[ CAS No. 578008-32-9 ] {[proInfo.proName]}

Name: 578008-32-9|tert-Butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate|97%
Brand: Ambeed
SKU: A194750
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Quality Control of [ 578008-32-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 578008-32-9 ]

Product Details of [ 578008-32-9 ]

CAS No. :	578008-32-9	MDL No. :	MFCD13252375
Formula :	C₉H₁₅N₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GJDCNROAKOCYIQ-UHFFFAOYSA-N
M.W :	197.23	Pubchem ID :	11321537
Synonyms :

Safety of [ 578008-32-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 578008-32-9 ]

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

Upstream synthesis route of [ 578008-32-9 ]
Downstream synthetic route of [ 578008-32-9 ]

[ 578008-32-9 ] Synthesis Path-Upstream 1~5

1
[ 31230-17-8 ]
[ 24424-99-5 ]
[ 1065204-79-6 ]
[ 578008-32-9 ]

Yield	Reaction Conditions	Operation in experiment
59%	With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2.5 h;	S-Ammo-S-methyl-pyrazole-l-carboxylic acid tert-butγl esterNaH (95percent, 0.57g, 22.7mmol) was added slowly to a 0⁰C solution of 3-Amino-5- methylpyrazole (2.Og, 20.6mmol) in THF (40ml). BoC₂O (4.94g, 22.7mmol) was added after 30 min and the mixture was allowed to warm to room temperature. After stirring for 2 h at room temperature, the mixture was poured into a saturated aqueous solution of NaHCO₃. The aqueous phase was extracted with CHCI₃. The combined organic phases were dried over Na₂SO₄. Removal of the solvent in vacuum gave a crude mixture of the title compound and its 2-carboxylic acid tert.- butyl ester isomer, which were separated by chromatography on silica in ethyl acetate / heptane 2:1. Yield 2.4g, 59percent.¹H-NMR: (400 MHz, D₆-DMSO) 5.60 (IH, s), 5.27 (2H, s), 2.34 (3H, s), 1.51 (9H, s); MS (ESI⁺) = 198.26 (MH-H)⁺.
48%	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 2.5 h;	Step E: Preparation of tert-butyl 3 -amino-5 -methyl- lH-pyrazole-1- carboxylate.To a stirred solution of 3 -amino-5 -methyl-pyrazole (1.94 g, 20 mmol) in N, N- dimethylformamide (20 mL) at 0 °C was added 60percent sodium hydride/mineral oil (880 mg, 22 mmol) and the resulting mixture was stirred at rt for 30 min. Di-tert-butyl dicarbonate (4.8 g, 22 mmol) was slowly added and the resulting mixture was stirred at rt for 2 h. The mixture was then poured into saturated aq sodium hydrogen carbonate and extracted with EtOAc. The combined organic layers were dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography to afford tert-butyl 3 -amino-5 -methyl- 1H- pyrazole-l-carboxylate (1.9 g, 48percent) and tert-butyl 5 -amino-3 -methyl- lH-pyrazole-1- carboxylate (1.1 g, 28percent). For tert-butyl 3 -amino-5 -methyl- lH-pyrazole-l-carboxylate 1H NMR (400 MHz, DMSO-d₆) δ 5.60 (s, 1H), 5.28 (s, 2H), 2.34 (s, 3H), 1.51 (s, 3H). For tert-butyl 5 -amino-3 -methyl- lH-pyrazole-l-carboxylate 1H NMR (400 MHz, DMSO-de) δ 6.22 (s, 2H), 5.15 (s, 1H), 2.00 (s, 3H), 1.54 (s, 3H); LC-MS (ESI) m/z 198 (M+H)⁺
38%	Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 20℃; for 5.5 h; Inert atmosphere	To a suspension of NaH (220 mg, 5.50 mmol) in anhydrous THF (3.5 mL) was added a solutionof 3-amino-5-methyl-1H-pyrazole (500 mg, 5.00 mmol) in anhydrous THF (6.5 mL) at 0 °C under argon atmosphere. After stirring for 30 min, Boc2O (1.31 mL, 5.50 mmol) was added and stirred at rt for 5.5 h. After the completion of the reaction, the mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (4 × 75 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation. Purification by column chromatography (1:1 → 1:2 hexanes/EtOAc) yielded S1r(377 mg, 38percent) as a light brown solid and S1r' (472 mg, 48percent) as a white solid.

Reference： [1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 9, p. 2114 - 2124
[2] Patent: WO2006/32518, 2006, A1, . Location in patent: Page/Page column 200
[3] Patent: WO2012/30944, 2012, A2, . Location in patent: Page/Page column 81-82
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 9, p. 2114 - 2124
[5] Nucleosides, Nucleotides and Nucleic Acids, 2014, vol. 33, # 8, p. 552 - 582

2
[ 31230-17-8 ]
[ 24424-99-5 ]
[ 578008-32-9 ]

Yield	Reaction Conditions	Operation in experiment
40%	Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h; Stage #2: at 0 - 20℃; for 2 h;	PREPARATION 19; feri-Butyl 3-amino- -methyl-1 H-pyrazole-1 -car boxy late; Sodium hydride (60percent dispersion in mineral oil, 0.81 g, 33.96 mmol) was added slowly to a stirred suspension of 5-methyl-1 H-pyrazol-3-amine (3.00 g, 30.90 mmol) in tetrahydrofuran (150 mL) at 0 °C. The mixture was stirred for 30 minutes, then di-tert- butyl dicarbonate (7.40 g, 33.96 mmol) was added to the reaction. The mixture was stirred and warmed to room temperature. After 2 hours, saturated aqueous sodium hydrogencarbonate solution was added to the reaction and the mixture was extracted with chloroform. The organic layer was washed with brine, dried (Na₂S0₄) and evaporated. Followed by purification of the crude product by flash chromatography (2.44 g, 40percent).LRMS (m/z): 198 (M+1 )⁺.1 H NMR (400 MHz, METHANOL-^) δ ppm 1.61 (s, 9 H) 2.10 (s, 3 H) 4.85 (s, 2 H) 5.24 (s, 1 H)
40%	Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h; Stage #2: at 20℃; for 2 h;	Sodium hydride (60percent dispersion in mineral oil, 0.81 g, 33.96 mmol) was added slowly to a stirred suspension of 5-methyl-1H-pyrazol-3-amine (3.00 g, 30.90 mmol) in tetrahydrofuran (150 mL) at 0 °C. The mixture was stirred for 30 minutes, then di-tert-butyl dicarbonate (7.40 g, 33.96 mmol) was added to the reaction. The mixture was stirred and warmed to room temperature. After 2 hours, saturated aqueous sodium hydrogencarbonate solution was added to the reaction and the mixture was extracted with chloroform. The organic layer was washed with brine, dried (Na₂SO₄) and evaporated. Followed by purification of the crude product by flash chromatography (2.44 g, 40percent).LRMS (m/z): 198 (M+1)⁺.1 H NMR (400 MHz, METHANOL-d₄) δ ppm 1.61 (s, 9 H) 2.10 (s, 3 H) 4.85 (s, 2 H) 5.24 (s, 1 H)

Reference： [1] Patent: WO2012/41476, 2012, A1, . Location in patent: Page/Page column 56
[2] Patent: EP2441755, 2012, A1, . Location in patent: Paragraph 0171
[3] Patent: WO2003/105853, 2003, A1, . Location in patent: Page 69
[4] Patent: WO2007/17649, 2007, A1, . Location in patent: Page/Page column 64
[5] Patent: WO2016/193939, 2016, A1, . Location in patent: Page/Page column 81; 82
[6] Bioorganic and Medicinal Chemistry Letters, 2018,

3
[ 24424-99-5 ]
[ 578008-32-9 ]

Yield	Reaction Conditions	Operation in experiment
23%	Stage #1: With sodium hydride In DMF (N,N-dimethyl-formamide) at 0℃; for 0.5 h; Stage #2: at 0 - 20℃; for 1.08333 h;	tert-ButYl 3-amino-5-methyl-lH-pyrazole-1-carboxylate; 5-Methyl-lH-pyrazol-3-amine (800 mg, 8.25 mmol) was dissolved in DMF (10 mL) at 0 °C and treated with sodium hydride (336 mg, 8.25 mmol) followed by stirring for a further 30 min. Warmed di-tert-butyl dicarbonate (1.80 g, 8.25 mmol) was then slowly added via syringe over 5 min and the reaction was allowed to warm to room temperature and stirred for a further 1 h. The reaction was taken up in saturated aqueous sodium hydrogencarbonate (50 mL) and ethyl acetate (100 mL). The organic layer was separated then dried (MgS04), filtered and evaporated. Purification by column chromatography (eluting with 1: 1 ethyl acetate: hexanes to 100percent ethyl acetate) afforded the title compound (380 mg, 23percent) as a colourless oil. 'H NMR 6 (CDC13) : 1.62 (s, 9H), 2.43 (s, 3H), 3. 87 (br. s, 2H), 5.60 (s, 1H)
23%	Stage #1: With sodium hydride In DMF (N,N-dimethyl-formamide) at 0℃; for 0.5 h; Stage #2: at 0 - 20℃; for 1.08333 h;	5-Methyl-1H pyrazol-3-arnine (800 mg, 8.25 mmol) was dissolved in DMF (10 mL) at 0 °C and treated with sodium hydride (336 mg, 8.25 mmol) followed by stirring for a further 30 min. Warmed di-tert-butyl dicarbonate (1.80 g, 8.25 mmol) was then slowly added via syringe over 5 min and the reaction was allowed to warm to RT and stirred for a further 1 h. The reaction was taken up in saturated aqueous sodium hydrogencarbonate (50 mL) and ethyl acetate (100 mL). The organic layer was separated then dried (MgS04), filtered and evaporated. Purification by column chromatography, eluting with 50percent to 100percent ethyl acetate in hexanes, afforded the title compound as a colourless oil (380 mg, 23percent). ¹H NMR No. (CDCl3) : 1.62 (s, 9H), 2.43 (s, 3H), 3.87 (br s, 2H), 5.60 (s, 1H).

Reference： [1] Patent: WO2005/80359, 2005, A1, . Location in patent: Page/Page column 100-101
[2] Patent: WO2005/121110, 2005, A1, . Location in patent: Page/Page column 94-95
[3] Patent: WO2007/7041, 2007, A1, . Location in patent: Page/Page column 222-223

4
[ 24424-99-5 ]
[ 1065204-79-6 ]
[ 578008-32-9 ]

Yield	Reaction Conditions	Operation in experiment
59%	Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: at 20℃; for 2 h;	3-Amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester: NaH (95percent, 0.57 g, 22.7 mmol) was added slowly to a 0° C. solution of 3-amino-5-methylpyrazole (2.0 g, 20.6 mmol) in THF (40 ml). Boc₂O (4.94 g, 22.7 mmol) was added after 30 min and the mixture was allowed to warm to RT. After stirring for 2 h at RT, the mixture was poured into a saturated aqueous solution of NaHCO₃. The aqueous phase was extracted with CHCl₃. The combined organic phases were dried over Na₂SO₄. Removal of the solvent in vacuum gave a crude mixture of the title compound and its 2-carboxylic acid tert.-butyl ester isomer, which were separated by chromatography on silica in EtOAc/heptane 2:1. Yield 2.4 g, 59percent. ¹H-NMR: (400 MHz, D₆-DMSO) 5.60 (1H, s), 5.27 (2H, s), 2.34 (3H, s), 1.51 (9H, s); MS (ESI⁺)=198.26 (M+H)⁺.

Reference： [1] Patent: US2007/219195, 2007, A1, . Location in patent: Page/Page column 55

5
[ 24424-99-5 ]
[ 85485-59-2 ]
[ 578008-32-9 ]

Yield	Reaction Conditions	Operation in experiment
1.48 g	With triethylamine In dichloromethane at 20℃; for 3 h;	First 5-methyl-1-phenyl-1H-pyrazol-3-amine(1.00 g of) wasdissolved in dichloromethane (50mL), trisEthylamine (1.58 mL) and di-tert-butyl dicarbonate (2.47g),and the resulting solution was stirred at room temperature3 hours. The reaction mixture was then washed with saturatedNaCl solution, and dried over sodium sulfate organic, Filtered and concentrated under reduced pressure. Bycolumn chromatography using cyclohexane / ethyl acetate on silica gel(3: 7) as eluent The crude product was purified.To give 1.48g of the title compound.

Reference： [1] Patent: CN105392365, 2016, A, . Location in patent: Paragraph 0779; 0780; 0781; 0782; 0783

[ 578008-32-9 ] Synthesis Path-Downstream 1~105

1
[ 75-44-5 ]
[ 578008-32-9 ]
N,N'-bis(1-tert-butyloxycarbonyl-5-methylpyrazol-3-yl)urea [ No CAS ]

Reference： [1]Synthesis,2003,p. 1815 - 1826

2
[ 3739-94-4 ]
[ 578008-32-9 ]
N,N'-bis(1-tert-butyloxycarbonyl-5-methylpyrazol-3-yl)pyridine-2,6-dicarboxylic acid diamide [ No CAS ]

Reference： [1]Synthesis,2003,p. 1815 - 1826

3
[ 79-37-8 ]
[ 578008-32-9 ]
N,N'-bis(1-tert-butyloxycarbonyl-5-methylpyrazol-3-yl)oxaldiamide [ No CAS ]

Reference： [1]Synthesis,2003,p. 1815 - 1826

4
[ 100-20-9 ]
[ 578008-32-9 ]
N,N'-bis(1-tert-butyloxycarbonyl-5-methylpyrazol-3-yl)terephthalic acid diamide [ No CAS ]

Reference： [1]Synthesis,2003,p. 1815 - 1826

5
[ 99-63-8 ]
[ 578008-32-9 ]
N,N'-bis(1-tert-butyloxycarbonyl-5-methylpyrazol-3-yl)isophthalic acid diamide [ No CAS ]

Reference： [1]Synthesis,2003,p. 1815 - 1826

6
[ 5659-93-8 ]
[ 578008-32-9 ]
N,N'-bis(1-tert-butyloxycarbonyl-5-methylpyrazol-3-yl)-2,2-dimethylmalonic acid diamide [ No CAS ]

Reference： [1]Synthesis,2003,p. 1815 - 1826

7
[ 24424-99-5 ]
[ 578008-32-9 ]

