[ CAS No. 1146629-75-5 ] {[proInfo.proName]}

Name: 1146629-75-5|(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate|97%
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COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1146629-75-5 ]

CAS No. :	1146629-75-5	MDL No. :	MFCD29060065
Formula :	C₁₂H₁₄ClN₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DTPDTZKIIYSQPO-UHFFFAOYSA-N
M.W :	267.71	Pubchem ID :	57868847
Synonyms :

Calculated chemistry of [ 1146629-75-5 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.42
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	68.86
TPSA :	57.01 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.87 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.91
Log Po/w (XLOGP3) :	2.9
Log Po/w (WLOGP) :	2.48
Log Po/w (MLOGP) :	1.62
Log Po/w (SILICOS-IT) :	2.0
Consensus Log Po/w :	2.38

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.43
Solubility :	0.0988 mg/ml ; 0.000369 mol/l
Class :	Soluble
Log S (Ali) :	-3.76
Solubility :	0.0468 mg/ml ; 0.000175 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.63
Solubility :	0.062 mg/ml ; 0.000232 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.23

Safety of [ 1146629-75-5 ]

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 [ 1146629-75-5 ]

* 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 [ 1146629-75-5 ]
Downstream synthetic route of [ 1146629-75-5 ]

[ 1146629-75-5 ] Synthesis Path-Upstream 1~2

1
[ 18997-19-8 ]
[ 3680-69-1 ]
[ 1146629-75-5 ]

Yield	Reaction Conditions	Operation in experiment
98.85%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 14 h;	4-chloro-7H-pyrrolo[2,3-d]pyrimidine (25 g; Formula III), potassium carbonate (27 g), and chloromethyl pivalate (27 g; Formula IV) were added to a reaction vessel containing N,N-dimethylformamide (100 mL) at ambient temperature. The reaction mixture was stirred for 14 hours. The progress of the reaction was monitored by thin layer chromatography. Water (250 mL) was added to the reaction mixture, and then the mixture was stirred for 2 hours. The reaction mixture was filtered, then washed with water (50 mL), and then dried under reduced pressure at 40°C to 45°C for 12 hours to obtain (4- chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate. Yield: 98.85percent
91%	Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere Stage #2: at 0 - 20℃; Inert atmosphere	(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f).; To a oven dried 2 L 4-neck round bottom flask equipped with overhead stirring, septa, thermocouple, 500 mL addition funnel and nitrogen inlet was charged sodium hydride (NaH, 60 wt percent, 29.7 g, 0.742 mol, 1.34 equiv) and anhydrous tetrahydrofuran (THF, 400 mL, 5.0 mol) and the resulting mixture was cooled to 0-3° C. To a oven dried 1 L round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 85.0 g, 0.553 mol) and tetrahydrofuran (600 mL, 7.0 mol) resulting in a slurry. This resulting slurry was then portion wise added to the suspension of sodium hydride in THF via large bore canula over 27 minutes at 0-5° C. The resulting solution was heterogeneous and green in color. Following the addition, the cold bath was removed and the mixture was gradually warmed to room temperature and allowed to stir at room temperature for 1 hour before being cooled to 0-5° C. Chloromethyl pivalate (pivaloyloxymethyl chloride, POM-Cl, 103 ml, 0.692 mol, 1.25 equiv) was added portion wise into the reaction mixture over 25 minutes via syringe with stirring at 0-5° C. The addition of chloromethyl pivalate (POM-Cl) was mildly exothermic and the reaction temperature went to as high as 14° C. After addition of chloromethyl pivalate (POM-Cl), the cooling bath was removed and the reaction mixture was allowed to return to room temperature and stirred at room temperature for overnight. When the reaction was deemed complete after about 16 hours, the reaction was quenched with 20percent aqueous brine (250 mL) and ethyl acetate (250 mL) producing a slurry. Additional amount of water (250 mL) was added until the mixture becomes a homogeneous solution. The two layers were separated and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic fractions were dried over magnesium sulfate (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 10percent to 15percent ethyl acetate/hexane gradient elution) to afford the desired product as yellow, crystalline solids (155 g). The combined solids were treated with hexanes (750 mL) and the resulting slurry was warmed to 55° C. to produce a homogeneous solution. The resulting solution was then gradually cooled to room temperature and stirred at room temperature for overnight before being cooled to 0-5° C. for 2 h. The solids were collected by filtration, washed with pre-cooled hexanes (2.x.30 mL), dried in vacuum to afford 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f, 134.9 g, 148.0 g theoretical, 91percent yield) as white solids. For 3f: ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 8.71 (s, 1H), 7.83 (d, 1H, J=3.7 Hz), 6.73 (d, 1H, J=3.8 Hz), 6.23 (s 2H), 1.06 (s, 9H); ¹³C NMR (DMSO-d₆, 100 MHz) δ ppm 176.9, 151.2, 151.1, 151.0, 131.6, 117.1, 99.9, 66.9, 38.3, 26.5; C₁₂H₁₄ClN₃O₂(MW, 267.71), LCMS (EI) m/e 268/270 (M⁺+H).
91.6%	Stage #1: With sodium t-butanolate In tetrahydrofuran at -10 - 20℃; Inert atmosphere Stage #2: at 20℃;	Under inert gas protection,Sodium tert-butoxide (40.7 g, 0.424 mol) and tetrahydrofuran (500 ml) were added to the reaction flask, stirred for 0.5 to 3 hours,Chloro-7H-pyrrolo [2,3-d] pyrimidine (50 g, 0.326 mol) was dissolved in tetrahydrofuran (500 ml)a solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine in tetrahydrofuran was added dropwise to the reaction flask at -10 ° C to 5 ° C,after completion of the dropwise addition, the mixture was allowed to stand at room temperature and stirred at that temperature for 5 to 8 hours and then cooled to -10 ° C to 5 ° C,the chloromethyl pivalate (58.8g, 0.39mol) was added to the reaction flask,after completion of the dropwise addition, the reaction was allowed to stand at room temperature and the reaction was stirred at that temperature for 10 to 12 hours.After completion of the reaction, the reaction was quenched with water, concentrated in tetrahydrofuran in the reverse solution, stirred with ethyl acetate and the aqueous phase was separated. The aqueous phase was extracted with ethyl acetate once and the organic phase was separated,Then, the ethyl acetate in the reaction solution was replaced with n-heptane, the reaction solution was cooled, filtered to obtain a wet product,The wet product was crystallized from n-heptane and dried to obtain 79.8 g of product, purity: 99.3percent, yield: 91.6percent.

