then EtOAc/MeOH (1 :0-7:3) to give (5) (82mg, 40%) as a yellow solid. 1 H NMR (500 MHz, Methanol-cf4), δΗ ppm: 8.60 (s, 1 H), 8.41 (d, J=5.2 Hz, 1 H), 8.29 (d, J=1.3 Hz, 1 H), 8.06 (d, J=2.5 Hz, 1 H), 7.97 (d, J^5.4 Hz, 1 H), 7.93 (d, J^8.3 Hz, 2H), 7.53 (s, 1 H), 7.49 (d, J=8.1 Hz, 2H), 7.34 (d, J^5.2 Hz, 1 H), 6.81-6.84 (m, 1 H), 6.81 (s, 1 H), 5.58 (s, 2H), 3.86 (s, 3H). LCMS (ES): Found 413.0 [M+H]+.
40% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In water; N,N-dimethyl-formamide at 90℃; for 2h; Inert atmosphere; SS To a suspension of (4) (200mg, 0.50mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyhdin-2-amine (132.3mg, 0.6mmol) and Cs2C03 (326mg, LOmmol) in DMF (4ml_) and H20 (1 mL) was added Pd(PPh3)4 (58mg, 0.05mmol). The mixture was flushed with N2(g) then it was heated up to 90°C for 2h. Once cooled down, H20 (20ml_) was added and a precipitate was left to settle at rt for 3h. After filtration, washings with H20 (2ml_) and drying, a pale orange solid was obtained, which was purified by flash column chromatography with heptane/EtOAc (4:1 -0:1 ) then EtOAc/MeOH (1 :0-7:3) to give (5) (82mg, 40%) as a yellow solid. 1 H NMR (500 MHz, Methanol-d4), δΗ ppm: 8.60 (s, 1 H), 8.41 (d, J=5.2 Hz, 1 H), 8.29 (d, J=1 .3 Hz, 1 H), 8.06 (d, J=2.5 Hz, 1 H), 7.97 (d, J=5.4 Hz, 1 H), 7.93 (d, J=8.3 Hz, 2H), 7.53 (s, 1 H), 7.49 (d, J=8.1 Hz, 2H), 7.34 (d, J=5.2 Hz, 1 H), 6.81 - 6.84 (m, 1 H), 6.81 (s, 1 H), 5.58 (s, 2H), 3.86 (s, 3H). LCMS (ES): Found 413.0 [M+H]+.
  • 12
  • [ 1195995-72-2 ]
  • [ 1915037-92-1 ]
  • [ 1915037-95-4 ]
YieldReaction ConditionsOperation in experiment
46% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In water; N,N-dimethyl-formamide at 90℃; for 2h; Inert atmosphere; Q 4-([4-(2-aminopyridin-4-yl)pyridin-2-yl](pyrazin-2-yl)amino}methyl)-3-fluoro-N-hydroxybenzamide To a suspension of (4) (700mg, 1.7mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2-amine (720mg, 3.27mmol) and Cs2C03 (1.1 g, 3.4mmol) in DMF (14ml_) and H20 (3.5mL) was added Pd(PPh3)4 (194mg, 0.17mmol). The reaction mixture was flushed with Ar(g) and heated up to 90°C for 2h. Once cooled down, it was partitioned between H20 (50ml_) and EtOAc (3 x 50ml_). The combined organic extracts were washed with brine (30ml_), dried over Na2S04, filtered and concentrated in vacuo. Purification by flash column chromatography with CH2CI2/MeOH (1 :0-19:1) yielded (5) (340mg, 46%) as a yellow oil. 1 H NMR (400 MHz, Chloroform-cO, δΗ ppm: 8.70 (m, 1 H), 8.42 (d, J^5.2 Hz, 1 H), 8.23 (m, 1 H), 8.15 (d, J^5.3 Hz, 1 H), 8.1 1 (d, J=2.5 Hz, 1 H), 7.69-7.71 (m, 2H), 7.40 (t, J^7.6 Hz, 1 H), 7.35 (m, 1 H), 7.16 (d, J=5.1 Hz, 1 H), 6.79 (d, J^5.2 Hz, 1 H), 6.62 (s, 1 H), 5.59 (s, 2H), 5.30 (m, 1 H), 4.57 (m, 1 H), 3.89 (s, 3H). LCMS (ES): Found 431.1 [M+H]+.
  • 13
  • [ 1195995-72-2 ]
  • [ 1349875-75-7 ]
  • [ 1931096-85-3 ]
YieldReaction ConditionsOperation in experiment
83% With potassium phosphate In 1,4-dioxane at 20℃; for 0.25h; Inert atmosphere; Synthesis of 4-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)pyridin-2-amine A suspension of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.0 g, 4.54 mmol), 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (2.365 g, 9.09 mmol) and tripotassium phosphate (2.89 g, 13.63 mmol) in 1,4-Dioxane (30 mL) stirred and degassed with argon at room temp for 15 mins.PdCl2(dppf)-CH2Cl2 adduct (0.186 g, 0.227 mmol) was added to the reaction mixture. Then the reaction mixture was stirred 4 hr at 90 °C. The reaction was monitored by TLC. The reaction mixture was cooled to room temp and filtered through celite and washed with EtOAc (20 ml). Take filtrate and concentrated and dissolved with EtOAc (20 ml). EtOAc layer washed with water (10 ml) followed by brine solution (10 ml) and dried out with Na2S04, filtered and concentrated to get crude product. The crude product was purified by column chromatography using neutral alumina and was eluted with 100% DCM (gradient system) to afford the desired product 4-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)pyridin-2-amine (0.8 g, 3.79 mmol, 83 % yield) as a brown solid, LCMS (m/z): 205.2 [M+H]+.
