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Product Details of [ 1227210-33-4 ]

CAS No. :1227210-33-4 MDL No. :MFCD17215187
Formula : C7H12N4 Boiling Point : -
Linear Structure Formula :- InChI Key :RWSWNQOCJVPCMF-UHFFFAOYSA-N
M.W : 152.20 Pubchem ID :58043933
Synonyms :

Safety of [ 1227210-33-4 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P332+P313-P337+P313-P362-P403+P233-P405-P501 UN#:
Hazard Statements:H302-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1227210-33-4 ]

* 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.

  • Downstream synthetic route of [ 1227210-33-4 ]

[ 1227210-33-4 ] Synthesis Path-Downstream   1~67

  • 1
  • 4-bromo-6-chloro-pyridazin-3(2H)-one [ No CAS ]
  • [ 1227210-33-4 ]
  • [ 1227210-34-5 ]
YieldReaction ConditionsOperation in experiment
74% With lithium hexamethyldisilazane In tetrahydrofuran; 1,4-dioxane for 3h; Inert atmosphere; Reflux; 2 6-Chloro4-(5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-α]pyrazin-2- ylamino)pyridazin-3(2H)-one [00169] A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (5.0 mL), 5- methyl-4,5,6,7-tetrahydropyrazolo[l,5-α]pyrazin-2-amine (152 mg, 1.00 mmol), A- bromo-6-chloropyridazin-3(2H)-one (209 mg, 1.00 mmol) and a 1 M THF solution of LiHMDS (5.0 mL, 5.00 mmol). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (49 mg, 0.05 mmol) and tris(dibenzylideneacetone) dipalladium(O) (59 mg, 0.085 mmol) were added, and the reaction mixture was heated at reflux for 3 h. After this time, the reaction was cooled to room temperature, and water (10 mL) was added. The pH was adjusted to 6.5 with 2 N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water (2 x 25 mL), absorbed on silica gel and purified by flash chromatography to afford a 74% yield (210 mg) of 6-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-α]pyrazin-2- ylamino)pyridazin-3(2H)-one as a light brown solid: 1H NMR (300 MHz, DMSO-J6) δ 12.94 (s, IH), 9.55 (s, IH), 7.68 (s, IH), 5.96 (s, IH), 4.04 (t, IH, J = 5.7 Hz), 3.53 (s, 2H), 2.82 (t, 2H, J = 5.7 Hz), 2.36 (s, 3H); MS (ESI+) m/z 281.1 (M+H).
74% With lithium hexamethyldisilazane In tetrahydrofuran; 1,4-dioxane for 3h; Inert atmosphere; Reflux; 1; 101.101f A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (5.0 mL), lOle (152 mg, 1.00 mmol), 4-bromo-6-chloropyridazin-3(2H)-one (209 mg, 1.00 mmol) and a 1 M THF solution of LiHMDS (5.0 mL, 5.00 mmol). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (49 mg, 0.05 mmol) and tris(dibenzylideneacetone) dipalladium(O) (59 mg, 0.085 mmol) were added, and the reaction mixture was heated at reflux for 3 h. After this time, the reaction was cooled to room temperature, and water (10 rriL) was added. The pH was adjusted to 6.5 with 2 N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water (2 x 25 iriL), absorbed on silica gel and purified by flash chromatography to afford a 74% yield (210 mg) of lOlf as a light brown solid: ]H NMR (300 MHz, DMSO- ) δ 12.94 (s, IH), 9.55 (s, IH), 7.68 (s, IH), 5.96 (s, IH), 4.04 (t, IH, / = 5.7 Hz), 3.53 (s, 2H), 2.82 (t, 2H, / = 5.7 Hz), 2.36 (s, 3H); MS (ESI+) m/z 281.1 (M+H)
74% Stage #1: 4-bromo-6-chloro-pyridazin-3(2H)-one; 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-amine With lithium hexamethyldisilazane In tetrahydrofuran; 1,4-dioxane for 0.5h; Inert atmosphere; Reflux; Stage #2: With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran; 1,4-dioxane for 3h; Reflux; Stage #3: With hydrogenchloride In tetrahydrofuran; 1,4-dioxane 101m A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (5.0 rriL), 5-methyl-4, 5,6,7- tetrahydropyrazolo[l,5-fl]pyrazin-2-amine 1011 (152 mg, 1.00 mmol), 4-bromo-6- chloropyridazin-3(2H)-one (209 mg, 1.00 mmol) and a 1 M THF solution of LiHMDS (5.0 rriL, 5.00 mmol). After bubbling nitrogen through the resulting solution for 30 min,Xantphos (49 mg, 0.05 mmol) and tris(dibenzylideneacetone) dipalladium(O) (59 mg, 0.085 mmol) were added, and the reaction mixture was heated at reflux for 3 h. After this time, the reaction was cooled to room temperature, and water (10 rriL) was added. The pH was adjusted to 6.5 with 2 N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water (2 x 25 rriL), absorbed on silica gel and purified by flash chromatography to afford a 74% yield (210 mg) of 6-chloro-4-(5-methyl-4,5,6,7- tetrahydropyrazolo[l,5-fl]pyrazin-2-ylamino)pyridazin-3(2H)-one 101m as a light brown solid: ]H NMR (300 MHz, DMSO-i¾ δ 12.94 (s, 1H), 9.55 (s, 1H), 7.68 (s, 1H), 5.96 (s, 1H), 4.04 (t, 1H, / = 5.7 Hz), 3.53 (s, 2H), 2.82 (t, 2H, / = 5.7 Hz), 2.36 (s, 3H); MS (ESI+) m/z 281.1 (M+H).
74% With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; lithium hexamethyldisilazane In tetrahydrofuran; 1,4-dioxane for 3h; Reflux; 6-Chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one (III) A 50-mL single-neck round-bottom flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (5.0 mL), 5- methyl -4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (II, 152 mg, 1.00 mmol), 4-bromo-6-chloropyridazin-3(2H)-one (I, 209 mg, 1.00 mmol) and a 1 M THF solution of LiHMDS (5.0 mL, 5.00 mmol). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (49 mg, 0.05 mmol) and tris(dibenzylideneacetone)dipalladium(0) (59 mg, 0.085 mmol) were added. The reaction mixture was heated at reflux for 3 h, before cooling to room temperature. Water (10 mL) was added and the pH of the mixture was adjusted to 6.5 with 2 N hydrochloric acid. After filtration, the resulting precipitate was washed with water (2 × 25 mL) and purified by silica gel flash chromatography to afford 6- chloro -4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one (210 mg, 74% yield) as a light brown solid.

  • 2
  • [ 1227210-32-3 ]
  • [ 1227210-33-4 ]
YieldReaction ConditionsOperation in experiment
100% With palladium 10% on activated carbon; hydrogen In ethanol I-18.5 A solution of 5-methyl-2-nitro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (1 .6 g, 8.7 mmo 1) in ethanol (20 mL) was treated with palladium on carbon (10%, 300 mg) and flushed with argon. The resulting mixture was stirred under a hydrogen (1 atm) overnight. The reaction mixture was filtered through a celite pad, and the pad washed with ethanol. The filtrate was concentrated in vacuo to give 5-methyl-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazin-2-amine (1.35 g, quantitative) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.30 (s, 3 H) 2.71 (t, J5.67 Hz, 2 H) 3.37 (s, 2 H) 3.74 (t, J=5.67 Hz, 2 H) 4.46 (s, 2 H) 5.14 (s, 1 H).