170 mg

Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.166667 h;
Stage #2: at 0 - 20℃; for 1.5 h;

4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.651 mmol) was dissolved in tetrahydrofuran (5 mL).
The temperature was lowered to 0° C., and sodium hydride (60percent in mineral oil, 52 mg, 1.30 mmol) was added to the reaction solution.
After 10 minutes, chloromethyl pivalate (0.19 mL, 1.30 mmol) was added at 0° C.
After stirring for 1.5 hours at room temperature, the reaction solution was put into a saturated ammonium chloride aqueous solution.
The organic layers were separated and the aqueous solution layer was extracted with ethyl acetate.
The collected organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel, EA:Hx=1:4) to obtain (4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl pivalate (170 mg, 0.635 mmol) as a white solid.
MS m/z [M+1] 268.01.

Reference： [1] Patent: WO2016/88094, 2016, A1, . Location in patent: Page/Page column 10
[2] Organic Letters, 2009, vol. 11, # 9, p. 1999 - 2002
[3] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 73-75
[4] Patent: CN107226814, 2017, A, . Location in patent: Paragraph 0039-0040; 0042; 0044; 0046; 0048; 0050
[5] Patent: US2009/233903, 2009, A1, . Location in patent: Page/Page column 67-68
[6] Patent: WO2011/52923, 2011, A2, . Location in patent: Page/Page column 42
[7] Patent: US2012/271048, 2012, A1, . Location in patent: Page/Page column 21
[8] Patent: US2018/50036, 2018, A1, . Location in patent: Paragraph 0111; 0112; 0113; 0114

2
[ 269410-08-4 ]
[ 1146629-75-5 ]
[ 1146629-77-7 ]

Yield	Reaction Conditions	Operation in experiment
82.27%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,4-dioxane; water for 14 h; Heating	(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate (10 g; Formula V), water (50 mL), and potassium carbonate (15.5 g) were added into a reaction vessel at ambient temperature. 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (8.7 g; Formula VIII), 1,4-dioxane (100 mL), and tetrakis(triphenylphosphine)palladium(0) (0.08 g) were added to the reaction mixture. The reaction mixture was heated to a temperature of 80°C to 85°C, and then stirred at the same temperature for 14 hours. The progress of the reaction was monitored by thin layer chromatography. On completion, ethyl acetate (100 mL) was added to the reaction mixture. The contents were stirred for 1 hour,then filtered through a Hyflo, and then washed with ethyl acetate (40 mL). The organic layer was separated, and then concentrated under reduced pressure to obtain [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl]methyl pivalate. Yield: 82.27percent

Reference： [1] Patent: WO2016/88094, 2016, A1, . Location in patent: Page/Page column 10

[ 1146629-75-5 ] Synthesis Path-Downstream 1~85

1
[ 1029716-44-6 ]
[ 1146629-75-5 ]
[ 1146629-76-6 ]

Yield	Reaction Conditions	Operation in experiment
		To the quenched reaction mixture, which contains crude POM-protected chlorodeazapurine (17) made as described above, was added 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (4, 200 g, 0.75 mol, 1.10 equiv) and solid potassium carbonate (K2CO3, 189 g, 1.37 mol, 2.0 equiv) at room temperature. The resulting mixture was degassed by passing a stream of nitrogen through the solution for 15 minutes before being treated with tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 7.9 g, 0.68 mmol, 0.01 equiv) and the resulting reaction mixture was heated at reflux (about 82 C.) for 10 hours. When the reaction was deemed complete by TLC (1:1 hexanes/ethyl acetate) and LCMS, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (2 L) and water (1 L). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (500 mL). The combined organic layers were washed with water (2×1 L) and brine (1 L) before being concentrated under reduced pressure to afford crude {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (18) as a pale-yellow oil, which was directly used in the subsequent de-protection reaction without further purification.
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; mineral oil; at 20 - 82℃;Inert atmosphere;Product distribution / selectivity;	To the quenched reaction mixture, which contains crude POM-protected chlorodeazapurine (2) made as described above, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3, 200 g, 0.75 mol, 1.10 equiv) and potassium carbonate (K2CO3, 189 g, 1.37 mol, 2.0 equiv) were added at room temperature. The resulting mixture was degassed by passing a stream of nitrogen through the solution for 15 minutes before being treated with tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 7.9 g, 0.68 mmol, 0.01 equiv) and the resulting reaction mixture was heated at reflux (about 82 C.) for 10 h. When the reaction was deemed complete as confirmed by TLC (1:1 hexanes/ethyl acetate) and LCMS, the reaction mixture was cooled down to room temperature and diluted with ethyl acetate (2 L) and water (1 L). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (EtOAc, 500 mL). The combined organic layers were washed with water (2×1 L) and brine (1 L) before being concentrated under reduced pressure to afford crude {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (4) as a pale-yellow oil, which was directly used in the subsequent de-protection reaction without further purification.
	With bis(1,5-cyclooctadiene)nickel (0); potassium carbonate; tricyclohexylphosphine; In water; tert-butyl alcohol; at 40℃; for 3h;Glovebox;	To an oven-dried tube with 8 (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (2 g, 7.47 mmol), 19 <strong>[1029716-44-6]1-<strong>[1029716-44-6](1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong></strong> (denoted as ETDH hereinafter) (2.49 g, 8.95 mmol) and 5 K2CO3 (3.1 g, 22.43 mmol) were added. The tube was taken into a glovebox, 16 Ni(COD)2 (0.126 g, 0.458 mmol) and 20 PCy3 (0.25 g, 0.89 mmol) was added. Degassed t-BuOH (15 mL) and degassed 7 water (15 mL) were added. The tube was capped and taken out of the glovebox. The mixture was heated at 40 C. for 3 hours to conduct reaction. When the reaction was deemed to complete, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (40 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic phase was dried over MgSO4 and the residue was evaporated under vacuum to give a crude 21 product containing a title compound (4.51 g) as an orange oil. 1H NMR(CDCl3-d,400 MHz): delta 8.82(s, 1H), 8.39(s, 1H), 8.23(s, 1H), 7.41(d, 1H, J=4 Hz), 6.72(d, 1H, J=3.6 Hz), 6.20(s, 2H), 5.45 18 5.42(m, 1H), 4.064.03(m, 1H), 3.733.66(m, 1H), 2.221.60(m, 6H), 1.11(s, 9H) ppm. LCMS calculated for C20H25N5O3 (M+H)+: 383.1957. Found: 384.4.

Reference： [1]Organic Letters,2009,vol. 11,p. 1999 - 2002
[2]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 67-68
[3]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 52-53
[4]Patent: US2019/202834,2019,A1 .Location in patent: Paragraph 0065; 0066
[5]Russian Journal of Organic Chemistry,2019,vol. 55,p. 1569 - 1574
Zh. Org. Khim.,2019,vol. 55,p. 1569 - 1574,6

2
[ 18997-19-8 ]
[ 3680-69-1 ]
[ 1146629-75-5 ]

Yield	Reaction Conditions	Operation in experiment
98.85%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 14h;	4-chloro-7H-pyrrolo[2,3-d]pyrimidine (25 g; Formula III), potassium carbonate (27 g), and chloromethyl pivalate (27 g; Formula IV) were added to a reaction vessel containing N,N-dimethylformamide (100 mL) at ambient temperature. The reaction mixture was stirred for 14 hours. The progress of the reaction was monitored by thin layer chromatography. Water (250 mL) was added to the reaction mixture, and then the mixture was stirred for 2 hours. The reaction mixture was filtered, then washed with water (50 mL), and then dried under reduced pressure at 40C to 45C for 12 hours to obtain (4- chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate. Yield: 98.85%
91%		(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f).; To a oven dried 2 L 4-neck round bottom flask equipped with overhead stirring, septa, thermocouple, 500 mL addition funnel and nitrogen inlet was charged sodium hydride (NaH, 60 wt %, 29.7 g, 0.742 mol, 1.34 equiv) and anhydrous tetrahydrofuran (THF, 400 mL, 5.0 mol) and the resulting mixture was cooled to 0-3 C. To a oven dried 1 L round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 85.0 g, 0.553 mol) and tetrahydrofuran (600 mL, 7.0 mol) resulting in a slurry. This resulting slurry was then portion wise added to the suspension of sodium hydride in THF via large bore canula over 27 minutes at 0-5 C. The resulting solution was heterogeneous and green in color. Following the addition, the cold bath was removed and the mixture was gradually warmed to room temperature and allowed to stir at room temperature for 1 hour before being cooled to 0-5 C. Chloromethyl pivalate (pivaloyloxymethyl chloride, POM-Cl, 103 ml, 0.692 mol, 1.25 equiv) was added portion wise into the reaction mixture over 25 minutes via syringe with stirring at 0-5 C. The addition of chloromethyl pivalate (POM-Cl) was mildly exothermic and the reaction temperature went to as high as 14 C. After addition of chloromethyl pivalate (POM-Cl), the cooling bath was removed and the reaction mixture was allowed to return to room temperature and stirred at room temperature for overnight. When the reaction was deemed complete after about 16 hours, the reaction was quenched with 20% aqueous brine (250 mL) and ethyl acetate (250 mL) producing a slurry. Additional amount of water (250 mL) was added until the mixture becomes a homogeneous solution. The two layers were separated and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic fractions were dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 10% to 15% ethyl acetate/hexane gradient elution) to afford the desired product as yellow, crystalline solids (155 g). The combined solids were treated with hexanes (750 mL) and the resulting slurry was warmed to 55 C. to produce a homogeneous solution. The resulting solution was then gradually cooled to room temperature and stirred at room temperature for overnight before being cooled to 0-5 C. for 2 h. The solids were collected by filtration, washed with pre-cooled hexanes (2×30 mL), dried in vacuum to afford 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f, 134.9 g, 148.0 g theoretical, 91% yield) as white solids. For 3f: 1H NMR (DMSO-d6, 400 MHz) delta ppm 8.71 (s, 1H), 7.83 (d, 1H, J=3.7 Hz), 6.73 (d, 1H, J=3.8 Hz), 6.23 (s 2H), 1.06 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) delta ppm 176.9, 151.2, 151.1, 151.0, 131.6, 117.1, 99.9, 66.9, 38.3, 26.5; C12H14ClN3O2 (MW, 267.71), LCMS (EI) m/e 268/270 (M++H).
91.6%		Under inert gas protection,Sodium tert-butoxide (40.7 g, 0.424 mol) and tetrahydrofuran (500 ml) were added to the reaction flask, stirred for 0.5 to 3 hours,Chloro-7H-pyrrolo [2,3-d] pyrimidine (50 g, 0.326 mol) was dissolved in tetrahydrofuran (500 ml)a solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine in tetrahydrofuran was added dropwise to the reaction flask at -10 C to 5 C,after completion of the dropwise addition, the mixture was allowed to stand at room temperature and stirred at that temperature for 5 to 8 hours and then cooled to -10 C to 5 C,the chloromethyl pivalate (58.8g, 0.39mol) was added to the reaction flask,after completion of the dropwise addition, the reaction was allowed to stand at room temperature and the reaction was stirred at that temperature for 10 to 12 hours.After completion of the reaction, the reaction was quenched with water, concentrated in tetrahydrofuran in the reverse solution, stirred with ethyl acetate and the aqueous phase was separated. The aqueous phase was extracted with ethyl acetate once and the organic phase was separated,Then, the ethyl acetate in the reaction solution was replaced with n-heptane, the reaction solution was cooled, filtered to obtain a wet product,The wet product was crystallized from n-heptane and dried to obtain 79.8 g of product, purity: 99.3%, yield: 91.6%.

85%		To a solution of 4-chloro-7H-pyrrolo[2,3-d] pyrimidine (15.4 g,0.100 mol) in tetrahydrofuran, 60% sodium hydride (8.0 g, 0.200 mol)was added in batches under ice bath. The reaction mixture was stirredunder ice bath for 0.5 h, and then chloromethyl pivalate (30.1 g,0.200 mol) was added to the mixture. Subsequently, the reaction wasstirred at room temperature for 1.5 h. After completed, the mixture waspoured into saturated ammonium chloride solution. The mixture wasextracted with ethyl acetate (50 ml×5), the organic layer was washedwith brine, dried over anhydrous Na2SO4, and then filtered and concentratedto yield 4 as a yellow solid (27.5 g, 85.0%). MS (ESI) m/z:268.4 [M+H]+
		To a oven dried 3 L 4-neck round bottom flask equipped with a stirring bar, a septa, a thermocouple, a 500 mL addition funnel and the nitrogen inlet was charged solid sodium hydride (NaH, 60 wt % in mineral oil, 32.82 g, 0.82 mol, 1.20 equiv) and anhydrous 1,2-dimethoxyethane (DME, 500 mL, 4.8 mol) and the resulting mixture was cooled to 0-3 C. To a oven dried 1 L round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1,105.0 g, 0.684 mol) and 1,2-dimethoxyethane (DME, 750 mL, 7.2 mol) and the resulting slurry was then portion wise added to the suspension of sodium hydride in DME via large bore cannula over 30 minutes at 5-12 C. The resulting reaction mixture was heterogeneous. Following the addition, the cold bath was removed and the mixture was gradually warmed to room temperature and allowed to stir at room temperature for 1 hour before being cooled to 0-5 C. