Name: 514816-42-3|Methyl 4-bromo-1-methyl-1H-pyrazole-5-carboxylate|98%
Brand: Ambeed
SKU: A670943
Price: 11.0 USD
Availability: InStock
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1
[ 67-56-1 ]
[ 84547-84-2 ]
[ 514816-42-3 ]

Yield	Reaction Conditions	Operation in experiment
65.4%	With thionyl chloride; for 18.0h;Reflux;	<strong>[84547-84-2]4-Bromo-2-methyl-2H-pyrazole-3-carboxylic acid</strong> (6 g, 29.3 mmol) was added to 150 mL of methanol treated with thionyl chloride (3.5 g, 29.3 mmol). The mixture was refluxed for 18 firs. Solvents were evaporated and the residue was extracted with dichloromethane and 0.5N sodium hydroxide solution. The organic layer was washed with brine and dried. After the evaporation of solvents, a white solid (4.19 g, 65.4percent yield) was obtained as the desired compound 4-bromo-2- methyl-2H-pyrazole-3-carboxylic acid methyl ester. 1H NMR (400 MHz, CDC13) delta ppm 3.97 (s, 3H), 4.19 (s, 3H), 7.51 (s, 1H). The aqueous extraction was filtered and neutralized with IN hydrochloric acid. The white solid was filtered and dried to give the unreacted starting material carboxylic acid (1.51 g).
63%		Part A. <strong>[84547-84-2]4-bromo-2-methyl-2H-pyrazole-3-carboxylic acid</strong> methyl ester To the suspension of <strong>[84547-84-2]4-Bromo-2-methyl-2H-pyrazole-3-carboxylic acid</strong> (0.205 g, 1 mmol) in methanol (2 mL) was added thionyl chloride (0.29 mL, 4 mmol). The suspension was heated at 90° C. for 18 h to give a clear solution. The solution was cooled to rt and then concentrated. The residue was dissolved in EtOAc (10 mL), and washed with sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give 0.137 g (63percent) of the methyl ester as a white solid. 1H NMR (400 MHz, CDCl3) delta: 3.95 (s, 3H), 4.17 (s, 3H), 7.53 (s, 1H). HRMS calc'd for C6H8BrN2O2: 218.9769. Found: 218.9770.

Reference： [1]Patent: WO2013/189862,2013,A1 .Location in patent: Page/Page column 17
[2]Patent: US2005/228000,2005,A1 .Location in patent: Page/Page column 30

2
[ 514816-42-3 ]
[ 98-80-6 ]
[ 23097-85-0 ]