  • 14
  • [ 107-20-0 ]
  • 4-(4,4,5 ,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)pyridin-2-amine [ No CAS ]
  • [ 908268-52-0 ]
YieldReaction ConditionsOperation in experiment
65% In ethanol; at 70℃; for 20h; In the three 500mL flask, 35g2- amino-4-boronic acid pinacol ester, 45.7 g of chloroacetaldehyde (40% aqueous solution), 350 mL of ethanol.It was heated at reflux for about 4 hours.By TLC, the reaction was complete, saturated aqueous sodium bicarbonate added directly to PH = alkali to about 8, 20mL of ethyl acetate was added, stirred for 3 hours a large number of solid precipitation, filtration, solid was slurried twice with ethyl acetate, to give the product imidazo [1,2-a] pyridine-7-boronic acid pinacol ester 26g, yield 67.3%
  • 15
  • [ 1195995-72-2 ]
  • [ 2107434-21-7 ]
  • [ 2107434-34-2 ]
YieldReaction ConditionsOperation in experiment
30% With palladium diacetate; potassium carbonate; tricyclohexylphosphine In 1,2-dimethoxyethane; water at 100℃; for 1.5h; To a solution of 1-48 (450 mg, 0.85 mmol), R-6 (374 mg, 1.7 mmol), tricyclohexylphosphine (48 mg, 0.17 mmol), and potassium carbonate (350 mg, 2.5 mmol) in DME (12 mL) and water (3 mL) is added palladium acetate (19 mg, 0.085 mmol). The mixture is heated at 100°C for 1.5 h then volatiles are removed in vacuo. The residue is extracted with EtOAc, washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography (S1O2, 0-5%MeOH in CH2C12) to give 1-53 (140 mg, 30%) m/z 543.3 [M+].
  • 16
  • [ 1195995-72-2 ]
  • [ 2107433-40-7 ]
  • [ 2107433-92-9 ]
  • [ 2107433-66-7 ]
YieldReaction ConditionsOperation in experiment
1: 39% 2: 53% With palladium diacetate; potassium carbonate; tricyclohexylphosphine In 1,2-dimethoxyethane; water at 100℃; for 1h; To a solution of 1-12 (800 mg, 1.3 mmol), R-6 (330 mg, 1.5 mmol), tricyclohexylphosphine (71 mg, 0.26 mmol), and potassium carbonate (350 mg, 2.5 mmol) in DME (8 mL) and water (2 mL) is added palladium acetate (29 mg, 0.13 mmol). The mixture is heated at 100°C for 1 h then cooled to ambient temperature and triturated with water (15 mL). The solid is filtered, rinsed with water (10 mL), collected and dried then purified by flash chromatography (Si02, EtOAc) to give 1-23 (280 mg, 53%) m/z 697.4 [M+H] and 1-33 (260 mg, 39%) m/z 527.3 [M+H]. 1-33 (260 mg) is dissolved in CH2C12 (10 mL) and treated with a 4.0M solution of HCl in dioxane (5 mL). The mixture is stirred for 1 h at ambient temperature then concentrated in vacuo to afford 1-34 (230 mg, 99%) m/z All.2 [M+H].
  • 17
  • [ 1195995-72-2 ]
  • [ 2183464-39-1 ]
  • [ 2183565-49-1 ]
YieldReaction ConditionsOperation in experiment
42% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; ethanol; water at 90 - 95℃; for 3h; Inert atmosphere; General procedure- 10: Generation the oxazolidinone analogs General procedure: A mixture of the desired aryl boronic ester/ or acid (1 mmol) and the desired aryl bromide (1 mmol), Pd(dppf)2Cl2 (0.05 mmol) and K2CO3 (4 mmol) in dioxane (3 mL), EtOH (1 mL) and H2O ( 1 mL) was added to a nitrogen purged 25 mL flask. The mixture was heated to 90-95 °C and stirred for 3 hrs. Then cooled to room temperature, filtrated and evaporated to dryness. Then the crude was dissolved in DMF (1 mL), and then it was purified by reversed phase column chromatography on prep- HPLC using gradient of (water/acetonitrile/ 0.1 %TFA). Those fractions containing pure product were pooled and lyophilized to give the pure products.