100% With palladium on activated charcoal; hydrogen In ethanol for 12h; Synthesis of 5-methyl-4,5,6,7-tetrahydropyrazolo [1,5-al pyrazin-2-amine (Precursor-09) To a stirred solution of 5-methyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1 ,5- a]pyrazine 24 (0.50 g, 0.27 mmol) in ethanol (50 mL), palladium-carbon (0.15 g) was charged and stirred under hydrogen pressure (1 atm) for 12 hour. The reaction mixture was filtered through celite bed. The filtrate was evaporated to obtain 5-methyl-2-amino- 4,5 ,6,7-tetrahydropyrazolo[ 1,5 -alpyrazine precursor-09 (0.45 g, quantitative yield) as brown sticky solid. ‘HNMR (400 MHz, DMSO-d6): 6 5.15 (s, 1H), 4.47 (s, 2H), 3.80 (t, 2H), 3.32 (s, 2H), 2.70 (t,2H), 2.31 (s, 3H). MS: 153.11 (M+H).
99% With hydrogen In ethanol for 2h; Inert atmosphere; 2 5-Methyl-4,5,6,7-tetrahydropyrazolo[l,5-α]pyrazin-2-amine [00168] A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of 5- methyl-2-nitro-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (4.00 g, 2.20 mmol) in ethanol (160 rnL). The bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2 x 75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 99% yield of 5-methyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-amine (3.31 g) as an orange solid: 1H NMR (300 MHz, CDCl3) δ 5.34 (s, IH), 3.98 (t, 2H, /= 5.4 Hz), 3.52 (s, 3H), 2.84 (t, 2H, / = 5.7 Hz), 2.45 (s, 3H); MS (ESI+) m/z 153.1 (M+H).
99% With hydrogen In ethanol for 2h; Inert atmosphere; 1; 101.101e A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of 5-methyl-2-nitro- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine 101c (4.00 g, 2.20 mmol) in ethanol (160 mL). The bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2 x 75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 99% yield of lOle (3.31 g) as an orange solid: ]H NMR (300 MHz, CDC13) δ 5.34 (s, 1H), 3.98 (t, 2H, / = 5.4 Hz), 3.52 (s, 3H), 2.84 (t, 2H, / = 5.7 Hz), 2.45 (s, 3H); MS (ESI+) m/z 153.1 (M+H)
99% With hydrogen In ethanol for 2h; 101l A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of 5-methyl-2-nitro- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine 101k (4.00 g, 2.20 mmol) in ethanol (160 mL). The bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2 x 75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 99% yield of 5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-amine (1011) (3.31 g) as an orange solid: ]H NMR (300 MHz, CDC13) δ 5.34 (s, 1H), 3.98 (t, 2H, J = 5.4 Hz), 3.52 (s, 3H), 2.84 (t, 2H, / = 5.7 Hz), 2.45 (s, 3H); MS (ESI+) m/z 153.1 (M+H).
99% With hydrogen In ethanol for 2h; Inert atmosphere; 103k Example 103k 5-Methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-amine 103k CGIPHARM60WO103kA 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of 5-methyl-2-nitro- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine 103j (4.00 g, 2.20 mmol) in ethanol (160 mL). The bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2 x 75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 99% yield of 5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-amine 103k (3.31 g) as an orange solid: ]H NMR (300 MHz, CDC13) δ 5.34 (s, 1H), 3.98 (t, 2H, / = 5.4 Hz), 3.52 (s, 3H), 2.84 (t, 2H, / = 5.7 Hz), 2.45 (s, 3H); MS (ESI+) m/z 153.1 (M+H).
99% With palladium 10% on activated carbon; hydrogen In ethanol for 2h; 128.b 5-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine 128b Example 128b 5-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine 128b A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of 128a (4.00 g, 2.20 mmol) in ethanol (160 mL). The bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. CELITE 521 (1.0 g) was added, and the mixture was filtered through a pad of CELITE 521. The filter cake was washed with ethanol (2*75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 99% yield of 128b (3.31 g) as an orange solid. 1H NMR (300 MHz, CDCl3) δ 5.34 (s, 1H), 3.98 (t, 2H, J=5.4 Hz), 3.52 (s, 3H), 2.84 (t, 2H, J=5.7 Hz), 2.45 (s, 3H); MS (ESI+) m/z 153.1 (M+H)
99% With palladium 10% on activated carbon; hydrogen In ethanol for 2h; 124e Example 124e 5-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine 124e A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of 124d (4.00 g, 2.20 mmol) in ethanol (160 mL). The bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2*75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 99% yield of 124e (3.31 g) as an orange solid: 1H NMR (300 MHz, CDCl3) δ 5.34 (s, 1H), 3.98 (t, 2H, J=5.4 Hz), 3.52 (s, 3H), 2.84 (t, 2H, J=5.7 Hz), 2.45 (s, 3H); MS (ESI+) m/z 153.1 (M+H)
99% With palladium 10% on activated carbon; hydrogen In ethanol for 2h; 113e Example 113e 5-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine 113e Example 113e 5-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine 113e A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of 113d (4.00 g, 2.20 mmol) in ethanol (160 mL). The bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. CELITE 521 (1.0 g) was added, and the mixture was filtered through a pad of CELITE 521. The filter cake was washed with ethanol (2 * 75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 99% yield of 113e (3.31 g) as an orange solid: 1H NMR (300 MHz, CDCl3) δ 5.34 (s, 1H), 3.98 (t, 2H, J = 5.4 Hz), 3.52 (s, 3H), 2.84 (t, 2H, J = 5.7 Hz), 2.45 (s, 3H); MS (ESI+) m/z 153.1 (M+H)
99% With palladium 10% on activated carbon; hydrogen In ethanol for 2h; Inert atmosphere; 5-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (II) A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of 5- methyl -2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (S4, 4.00 g, 2.20 mmol) in ethanol (160 mL). The bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi, and shaken for 2 h. Subsequently the hydrogen was evacuated and nitrogen was charged into the bottle. The mixture was filtered through a pad of Celite 521 (1 g). The filter cake was washed with ethanol (2 × 75 mL). The combined filtrate and washings were concentrated in vacuo to afford 5- methyl -4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (3.31 g , 99% yield) as an orange solid.
With hydrogen In ethanol 59 To a solution of 5-methyl-2-nitro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (67 mg, 0.37 mmol) in ethanol (15 mL) was treated with palladium on carbon (10%, 20 mg) and flushed with argon. The resulting mixture was stirred under a hydrogen (1 atm) overnight. The reaction mixture was filtered through a celite pad, and the pad washed with ethanol. The filtrate was concentrated in vacuo to give 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (72 mg, quantitative) as a light yellow oil.
420 g With 5%-palladium/activated carbon; hydrogen In methanol at 35℃; for 40h; Inert atmosphere;
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; 8.3 Step 3: 5-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine Add 5-methyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.20 g, 1.1 mmol) and 8 mL of methanol and 0.04 to a 25 mL vial g 10% Pd/C, hydrogenation at room temperature under normal pressure overnight,The reaction was completed by TLC, the Celite was filtered, and the filter cake was washed with 10 mL of EA.0.16 g of a white solid was obtained which was directly taken to the next reaction. Yield 96%,

Reference: [1]Current Patent Assignee: ROCHE HOLDING AG - WO2013/24078, 2013, A1 Location in patent: Page/Page column 95
[2]Current Patent Assignee: JUBILANT PHARMOVA LTD - WO2015/25197, 2015, A1 Location in patent: Paragraph 00089
[3]Current Patent Assignee: GILEAD SCIENCES INC; ROCHE HOLDING AG - WO2010/56875, 2010, A1 Location in patent: Page/Page column 98; 101
[4]Current Patent Assignee: GILEAD SCIENCES INC; ROCHE HOLDING AG - WO2011/140488, 2011, A1 Location in patent: Page/Page column 111; 117
[5]Current Patent Assignee: GILEAD SCIENCES INC - WO2012/30990, 2012, A1 Location in patent: Page/Page column 58
[6]Current Patent Assignee: GILEAD SCIENCES INC; ROCHE HOLDING AG - WO2012/31004, 2012, A1 Location in patent: Page/Page column 73-74
[7]Current Patent Assignee: ROCHE HOLDING AG - US2013/116246, 2013, A1 Location in patent: Paragraph 0390
[8]Current Patent Assignee: ROCHE HOLDING AG - US2013/116262, 2013, A1 Location in patent: Paragraph 0377
[9]Current Patent Assignee: ROCHE HOLDING AG - EP2773638, 2015, B1 Location in patent: Paragraph 0279; 0280
[10]Young, Wendy B.; Barbosa, James; Blomgren, Peter; Bremer, Meire C.; Crawford, James J.; Dambach, Donna; Eigenbrot, Charles; Gallion, Steve; Johnson, Adam R.; Kropf, Jeffrey E.; Lee, Seung H.; Liu, Lichuan; Lubach, Joseph W.; MacAluso, Jen; MacIejewski, Pat; Mitchell, Scott A.; Ortwine, Daniel F.; Di Paolo, Julie; Reif, Karin; Scheerens, Heleen; Schmitt, Aaron; Wang, Xiaojing; Wong, Harvey; Xiong, Jin-Ming; Xu, Jianjun; Yu, Christine; Zhao, Zhongdong; Currie, Kevin S. [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 2, p. 575 - 579]
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  • 3
  • [ 1178884-53-1 ]
  • [ 1227210-33-4 ]
  • [ 1346672-51-2 ]
YieldReaction ConditionsOperation in experiment
76% With lithium hexamethyldisilazane In tetrahydrofuran; 1,4-dioxane at 0℃; for 2h; Inert atmosphere; Reflux; 103.103f A 250-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 4-bromo-6-chloro-2-methylpyridazin- 3(2H)-one 103e (1.90 g, 8.53 mmol), lOle (1.18 g, 7.75 mmol) and 1,4-dioxane (40 mL). The flask was purged with nitrogen and cooled to 0 °C. A 1 M solution of lithium hexamethyldisilazide in THF (39 mL, 39.0 mmol) was added. After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (381 mg, 0.659 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (355 mg, 0.388 mmol) were added, and the reaction mixture was heated at reflux for 2 h. After this time, the mixture was cooled to room temperature and diluted with water (10 mL). The pH of the solution was adjusted to 7.6 with 2 N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica to afford a 76% yield (1.74 g) of 103f as an off-white solid: mp 184-186 °C; ]H NMR (300 MHz, DMSO-i¾) δ 9.62 (s, 1H), 7.72 (s, 1H), 6.00 (s, 1H), 4.04 (t, 2H, / = 5.1 Hz), 3.65 (s, 3H), 3.53 (s, 2H), 2.82 (t, 2H, / = 5.1 Hz), 2.37 (s, 3H); MS (ESI+) m/z 295.1 (M+H).
76% Stage #1: 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one; 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-amine With lithium hexamethyldisilazane In tetrahydrofuran; 1,4-dioxane at 0℃; for 0.5h; Inert atmosphere; Stage #2: With 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran; 1,4-dioxane for 2h; Reflux; Stage #3: With hydrogenchloride In tetrahydrofuran; 1,4-dioxane 106f A 250-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 103a (1.90 g, 8.53 mmol), 1011 (1.18 g, 7.75 mmol) and 1,4-dioxane (40 mL). The flask was purged with nitrogen and cooled to 0 °C. A I M solution of lithium hexamethyldisilazide in THF (39 mL, 39.0 mmol) was added. After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (381 mg, 0.659 mmol) and tris(dibenzylideneacetone)dipalladium(0) (355 mg, 0.388 mmol) were added, and the reaction mixture was heated at reflux for 2 h. After this time, the mixture was cooled to room temperature and diluted with water (10 mL). The pH of the solution was adjusted to 7.6 with 2 N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica to afford a 76% yield (1.74 g) of 106f as an off-white solid: mp 184-186 °C; ]H NMR (300 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.72 (s, 1H), 6.00 (s, 1H), 4.04 (t, 2H, / = 5.1 Hz), 3.65 (s, 3H), 3.53 (s, 2H), 2.82 (t, 2H, / = 5.1 Hz), 2.37 (s, 3H); MS (ESI+) m/z 295.1 (M+H).
76% With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; lithium hexamethyldisilazane In tetrahydrofuran; 1,4-dioxane for 2h; Inert atmosphere; Reflux; 133a Example 133a 6-Chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one 133a Example 133a 6-Chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one 133a A 250-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (1.90 g, 8.53 mmol): 113e (1.18 g, 7.75 mmol) and 1,4-dioxane (40 mL). The flask was purged with nitrogen and cooled to 0 °C. A 1 M solution of lithium hexamethyldisilazide in THF (39 mL, 39.0 mmol) was added. After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (381 mg, 0.659 mmol) and tris(dibenzylidene-acetone)dipalladium(0) (355 mg, 0.388 mmol) were added, and the reaction mixture was heated at reflux for 2 h. After this time, the mixture was cooled to room temperature and diluted with water (10 mL). The pH of the solution was adjusted to 7.6 with 2 N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 * 40 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica to afford a 76% yield (1.74 g) of 133a as an off-white solid: mp 184-186 °C; 1H NMR (300 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.72 (s, 1H), 6.00 (s, 1H), 4.04 (t, 2H, J= 5.1 Hz), 3.65 (s, 3H), 3.53 (s, 2H), 2.82 (t, 2H, J= 5.1 Hz), 2.37 (s, 3H); MS (ESI+) m/z 295.1 (M+H).
69% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 110℃; for 18h; Sealed tube; I-18 Preparation of 1-18 A solution of 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (342 mg, 2.25 mmo 1), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (527 mg, 2.36 mmol), cesium carbonate (2.2 g, 6.74 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethlxanthene (195 mg, 0.34 mmol) in dioxane (15 ml) was flushed with argon before tris(dibenzylideneacetone)dipalladium(0) (154 mg, 0.17 mmol) was added and the resulting solution was heated in a sealed tube at 110 °C for 18 h. The mixture was cooled to room temperature and filtered through celite. The cake was washed with dichloromethane. The combined filtrate and washes were diluted with 3M HCl and separated. The DCM layer was back extracted with aqueous HCl and discarded. The combined aqueous HCl extracts were made basic with 3M NaOH. The resulting aqueous phase was extracted 2 times with DCM. The combined DCM extracts were concentrated in vacuo and the resulting solid was triturated with ethyl ether, filtered, and dried to give 6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3 (2H)-one (455 mg, 69%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.35 (s, 3 H) 2.81 (t, J5.48 Hz, 2 H) 3.51 (s, 2 H) 3.63 (s, 3 H) 4.03 (t, J=5.48 Hz, 2 H) 5.98 (s, 1 H) 7.71 (s, 1 H) 9.60 (s, 1 H).
60% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; for 2h; Inert atmosphere; 153.a 6-Chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one 153a Example 153a 6-Chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one 153a A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (30 mL), 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine 128b (1.70 g, 11.2 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (2.68 g, 12.0 mmol), and cesium carbonate (7.30 g, 22.4 mmol). After bubbling nitrogen through the suspension for 30 minutes, Xantphos (0.59 g, 1.02 mmol) and tris(dibenzylideneacetone)dipalladium(0) (467 mg, 0.51 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and heated at 90° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 153a (1.9 g, 60%) as a brown solid. LCMS: [M+H]+ 295.1
57% With caesium carbonate In 1,4-dioxane at 90℃; for 18h; Inert atmosphere; 59 A solution of 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (55.7 mg, 0.37 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (81.8 mg, 0.37 mmol) cesium carbonate (417 mg, 1.28 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethlxanthene (31.8 mg, 0.05 mmol) in dioxane (6 ml) was flushed with argon before tris(dibenzylideneacetone)dipalladium(0) (25.1 mg, 0.03 mmol) was added and the resulting solution was heated at 90° C. for 18 h. The mixture was cooled to room temperature and diluted with dichloromethane (50 mL) and water. The layers were separated and the aqueous layer was extracted with dichloromethane (2*25 mL). The organic layers were combined, dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 2% to 7% methanol in dichloromethane) to give 6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one (61 mg, 57%) as a light yellow solid.

  • 4
  • [ 1178884-53-1 ]
  • [ 1227210-33-4 ]
  • [ 1346669-52-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: lithium hexamethyldisilazane / 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; tris-(dibenzylideneacetone)dipalladium(0) / 1,4-dioxane; tetrahydrofuran / 2 h / 0 °C / Inert atmosphere; Reflux 2: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide; 1,4-dioxane; water / 14 h / Inert atmosphere; Reflux
  • 5
  • [ 1227210-30-1 ]
  • [ 1227210-33-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: phosphorus tribromide / chloroform / 2 h / -5 °C / Inert atmosphere; Reflux 2: tetrahydrofuran / 72 h / 20 °C / Inert atmosphere 3: hydrogen / palladium 10% on activated carbon / ethanol / 2 h / 2327.23 Torr / Inert atmosphere
Multi-step reaction with 3 steps 1.1: phosphorus tribromide / chloroform / 0 - 20 °C 1.2: pH 8.5 2.1: tetrahydrofuran / 76 h / 20 °C 3.1: hydrogen / palladium 10% on activated carbon / ethanol / 760.05 Torr
Multi-step reaction with 3 steps 1.1: phosphorus tribromide / chloroform / 2 h / -5 °C / Inert atmosphere; Reflux 1.2: pH 8.5 2.1: tetrahydrofuran / 72 h / 20 °C 3.1: hydrogen / palladium 10% on activated carbon / ethanol / 2 h / 2327.23 Torr
Multi-step reaction with 3 steps 1.1: phosphorus tribromide / chloroform / 2 h / -5 °C / Reflux; Inert atmosphere 1.2: -5 °C / pH 8.5 2.1: tetrahydrofuran / 72 h / 20 °C / Inert atmosphere 3.1: hydrogen / palladium 10% on activated carbon / ethanol / 2 h / 2327.23 Torr / Inert atmosphere
Multi-step reaction with 3 steps 1: phosphorus tribromide / chloroform / 2 h / -5 °C / Reflux 2: tetrahydrofuran / 72 h / 20 °C 3: palladium 10% on activated carbon; hydrogen / ethanol / 2 h / 2327.23 Torr
Multi-step reaction with 3 steps 1: phosphorus tribromide / chloroform / 2 h / -5 °C / Reflux 2: tetrahydrofuran / 72 h / 20 °C 3: palladium 10% on activated carbon; hydrogen / ethanol / 2 h / 2327.23 Torr
Multi-step reaction with 3 steps 1: phosphorus tribromide / chloroform / 2 h / Reflux 2: tetrahydrofuran / 72 h / 0 - 27 °C 3: hydrogen; palladium on activated charcoal / ethanol / 12 h / 760.05 Torr
Multi-step reaction with 3 steps 1: phosphorus tribromide / chloroform / 2 h / -5 °C / Inert atmosphere; Reflux 2: tetrahydrofuran / 72 h / 20 °C / Inert atmosphere 3: palladium 10% on activated carbon; hydrogen / ethanol / 2 h / 2327.23 Torr
Multi-step reaction with 3 steps 1: phosphorus tribromide / chloroform / 2 h / -5 °C / Inert atmosphere; Reflux 2: tetrahydrofuran / 72 h / 20 °C 3: palladium 10% on activated carbon; hydrogen / ethanol / 2 h / 2327.23 Torr / Inert atmosphere

  • 6
  • [ 1227210-31-2 ]
  • [ 1227210-33-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tetrahydrofuran / 72 h / 20 °C / Inert atmosphere 2: hydrogen / palladium 10% on activated carbon / ethanol / 2 h / 2327.23 Torr / Inert atmosphere
Multi-step reaction with 2 steps 1: tetrahydrofuran / 76 h / 20 °C 2: hydrogen / palladium 10% on activated carbon / ethanol / 760.05 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / 72 h / 20 °C 2: hydrogen / palladium 10% on activated carbon / ethanol / 2 h / 2327.23 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / 72 h / 20 °C 2: palladium 10% on activated carbon; hydrogen / ethanol / 2 h / 2327.23 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / 72 h / 20 °C 2: palladium 10% on activated carbon; hydrogen / ethanol / 2 h / 2327.23 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / 72 h / 0 - 27 °C 2: hydrogen; palladium on activated charcoal / ethanol / 12 h / 760.05 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / 72 h / 20 °C / Inert atmosphere 2: palladium 10% on activated carbon; hydrogen / ethanol / 2 h / 2327.23 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / 72 h / 20 °C 2: palladium 10% on activated carbon; hydrogen / ethanol / 2 h / 2327.23 Torr / Inert atmosphere
Multi-step reaction with 2 steps 1: tetrahydrofuran / 76 h / 20 °C 2: palladium 10% on activated carbon; hydrogen / ethanol / 760.05 Torr

  • 7
  • [ 1227210-33-4 ]
  • [ 1346669-50-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: lithium hexamethyldisilazane / 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; tris-(dibenzylideneacetone)dipalladium(0) / 1,4-dioxane; tetrahydrofuran / 3 h / Inert atmosphere; Reflux 2: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide; 1,4-dioxane; water / 15 h / 100 °C / Inert atmosphere
  • 8
  • [ 1227210-33-4 ]
  • [ 1346669-51-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: lithium hexamethyldisilazane / 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; tris-(dibenzylideneacetone)dipalladium(0) / 1,4-dioxane; tetrahydrofuran / 3 h / Inert atmosphere; Reflux 2: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide; 1,4-dioxane; water / 14 h / Inert atmosphere; Reflux
  • 9
  • [ 1227210-33-4 ]
  • [ 1360055-93-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: caesium carbonate / 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; tris-(dibenzylideneacetone)dipalladium(0) / 1,4-dioxane / 18 h / 90 °C / Inert atmosphere 2.1: potassium phosphate / XPhos / butan-1-ol; water / 2 h / 100 °C 2.2: 20 °C
  • 10
  • [ 1360057-00-6 ]
  • [ 1227210-33-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 2.1: phosphorus tribromide / chloroform / 0 - 20 °C 2.2: pH 8.5 3.1: tetrahydrofuran / 76 h / 20 °C 4.1: hydrogen / palladium 10% on activated carbon / ethanol / 760.05 Torr
Multi-step reaction with 4 steps 1: lithium borohydride / tetrahydrofuran / 4 h / 0 °C 2: phosphorus tribromide / chloroform / 2 h / Reflux 3: tetrahydrofuran / 72 h / 0 - 27 °C 4: hydrogen; palladium on activated charcoal / ethanol / 12 h / 760.05 Torr
  • 11
  • [ 1178884-53-1 ]
  • [ 1227210-33-4 ]
  • [ 1361386-70-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: lithium hexamethyldisilazane / 1,4-dioxane; tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere 1.2: 2 h / Reflux 1.3: pH 7.6 2.1: sodium carbonate / N,N-dimethyl-formamide; 1,4-dioxane; water / 0.5 h / Inert atmosphere 2.2: 16 h / Reflux 2.3: 16 h / 20 °C
  • 12
  • [ 1227210-33-4 ]
  • [ 1361386-75-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / 1,4-dioxane; tetrahydrofuran / 0.5 h / Inert atmosphere; Reflux 1.2: 3 h / Reflux 1.3: pH 6.5 2.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 18 h / 100 °C / Inert atmosphere 3.1: methanol / 4 h / 20 - 60 °C / Inert atmosphere; Reflux
  • 13
  • [ 1227210-33-4 ]
  • [ 1361386-51-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: lithium hexamethyldisilazane / 1,4-dioxane; tetrahydrofuran / 0.5 h / Inert atmosphere; Reflux 1.2: 3 h / Reflux 1.3: pH 6.5 2.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 18 h / 100 °C / Inert atmosphere
  • 14
  • [ 1227210-33-4 ]
  • [ 1361386-74-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: lithium hexamethyldisilazane / 1,4-dioxane; tetrahydrofuran / 0.5 h / Inert atmosphere; Reflux 1.2: 3 h / Reflux 1.3: pH 6.5 2.1: sodium carbonate / N,N-dimethyl-formamide; 1,4-dioxane; water / 0.5 h / Inert atmosphere 2.2: 16 h / Reflux
  • 15
  • [ 14529-54-5 ]
  • [ 1227210-33-4 ]
  • [ 1346673-59-3 ]
YieldReaction ConditionsOperation in experiment
91% Example 1031 5-Bromo-l-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[l,5- fl]pyrazin-2-ylamino)pyridin-2(iH)-one 1031A 15-mL pressure tube equipped with a magnetic stirrer and screw cap with a septum was charged with 103k (100 mg, 0.657 mmol), 3,5-dibromo-l-methylpyridin-2(lH)-one (351 mg, 1.30 mmol), cesium carbonate (644 mg, 1.98 mmol), and 1,4-dioxane (5 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (33 mg, 0.057 mmol) and tris(dibenzylideneacetone)dipalladium(0) (31 mg, 0.034 mmol) were added; the tube was sealed, and the reaction mixture was heated for 16 h in a 130 C bath. After this time, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica to afford a 91% yield (204 mg) of 1031 as an off-white solid: mp 174-176 C; ]H NMR (300 MHz, DMSO- ) delta 8.42 ( 1H), 8.00 (d, 1H, J = 2.6 Hz), 7.37 (d, 1H, J = 2.6 Hz), 5.86 (s, 1H), 3.99 (t, 2H, / = 5.0 3.49 (m, 5H), 2.81 (t, 2H, / = 5.4 Hz), 2.36 (s, 3H); MS (ESI+) m/z 338.1 (M+H). CGIPHARM60WO
14% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 110℃; for 2h;Inert atmosphere; Example 128c 5-Bromo-1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one 128c A sealed tube equipped with a magnetic stirrer was charged with 128b (1.02 g, 6.7 mmol), <strong>[14529-54-5]3,5-dibromo-1-methylpyridin-2(1H)-one</strong> (2.15 g, 8.1 mmol), Pd2(dba)3 (610 mg, 0.67 mmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (775 mg, 1.34 mmol), cesium carbonate (4.37 g, 13.6 mmol), and 1,4-dioxane (30 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110 C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (15:1, V/V) to afford 128c (380 mg, 14%) as a white solid. LCMS: [M+H]+ 338
14% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 110℃; for 2h;Sealed tube; Inert atmosphere; Example 113f 5-Bromo-1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- ylamino) pyridin-2(1H)-one 113f A sealed tube equipped with a magnetic stirrer was charged with 113e (1.02 g, 6.7 mmol), <strong>[14529-54-5]3,5-dibromo-1-methylpyridin-2(1H)-one</strong> (2.15 g, 8.1 mmol), Pd2(dba)3 (610 mg, 0.67mmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (775 mg, 1.34 mmol), cesium carbonate (4.37 g, 13.6 mmol), and 1,4-dioxane (30 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110C for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (15:1, V/V) to afford 113f (380 mg, 14%) as a white solid. LCMS: [M+H]+ 338
  • 16
  • [ 1227210-33-4 ]
  • [ 1361941-13-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: caesium carbonate / 1,4-dioxane / 0.5 h / Inert atmosphere 1.2: 16 h / 130 °C 2.1: sodium carbonate / 1,4-dioxane; water / 0.5 h / Inert atmosphere; Reflux 2.2: 3 h / Reflux
  • 17
  • [ 1227210-33-4 ]
  • [ 1361940-94-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: caesium carbonate / 1,4-dioxane / 0.5 h / Inert atmosphere 1.2: 16 h / 130 °C 2.1: sodium carbonate / N,N-dimethyl-formamide; 1,4-dioxane; water / 0.5 h / Inert atmosphere; Reflux 2.2: 14 h / Reflux
  • 18
  • [ 1227210-33-4 ]
  • [ 1346672-51-2 ]
  • 6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-2-H-pyridazin-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
87.2% Stage #1: 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-amine With sodium tert-pentoxide In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 6-chloro-2-methyl-4-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyridazin-3(2H)-one In tetrahydrofuran at 35℃;