Yield	Reaction Conditions	Operation in experiment
89.8%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; caesium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; Inert atmosphere;	1 Methyl 4-bromo-2-methyl-2H-pyrazole-3-carboxylate (438.1 mg, 2.0 mmol), phenylboronic acid (244 mg, 2.0 mmol) and cesium carbonate (1.3 g, 4.0 mmol) were dissolved in DMF and the solution was degassed with argon. To this mixture was added Pd(PPh3)4 (139 mg, 0.12 mmol). The mixture was stirred at 80 °C for 12 fir. The resulting mixture was cooled to room temperature and filtered. The solid was rinsed with THF. The filtrate was concentrated and purified by ISCO flash column chromatography (0% to 25% ethyl acetate in hexanes, 40 g silica gel) to give an oily material as methyl 2-methyl-4-phenyl-2H-pyrazole-3-carboxylate (388.6 mg, 89.8% yield). 1H NMR (400 MHz, CDC13) δ ppm 3.77 (s, 3H), 4.21 (s, 3H), 7.31-7.36 (m, 1H), 7.37-7.42 (m, 4H), 7.52 (s, 1H); LC/MS calcd for C12H12N2O2 216.0, obsd 217.0 (M+H, ES+).
89.8%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; caesium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; Inert atmosphere;
47.3%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; caesium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; Inert atmosphere;	132 [1198] compound 240a (2.0 g, 9.1 mmol), phenylboronic acid (1.3 g, 11.0 mmol),Cs2CO3 (8.9 g, 27.4 mmol) and pd(pph3)4 (211 mg, 183 umol) in DMF(30 ml) was de-gassed and then heated to 80°c for 16 hours under N2. The reaction mixture was filtered, the cake washed with ethyl acetate (30 ml x 2). The filtrate was washed with water (20 ml x 4) and the aqueous phase extracted with ethyl acetate (50 ml). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to dryness. The crude product which was purified by fcc (gradient eluent: petroleum ether/ethyl acetate from 100/0 to 50/50) to afford the title compound 240c (1.0 g, yield 47.3%) as a light yellow solid. Compound 240c: 1H NMR (400mhz, CDCl3): δ 7.52 (s, 1h), 7.40 - 7.36 (m, 4h), 7.35 - 7.31 (m, 1h), 4.20 (s, 3h), 3.76 (s, 3h). MS (ESI) m/z (M+H)+ 217.0.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2013/189862, 2013, A1 Location in patent: Page/Page column 17; 18
[2]Qian, Yimin; Hamilton, Matthew; Sidduri, Achyutharao; Gabriel, Stephen; Kondru, Rama; Narayanan, Arjun; Lucas, Matthew; Schoenfeld, Ryan C.; Laine, Dramane; Ren, Yonglin; Peng, Ruoqi; Chang, Kung-Ching; Fuentes, Maria E.; Stevenson, Christopher S.; Budd, David C.; Truitt, Terry; Hamid, Rachid; Chen, Yun; Zhang, Lin; Fretland, Adrian J.; Sanchez, Ruben Alvarez [Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7920 - 7939,20]
[3]Current Patent Assignee: BLADE THERAPEUTICS INC - WO2018/64119, 2018, A1 Location in patent: Paragraph 1198

3
[ 514816-42-3 ]
[ 5720-07-0 ]
C₁₃H₁₄N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; caesium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; Inert atmosphere;

Reference： [1]Qian, Yimin; Hamilton, Matthew; Sidduri, Achyutharao; Gabriel, Stephen; Kondru, Rama; Narayanan, Arjun; Lucas, Matthew; Schoenfeld, Ryan C.; Laine, Dramane; Ren, Yonglin; Peng, Ruoqi; Chang, Kung-Ching; Fuentes, Maria E.; Stevenson, Christopher S.; Budd, David C.; Truitt, Terry; Hamid, Rachid; Chen, Yun; Zhang, Lin; Fretland, Adrian J.; Sanchez, Ruben Alvarez [Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7920 - 7939,20]

4
[ 514816-42-3 ]
[ 5122-94-1 ]
C₁₈H₁₆N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; caesium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; Inert atmosphere;

Reference： [1]Qian, Yimin; Hamilton, Matthew; Sidduri, Achyutharao; Gabriel, Stephen; Kondru, Rama; Narayanan, Arjun; Lucas, Matthew; Schoenfeld, Ryan C.; Laine, Dramane; Ren, Yonglin; Peng, Ruoqi; Chang, Kung-Ching; Fuentes, Maria E.; Stevenson, Christopher S.; Budd, David C.; Truitt, Terry; Hamid, Rachid; Chen, Yun; Zhang, Lin; Fretland, Adrian J.; Sanchez, Ruben Alvarez [Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7920 - 7939,20]

5
[ 514816-42-3 ]
[ 1765-93-1 ]
4-(4-fluorophenyl)-2-methyl-2H-pyrazol-3-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43.6%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; caesium carbonate In toluene at 90℃; Inert atmosphere; Sealed tube;	11 4-Fluorophenylboronic acid (211 mg, 1.51 mmol), methyl 4-bromo-l-methyl-lH-pyrazole-5- carboxylate (300 mg, 1.37 mmol), cesium carbonate (893 mg, 2.74 mmol) and Pd(PPh3)4 (95 mg, 0.082 mmol) were mixed in toluene (12 mL). The mixture was degassed with nitrogen and sealed. The mixture was stirred at 90 °C overnight and then concentrated. The residue was extracted with ethyl acetate and water. The organic layer was dried and evaporated. The residue was purified by ISCO flash column chromatography (40 g silica gel, 0% to 30% ethyl acetate in hexanes) to give an oily material as 4-(4-fluorophenyl)-2-methyl-2H-pyrazol-3-carboxylic acid methyl ester (140 mg, 43.6% yield). 1H-NMR (400 MHz, CDC13) δ ppm 3.78 (s, 3H), 4.21 (s, 3H), 7.08 (t, J=8.5 Hz, 2H), 7.35 (m, 2H), 7.49 (s, 1H).
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; caesium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; Inert atmosphere;