  • 18
  • [ 1195995-72-2 ]
  • [ 1636895-41-4 ]
  • [ 1636895-45-8 ]
YieldReaction ConditionsOperation in experiment
40% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In water; N,N-dimethyl-formamide at 90℃; for 2h; Inert atmosphere; SS Example SS (0588) 4-([5-(2-Aminopyridin-4-yl)pyridin-2-yl](pyrazin-2-yl)amino}methyl)-N- (0589) (0590) To a suspension of (4) (200mg, 0.50mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2-amine (132.3mg, 0.6mmol) and Cs2C03 (326mg, I .Ommol) in DMF (4ml_) and H20 (1 ml_) was added Pd(PPh3)4 (58mg, 0.05mmol). The mixture was flushed with N2(g) then it was heated up to 90°C for 2h. Once cooled down, H20 (20mL) was added and a precipitate was left to settle at rt for 3h. After filtration, washings with H20 (2ml_) and drying, a pale orange solid was obtained, which was purified by flash column chromatography with heptane/EtOAc (4: 1-0: 1) then EtOAc/MeOH (1 :0-7:3) to give (5) (82mg, 40%) as a yellow solid. 1 H NMR (500 MHz, Methanol-d4), δΗ ppm: 8.60 (s, 1 H), 8.41 (d, J=5.2 Hz, 1 H), 8.29 (d, J=1.3 Hz, 1 H), 8.06 (d, J=2.5 Hz, 1 H), 7.97 (d, J=5.4 Hz, 1 H), 7.93 (d, J=8.3 Hz, 2H), 7.53 (s, 1 H), 7.49 (d, J=8.1 Hz, 2H), 7.34 (d, J=5.2 Hz, 1 H), 6.81-6.84 (m, 1 H), 6.81 (s, 1 H), 5.58 (s, 2H), 3.86 (s, 3H). (0591) LCMS (ES): Found 413.0 [M+H]+.
  • 19
  • [ 1195995-72-2 ]
  • [ 2173353-51-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
97% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate In 1,4-dioxane; water at 120℃; for 6h; 10.A; 11A To a mixture of degassed 1 ,4-dioxane (8.7 mL) and water (2 mL) in a microwave vial was added [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloro- methane (0.017 g, 0.02 mmol), followed by the title compound from Preparative Example B (0.2 g, 0.4 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-2-amine (0.110 g, 0.5 mmol) and cesium carbonate (0.272 g, 0.84 mmol). The reaction mixture was then heated at ~120°C in a sand-bath for 6 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and water (40 mL), the organic phase separated, dried over Na2S04, filtered and the solvents evaporated in vacuo. The dark residue was purified by chromatography on silica (25 g puriFlash, Interchim) using a Biotage Isolera system employing dichloromethane/methanol gradient (100/0 -> 97/3 -> 95/5 -> 95/5) to afford the title compound as off-white solid (0.2 g, 97 %). 1H-NMR (400 MHz, CDCI3) δ = 9.26 (s, 1 H); 8.40 (d, 1H), 8.30 (d, 1H), 8.01 (d, 1 H), 7.73 (d, 1H), 7.65-7.59 (m, 5H), 7.31-7.24 (m, 10H), 6.98 (dd, 1H), 6.67 (d, 1 H), 6.43 (d, 1 H), 4.80 (br-s, 2H)
  • 20
  • [ 65370-42-5 ]
  • [ 73183-34-3 ]
  • 4-(4,4,5 ,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)pyridin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% Under nitrogen protection, 550 mL of dioxane, <strong>[65370-42-5]2-nitro-4-chloropyridine</strong> (15.8 g, 0.10 mol) and pinacol borate (25.4 g, 0.10 mol) were sequentially added to the reaction flask. After stirring potassium acetate (14.7 g, 0.15 mol), Finally, the catalyst PdCl2dppf (0.74 g, 0.001 mol) was added, and the temperature was slowly raised to 80-90 C, and the reaction was stirred for 2-3 h. After the completion of the GC reaction, the reaction was stopped by cooling, and the reaction solution was filtered through celite to obtain a dark-black reaction solution. After charging at 1 atm of hydrogen, the mixture was reacted at room temperature overnight. After the reaction was completed, the activated carbon was decolorized, and the filtrate was distilled under reduced pressure until no liquid was poured. /Heptane mixed solvent is cooled and beaten for half an hour, filtered to obtain a light gray crude product, heated again with ethanol, and then cooled down, and the filter cake is rinsed with -20 C anhydrous ethanol, and dried to obtain 16.5 g of an off-white solid. 75%, HPLC purity 99.1%,
  • 21
  • [ 1195995-72-2 ]
  • [ 2275776-52-6 ]
  • [ 2275774-89-3 ]
YieldReaction ConditionsOperation in experiment