Yield	Reaction Conditions	Operation in experiment
23%		tert-ButYl 3-amino-5-methyl-lH-pyrazole-1-carboxylate; 5-Methyl-lH-pyrazol-3-amine (800 mg, 8.25 mmol) was dissolved in DMF (10 mL) at 0 C and treated with sodium hydride (336 mg, 8.25 mmol) followed by stirring for a further 30 min. Warmed di-tert-butyl dicarbonate (1.80 g, 8.25 mmol) was then slowly added via syringe over 5 min and the reaction was allowed to warm to room temperature and stirred for a further 1 h. The reaction was taken up in saturated aqueous sodium hydrogencarbonate (50 mL) and ethyl acetate (100 mL). The organic layer was separated then dried (MgS04), filtered and evaporated. Purification by column chromatography (eluting with 1: 1 ethyl acetate: hexanes to 100% ethyl acetate) afforded the title compound (380 mg, 23%) as a colourless oil. 'H NMR 6 (CDC13) : 1.62 (s, 9H), 2.43 (s, 3H), 3. 87 (br. s, 2H), 5.60 (s, 1H)
23%		5-Methyl-1H pyrazol-3-arnine (800 mg, 8.25 mmol) was dissolved in DMF (10 mL) at 0 C and treated with sodium hydride (336 mg, 8.25 mmol) followed by stirring for a further 30 min. Warmed di-tert-butyl dicarbonate (1.80 g, 8.25 mmol) was then slowly added via syringe over 5 min and the reaction was allowed to warm to RT and stirred for a further 1 h. The reaction was taken up in saturated aqueous sodium hydrogencarbonate (50 mL) and ethyl acetate (100 mL). The organic layer was separated then dried (MgS04), filtered and evaporated. Purification by column chromatography, eluting with 50% to 100% ethyl acetate in hexanes, afforded the title compound as a colourless oil (380 mg, 23%). ¹H NMR No. (CDCl3) : 1.62 (s, 9H), 2.43 (s, 3H), 3.87 (br s, 2H), 5.60 (s, 1H).
		5-Methyl-lH-pyrazol-3-amine (800 mg, 8.25 mmol) was dissolved in DMF (10 mL) at 0 0C and treated with sodium hydride (336 mg, 8.25 mmol) followed by stirring for a further 30 minutes. Warmed di-fert-butyl dicarbonate (1.80 g, 8.25 mmol) was then slowly added via syringe over 5 min and the reaction was allowed to warm to RT and stirred for a further 1 hour. The reaction was taken up in saturated aqueous sodium hydrogencarbonate (50 mL) and ethyl acetate (100 mL). The organic layer was separated then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 50-100% ethyl acetate in isohexane, afforded the title compound as a colourless oil (380 mg). 1E NMR delta (CDCl3): 1.62 (s, 9H), 2.43 (s, 3H), 3.87 (br. s, 2H), 5.60 (s, IH)

Reference： [1]Patent: WO2005/80359,2005,A1 .Location in patent: Page/Page column 100-101
[2]Patent: WO2005/121110,2005,A1 .Location in patent: Page/Page column 94-95
[3]Patent: WO2007/7041,2007,A1 .Location in patent: Page/Page column 222-223

8
[ 578008-32-9 ]
[ 1056156-03-6 ]

Reference： [1]Patent: WO2003/105853,2003,A1 .Location in patent: Page 69

9
[ 863504-75-0 ]
[ 578008-32-9 ]
tert-butyl 3-({3-[(1S)-2-methoxy-1-methylethyloxy]-5-[4-(methylsulfonyl)phenoxy]benzoyl}amino)-5-methyl-1H-pyrazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); for 72h;	tert-Butyl 3-({3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-[4- (methylsulfonyl)phenoxy]benzoyl}amino)-5-methyl-1H-pyrazole-1-carboxylate; HATU (500 mg, 1.31 mmol) was added to 3-{(1S)-2-methoxy-(1-methylethyl)oxy}-5-[4- (methylsulfonyl) phenyl] oxy} benzoic acid (400 mg, 1.05 mmol) followed by addition of DMF (6 mL), DIPEA (0.47 mL) and tert-butyl 3-amino-5-methyl-lH-pyrazole-l-carboxylate (380 mg, 1.93 mmol). The reaction was stirred under argon for 72 h, then dissolved in saturated aqueous sodium hydrogencarbonate (30 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated aqueous ammonium chloride (30 mL), then dried (MgS04), filtered and evaporated. Purification by column chromatography eluting with 1: 1 to 2: 1 ethyl acetate : hexanes afforded the title compound (500 mg, 85%) as a foam. 1H NMR 8 (CDC13) : 1.37 (d, 3H), 1.62 (s, 9H), 2.54 (s, 3H), 3.08 (s, 3H), 3.40 (s, 3H), 3.58 (m, 2H), 4.60 (m, 1H), 6. 82 (m, 2H), 7. 08 (m, 1H), 7.15 (d, 2H), 7.30 (s, 1H), 7.93 (d, 2H), 8.52 (brs, 1H); only 558 (M-H)-

Reference： [1]Patent: WO2005/80359,2005,A1 .Location in patent: Page/Page column 100

10
[ 31230-17-8 ]
[ 24424-99-5 ]
[ 1065204-79-6 ]
[ 578008-32-9 ]

Yield	Reaction Conditions	Operation in experiment
59%	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 2.5h;	S-Ammo-S-methyl-pyrazole-l-carboxylic acid tert-butgammal esterNaH (95%, 0.57g, 22.7mmol) was added slowly to a 00C solution of 3-Amino-5- methylpyrazole (2.Og, 20.6mmol) in THF (40ml). BoC2O (4.94g, 22.7mmol) was added after 30 min and the mixture was allowed to warm to room temperature. After stirring for 2 h at room temperature, the mixture was poured into a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with CHCI3. The combined organic phases were dried over Na2SO4. Removal of the solvent in vacuum gave a crude mixture of the title compound and its 2-carboxylic acid tert.- butyl ester isomer, which were separated by chromatography on silica in ethyl acetate / heptane 2:1. Yield 2.4g, 59%.1H-NMR: (400 MHz, D6-DMSO) 5.60 (IH, s), 5.27 (2H, s), 2.34 (3H, s), 1.51 (9H, s); MS (ESI+) = 198.26 (MH-H)+.
28%; 48%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 2.5h;	Step E: Preparation of tert-butyl 3 -amino-5 -methyl- lH-pyrazole-1- carboxylate.To a stirred solution of 3 -amino-5 -methyl-pyrazole (1.94 g, 20 mmol) in N, N- dimethylformamide (20 mL) at 0 C was added 60% sodium hydride/mineral oil (880 mg, 22 mmol) and the resulting mixture was stirred at rt for 30 min. Di-tert-butyl dicarbonate (4.8 g, 22 mmol) was slowly added and the resulting mixture was stirred at rt for 2 h. The mixture was then poured into saturated aq sodium hydrogen carbonate and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography to afford tert-butyl 3 -amino-5 -methyl- 1H- pyrazole-l-carboxylate (1.9 g, 48%) and tert-butyl 5 -amino-3 -methyl- lH-pyrazole-1- carboxylate (1.1 g, 28%). For tert-butyl 3 -amino-5 -methyl- lH-pyrazole-l-carboxylate 1H NMR (400 MHz, DMSO-d6) delta 5.60 (s, 1H), 5.28 (s, 2H), 2.34 (s, 3H), 1.51 (s, 3H). For tert-butyl 5 -amino-3 -methyl- lH-pyrazole-l-carboxylate 1H NMR (400 MHz, DMSO-de) delta 6.22 (s, 2H), 5.15 (s, 1H), 2.00 (s, 3H), 1.54 (s, 3H); LC-MS (ESI) m/z 198 (M+H)+
48%; 38%		To a suspension of NaH (220 mg, 5.50 mmol) in anhydrous THF (3.5 mL) was added a solutionof 3-amino-5-methyl-1H-pyrazole (500 mg, 5.00 mmol) in anhydrous THF (6.5 mL) at 0 C under argon atmosphere. After stirring for 30 min, Boc2O (1.31 mL, 5.50 mmol) was added and stirred at rt for 5.5 h. After the completion of the reaction, the mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (4 × 75 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation. Purification by column chromatography (1:1 ? 1:2 hexanes/EtOAc) yielded S1r(377 mg, 38%) as a light brown solid and S1r' (472 mg, 48%) as a white solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 2114 - 2124
[2]Patent: WO2006/32518,2006,A1 .Location in patent: Page/Page column 200
[3]Patent: WO2012/30944,2012,A2 .Location in patent: Page/Page column 81-82
[4]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 2114 - 2124
[5]Nucleosides, nucleotides and nucleic acids,2014,vol. 33,p. 552 - 582