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2013/189862, 2013, A1 Location in patent: Page/Page column 27; 28
[2]Qian, Yimin; Hamilton, Matthew; Sidduri, Achyutharao; Gabriel, Stephen; Kondru, Rama; Narayanan, Arjun; Lucas, Matthew; Schoenfeld, Ryan C.; Laine, Dramane; Ren, Yonglin; Peng, Ruoqi; Chang, Kung-Ching; Fuentes, Maria E.; Stevenson, Christopher S.; Budd, David C.; Truitt, Terry; Hamid, Rachid; Chen, Yun; Zhang, Lin; Fretland, Adrian J.; Sanchez, Ruben Alvarez [Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7920 - 7939,20]

6
[ 514816-42-3 ]
[ 142598-53-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 12 h / 80 °C / Inert atmosphere 2: lithium hydroxide / tetrahydrofuran / 2 h / 60 °C
	Multi-step reaction with 2 steps 1: caesium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 16 h / 80 °C / Inert atmosphere 2: sodium hydroxide; water / tetrahydrofuran; methanol / 16 h / 25 °C
	Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; caesium carbonate / N,N-dimethyl-formamide / 12 h / 80 °C / Inert atmosphere 2: lithium hydroxide / tetrahydrofuran; water / 2 h / 60 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2013/189862, 2013, A1
[2]Current Patent Assignee: BLADE THERAPEUTICS INC - WO2018/64119, 2018, A1
[3]Qian, Yimin; Hamilton, Matthew; Sidduri, Achyutharao; Gabriel, Stephen; Kondru, Rama; Narayanan, Arjun; Lucas, Matthew; Schoenfeld, Ryan C.; Laine, Dramane; Ren, Yonglin; Peng, Ruoqi; Chang, Kung-Ching; Fuentes, Maria E.; Stevenson, Christopher S.; Budd, David C.; Truitt, Terry; Hamid, Rachid; Chen, Yun; Zhang, Lin; Fretland, Adrian J.; Sanchez, Ruben Alvarez [Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7920 - 7939,20]

7
[ 514816-42-3 ]
[ 483315-65-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / toluene / 90 °C / Inert atmosphere; Sealed tube 2: lithium hydroxide / tetrahydrofuran / 4 h / 20 °C
	Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; caesium carbonate / N,N-dimethyl-formamide / 12 h / 80 °C / Inert atmosphere 2: lithium hydroxide / tetrahydrofuran; water / 2 h / 60 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2013/189862, 2013, A1
[2]Qian, Yimin; Hamilton, Matthew; Sidduri, Achyutharao; Gabriel, Stephen; Kondru, Rama; Narayanan, Arjun; Lucas, Matthew; Schoenfeld, Ryan C.; Laine, Dramane; Ren, Yonglin; Peng, Ruoqi; Chang, Kung-Ching; Fuentes, Maria E.; Stevenson, Christopher S.; Budd, David C.; Truitt, Terry; Hamid, Rachid; Chen, Yun; Zhang, Lin; Fretland, Adrian J.; Sanchez, Ruben Alvarez [Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7920 - 7939,20]

8
[ 514816-42-3 ]
methyl 1-methyl-4-(3-methylpyridin-2-yl)-1H-pyrazol-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / 1,4-dioxane / 1 h / 100 °C / Inert atmosphere 2: bis(dibenzylideneacetone)-palladium⁽⁰⁾; XPhos; potassium carbonate / 1,4-dioxane / 1 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: MOCHIDA PHARMACEUTICAL CO LTD - US2014/378447, 2014, A1