  • 20
  • 5-methyl-2-nitro-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one [ No CAS ]
  • [ 1227210-33-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: triethylamine / N,N-dimethyl-formamide 2: borane-THF / tetrahydrofuran / 6 h / 60 °C 3: methanol / 1 h / 55 °C 4: 5%-palladium/activated carbon; hydrogen / methanol / 40 h / 35 °C / 10343.2 Torr / Inert atmosphere
  • 21
  • 5-methyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrazine [ No CAS ]
  • [ 1227210-33-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: methanol / 1 h / 55 °C 2: 5%-palladium/activated carbon; hydrogen / methanol / 40 h / 35 °C / 10343.2 Torr / Inert atmosphere
  • 22
  • [ 1227210-33-4 ]
  • [ 1423130-40-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 18 h / 110 °C / Sealed tube 2.1: potassium acetate; palladium diacetate; bis(pinacol)diborane; XPhos / 1,4-dioxane / 0.67 h / 100 °C / Inert atmosphere 2.2: 1.5 h / 80 °C
  • 23
  • [ 1227210-33-4 ]
  • [ 1423130-15-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 18 h / 110 °C / Sealed tube 2.1: potassium acetate; palladium diacetate; bis(pinacol)diborane; XPhos / 1,4-dioxane / 0.67 h / 100 °C / Inert atmosphere 2.2: 1.5 h / 80 °C 3.1: methanol; sodium tetrahydroborate / dichloromethane / 0.67 h / 0 °C 3.2: 2 h / 20 °C
  • 24
  • [ 1227210-33-4 ]
  • [ 1433853-11-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Inert atmosphere 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere
  • 25
  • [ 1227210-33-4 ]
  • [ 1433853-16-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Inert atmosphere 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium acetate; potassium phosphate / water; acetonitrile / 1 h / 100 °C / Inert atmosphere
  • 26
  • [ 1227210-33-4 ]
  • [ 1433847-07-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Inert atmosphere 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium acetate; potassium phosphate / water; acetonitrile / 1 h / 100 °C / Inert atmosphere 4: methanol; sodium tetrahydroborate / dichloromethane / 1 h / 20 °C
  • 27
  • [ 1227210-33-4 ]
  • [ 1433858-03-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 2 h / 90 °C / Inert atmosphere 2: potassium acetate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / 1,4-dioxane / 2 h / 50 °C / Inert atmosphere
  • 28
  • [ 1227210-33-4 ]
  • [ 1433858-13-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 2 h / 90 °C / Inert atmosphere 2: potassium acetate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / 1,4-dioxane / 2 h / 50 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium acetate; potassium phosphate / water; acetonitrile / 1 h / 100 °C / Inert atmosphere
  • 29
  • [ 1227210-33-4 ]
  • [ 1423130-01-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 2 h / 90 °C / Inert atmosphere 2: potassium acetate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / 1,4-dioxane / 2 h / 50 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium acetate; potassium phosphate / water; acetonitrile / 1 h / 100 °C / Inert atmosphere 4: methanol; sodium tetrahydroborate / 0.5 h / 20 °C
  • 30
  • [ 1227210-33-4 ]
  • tert-butyl 4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate [ No CAS ]
  • tert-butyl 2-methyl-4-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In 1,4-dioxane at 100℃; for 2h; Inert atmosphere; 54 Preparation of tert-butyl 2-rn ethyl-4-(2-((5-rnethyl-4,5, 6, 7-t etrahydropyrazolo[1 , 5-aJpyrazin-2- yl)arnino)pyrirnidin-4-yl)benzylcarbarnate [01411 To a solution of tert-butyl 4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate (333 mg, 1.0 mmol) and 1-methyl-pyrazol-4-amine (126 mg, 1.3 mmol) in 1,4-dioxane (5 mL), Pd2(dba)3 (92 mg, 0.1 mmol), S-Phos (82 mg, 0.2 mmol) and Cs2CO3 (650 mg, 2.0 mmol) were added under N2. The mixture was stirred at 120 °C for 2 h. After cooling to rt, the mixture was diluted with H20 (40 mL) and extracted with EA (60 mLx2). The organic layers were dried and concentrated. The residue was purified by column chromatography (silica, petroleum ether/EtOAc = 3:1 to 1:1) to give tert-butyl 2-methyl-4-(2-(( 1-methyl-i H-pyrazol-4- yl)amino)pyrimidin-4-yl)benzylcarbamate (248 mg, yield 63%) as white solid.[0263j Synthesis of tert-butyl 2-methyl-4-(2-((5 -methyl-4 ,5 ,6,7-tetrahydropyrazolo [1,5 - a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzylcarbamate was similar to that of tert-butyl 2-methyl- 4-(2-(( 1-methyl-i H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate. The crude was purified by pre-TLC (MeOH/DCM = 1/20) to give product tert-butyl 2-methyl-4-(2-((5 -methyl- 4,5 ,6,7-tetrahydropyrazolo [1,5 -a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzylcarbamate as a yellow solid (50 mg, yield: 37 %). ESI-MS (M+H) : 449.9.
  • 31
  • [ 1227210-33-4 ]
  • tert-butyl (6-(6-chloropyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate [ No CAS ]
  • tert-butyl(6-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
28% With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate In 1,4-dioxane at 100℃; for 1h; Inert atmosphere; Microwave irradiation; 133 Synthesis of tert-butyl (6-(6-((5-methyl-4,5, 6, 7-t etrahydropyrazolo[1 , 5-aJpyrazin-2- yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate [01411 To a solution of tert-butyl 4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate (333 mg, 1.0 mmol) and 1-methyl-pyrazol-4-amine (126 mg, 1.3 mmol) in 1,4-dioxane (5 mL), Pd2(dba)3 (92 mg, 0.1 mmol), S-Phos (82 mg, 0.2 mmol) and Cs2CO3 (650 mg, 2.0 mmol) were added under N2. The mixture was stirred at 120 °C for 2 h. After cooling to rt, the mixture was diluted with H20 (40 mL) and extracted with EA (60 mLx2). The organic layers were dried and concentrated. The residue was purified by column chromatography (silica, petroleum ether/EtOAc = 3:1 to 1:1) to give tert-butyl 2-methyl-4-(2-(( 1-methyl-i H-pyrazol-4- yl)amino)pyrimidin-4-yl)benzylcarbamate (248 mg, yield 63%) as white solid. [0432j Synthesis of tert-butyl (6-(6-((5 -methyl-4,5 ,6,7-tetrahydropyrazolo [1,5 -a]pyrazin2-yl)amino)pyrimidin-4-yl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)carbamate was similar to that of tert-butyl 2-methyl-4-(2-(( 1-methyl-i H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate. Obtained tert-butyl (6-(6-((5-methyl-4,5 ,6,7-tetrahydropyrazolo [1,5 -a]pyrazin-2- yl)amino)pyrimidin-4-yl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)carbamate (100 mg, yield: 28%) as a yellow solid. ESI-MS (M+H) : 476.1. ‘H NMR (400 MHz, CDC13) (5: 8.74 (s, 1H), 8.15 (s, 1H), 7.77 (s, 1H), 7.74 (d, J= 8.4 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J= 8.0 Hz, 1H), 6.09 (s, 1H),4.89-4.87 (m, 2H), 4.13 (t, J 6.0 Hz, 2H), 3.64 (s, 2H), 2.92 (t, J= 5.6 Hz, 2H), 2.85-2.82 (m, 2H), 2.50 (s, 3H), 2.08-2.05 (m, 1H), 1.84-1.80 (m, 3H), 1.49 (s, 9H).