61% With chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); potassium carbonate; XPhos In 1,4-dioxane at 80℃; for 1h; Inert atmosphere; Sealed tube; 165 Example 165 (6S)-5-[4-(2-Aminopyridin-4-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4- oxadiazin-2-one (6S)-5-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2- one (97%, 200 mg, 0.66 mmol, Intermediate 74), 2-aminopyridine-4-boronic acid pinacol ester (219 mg, 0.66 mmol),2-(Dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl [XPhos] (19 mg, 39.78 Mmol) and K2C03 (0.88 mL, 1.33 mmol) were stirred in 1,4- Dioxane (2.65 mL). The mixture was thouroughly degassed with nitrogen for 5 mins. Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1 '-biphenyl)[2-(2'-amino-1,1 '- biphenyl)]palladium(ll), X-Phos aminobiphenyl palladium chloride precatalyst [XPhos-Pd- G2] (31 mg, 19.89 Mmol) was then added and the resulting mixture was heated in a sealed tube at 80 for 1 h. The mixture was allowe d to cool to RT then was diluted with EtOAc (10 mL) and washed with brine (10 mL). The aqueous layer was washed with EtOAc (10 mL), the organics combined, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by Biotage Isolera chromatography (10 g KP-Sil, eluting with heptanes-EtOAc, 1 :0 to 0:1) to afford the title compound (146.3 mg, 61 %, 97% purity) as a beige solid. LCMS (Method 4, 7 min) Rt= 1.33 min, MS (ESIPos): m/z = 351.1 (M+H)+ 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1 1.32 (s, 1H), 8.14 (d, 1H), 8.04 (dd, 1H), 7.95 (d, 1H), 7.49 (d, 1H), 6.43 (d, 1H), 6.36 (s, 1H), 6.10 (s, 2H), 6.00-5.86 (m, 1H), 1.46 (d, 3H)
  • 22
  • 4-(4,4,5 ,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)pyridin-2-amine [ No CAS ]
  • [ 6840-45-5 ]
  • 4-(imidazo[1,2-a]pyrimidin-3-yl)pyridin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 16h;Inert atmosphere; Sealed tube; A mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.0g, 4.54mmol), 3-bromoimidazo[1 ,2-a]pyrimidine (899mg, 4.54mmol) and Na2C03 (963mg, 9.09mmol) in DMF:H20 (3: 1 , 20ml_) was degassed with N2 for 15 min at rt. Pd(PPh3)4 (525mg, 0.45mmol) was added to this degassed mixture at rt. The reaction mixture was again purged with N2 for 5 min. The reaction vessel was sealed and stirred at 90 C for 16h. The TLC showed reaction to be complete. The reaction mixture was allowed to cool to rt and concentrated under reduced pressure. The crude residue was triturated with MeOH (25ml_) and the precipitated solid was filtered through the sintered funnel. The filtrate was concentrated under reduced pressure. The residue was purified by combiflash chromatography using 12g silica column, eluting with 10% MeOH in DCM to afford 4-(imidazo[1 ,2-a]pyrimidin-3- yl)pyridin-2-amine as a brown solid. Yield: 500mg (51 %); MS (ESI+) for CHNOS m/z 212.0[M+H]+; 1 H NMR (400 MHz, DMSO-d6): <5 8.96-9.05 (m, 1 H), 8.55-8.61 (m, 1 H), 8.40 (s, 1 H), 7.94-8.01 (m, 1 H), 6.98-7.15 (m, 3H), 6.05-6.15 (bs, 2H).
  • 23
  • [ 1195995-72-2 ]
  • [ 2766756-43-6 ]
  • [ 2570464-02-5 ]
YieldReaction ConditionsOperation in experiment
41% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 95℃; for 12h; Inert atmosphere; 3-(3-fluorobenzyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)thieno[2,3-d]pyrimidin-4(3H)-one (10a) General procedure: Intermediate 9a (40 mg, 0.118 mmol), K2CO3 (49 mg, 0.354 mmol), Pd(PPh3)4 (27 mg, 0.024 mmol), and 7-azaindole-4-boronic acid pinacol ester (29 mg, 0.118 mmol) were stirred in 1,4-dioxane and water (6 mL, v/v, 5/1) and heated at 95 °C for 12 h under nitrogen protection. The mixture was filtrated and subsequently evaporated. The residue was puried by chromatography (petroleum ether/ethyl acetate, 1/5) to generate target compound as a pale yellow solid in 37% yield.
  • 24
  • [ 1195995-72-2 ]
  • [ 2766756-44-7 ]
  • [ 2570464-03-6 ]
YieldReaction ConditionsOperation in experiment
44% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 95℃; for 12h; Inert atmosphere; 3-(3-fluorobenzyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)thieno[2,3-d]pyrimidin-4(3H)-one (10a) General procedure: Intermediate 9a (40 mg, 0.118 mmol), K2CO3 (49 mg, 0.354 mmol), Pd(PPh3)4 (27 mg, 0.024 mmol), and 7-azaindole-4-boronic acid pinacol ester (29 mg, 0.118 mmol) were stirred in 1,4-dioxane and water (6 mL, v/v, 5/1) and heated at 95 °C for 12 h under nitrogen protection. The mixture was filtrated and subsequently evaporated. The residue was puried by chromatography (petroleum ether/ethyl acetate, 1/5) to generate target compound as a pale yellow solid in 37% yield.
  • 25
  • [ 1195995-72-2 ]
  • [ 2580939-18-8 ]
  • [ 2570464-04-7 ]
YieldReaction ConditionsOperation in experiment
42% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 95℃; for 12h; Inert atmosphere; 3-(3-fluorobenzyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)thieno[2,3-d]pyrimidin-4(3H)-one (10a) General procedure: Intermediate 9a (40 mg, 0.118 mmol), K2CO3 (49 mg, 0.354 mmol), Pd(PPh3)4 (27 mg, 0.024 mmol), and 7-azaindole-4-boronic acid pinacol ester (29 mg, 0.118 mmol) were stirred in 1,4-dioxane and water (6 mL, v/v, 5/1) and heated at 95 °C for 12 h under nitrogen protection. The mixture was filtrated and subsequently evaporated. The residue was puried by chromatography (petroleum ether/ethyl acetate, 1/5) to generate target compound as a pale yellow solid in 37% yield.