9
[ 514816-42-3 ]
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / 1,4-dioxane / 1 h / 100 °C / Inert atmosphere 2: potassium carbonate / 1,4-dioxane / 1 h 3: water; sodium hydroxide / methanol / 1 h / 50 °C
	Multi-step reaction with 2 steps 1.1: dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; bis(dibenzylideneacetone)-palladium⁽⁰⁾; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane; triethylamine / 1,4-dioxane / 0.5 h / 100 °C / Inert atmosphere 1.2: 1.5 h / 100 °C / Inert atmosphere 2.1: water; sodium hydroxide / methanol / 1 h / 50 °C

Reference： [1]Current Patent Assignee: MOCHIDA PHARMACEUTICAL CO LTD - US2014/378447, 2014, A1
[2]Current Patent Assignee: MOCHIDA PHARMACEUTICAL CO LTD - JP2017/95411, 2017, A

10
[ 514816-42-3 ]
4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / 1,4-dioxane / 1 h / 100 °C / Inert atmosphere 2: potassium carbonate / 1,4-dioxane / 1 h 3: water; sodium hydroxide / methanol / 1 h / 50 °C 4: 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium; N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 80 °C
	Multi-step reaction with 3 steps 1.1: dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; bis(dibenzylideneacetone)-palladium⁽⁰⁾; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane; triethylamine / 1,4-dioxane / 0.5 h / 100 °C / Inert atmosphere 1.2: 1.5 h / 100 °C / Inert atmosphere 2.1: water; sodium hydroxide / methanol / 1 h / 50 °C 3.1: 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium; diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 80 °C

Reference： [1]Current Patent Assignee: MOCHIDA PHARMACEUTICAL CO LTD - US2014/378447, 2014, A1
[2]Current Patent Assignee: MOCHIDA PHARMACEUTICAL CO LTD - JP2017/95411, 2017, A

11
[ 514816-42-3 ]
[ 201733-56-4 ]
methyl 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In dimethyl sulfoxide at 100℃; for 4h; Inert atmosphere;	1.1.1 Synthesis of methyl 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole-5-carboxylate A 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.37 g) and potassium acetate (3.5 g) were added to a dimethyl sulfoxide (10 ml) solution of 4-bromo-1-methyl-1H-pyrazole-5-carboxylate (2.0 g) and 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (4.1 g). The obtained mixture was stirred in a nitrogen atmosphere at 100° C. for 4 hours. Thereafter, the reaction solution was cooled, and water (50 ml) was then added thereto, followed by extraction with ethyl acetate (100 ml) twice. Organic layers were gathered. The gathered organic layer was successively washed with water and a saturated saline, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=90:10-40:60), so as to obtain the title compound (1.0 g) in the form of a brown liquid.
1 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In dimethyl sulfoxide at 100℃; for 4h; Inert atmosphere;	15.1 <Step 1> Synthesis of methyl-4-(5,5-dimethyl-1,3,2-dioxaborinan)-2-yl)-1-methyl-1H-pyrazole-5-carboxylate A 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (0.37 g, 0.46 mmol) and 126 potassium acetate (3.6 g, 37 mmol) were added to a 84 dimethyl sulfoxide solution (10 mL) of 90 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (CAS No.: 514816-42-3, 2.0 g, 9.1 mmol) and 127 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (4.1 g, 18 mmol), and stirred for 4 hours at 100° C. in a nitrogen atmosphere. The reaction solution was cooled, 12 water (50 mL) was added, and the reaction solution was extracted twice using 24 ethyl acetate (100 mL). An organic layer was combined, and the obtained mixture was washed with water and a saturated saline solution in that order, and then dried with anhydrous sodium sulfate. A residue obtained by distilling of the solvent under reduced pressure was purified by means of silica gel column chromatography (silica gel: eluate; heptane:ethyl acetate 90:10 to 40:60), and the 128 title compound (1.0 g) was obtained as a brown solid. (Physical property data) LC-MS: M=252, RT=0.67 (min), [M+1-1]+ of corresponding boronic acid=185. 1H-NMR (300 MHz, CDCl3, δ ppm): 7.58 (1H, s), 4.11 (3H, s), 3.88 (3H, s), 3.74 (4H, s), 1.05 (6H, s)

Reference： [1]Current Patent Assignee: MOCHIDA PHARMACEUTICAL CO LTD - US2014/378447, 2014, A1 Location in patent: Paragraph 0538
[2]Current Patent Assignee: MOCHIDA PHARMACEUTICAL CO LTD - US2017/217958, 2017, A1 Location in patent: Paragraph 0361-0364

12
[ 514816-42-3 ]
[ 25015-63-8 ]
methyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; triethylamine In 1,4-dioxane at 100℃; for 1h; Inert atmosphere;	3.22 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.5 ml) was added to a 1,4-dioxane (19 ml) solution of methyl 4-bromo-1-methyl-1H-pyrazole-5-carboxylate (1.9 g), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (0.15 g), Tris(dibenzylideneacetone)dipalladium(0) (0.16 g), and triethylamine (3.7 ml). The obtained mixture was stirred in a nitrogen atmosphere at 100° C. for 30 minutes. Thereafter, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 ml) was added to the reaction solution, and the obtained mixture was then stirred for 30 minutes at the same temperature as described above. Thereafter, an aqueous solution (3.9 ml) of potassium carbonate (3.6 g) and a 1,4-dioxane (4 ml) solution of 4-chloro-2,5-dimethylpyrimidine (1.0 g) were successively added to the reaction solution, and the obtained mixture was then stirred at the same temperature as described above for 1 hour. Thereafter, water was added to the reaction solution, and the mixed solution was extracted with ethyl acetate and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=3:1-1:1-0:1), so as to obtain the title compound (1.9 g) in the form of an orange liquid.

Reference： [1]Current Patent Assignee: MOCHIDA PHARMACEUTICAL CO LTD - US2014/378447, 2014, A1 Location in patent: Paragraph 0675

13
[ 75712-74-2 ]
[ 514816-42-3 ]
methyl 4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.9 g	Stage #1: 4-bromo-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; triethylamine; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane; bis(dibenzylideneacetone)-palladium⁽⁰⁾ In 1,4-dioxane at 100℃; for 0.5h; Inert atmosphere; Stage #2: 4-chloro-2,5-dimethylpyrimidine With potassium carbonate In 1,4-dioxane; water at 100℃; for 1.5h; Inert atmosphere;	1.1 Step-1 ; Synthesis of methyl 4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1 H-pyrazole-5-carboxylate Methyl 4-bromo-1-methyl-1 H-pyrazole-5-carboxylate (1.9 g), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (0.15 g), tris (dibenzylideneacetone)dipalladium (0) (0.16 g) and triethylamine (3.7 mL) in 1,4-dioxane (19 mL), 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.5 mL) was added, under a nitrogen atmosphere, followed by stirring at 100 °C. for 30 minutes. To the reaction solution, 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.5 mL) was added, after stirring at the same temperature for 30 minutes, an aqueous solution (3.9 mL) of potassium carbonate (3.6 g) and 4-chloro-2,5-dimethylpyrimidine (CAS registry number: 75712-74-2) (1.0 g) and a solution of 1,4-dioxane (4 mL) were sequentially added and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography = 3: 1 to 1: 1 to 0: 1) to give the title compound (1.9 g) as an orange liquid.

Reference： [1]Current Patent Assignee: MOCHIDA PHARMACEUTICAL CO LTD - JP2017/95411, 2017, A Location in patent: Paragraph 0163-0165

14
[ 514816-42-3 ]
[ 1801-06-5 ]
methyl 4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		<Step 1> Synthesis of methyl 4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate Using 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (CAS No.: 514816-42-3, 2.52 g, 11.5 mmol) and <strong>[1801-06-5]4-chloro-5-fluoro-2-methoxypyrimidine</strong> (1.5 g), methyl 4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.6 g) was obtained as a pale yellow liquid using a method similar to that in <Step 1> in Working Example 3 or a method based on this method. (Physical property data) LC-MS: M=266, RT=0.91 (min), [M+H]+=267. 1H-NMR (300 MHz, CDCl3, delta ppm): 8.35 (1H, d, J=2 Hz), 7.86 (1H, d, J=1 Hz), 4.15 (3H, s), 4.00 (3H, s), 3.86 (3H, s).

Reference： [1]Patent: US2017/210740,2017,A1

15
[ 4994-86-9 ]
[ 514816-42-3 ]
methyl 1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		<Step 1> Synthesis of methyl 1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate Using 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (CAS No.: 514816-42-3, 2.0 g, 9.1 mmol) and <strong>[4994-86-9]4-chloro-2-methylpyrimidine</strong> (0.94 g), methyl 1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate (1.26 g) was obtained as a yellow oily substance using a method similar to that in <Step 1> in Working Example 3 or a method based on this method. (Physical property data) LC-MS: M=232, RT=0.75 (min), [M+H]+=233. 1H-NMR (300 MHz, CDCl3, delta ppm): 8.62 (1H, d, J=5 Hz), 7.85 (1H, s), 7.29 (1H, d, J=5 Hz), 4.15 (3H, s), 3.87 (3H, s), 2.74 (3H, s).

Reference： [1]Patent: US2017/210740,2017,A1

16
[ 81190-89-8 ]
[ 74-88-4 ]
[ 514816-42-3 ]
[ 211738-66-8 ]

Yield	Reaction Conditions	Operation in experiment
51.8%; 43.7%	With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 25℃; for 16h;Inert atmosphere;	[1197] to a mixture of methyl 4-bromo-1H-pyrazole-3-carboxylate (15.0 g, 73.2 mmol,) andCs2CO3 (59.6 g, 182.9 mmol) in DMF(150 ml) was added mel (14.7 ml, 236.0 mmol) drop-wise at 0c under N2. The mixture was stirred at 25 C for 16 hours. The reaction mixture was filtered, the cake washed with ethyl acetate (200 ml x 2). The filtrate was washed with water (70 ml x 4) and the aqueous phase extracted with ethyl acetate (150 ml). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to dryness. The crude product which was purified by fcc (gradient eluent: petroleum ether/ethyl acetate from 100/0 to 50/50) to afford the title compound 240a (8.3 g, yield 51.8%) as a white solid and the title compound 240b (7.0 g, yield 43.7%) as white solid. Compound 240a: 1H NMR (400mhz, CDCl3): delta 7.48 (s, 1h), 4.15 (s, 3h), 3.93 (s, 3h). MS (ESI) m/z (M+H)+ 219.0.

Reference： [1]Patent: WO2018/64119,2018,A1 .Location in patent: Paragraph 1197

17
[ 514816-42-3 ]
1-methyl-4-vinyl-1H-pyrazole-5-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 100 °C / Inert atmosphere 2: lithium hydroxide; water / tetrahydrofuran / 20 °C

Reference： [1]Current Patent Assignee: IDEAYA BIOSCIENCES INC. - WO2019/156987, 2019, A1 Current Patent Assignee: IDEAYA BIOSCIENCES INC. - WO2019/236766, 2019, A1

18
[ 514816-42-3 ]
1-methyl-4-vinyl-1H-pyrazole-5-carbonyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 100 °C / Inert atmosphere 2: lithium hydroxide; water / tetrahydrofuran / 20 °C 3: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: IDEAYA BIOSCIENCES INC. - WO2019/156987, 2019, A1 Current Patent Assignee: IDEAYA BIOSCIENCES INC. - WO2019/236766, 2019, A1

19
[ 514816-42-3 ]
N-(4-bromo-2-methylphenyl)-1-methyl-4-vinyl-1H-pyrazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 100 °C / Inert atmosphere 2: lithium hydroxide; water / tetrahydrofuran / 20 °C 3: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 0 - 20 °C 4: triethylamine / dichloromethane / 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: IDEAYA BIOSCIENCES INC. - WO2019/156987, 2019, A1 Current Patent Assignee: IDEAYA BIOSCIENCES INC. - WO2019/236766, 2019, A1