  • 32
  • [ 1227210-33-4 ]
  • (4-(1-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-3-yl)methyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile / 2 h / 110 °C / Sealed tube; Inert atmosphere
  • 33
  • [ 1227210-33-4 ]
  • 2-(3-(hydroxymethyl)-4-(1-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile / 2 h / 110 °C / Sealed tube; Inert atmosphere 3: lithium hydroxide monohydrate; water / tetrahydrofuran; isopropyl alcohol / 2 h / 30 °C
  • 34
  • [ 1227210-33-4 ]
  • 4-(1-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)-2-(4-oxo-7,8,9,10-tetrahydropyridazino[4,5-a]indolizin-3(4H)-yl)nicotinaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile; water / 3 h / 100 °C / Inert atmosphere
  • 35
  • [ 1227210-33-4 ]
  • 3-[3-(hydroxymethyl)-4-[1-methyl-5-[(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl)amino]-6-oxo-3-pyridyl]-2-pyridyl]-7,8,9,10-tetrahydropyridazino[4,5-a]indolizin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile; water / 3 h / 100 °C / Inert atmosphere 4: methanol; sodium tetrahydroborate / 2 h / 20 °C
  • 36
  • [ 1227210-33-4 ]
  • 4-(1-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)-2-(1-oxo-6,7,8,9-tetrahydropyridazino[4,5-b]indolizin-2(1H)-yl)nicotinaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile; water / 3 h / 100 °C / Inert atmosphere
  • 37
  • [ 1227210-33-4 ]
  • 2-[3-(hydroxymethyl)-4-[1-methyl-5-[(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl)amino]-6-oxo-3-pyridyl]-2-pyridyl]-6,7,8,9-tetrahydropyridazino[4,5-b]indolizin-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile; water / 3 h / 100 °C / Inert atmosphere 4: methanol; sodium tetrahydroborate / 2 h / 20 °C
  • 38
  • [ 1227210-33-4 ]
  • 2-{10-fluoro-1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrido[3,4-b]indolizin-2-yl}-4-[1-methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]pyridine-3-carbaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / N,N-dimethyl-formamide; water / 1 h / 70 °C / Inert atmosphere
  • 39
  • [ 1227210-33-4 ]
  • 10-fluoro-2-[3-(hydroxymethyl)-4-[1-methyl-5-[(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl)amino]-6-oxo-3-pyridyl]-2-pyridyl]-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / N,N-dimethyl-formamide; water / 1 h / 70 °C / Inert atmosphere 4: methanol; sodium tetrahydroborate / 1.5 h / 0 - 25 °C
  • 40
  • [ 1227210-33-4 ]
  • (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-[1-methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]pyridin-3-yl)methyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium(0); lithium hexamethyldisilazane; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane; tetrahydrofuran / 2 h / Inert atmosphere; Reflux 2: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile; water / 1 h / 100 °C / Inert atmosphere
  • 41
  • [ 1227210-33-4 ]
  • C30H35N9O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); lithium hexamethyldisilazane; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane; tetrahydrofuran / 2 h / Inert atmosphere; Reflux 2: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile; water / 1 h / 100 °C / Inert atmosphere 3: lithium hydroxide monohydrate; water / tetrahydrofuran; isopropyl alcohol / 0.5 h / 40 °C
  • 42
  • [ 1227210-33-4 ]
  • 2-(3-(hydroxymethyl)-4-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-3,4,6,7,8,9-hexahydro-6,9-methanopyrazino[1,2-a]indol-1(2H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile; water / 3 h / 100 °C / Inert atmosphere 4: methanol; sodium tetrahydroborate / 2 h / 20 °C
  • 43
  • [ 1227210-33-4 ]
  • 2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(1-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile / 4 h / 100 °C / Inert atmosphere
  • 44
  • [ 1227210-33-4 ]
  • 10-fluoro-2-[3'-hydroxymethyl-1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl]-3,4,6,7,8,9-hexahydro-2H-pyrazino[1,2-a]indol-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile / 4 h / 100 °C / Inert atmosphere 4: methanol; sodium tetrahydroborate / 3 h / 20 °C
  • 45
  • [ 1227210-33-4 ]
  • 3-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-5-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)isonicotinaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile / 2 h / 100 °C / Inert atmosphere
  • 46
  • [ 1227210-33-4 ]
  • 2-[4-hydroxymethyl-1'-methyl-5'-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6'-oxo-1',6'-dihydro-[3,3'-bipyridin]-5-yl]-3,4,6,7,8,9-hexahydro-2H-pyrazino[1,2-a]indol-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile / 2 h / 100 °C / Inert atmosphere 4: methanol; sodium tetrahydroborate / 2 h / 20 °C
  • 47
  • [ 1227210-33-4 ]
  • 2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-[1-methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]pyridine-3-carbaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / N,N-dimethyl-formamide / 2 h / 110 °C / Inert atmosphere
  • 48
  • [ 1227210-33-4 ]
  • 2-[3'-hydroxymethyl-1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl]-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / N,N-dimethyl-formamide / 2 h / 110 °C / Inert atmosphere 4: methanol; sodium tetrahydroborate / 0.5 h / 20 °C
  • 49
  • [ 1227210-33-4 ]
  • 2-(3-formyl-4-(1-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1(2H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate tribasic trihydrate; potassium acetate / acetonitrile; water / 3 h / 100 °C / Inert atmosphere
  • 50
  • [ 1227210-33-4 ]
  • 2-(3-(hydroxymethyl)-4-(1-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1(2H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate tribasic trihydrate; potassium acetate / acetonitrile; water / 3 h / 100 °C / Inert atmosphere 4: methanol; sodium tetrahydroborate / 1 h / 25 °C
  • 51
  • [ 1227210-33-4 ]
  • 3-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-5-[1-methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]pyridine-4-carbaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate tribasic trihydrate; potassium acetate / acetonitrile; water / 2 h / 110 °C / Inert atmosphere
  • 52
  • [ 1227210-33-4 ]
  • 2-[4-hydroxymethyl-1'-methyl-5'-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6'-oxo-1',6'-dihydro-[3,3'-bipyridin]-5-yl]-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate tribasic trihydrate; potassium acetate / acetonitrile; water / 2 h / 110 °C / Inert atmosphere 4: methanol; sodium tetrahydroborate / 0.5 h / 0 - 20 °C
  • 53
  • [ 1227210-33-4 ]
  • 4-[1-methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-2-[(1S,11R)-7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl]pyridine-3-carbaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile; water / 3 h / 100 °C / Inert atmosphere
  • 54
  • [ 1227210-33-4 ]
  • 2-(3-(hydroxymethyl)-4-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-3,4,6,7,8,9-hexahydro-6,9-methanopyrazino[1,2-a]indol-1(2H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile; water / 3 h / 100 °C / Inert atmosphere 4: methanol; sodium tetrahydroborate / 2 h / 20 °C
  • 55
  • [ 1227210-33-4 ]
  • 4-[1-methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-2-[(1R,11S)-7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl]pyridine-3-carbaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile; water / 3 h / 100 °C / Inert atmosphere
  • 56
  • [ 1227210-33-4 ]
  • 4-[1-methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}pyridine-3-carbaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile; water / 2 h / 100 °C / Inert atmosphere
  • 57
  • [ 1227210-33-4 ]
  • 3-[3'-hydroxymethyl-1-methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl]-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyridazin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile; water / 2 h / 100 °C / Inert atmosphere 4: methanol; sodium tetrahydroborate / 1 h / 30 °C
  • 58
  • [ 1227210-33-4 ]
  • 2-(3-(formyl)-4-(1-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-6,7,8,9-tetrahydropyrazino[1,2-a]indol-1(2H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile; water / 2 h / Inert atmosphere; Reflux
  • 59
  • [ 1227210-33-4 ]
  • 2-[3-(hydroxymethyl)-4-[1-methyl-5-[(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl)amino]-6-oxo-3-pyridyl]-2-pyridyl]-6,7,8,9-tetrahydropyrazino[1,2-a]indol-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 2 h / 110 °C / Sealed tube; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; potassium acetate / 1,4-dioxane / 15 h / 60 °C / Inert atmosphere 3: sodium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate / acetonitrile; water / 2 h / Inert atmosphere; Reflux 4: methanol; sodium tetrahydroborate / 0.5 h / 0 °C
  • 60
  • [ 1227210-33-4 ]
  • [ 1227206-13-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; lithium hexamethyldisilazane / 1,4-dioxane; tetrahydrofuran / 3 h / Reflux 2: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 0.33 h / 150 °C / Inert atmosphere; Microwave irradiation
  • 61
  • [ 1227210-33-4 ]
  • C7H11BrN4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With N-Bromosuccinimide In dichloromethane at 20℃; for 12h; A19b Preparation of intermediate 84b: NBS (1.93 g, 10.81 mmol) was added portionwise to a solution of intermediate 50b (1.50g, 9.86 mmol) in DCM (85.22 mL). The reaction mixture was stirred at room temperaturefor 12 hours. The reaction mixture was poured onto ice and water and basified with K2C03powder. The mixture was extracted with DCM, dried over Mg504, filtered and evaporatedunder vacuum to give 2.15 g of intermediate 84b (94% yield).
  • 62
  • [ 1227210-33-4 ]
  • C10H16N4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-Bromosuccinimide / dichloromethane / 12 h / 20 °C 2: (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride / tetrahydrofuran; water / 0.25 h / 130 °C / Sealed tube; Microwave irradiation
  • 63
  • [ 1227210-33-4 ]
  • C10H18N4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-Bromosuccinimide / dichloromethane / 12 h / 20 °C 2: (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride / tetrahydrofuran; water / 0.25 h / 130 °C / Sealed tube; Microwave irradiation 3: hydrogen; palladium 10% on activated carbon / methanol; ethyl acetate / 12 h / 20 °C / 2250.23 Torr
  • 64
  • [ 1227210-33-4 ]
  • C20H16N2O3 [ No CAS ]
  • C27H26N6O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
8 mg With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h; 1.3 Example 1. Synthesis of Compound ID1. Step 3. To a solution of IB (7 mg, 0.02 mmol) and 5-methyl-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazin-2 -amine (6 mg, 0.04 mmol) in DMF were added diisopropylethylamine (DIEA, 0.007 mL, 0.04 mmol) and HATU (15 mg, 0.04 mmol). The reaction was stirred at room temperature for 2 hrs and diluted with water. The mixture was concentrated and purified by C-18 column chromatography to give ID1 (8 mg).
  • 65
  • [ 1201935-41-2 ]
  • [ 1227210-33-4 ]
  • 2-({5-chloro-2-[(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino]pyridin-4-yl}amino)-N-methoxybenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
15% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 150℃; for 0.833333h; Microwave irradiation; 8.4 Step 4: 2-({5-Chloro-2-[(5-methyl-4,5,6,7-tetrahydropyrrolo[1,5-a]pyrazin-2-yl)amino]pyridine- 4-yl}amino)-N-methoxybenzamide Add 2-[(2,5-dichloropyridin-4-yl)amino]-N-methoxybenzamide to a 20 mL microwave tube(0.250g, 0.801mmol),5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (0.16 g, 1.05 mmol),Barium carbonate (0.652 g, 2.0 mmol), XantPhos (0.139 g, 0.24 mol), Pd2 (dba) 3 (0.149 g, 0.16 mmol),And 10mL of 1,4-dioxane, under nitrogen protection,The reaction was carried out in a microwave reactor at 150 ° C for 50 min.After the reaction was completed by TLC, celite was filtered, washed with EtOAc (30 mL), EtOAc, EtOAc EtOAc EtOAc. After 30 min, suction filtration gave 0.05 g of dry white solid, yield 15%.
  • 66
  • 1-(2-bromoethyl)-3-nitro-1H-pyrazole-5-carboxylic acid ethyl ester [ No CAS ]
  • [ 1227210-33-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: water / 1 h / 20 °C 2: borane-THF / tetrahydrofuran / 6 h / 45 °C 3: palladium 10% on activated carbon; hydrogen / methanol / 20 °C / 760.05 Torr
  • 67
  • [ 1227210-33-4 ]
  • 8-cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile [ No CAS ]
  • 8-cyclopentyl-2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
In toluene at 100℃; for 1h; S16.1 Step-1: Synthesis of 8-cyclopentyl-2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile To a stirred solution of 8-cyclopentyl-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine- 6-carbonitrile (100 mg, 0.33 mmol, 1 equiv) in toluene (5 mL), was added 5-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-amine (55 mg, 0.36 mmol, 1.1 equiv). The resultant reaction mixture was stir at 100°C for 1h. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was removed und reduced pressure to obtain crude which was purified by recrystallization with methanol to obtain desired product. LCMS: 391 [M+H] +
Same Skeleton Products
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