  • 26
  • [ 1195995-72-2 ]
  • [ 2580939-50-8 ]
  • [ 2570464-05-8 ]
YieldReaction ConditionsOperation in experiment
52% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 95℃; for 12h; Inert atmosphere; 3-(3-fluorobenzyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)thieno[2,3-d]pyrimidin-4(3H)-one (10a) General procedure: Intermediate 9a (40 mg, 0.118 mmol), K2CO3 (49 mg, 0.354 mmol), Pd(PPh3)4 (27 mg, 0.024 mmol), and 7-azaindole-4-boronic acid pinacol ester (29 mg, 0.118 mmol) were stirred in 1,4-dioxane and water (6 mL, v/v, 5/1) and heated at 95 °C for 12 h under nitrogen protection. The mixture was filtrated and subsequently evaporated. The residue was puried by chromatography (petroleum ether/ethyl acetate, 1/5) to generate target compound as a pale yellow solid in 37% yield.
  • 27
  • [ 1195995-72-2 ]
  • [ 2766756-45-8 ]
  • [ 2570464-06-9 ]
YieldReaction ConditionsOperation in experiment
55% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 95℃; for 12h; Inert atmosphere; 3-(3-fluorobenzyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)thieno[2,3-d]pyrimidin-4(3H)-one (10a) General procedure: Intermediate 9a (40 mg, 0.118 mmol), K2CO3 (49 mg, 0.354 mmol), Pd(PPh3)4 (27 mg, 0.024 mmol), and 7-azaindole-4-boronic acid pinacol ester (29 mg, 0.118 mmol) were stirred in 1,4-dioxane and water (6 mL, v/v, 5/1) and heated at 95 °C for 12 h under nitrogen protection. The mixture was filtrated and subsequently evaporated. The residue was puried by chromatography (petroleum ether/ethyl acetate, 1/5) to generate target compound as a pale yellow solid in 37% yield.
  • 28
  • [ 1195995-72-2 ]
  • [ 2570464-13-8 ]
  • [ 2570464-00-3 ]
YieldReaction ConditionsOperation in experiment
42% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In 1,4-dioxane; water at 95℃; for 12h; Inert atmosphere; 3-(3-methoxybenzyl)-6-(1H-indazol-5-yl)thieno[2,3-d]pyrimidin-4(3H)-one (8a) General procedure: Intermediate 7 (45 mg, 0.128 mmol), Cs2CO3 (125 mg, 0.384 mmol), Pd(PPh3)4 (44 mg, 0.038 mmol), and 1H-indazole-5-boronic acid pinacol ester (31 mg, 0.128 mmol) were stirred in 1,4-dioxane and water (6 mL, v/v, 5/1) at RT and then heated at 95 °C for 12 h under nitrogen protection. The mixture was filtrated and the solvent was evaporated. The residue was puried by chromatography (petroleum ether/ethyl acetate, 1/3) to generate title compound as a pale yellow solid in 21% yield.
  • 29
  • [ 1195995-72-2 ]
  • [ 2410299-38-4 ]
  • [ 2410298-15-4 ]
YieldReaction ConditionsOperation in experiment
35% With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In 1,4-dioxane; water at 140℃; for 0.666667h; Inert atmosphere; Microwave irradiation; I.3 Scheme 36, Step 3 A 2-5 mL Biotage microwave vial loaded with 4-(4-(6-bromo-7-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)phenyl)morpholine 127-B (55 mg, 0.141 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (34.1 mg, 0.155 mmol), Pd(PPh3)4 (13 mg, 0.011 mmol), and NaHCO3 (47.4 mg, 0.564 mmol), was capped, purged with argon, then injected with degassed dioxane: H2O (0.78 mL: 0.157 mL, 5:1 v/v), and heated to 140° for 40 min in a Biotage Microwave Reactor. The reaction was cooled, diluted with DCM, filtered through celite, concentrated, dryloaded onto silica gel and purified on a 12 g silica gel column (DCM/MeOH, 0-10%), affording 4-(7-fluoro-2-methyl-1-(4-morpholinophenyl)-1H-benzo[d]imidazol-6-yl)pyridin-2-amine 127 as a tan solid (20 mg, 0.050 mmol, 35% yield, 10% MeOH in DCM). 1H NMR (DMSO) δ: 7.93 (d, J=5.3 Hz, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.29 (t, J=8.5, 7.7 Hz, 1H), 7.09 (d, J=8.7 Hz, 2H), 6.67-6.56 (m, 2H), 5.94 (s, 2H), 3.88-3.69 (m, 4H), 3.28-3.19 (m, 4H), 2.36 (s, 3H).
  • 30
  • [ 1195995-72-2 ]
  • [ 2410299-40-8 ]
  • [ 2410298-16-5 ]
YieldReaction ConditionsOperation in experiment
86% With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In 1,4-dioxane; water at 140℃; for 0.833333h; Inert atmosphere; Microwave irradiation; I.3 Scheme 37, Step 3 A 2-5 mL Biotage microwave vial loaded with 4-(4-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyrazin-1-yl)phenyl)morpholine 9-1 (55 mg, 0.147 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 128-B (35.6 mg, 0.162 mmol), Pd(PPh3)4 (13.59 mg, 0.012 mmol), and NaHCO3 (49.4 mg, 0.588 mmol), was capped, purged with argon, then injected with degassed dioxane: H2O (1.225 mL: 0.245 mL, 5:1 v/v), and heated to 140° for 50 min in a Biotage Microwave Reactor. The reaction was cooled, diluted with DCM, filtered through celite, concentrated, dryloaded onto silica gel and purified on a 12 g silica gel column (DCM/MeOH, 0-20%), affording 4-(2-methyl-1-(4-morpholinophenyl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridin-2-amine 128 as a white solid (49 mg, 0.126 mmol, 86% yield, 10% MeOH in DCM). 1H NMR (CDCl3) δ: 8.99 (s, 1H), 8.17 (d, J=5.4 Hz, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.26 (d, J=5.5 Hz, 1H), 7.18-7.07 (m, 3H), 4.57 (s, 2H), 4.11-3.84 (m, 4H), 3.47-3.10 (m, 4H), 2.68 (s, 3H).
  • 31
  • [ 1195995-72-2 ]
  • [ 2410299-41-9 ]
  • [ 2410298-18-7 ]
YieldReaction ConditionsOperation in experiment
55% With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In 1,4-dioxane; water at 140℃; for 1h; Inert atmosphere; Microwave irradiation; I.3 Scheme 38, Step 3 A 2-5 mL Biotage microwave vial loaded with 1-(1H-benzo[d]imidazol-5-yl)-6-bromo-2-methyl-1H-imidazo[4,5-b]pyrazine 130-B (50 mg, 0.122 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (29.4 mg, 0.134 mmol), Pd(PPh3)4 (11.23 mg, 0.00972 mmol), and NaHCO3 (40.8 mg, 0.486 mmol), was capped, purged with argon, then injected with degassed dioxane: H2O (1 mL: 0.2 mL, 5:1 v/v), and heated to 140° for 1 h in a Biotage Microwave Reactor. The reaction was cooled, diluted with DCM, filtered through celite, concentrated, dryloaded onto silica gel and purified on a 12 g silica gel column (DCM/MeOH, 0-20%), affording 4-(1-(1H-benzo[d]imidazol-5-yl)-2-methyl-1H-imidazo[4,5-b]pyrazin-6-yl)pyridin-2-amine 130 as a white solid (21 mg, 0.067 mmol, 55% yield, 20% MeOH in DCM) 1H NMR (DMSO) δ: 12.85 (bs, 1H), 9.04 (s, 1H), 8.43 (s, 1H), 7.98 (d, J=5.5 Hz, 1H), 7.92 (bs, 1H), 7.83 (bs, 1H), 7.43 (dd, J=8.4, 2.0 Hz, 1H), 7.14 (dd, J=5.5, 1.6 Hz, 1H), 7.03 (s, 1H), 6.15 (bs, 2H), 2.56 (s, 3H).
  • 32
  • [ 1195995-72-2 ]
  • [ 2639959-09-2 ]
  • [ 2639958-07-7 ]
YieldReaction ConditionsOperation in experiment
58% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 80℃; for 2h; Inert atmosphere; 82 Example 82: (3S)-N-[3-(2'-amino-6-[[(2R)-1-hydroxypropan-2-yl]amino]-[2,4'-bipyridin]-4- yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide To a stirred mixture of (3S)-N-[3-(2-chloro-6-[[(2R)-1-hydroxypropan-2-yl]amino]pyridin-4- yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (150 mg, 0.319 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (84 mg, 0.382 mmol) and K2CO3(88 mg, 0.637 mmol) in dioxane (2 ml) and H2O (0.5 ml) was added Pd(PPh3)4 (37 mg, 0.032 mmol). The reaction mixture was stirred for 2 h at 80 °C under N2 atmosphere. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (3 x 40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA/PE/EtOH = 12/3/1). The fractions containing the desired product were collected and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with CH3CN in water (with 10 mmol/mL NH4HCO3). The fractions containing the desired product were collected and concentrated under reduced pressure to afford (3S)-N-[3-(2'-amino-6- [[(2R)-1-hydroxypropan-2-yl]amino]-[2,4'-bipyridin]-4-yl)-4-methylphenyl]-3-(2,2,2- trifluoroethyl)pyrrolidine-1-carboxamide (101 mg, 58%) as a white solid. MS ESI calculated for C27H31F3N6O2[M + H]+, 529.25, found 529.30;1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.95 (dd, J = 5.2, 0.8 Hz, 1H), 7.51-7.42 (m, 2H), 7.19-7.07 (m, 3H), 6.90 (d, J = 1.2 Hz, 1H), 6.51-6.44 (m, 2H), 5.91 (s, 2H), 4.75 (t, J = 5.5 Hz, 1H), 4.14 (p, J = 6.4 Hz, 1H), 3.67 (dd, J = 10.2, 6.9 Hz, 1H), 3.59-3.50 (m, 2H), 3.40 (dt, J = 10.4, 5.9 Hz, 1H), 3.29 (d, J = 6.7 Hz, 1H), 3.03 (t, J = 9.4 Hz, 1H), 2.49-2.36 (m, 3H), 2.21 (s, 3H), 2.13-2.05 (m, 1H), 1.66 (p, J = 10.1 Hz, 1H), 1.20 (d, J = 6.6 Hz, 3H).
  • 33
  • [ 1195995-72-2 ]
  • [ 2765167-01-7 ]
  • [ 2765166-55-8 ]
YieldReaction ConditionsOperation in experiment
74% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate In 1,4-dioxane; water monomer at 80℃; for 16h; Inert atmosphere; 40 Example 40: (3S)-N-[3-[2'-amino-6-(morpholin-4-yl)-[2,4'-bipyridin]-4-yl]-4- methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (109 mg, 0.497 mmol), (3S)-N-[3-[2-chloro-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2- trifluoroethyl)pyrrolidine-1-carboxamide (120 mg, 0.248 mmol), Pd(dppf)Cl2.CH2Cl2 (20 mg, 0.025 mmol) and K2CO3 (103 mg, 0.745 mmol) in dioxane (4 mL) and H2O (1 mL) was stirred at 80 degrees C for 16 h under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc/EtOH (4/3/1 to 2/3/1). The crude product was purified by reverse flash chromatography with the following conditions: Column: C18 Column 120 g; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 40% B to 70% B in 40 min; 254/220 nm to afford (3S)-N-[3-[2'-amino-6-(morpholin-4-yl)-[2,4'-bipyridin]-4-yl]-4-methylphenyl]-3- (2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (99 mg, 74%) as a white solid. MS ESI calculated for C28H31F3N6O2 [M + H]+, 541.25 found 541.20.1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.97 (d, J = 5.4 Hz, 1H), 7.51-7.49 (m, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.18 (t, J = 4.1 Hz, 2H), 7.13 (d, J = 3.8 Hz, 2H), 6.78 (s, 1H), 5.97 (s, 2H), 3.79-3.72 (m, 4H), 3.68- 3.53 (m, 6H), 3.30-3.29 (m, 1H), 3.03 (t, J = 9.4 Hz, 1H), 2.42-2.35 (m, 3H), 2.21 (s, 3H), 2.13-2.05 (m, 1H), 1.71-1.60 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -63.37 (3F).
74% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate In 1,4-dioxane; water monomer at 80℃; for 16h; Inert atmosphere; 40 Example 40: (3S)-N-[3-[2'-amino-6-(morpholin-4-yl)-[2,4'-bipyridin]-4-yl]-4- methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (109 mg, 0.497 mmol), (3S)-N-[3-[2-chloro-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2- trifluoroethyl)pyrrolidine-1-carboxamide (120 mg, 0.248 mmol), Pd(dppf)Cl2.CH2Cl2 (20 mg, 0.025 mmol) and K2CO3 (103 mg, 0.745 mmol) in dioxane (4 mL) and H2O (1 mL) was stirred at 80 degrees C for 16 h under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc/EtOH (4/3/1 to 2/3/1). The crude product was purified by reverse flash chromatography with the following conditions: Column: C18 Column 120 g; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 40% B to 70% B in 40 min; 254/220 nm to afford (3S)-N-[3-[2'-amino-6-(morpholin-4-yl)-[2,4'-bipyridin]-4-yl]-4-methylphenyl]-3- (2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (99 mg, 74%) as a white solid. MS ESI calculated for C28H31F3N6O2 [M + H]+, 541.25 found 541.20.1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.97 (d, J = 5.4 Hz, 1H), 7.51-7.49 (m, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.18 (t, J = 4.1 Hz, 2H), 7.13 (d, J = 3.8 Hz, 2H), 6.78 (s, 1H), 5.97 (s, 2H), 3.79-3.72 (m, 4H), 3.68- 3.53 (m, 6H), 3.30-3.29 (m, 1H), 3.03 (t, J = 9.4 Hz, 1H), 2.42-2.35 (m, 3H), 2.21 (s, 3H), 2.13-2.05 (m, 1H), 1.71-1.60 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -63.37 (3F).
  • 34
  • [ 1195995-72-2 ]
  • [ 2765268-39-9 ]
  • [ 2765262-72-2 ]
YieldReaction ConditionsOperation in experiment
54% With cataCXium Pd G4; Cs2CO3 In tert-Amyl alcohol; lithium hydroxide monohydrate at 90℃; for 2h; Inert atmosphere; 10 Example 10: (S)-4-(5-Fluoro-2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- yl)pyridin-2-amine. (S)-3-Bromo-5-fluoro-2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (Intermediate 41, 35 mg, 0.117 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (103 mg, 0.468 mmol), CataXcium Pd G4 (4.3 mg, 0.0059 mmol), and Cs2CO3 (116 mg, 0.351 mmol) were dissolved in a mixture of 2-methyl-2-butanol (2 mL) and water (1 mL). The biphasic mixture was stirred at 90 °C for 2 hours, then stirred overnight at 110 °C. The reaction mixture was allowed to cool to room temperature, partitioned between DCM and water, and the aqueous layer was extracted 2x with DCM. The combined organics were concentrated and the residue was purified HPLC Method D: to obtain 19.7 mg (0.631 mmol, 54% yield) of the title compound. MS (ESI): mass calcd. for C17H14F2N4, 312.1; m/z found, 313.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 5.4, 0.7 Hz, 1H), 7.45 - 7.34 (m, 2H), 7.00 - 6.91 (m, 2H), 6.41 (dd, J = 5.3, 1.5 Hz, 1H), 6.27 - 6.19 (m, 1H), 5.87 - 5.59 (m, 1H), 4.43 (d, J = 3.0 Hz, 1H), 4.38 - 4.34 (m, 1H), 4.26 (s, 2H), 3.43 - 3.14 (m, 2H).
54% With cataCXium Pd G4; Cs2CO3 In tert-Amyl alcohol; lithium hydroxide monohydrate at 90℃; for 2h; Inert atmosphere; 10 Example 10: (S)-4-(5-Fluoro-2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- yl)pyridin-2-amine. (S)-3-Bromo-5-fluoro-2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (Intermediate 41, 35 mg, 0.117 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (103 mg, 0.468 mmol), CataXcium Pd G4 (4.3 mg, 0.0059 mmol), and Cs2CO3 (116 mg, 0.351 mmol) were dissolved in a mixture of 2-methyl-2-butanol (2 mL) and water (1 mL). The biphasic mixture was stirred at 90 °C for 2 hours, then stirred overnight at 110 °C. The reaction mixture was allowed to cool to room temperature, partitioned between DCM and water, and the aqueous layer was extracted 2x with DCM. The combined organics were concentrated and the residue was purified HPLC Method D: to obtain 19.7 mg (0.631 mmol, 54% yield) of the title compound. MS (ESI): mass calcd. for C17H14F2N4, 312.1; m/z found, 313.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 5.4, 0.7 Hz, 1H), 7.45 - 7.34 (m, 2H), 7.00 - 6.91 (m, 2H), 6.41 (dd, J = 5.3, 1.5 Hz, 1H), 6.27 - 6.19 (m, 1H), 5.87 - 5.59 (m, 1H), 4.43 (d, J = 3.0 Hz, 1H), 4.38 - 4.34 (m, 1H), 4.26 (s, 2H), 3.43 - 3.14 (m, 2H).
  • 35
  • [ 1195995-72-2 ]
  • [ 2765269-55-2 ]
  • [ 2765269-60-9 ]
YieldReaction ConditionsOperation in experiment
42% With [(di(1-adamantyl)-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate; Cs2CO3 In tert-Amyl alcohol; lithium hydroxide monohydrate at 90℃; for 16h; Inert atmosphere; Intermediate 104: 4-(2-(5-Fluoropyridin-2-yl)-6,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1- c][1,4]oxazin-3-yl)pyridin-2-amine. 3-Bromo-2-(5-fluoropyridin-2-yl)-6,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (Intermediate 101, 400 mg, 1.23 mmol), 2-aminopyridine-4-boronic acid pinacol ester (337 mg, 1.53 mmol), Cs2CO3 (1.21 g, 3.68 mmol) and CataCXium A Pd G3 (45 mg, 0.06 mmol) were combined in 2-methyl-2-butanol (9.8 mL) and water (2.4 mL). Nitrogen was bubbled through the reaction mixture for 2 minutes the resulting mixture was heated to 90 C for 16 hours. The reaction mixture was extracted with EtOAc (3 x 25 mL) and the combined organic layers were dried over Na2SO4, filtered and evaporated. The resulting residue was purified by FCC (SiO2, 10% MeOH containing 2M NH3 in DCM, 0-50%) gave the title compound (174 mg, 42%). MS (ESI): mass calcd. for C18H18FN5O, 339.1; m/z found, 340.1 [M+H]+.
42% With [(di(1-adamantyl)-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate; Cs2CO3 In tert-Amyl alcohol; lithium hydroxide monohydrate at 90℃; for 16h; Inert atmosphere; Intermediate 104: 4-(2-(5-Fluoropyridin-2-yl)-6,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1- c][1,4]oxazin-3-yl)pyridin-2-amine. 3-Bromo-2-(5-fluoropyridin-2-yl)-6,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (Intermediate 101, 400 mg, 1.23 mmol), 2-aminopyridine-4-boronic acid pinacol ester (337 mg, 1.53 mmol), Cs2CO3 (1.21 g, 3.68 mmol) and CataCXium A Pd G3 (45 mg, 0.06 mmol) were combined in 2-methyl-2-butanol (9.8 mL) and water (2.4 mL). Nitrogen was bubbled through the reaction mixture for 2 minutes the resulting mixture was heated to 90 C for 16 hours. The reaction mixture was extracted with EtOAc (3 x 25 mL) and the combined organic layers were dried over Na2SO4, filtered and evaporated. The resulting residue was purified by FCC (SiO2, 10% MeOH containing 2M NH3 in DCM, 0-50%) gave the title compound (174 mg, 42%). MS (ESI): mass calcd. for C18H18FN5O, 339.1; m/z found, 340.1 [M+H]+.
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