20
[ 514816-42-3 ]
N-(4-bromo-2-methylphenyl)-4-(1,2-dihydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 100 °C / Inert atmosphere 2: lithium hydroxide; water / tetrahydrofuran / 20 °C 3: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 0 - 20 °C 4: triethylamine / dichloromethane / 2 h / 0 - 20 °C 5: 4-methylmorpholine N-oxide; osmium(VIII) oxide / tetrahydrofuran; water / 4 h / 20 °C / Sealed tube; Inert atmosphere

Reference： [1]Current Patent Assignee: IDEAYA BIOSCIENCES INC. - WO2019/156987, 2019, A1 Current Patent Assignee: IDEAYA BIOSCIENCES INC. - WO2019/236766, 2019, A1

21
[ 514816-42-3 ]
N-(4-bromo-2-methylphenyl)-4-formyl-1-methyl-1H-pyrazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 100 °C / Inert atmosphere 2: lithium hydroxide; water / tetrahydrofuran / 20 °C 3: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 0 - 20 °C 4: triethylamine / dichloromethane / 2 h / 0 - 20 °C 5: 4-methylmorpholine N-oxide; osmium(VIII) oxide / tetrahydrofuran; water / 4 h / 20 °C / Sealed tube; Inert atmosphere 6: sodium periodate / water; methanol / 4 h / 20 °C / Sealed tube

Reference： [1]Current Patent Assignee: IDEAYA BIOSCIENCES INC. - WO2019/156987, 2019, A1 Current Patent Assignee: IDEAYA BIOSCIENCES INC. - WO2019/236766, 2019, A1

22
[ 514816-42-3 ]
N-(4-bromo-2-methylphenyl)-4-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 100 °C / Inert atmosphere 2: lithium hydroxide; water / tetrahydrofuran / 20 °C 3: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 0 - 20 °C 4: triethylamine / dichloromethane / 2 h / 0 - 20 °C 5: 4-methylmorpholine N-oxide; osmium(VIII) oxide / tetrahydrofuran; water / 4 h / 20 °C / Sealed tube; Inert atmosphere 6: sodium periodate / water; methanol / 4 h / 20 °C / Sealed tube 7: methanol; sodium tetrahydroborate / 4 h / 0 - 20 °C / Sealed tube; Inert atmosphere

Reference： [1]Current Patent Assignee: IDEAYA BIOSCIENCES INC. - WO2019/156987, 2019, A1 Current Patent Assignee: IDEAYA BIOSCIENCES INC. - WO2019/236766, 2019, A1

23
[ 514816-42-3 ]
(5-((4-bromo-2-methylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)methyl methanesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 100 °C / Inert atmosphere 2: lithium hydroxide; water / tetrahydrofuran / 20 °C 3: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 0 - 20 °C 4: triethylamine / dichloromethane / 2 h / 0 - 20 °C 5: 4-methylmorpholine N-oxide; osmium(VIII) oxide / tetrahydrofuran; water / 4 h / 20 °C / Sealed tube; Inert atmosphere 6: sodium periodate / water; methanol / 4 h / 20 °C / Sealed tube 7: methanol; sodium tetrahydroborate / 4 h / 0 - 20 °C / Sealed tube; Inert atmosphere 8: triethylamine / dichloromethane / 20 h / 0 - 20 °C / Sealed tube
	Multi-step reaction with 8 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 100 °C / Inert atmosphere 2: lithium hydroxide; water / tetrahydrofuran / 20 °C 3: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 0 - 20 °C 4: triethylamine / dichloromethane / 2 h / 0 - 20 °C 5: 4-methylmorpholine N-oxide; osmium(VIII) oxide / tetrahydrofuran; water / 4 h / 20 °C / Sealed tube; Inert atmosphere 6: sodium periodate / water; methanol / 4 h / 20 °C / Sealed tube 7: methanol; sodium tetrahydroborate / 4 h / 0 - 20 °C / Sealed tube; Inert atmosphere 8: triethylamine / dichloromethane / 2 h / 0 - 20 °C / Sealed tube