11
4-Bromo-2-(2-chloro-4-trifluoromethyl-phenyl)-2H-phthalazin-1-one [ No CAS ]
[ 578008-32-9 ]
2-(2-chloro-4-trifluoromethyl-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-phthalazin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 18h;	Typical procedure for the Buchwald reaction with terf-butoxycarbonyl protected pyrazole:2-(2-Chloro-4-trifluoromethyl-phenyl)-4-(5-methyl-lH-pyrazol-3-ylamino)-2H- phthalazin- 1 -one4-Bromo-2-(2-cUoro-4-trifluoromethyl-phenyl)-2H-phthalazin-l-one (obtained from the above phthalazine-l,4-dione by bromination with POBr3 in analogy to Method R, as reported above) (0.15g, 0.37mmol), 3-amino-5-methyl-pyrazole-l- carboxylic acid tert-butyl ester (0.08Og, 0.41mmol), Cs2CO3 (0.033g, 0.34mmol), tris-(dibenzylideneacetone)-dipalladium (0.017g, 0.019mmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (0.022g, 0.037mmol) in 2 ml dry dioxane under nitrogen were heated to 100C for 18 hours, and then allowed to cool to room temperature. H2O was added and the solvent was evaporated in vacuum. The resulting solid was collected by filtration. Purification of the raw product by preparative HPLC gave the title compound (0.069g, 44% yield). 1H- EPO <DP n="202"/>NMR: (400 MHz, D6-DMSO) 11.92 (IH, s), 9.34 (IH, s), 8.54 (IH, d), 8.35 (IH, d), 8.14 (IH, s), 8.01 (IH, t), 7.92 (3H, m), 6.06 (IH, s), 2.14 (3H, s); MS (ESI+) = 420.23 (M+H)+.
44%	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 18h;	2-(2-Chloro-4-trifluoromethyl-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-phthalazin-1-one: 4-Bromo-2-(2-chloro-4-trifluoromethyl-phenyl)-2H-phthalazin-1-one (obtained from the above phthalazine-1,4-dione by bromination with POBr3 in analogy to Method R, as reported above) (0.15 g, 0.37 mmol), <strong>[578008-32-9]3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester</strong> (0.080 g, 0.41 mmol), Cs2CO3 (0.033 g, 0.34 mmol), tris-(dibenzylideneacetone)-dipalladium (0.017 g, 0.01 9 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.022 g, 0.037 mmol) in 2 ml dry dioxane under nitrogen were heated to 100 C. for 18 hours, and then allowed to cool to RT. H2O was added and the solvent was evaporated in vacuum. The resulting solid was collected by filtration. Purification of the raw product by preparative HPLC gave the title compound (0.069 g, 44% yield). 1H-NMR: (400 MHz, D6-DMSO) 11.92 (1H, s), 9.34 (1H, s), 8.54 (1H, d), 8.35 (1H, d), 8.14 (1H, s), 8.01 (1H, t), 7.92 (3H, m), 6.06 (1H, s), 2.14 (3H, s); MS (ESI+)=420.23 (M+H)+.

Reference： [1]Patent: WO2006/32518,2006,A1 .Location in patent: Page/Page column 200; 201
[2]Patent: US2007/219195,2007,A1 .Location in patent: Page/Page column 55-56

12
[ 880488-51-7 ]
[ 578008-32-9 ]
N-Ethyl-N-{4-[4-(5-methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-phthalazin-2-yl]-phenyl}-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); at 100℃; for 18h;	JV-Ethyl-N-{4- [4- ( 5-methyl- lH-pyrazol-3-ylamino)- 1-oxo- lH-phthalazin-2-yl] - phenylj-acetamideN-[4-(4-Bromo-l-oxo-lH-phthalazin-2-yl)-phenyl]-iV-ethyl-acetamide (O.lOg, 0.027mmol), 3-arnino-5-methyl-pyrazole-l-carboxylic acid tert-butyl ester (0.006g,0.03mmol), Cs2CO3 (O.Olg, 0.03mmol), tris-(dibenzylideneacetone)-dipalladium(O.OOlg, O.OOlmmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(0.002g, 0.003mmol) under nitrogen were heated to 1000C for 18 hours, and then allowed to cool to room temperature. H2O was added and the solvent was evaporated in vacuum. Purification via chromatography gave the title compound(0.003g, 23% yield).1H-NMR: (400 MHz, D6-DMSO) 9.28 (IH, s), 8.51 (IH, d), 8.38 (IH, d), 7.99 (IH, t), 7.91 (IH, t), 7.87 (2H, d), 7.41 (2H, d), 6.25 (IH, s), 3.69 (2H, q), 2.20 (3H, s), 1.81 (3H, s), 1.O7 (3H, t); MS (ESI+) = 403.34 (M+H)+.

Reference： [1]Patent: WO2006/32518,2006,A1 .Location in patent: Page/Page column 204

13
[ 24424-99-5 ]
[ 1065204-79-6 ]
[ 578008-32-9 ]

Yield	Reaction Conditions	Operation in experiment
59%		3-Amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester: NaH (95%, 0.57 g, 22.7 mmol) was added slowly to a 0 C. solution of 3-amino-5-methylpyrazole (2.0 g, 20.6 mmol) in THF (40 ml). Boc2O (4.94 g, 22.7 mmol) was added after 30 min and the mixture was allowed to warm to RT. After stirring for 2 h at RT, the mixture was poured into a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with CHCl3. The combined organic phases were dried over Na2SO4. Removal of the solvent in vacuum gave a crude mixture of the title compound and its 2-carboxylic acid tert.-butyl ester isomer, which were separated by chromatography on silica in EtOAc/heptane 2:1. Yield 2.4 g, 59%. 1H-NMR: (400 MHz, D6-DMSO) 5.60 (1H, s), 5.27 (2H, s), 2.34 (3H, s), 1.51 (9H, s); MS (ESI+)=198.26 (M+H)+.

Reference： [1]Patent: US2007/219195,2007,A1 .Location in patent: Page/Page column 55

14
[ 1271-42-7 ]
[ 76-05-1 ]
[ 578008-32-9 ]
[ 850134-92-8 ]

Reference： [1]Inorganica Chimica Acta,2005,vol. 358,p. 1151 - 1161

16
[ 1065266-69-4 ]
[ 578008-32-9 ]
[ 1065267-52-8 ]

Yield	Reaction Conditions	Operation in experiment
		A reaction vessel was charged with 6-chloro-N-[(l£)-l-(5-fluoropyrimidm-2-yl)emyl]pyrazm-2- amine (Intermediate 9, 118 mg, 0.47 mmol), tert-butyl 3-amino-5-methyl-lH-pyrazole-l- carboxylate (Intermediate 10, 103 mg, 0.52 mmol), Cs2CO3 (459 mg, 1.14 mmol), Xantphos (14 mg, 0.024 mmol) and Pd2(dba)3 (7 mg, 0.012 mmol) and purged with nitrogen for 10 minutes. Dioxane (0.15 M) was then added to the tube and the reaction mixture was purged with nitrogen for another 10 minutes. The reaction mixture was heated at 1000C overnight. The reaction mixture was filtered through a plug of diatomaceous earth, diluted with EtOAc, washed with nuaetaCO3(aq) and brine, and dried (Na2SO4). The solvent was removed in vacuo to give a yellow residue (181 mg), which was purified with a Gilson column (10-35% MeCN/H2O, 15 min). The title compound was collected as a yellow solid (18.9 mg). LCMS: [M+H]+ 315. 1H NMR (300 MHz5 DMSO-d6) delta: 9.69 (s, 1 H) 8.94 (s, 2 H) 7.77 (br.s, 1 H) 7.53 (s, 1 H) 7.43 <n="81"/>(s, 1 H) 6.03 (s, 1 H) 5.68 (s, 1 H) 5.24 (m, 1 H) 2.27 (s, 3 H) 1.60 (d, 3 H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6524 - 6528
[2]Patent: WO2008/117050,2008,A1 .Location in patent: Page/Page column 79-80

17
[ 1075757-05-9 ]
[ 578008-32-9 ]
[ 1075757-34-4 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 95℃; for 8h;	Intermediate 90(S)-4-(3-((tert-Butyldimethylsilyloxy)methyl)morpholino)-6-(l-(3,5-difluoropyridin-2-vD-2- methoxyethoxy)-5-fluoro-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-2-amine (3,S<)-3-([fert-Butyl(dimethyl)silyl]oxy}methyl)-4-{2-chloro-6-[l-(3,5-difluoropyridin-2-yl)-2- methoxyethoxy]-5-fluoropyrimidin-4-yl}morpholine (Intermediate 62), tert-butyl 3-amino-5- methyl-lH-pyrazole-1-carboxylate (Intermediate 10), BINAP, Pd2(dba)3, and CS2CO3 in dioxane (2 ml) was heated at 950C for 8h. LCMS indicated complete reaction. Methanol (1 ml) was added and the reaction was stirred at r.t for Ih. Solvent was removed under reduced pressure and the reaction mixture was purified by ISCO column. The material obtained was directly used in the subsequent step without further purification. LCMS: 610[M+eta]+.

Reference： [1]Patent: WO2008/132502,2008,A1 .Location in patent: Page/Page column 110

18
[ 1088937-39-6 ]
[ 578008-32-9 ]
[ 1088937-43-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 140 - 170℃; for 1h;microwave irradiarion;	Nitrogen was bubbled through a mixture of (S) -2,6- dichloro-4- (3-fluororhoyrrolidin-1-yl) pyridine (600 mg, 2.6 mmol) , tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate(510 mg, 2.6 mmol), Pd2dba3 (119 mg) , xantphos (150 mg) , and sodium carbonate (382 mg, 3.6 mmol) in dioxane (10 mL) . The mixture was heated to 140 0C for 45 minutes and then to 170 0C for 15 minutes in the microwave. After filtration through Celite and a dioxane rinse, the solvents were removed under reduced pressure. The residue was purified by column chromatography (SiO2 (75 mL) , CH2C12/2.5-7% 2-propanol; TLC: CH2C12/5% 2-propanol, Rf=O.3) to yield 230 mg of the desired product as an off-white solid (HPLC: Rf=7.341 minutes) .

Reference： [1]Patent: WO2008/147626,2008,A2 .Location in patent: Page/Page column 39-40

19
[ 31230-17-8 ]
[ 24424-99-5 ]
[ 578008-32-9 ]

Yield	Reaction Conditions	Operation in experiment
40%		PREPARATION 19; feri-Butyl 3-amino- -methyl-1 H-pyrazole-1 -car boxy late; Sodium hydride (60% dispersion in mineral oil, 0.81 g, 33.96 mmol) was added slowly to a stirred suspension of 5-methyl-1 H-pyrazol-3-amine (3.00 g, 30.90 mmol) in tetrahydrofuran (150 mL) at 0 C. The mixture was stirred for 30 minutes, then di-tert- butyl dicarbonate (7.40 g, 33.96 mmol) was added to the reaction. The mixture was stirred and warmed to room temperature. After 2 hours, saturated aqueous sodium hydrogencarbonate solution was added to the reaction and the mixture was extracted with chloroform. The organic layer was washed with brine, dried (Na2S04) and evaporated. Followed by purification of the crude product by flash chromatography (2.44 g, 40%).LRMS (m/z): 198 (M+1 )+.1 H NMR (400 MHz, METHANOL-^) delta ppm 1.61 (s, 9 H) 2.10 (s, 3 H) 4.85 (s, 2 H) 5.24 (s, 1 H)
40%		Sodium hydride (60% dispersion in mineral oil, 0.81 g, 33.96 mmol) was added slowly to a stirred suspension of 5-methyl-1H-pyrazol-3-amine (3.00 g, 30.90 mmol) in tetrahydrofuran (150 mL) at 0 C. The mixture was stirred for 30 minutes, then di-tert-butyl dicarbonate (7.40 g, 33.96 mmol) was added to the reaction. The mixture was stirred and warmed to room temperature. After 2 hours, saturated aqueous sodium hydrogencarbonate solution was added to the reaction and the mixture was extracted with chloroform. The organic layer was washed with brine, dried (Na2SO4) and evaporated. Followed by purification of the crude product by flash chromatography (2.44 g, 40%).LRMS (m/z): 198 (M+1)+.1 H NMR (400 MHz, METHANOL-d4) delta ppm 1.61 (s, 9 H) 2.10 (s, 3 H) 4.85 (s, 2 H) 5.24 (s, 1 H)
		1.1 -Diniethylethyl 3-amino-5-methyl- lH-pyrazole- 1 -carboxylate; 5-Methyl-lH-pyrazol-3-amine (800 mg, 8.25 mmol) was dissolved in DMF (10 mL) at 0 0C and treated with sodium hydride (336 mg, 8.25 mmol) followed by stirring for a further 30 minutes. Warmed di-tert-butyl dicarbonate (1.80 g, 8.25 mmol) was then slowly added via syringe over 5 min and the reaction was allowed to warm to RT and stirred for a further 1 hour. The reaction was taken up in saturated aqueous sodium hydrogencarbonate (50 mL) and ethyl acetate (100 mL). The organic layer was separated then dried (MgSO4), filtered and evaporated. Purification by column chromatography,eluting with 50-100% ethyl acetate in isohexane, afforded the title compound as a colourless oil (380 mg). 1R NMR delta (CDCl3): 1.62 (s, 9Eta), 2.43 (s, 3H), 3.87 (s, 2H), 5.60 (s, IH)

		60% NaH (0.Sg, 20.6mmol) was added to a stined solution of S-methyl-1H-pyrazol-3- amine (2g, 20.6mmol) in THF (SOmL) at 0 C over a period of 10mm followed by the addition of Boc anhydride (4.SmL, 20.6mmol). The reaction mass was stined at room temperature over a period of 2h. The reaction mass was diluted with ethyl acetate and water. The separated organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure, the residue was purified by combiflash by eluting with 30% ethyl acetate-hexane system to afford the title compound (1.8g, 80%) LCMS: mlz = 198.0 (M+H).
	With potassium hydroxide; In dichloromethane; water; at 20℃; for 3h;	General procedure: In a one neck round bottom flask placed, taken 3-substituted-1H-pyrazol-5-amine (1eq) in dichloromethane and added 4N KOH (8eqin water). The reaction mixture was allowed to stir at room temperature followed by addition ofBocanhydride (1.2eq) in small batches. The reaction mixture was allowed to stir for 3h and reaction completion was monitored by thin layer chromatography (1:1 hexane: ethyl acetate). The reaction mixture was diluted in CH2Cl2, washed brine and dried with MgSO4. The crude product was purified using silica gel column chromatography.

Reference： [1]Patent: WO2012/41476,2012,A1 .Location in patent: Page/Page column 56
[2]Patent: EP2441755,2012,A1 .Location in patent: Paragraph 0171
[3]Patent: WO2003/105853,2003,A1 .Location in patent: Page 69
[4]Patent: WO2007/17649,2007,A1 .Location in patent: Page/Page column 64
[5]Patent: WO2016/193939,2016,A1 .Location in patent: Page/Page column 81; 82
[6]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 3736 - 3740

20
[ 4774-14-5 ]
[ 578008-32-9 ]
[ 1172620-95-9 ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane; at 90℃; for 1h;Product distribution / selectivity;	2,6-Dichloropyrazine (5.0 g, 33.6 mmol), tert-butyl 3-amino-5-methyl-lH- pyrazole-1-carboxylate (6.62 g, 33.6 mmol), palladium(II) acetate (0.75 g, 3.36 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.88 g, 6.71 mmol), potassium carbonate (46.4 g, 336 mmol), and dioxane (224 mL) were combined and the mixture was degassed with nitrogen for 2 minutes before heating to 90C for one hour. The reaction was cooled to room temperature and filtered through Celite followed by washing with dichloromethane. The filtrate was condensed and the crude material was purified by silica gel chromatography (10-70% ethyl acetate in hexanes) to give the title compound as a white solid (6.43 g, 20.8 mmol, 62% yield); MS (ESI) MS (ESI) m/z 310.5 [M+l]+.

Reference： [1]Patent: WO2009/89042,2009,A1 .Location in patent: Page/Page column 109

21
[ 330786-09-9 ]
[ 578008-32-9 ]
[ 1172621-09-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane; at 90℃; for 1h;	Methyl 3,5-dichloropyrazine-2-carboxylate (2.83 g,13.7 mmol), palladium acetate (302 mg, 1.33 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (1.63 g, 2.82 mmol), potassium carbonate (18.5 g, 135 mmol), and tert- butyl 3-amino-5-methyl-lH-pyrazole-l-carboxylate (2.70 g, 13.7 mmol) were suspended in anhydrous dioxane (95 mL). The resulting mixture was degassed with nitrogen for5 minutes and stirred at 90C for one hour. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3 x 200 mL), and the organic layers were combined and dried over magnesium sulfate. After filtration, the solvent was removed in vacuo. The residue was purified by silica gel chromatography (0-60% ethyl acetate in hexanes) to give the title compound as a yellow solid (4.2Og, 11.42 mmol, 84% yield); IH NMR (400 MHz, DMSO-^6) delta ppm 1.55 (s, 9 H), 2.21 (s, 3 H), 3.86 (s, 3 H), 6.66 (s, 1 H), 8.57 (s, 1 H), 10.43 (s, 1 H); MS (ESI) m/z 368.3 [M+l]+.

Reference： [1]Patent: WO2009/89042,2009,A1 .Location in patent: Page/Page column 113

22
[ 642459-03-8 ]
[ 578008-32-9 ]
[ 1172620-93-7 ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane; at 90℃; for 1h;	tert-Buty 5-methyl-3-[6-(phenylamino)pyrazin-2-yl]amino}pyrazole- carboxylate. 6-Chloro-N-phenylpyrazin-2-amine (84 mg, 0.4 mmol), tert-butyl 3-amino-5- methyl-lH-pyrazole-1-carboxylate (98 mg, 0.5 mmol), palladium acetate (10 mg, 0.04 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (55 mg, 0.1 mmol), and potassium carbonate (560 mg, 4.0 mmol) were suspended in anhydrous dioxane (3 mL). The resulting mixture was degassed with nitrogen for 5 minutes and stirred at 90C for one hour. The reaction was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3 x 20 mL), and the organic layers were combined and dried over magnesium sulfate. After filtration, the solvent was removed in vacuo. The residue was purified by silica gel chromatography (15-75% ethyl acetate in hexanes) to give <n="95"/>the title compound as an off-white solid (68 mg, 0.19 mmol, 46% yield); 1H NMR (DMSO-^6) delta 9.45 (s, IH), 9.33 (s, IH), 7.81 (s, IH), 7.71 (s, IH), 7.52 (d, J= 8.4 Hz, 2H), 7.32 (t, J= 8.4 Hz, 2H), 7.01 (t, J= 7.6 Hz, IH), 6.53 (s, IH), 2.13 (s, 3H), 1.57 (s, 9H); MS (ESI) MS (ESI) m/z 367.3 [M+l]+.

Reference： [1]Patent: WO2009/89042,2009,A1 .Location in patent: Page/Page column 93-94

23
[ 41270-62-6 ]
[ 578008-32-9 ]
[ 1172621-06-5 ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane; at 90℃; for 1h;	2-Chloro-6-phenylpyrazine (108 mg, 0.56 mmol), tert-butyl 3-amino-5- methyl-lH-pyrazole-1-carboxylate (142 mg, 0.72 mmol), palladium(II) acetate (15 mg, 0.07 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (65 mg, 0.1 mmol), potassium carbonate (820 mg, 5.9 mmol), and dioxane (4 mL) were combined and the mixture degassed with nitrogen for 2 minutes before heating to 90C for one hour. The reaction was partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate (3x), organics were combined, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (10-65% ethyl acetate in hexanes) to give the title compound as a white solid (92 mg, 0.26 mmol, 46% yield); MS (ESI) MS (ESI) m/z 352.4 [M+l]+.

Reference： [1]Patent: WO2009/89042,2009,A1 .Location in patent: Page/Page column 108

24
[ 1172621-07-6 ]
[ 578008-32-9 ]
[ 1172621-08-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane; at 50℃; for 0.5h;	l-(3,5-Dichloropyrazin-2-yl)propan-l-one (366 mg, 1.79 mmol), tert-butyl 3 -amino-5 -methyl- l//-pyrazole-l-carboxylate (352 mg, 1.78 mmol), palladium(II) acetate (62 mg, 0.28 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (312 mg, 0.54mmol), and potassium carbonate (2.42 g, 17.5 mmol) were suspended in anhydrous dioxane (1 1 mL). The resulting mixture was degassed with nitrogen for 2 minutes and stirred at 50C for 30 minutes. The reaction was filtered through Celite, washing thoroughly with dichloromethane. The filtrate was concentrated and the crude residue was purified by silica gel chromatography (0-60% ethyl acetate in hexanes) to give the desired product as a red solid (481 mg, 1.31 mmol, 73%): 1H-NMR (CDCl3) delta 10.40 (s, IH), 8.13 (s, IH), 6.88 (s, IH), 3.12 (q, J= 7.2 Hz, 2H), 2.34 (s, 3H), 1.71 (s, 9H), 1.20 (t, J= 7.2 Hz, 3H); MS (ESI) m/z 366.3 [M+l]+.

Reference： [1]Patent: WO2009/89042,2009,A1 .Location in patent: Page/Page column 111

25
[ 1172620-94-8 ]
[ 578008-32-9 ]
C₂₀H₂₁N₇O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane; at 90℃; for 1h;	3-(6-(5-Methyl-lH-pyrazol-3-ylamino)pyrazin-2- ylamino)benzonitrile. 3-(6-chloropyrazin-2-ylamino)benzonitrile (0.32 g, 1.39 mmol), tert-butyl 3-amino-5-methyl-lH-pyrazole-l-carboxylate (0.3 g, 1.53 mmol), palladium acetate (31 mg, 10 mol%), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (160 mg, 20 mol%), and potassium carbonate (0.96g, 6.95 mmol) were suspended in dioxane (8 mL). The mixture was stirred in a sealed flask at 9O0C for 1 hour. The reaction mixture was cooled, diluted with ethyl acetate (50 mL), washed with water (50 mL), and then with brine (30 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated. The crude residue was dissolved in chloroform (20 mL) and 4N HCl in dioxane (3 mL) was added. The mixture was stirred at room temperature for 2 hours and the solvent evaporated. The crude product was purified by reverse-phase preparative HPLC (10-70% acetonitrile + 0.1% TFA in H2O + 0.1% TFA, over 30 min). Fractions containing product were condensed and neutralized on a Strata-XC ion exchange column (Phenomenex). The product was loaded and the column washed successively with water, acetonitrile, and methanol. The product was released with 5% ammonium hydroxide in methanol and product containing eluent was concentrated under reduced pressure and dried to give the title compound as a white solid (0.29g, 72% yield); m.p. 260-262C; 1H NMR (300 MHz, DMSCW6) delta 11.89 (br s, IH), 9.50 (s, IH), 9.38 (s, IH), 8.34 (s, IH), 7.89 (s, IH), 7.69 (dd, J, = 8.4 Hz, J2= 1.2 Hz, IH), 7.52 (s, IH), 7.43 (t, J= 8.4 Hz, IH), 7.31 (d, J= 7.6 Hz, IH), 6.05 (s, IH), 2.21 (s, 3H); MS (ESI) MS (ESI) m/z 292.0 [M+ 1]+.

Reference： [1]Patent: WO2009/89042,2009,A1 .Location in patent: Page/Page column 95

26
[ 578008-32-9 ]
[ 1187467-95-3 ]

Yield	Reaction Conditions	Operation in experiment
	With iodine; isopentyl nitrite; In dichloromethane; at 20℃;	Synthesis 40; 5-(5-Methyl-1H-pyrazol-3-yl)-thiophene-3-carboxylic acid methyl ester; Iodine (0.774 g, 3.0 mmol) was dissolved in DCM (5 ml_) then isoamyl nitrite (0.682 ml_, 5.1 mmol) was added followed by the slow addition of 3-amino-5-methyl-pyrazole-1- carboxylic acid tert-butyl ester (0.50 g, 2.54 mmol) as a solution in DCM (4 ml_). The reaction mixture was stirred at room temperature for 1.5 hours and then poured onto saturated sodium thiosulfate solution. The phases were separated and the aqueous layer was extracted with DCM (* 3). The organics were washed with brine then dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography on a silica Il cartridge, eluting with 2-6% ethyl acetate in pentane to give 3-iodo-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester as a solid (0.13 g).

Reference： [1]Patent: WO2009/112845,2009,A1 .Location in patent: Page/Page column 115

27
[ 1065266-78-5 ]
[ 578008-32-9 ]
[ 1065267-55-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6524 - 6528

28
3-[4-(azetidin-1-ylcarbonyl)phenyl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid [ No CAS ]
[ 578008-32-9 ]
3-[4-(azetidin-1-ylcarbonyl)phenyl]oxy}-N-(5-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 10; 3-[4-(Azetidin-l-ylcarbonyl)phenvnoxy}-iV-(5-methyl-lH-pyrazol-3-yl)- 5- [(3S)-tetr ahydrofur an-3-yloxyl benzamide; l-Chloro-N,N,2-trimethyl-l-propenylamine (0.145 mL, 1.10 mmol) was added to a solution of 3-{ [4-(azetidin- 1 -ylcarbonyl)phenyl]oxy } -5-[(3S)-tetrahydrofuran-3- yloxy]benzoic acid (350 mg, 0.92 mmol) in DCM (6 mL) and stirred at RT for 30 - 40min. 1,1-Dimethylethyl 3-amino-5-methyl-lH-pyrazole-l-carboxylate (361 mg, 1.83 mmol) and pyridine (0.148 mL, 1.83 mmol) were added and the reaction stirred at RT for 2 hours. The solvent was removed in vacuo, water (20 mL) added and the mixture extracted with ethyl acetate (3 x 20 mL). The extracts were combined and washed with 2Nu hydrochloric acid (20 mL), a saturated solution of sodium bicarbonate (20 mL), water (20 mL), brine (20 mL), dried (MgSO4) and evaporated in vacuo. The crude product was chromatographed on silica, eluting with a gradient of 0- 10% methanol in DCM, to give a white solid which was taken up in acetonitrile (2 mL) and heated in a microwave reactor at 160C for 10 minutes. EPO <DP n="62"/>The reaction mixture was evaporated and the residue chromatographed on silica, eluting with 0-5% methanol in DCM, to give the desired compound as a white foam (50 mg). 1H NMR delta (CDCl3): 2.11 - 2.29 (m, 2H), 2.32 (s, 3H), 2.32 - 2.40 (m, 2H), 3.88 - 4.02 (m, 4H), 4.23 (t, 2H), 4.35 (t, 2H), 4.95 - 4.99 (m, IH), 6.56 (s, IH), 6.71 (t, IH), 7.02 (d, 2H), 7.13 (s, IH), 7.21 (s, IH), 7.64 (d, 2H), 9.06 (s, IH); m/z 463 (M+H)+, 461 (M-H)'

Reference： [1]Patent: WO2007/17649,2007,A1 .Location in patent: Page/Page column 60-61

29
[ 1361310-88-4 ]
[ 578008-32-9 ]
[ 1361310-89-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;	Step C: To 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazoline (355 mg, 0.91 mmol) in DMF (5.0 mL) at rt were added <strong>[578008-32-9]tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate</strong> (0.448 g, 2.27 mmol) and DIEA (0.40 mL, 2.3 mmol), and the mixture was stirred at rt for 3 h. The mixture was purified by preparative reverse-phase HPLC using TFA as a modifier, and the fractions containing the desired product were neutralized with saturated aq NaHCO3 and extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (2×10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford tert-butyl 3-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazolin-4-ylamino)-5-methyl-1H-pyrazole-1-carboxylate as a clear oil (104 mg).

Reference： [1]Patent: US2012/53174,2012,A1 .Location in patent: Page/Page column 46

30
[ 1361311-02-5 ]
[ 578008-32-9 ]
[ 1361310-25-9 ]

Yield	Reaction Conditions	Operation in experiment
16%	With acetic acid; In ISOPROPYLAMIDE; at 100℃; for 5h;	Step D: To 4,8-dichloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline (263 mg, 0.77 mmol) in DMA (2.0 mL) were added <strong>[578008-32-9]tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate</strong> (300 mg, 1.53 mmol) and HOAc (0.102 mL), and the mixture was heated at 100 C. for 5 h. The mixture was allowed to cool to rt and was purified by preparative reverse-phase HPLC (diphenyl column eluting over 40 mins with a gradient of 25 to 80% acetonitrile (containing 0.05% HOAc) and water (containing 0.05% HOAc) to afford 8-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as a colorless solid (51 mg, 16%). 1H NMR (300 MHz, DMSO-d6) delta 12.23 (br s, 1H), 10.87 (br s, 1H), 8.65-8.67 (m, 2H), 8.01-8.08 (m, 3H), 7.61 (dd, J=9, 6 Hz, 1H), 5.94 (s, 1H), 2.17 (s, 3H). LCMS (ESI) m/z 405 (M+H)+.

Reference： [1]Patent: US2012/53174,2012,A1 .Location in patent: Page/Page column 50

31
[ 578008-32-9 ]
[ 1362689-58-4 ]

Reference： [1]Patent: WO2012/30944,2012,A2

32
[ 1362689-45-9 ]
[ 578008-32-9 ]
[ 1362689-46-0 ]

Yield	Reaction Conditions	Operation in experiment
51%	With CsCO3;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4a,9a-dihydro-9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene; at 70 - 100℃; for 4h;	Step F: A stirred mixture of (l-chloroisoquinolin-3-yl)(4- fluoropfienyl)methanone from Step D (125 mg, 0.44 mmol), tert-butyl 3-amino-5- methyl-lH-pyrazole-l-carboxylate from Step E (130 mg, 0.66 mmol),tris(dibenzylideneacetone)dipalladium (0) (40 mg, 0.044 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (25 mg, 0.044 mmol), and cesium carbonate (143 mg, 0.44 mmol) was heated at 70 C for 2 h and then at 100 C for 2 h. After cooling to rt, the mixture was concentrated under reduced pressure and purified by silica gel flash chromatography to afford tert-butyl 3-(3-(4- fluorobenzoyl)isoquinolin- 1 -ylamino)-5 -methyl- 1 H-pyrazole- 1 -carboxylate as a yellow solid (100 mg, 51%). LC-MS (ESI) m/z 447 (M+H)+.

Reference： [1]Patent: WO2012/30944,2012,A2 .Location in patent: Page/Page column 82

33
[ 1362689-55-1 ]
[ 578008-32-9 ]
[ 1362689-56-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium carbonate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4a,9a-dihydro-9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene; In water; toluene; at 80℃; for 15h;Inert atmosphere;	[00253] Step E: A mixture of l-bromo-3-(4-fluorophenylsulfmyl)isoquinoline(200 mg, 0.571 mmol), tert-butyl 3 -amino-5 -methyl- lH-pyrazole-l-carboxylate from Example 1 Step E (135 mg, 0.686 mmol), 4,5-bis-(diphenylphosphino)-9,9- dimethylxanthene (20 mg, 0.0343 mmol), tris(dibenzylideneacetone)dipalladium (0) (10 mg, 0.0114 mmol), 2M aq sodium carbonate (0.4 mL, 0.86 mmol), and toluene (4 mL) was degassed under Ar for 20 min, heated at 80 C for 15 h, and allowed to cool to rt. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The separated aqueous phase was extracted three times with EtOA, and the combined organic phases were dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-50% EtOAc/hexane to afford tert-butyl 3 -(3- (4-fluorophenylsulfinyl)isoquinolin- 1 -ylamino)-5 -methyl- 1 H-pyrazole- 1 -carboxylate as a pale yellow solid (216 mg, 81%). 1H NMR (300 MHz, DMSO-t/6) delta 10.45 (s, 1H), 8.65 (d, J= 8.4 Hz, 1H), 8.06 (d, J= 7.5 Hz, 1H), 7.88-7.79 (m, 4H), 7.69 (t, J = 8.4 Hz, 1H), 7.41 (t, J= 9 Hz, 2H), 6.32 (s, 1H), 3.29 (s, 3H), 1.58 (s, 9H); LC-MS (ESI) m/z 367 ([M-Boc] + H)+.
40%	With sodium carbonate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4a,9a-dihydro-9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene; In water; toluene; at 100℃; for 3.5h;Sealed tube; Microwave irradiation;	Example 13Preparation of 3-(4-fluorophenylsulfinyl)-N-( -methyl-lH-pyrazol-3- vDisoq uinolin- 1-amine[00258] A sealed tube was charged with Pd2(dibenzylideneacetone)3 (14 mg,0.016 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (26 mg, 0.047 mmol), tert-butyl 3 -amino-5 -methyl- lH-pyrazole-l-carboxylate from Example 1 Step D (177 mg, 0.89 mmol), Na2C03 (1 10 mg, 1.04 mmol), l-bromo-3-(4- fluorophenylsulfinyl)isoquinoline from Example 10 Step D (260 mg, 0.74 mmol) and degassed toluene (5.2 mL), and then water (0.014 mL) was added with stirring. The sealed tube was heated in an oil bath at 100 C for 2 h, and then in a microwave synthesizer at 100 C for 1.5 h. The mixture was filtered and the filtrate was concentrated. The solid residue was triturated with MeOH and collected by filtration and dried under reduced pressure to afford tert-butyl 3-(3-(4- fluorophenylsulfinyl)isoquinolin- 1 -ylamino)-5 -methyl- 1 H-pyrazole- 1 -carboxylate (166 mg, 40 %) as a white solid. JH NMR (300 MHz, DMSO-t/6) delta 1.52 (s, 9H), 2.25 (s, 3H), 6.46 (s, 1H), 7.40 (t, 2H), 7.83-7.90 (m, 4H), 8.00-8.03 (m, 2H), 8.17 (d, 1H), 10.61 (s, 1H); LC-MS (ESI) m/z 467 (M + H)+.

Reference： [1]Patent: WO2012/30944,2012,A2 .Location in patent: Page/Page column 91-92
[2]Patent: WO2012/30944,2012,A2 .Location in patent: Page/Page column 94-95

34
[ 1361310-96-4 ]
[ 578008-32-9 ]
[ 1361310-22-6 ]

Yield	Reaction Conditions	Operation in experiment
13%	With acetic acid; at 110℃; for 6.5h;	Step D: To 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-methylquinazoline (0.255 g, 0.79 mmol) in DMA (2 mL) were added <strong>[578008-32-9]3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester</strong> prepared according to US2007/219195 (0.31 g, 1.58 mmol) and acetic acid (0.15 mL) and the mixture was heated at 100 C. for 6.5 h. The mixture was allowed to cool to rt and then was purified by reverse phase HPLC using an ammonium acetate modifier. Fraction 1 containing pure product were combined, treated with saturated aq NaHCO3 and concentrated under reduced pressure. The aqueous residue was extracted with DCM and the combined extracts were washed with saturated aq NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (28 mg, 13%). 1H NMR (300 MHz, DMSO-d6) delta 12.15 (br s, 1H), 10.57 (s, 1H), 8.67 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.92-8.11 (m, 2H), 7.75 (d, J=7.0 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 5.96 (s, 1H), 2.59 (s, 3H), 2.17 (s, 3H); LC-MS (ESI) m/z 385 (M+H)+.

Reference： [1]Patent: US2012/53174,2012,A1 .Location in patent: Page/Page column 48

35
[ 1361310-98-6 ]
[ 578008-32-9 ]
[ 1361310-23-7 ]

Yield	Reaction Conditions	Operation in experiment
20%	With acetic acid; In ISOPROPYLAMIDE; at 100℃; for 5h;	Step D: To 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-bromo-quinazoline (0.19 g, 0.49 mmol) in DMA (1.0 mL) were added <strong>[578008-32-9]3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester</strong> (0.30 g, 1.53 mmol) and HOAc (0.065 mL, 1.1 mmol) and the mixture was heated to 100 C. for 5 h. The mixture was allowed to cool to rt and purified by reverse phase HPLC (ammonium acetate modifier). Fraction 1 containing pure product was treated with saturated aq NaHCO3 (2-4 mL) and concentrated under reduced pressure. The aqueous residue was extracted with DCM (3×30 mL) and the combined extracts were washed with sat aqueous NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to afford 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (48 mg, 20%) as a white solid. 1H NMR (300 MHz, DMSO-d6) delta 12.22 (br s, 1H), 10.87 (br s, 1H), 8.57-8.81 (m, 2H), 8.24 (d, J=7.5 Hz, 1H), 8.02 (d, J=5.3 Hz, 2H), 7.54 (t, J=7.9 Hz, 1H), 5.95 (s, 1H), 2.17 (s, 3H); LC-MS (ESI) m/z 449/451 (M+H+).

Reference： [1]Patent: US2012/53174,2012,A1 .Location in patent: Page/Page column 49

36
[ 1361311-00-3 ]
[ 578008-32-9 ]
[ 1361310-24-8 ]

Yield	Reaction Conditions	Operation in experiment
4%	With acetic acid; In ISOPROPYLAMIDE; at 100℃; for 6.5h;	Step D: To 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoroquinazoline (295 mg, 0.90 mmol) in DMA (2.2 mL) were added <strong>[578008-32-9]tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate</strong> and acetic acid (0.12 mL), and the mixture was heated at 100 C. for 6.5 h. The mixture was allowed to cool to rt and was purified by preparative reverse-phase HPLC using an ammonium acetate modifier. A later eluting fraction was treated with saturated aq NaHCO3 and concentrated under reduced pressure. The aqueous residue was extracted with DCM (3×30 mL) and the combined extracts were washed with saturated aq NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM, whereupon a precipitate formed, which was collected by filtration to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as a colorless solid (13 mg, 4%). 1H NMR (300 MHz, DMSO-d6) delta 12.23 (br s, 1H), 10.86 (br s, 1H), 8.67 (s, 1H), 8.52 (d, J=9 Hz, 1H), 8.00-8.02 (m, 2H), 7.77 (m, 1H), 7.63 (m, 1H), 5.97 (s, 1H), 2.17 (s, 3H). LCMS (ESI) m/z 389 (M+H)+.

Reference： [1]Patent: US2012/53174,2012,A1 .Location in patent: Page/Page column 49-50

37
[ 1075756-62-5 ]
[ 578008-32-9 ]
[ 1075757-37-7 ]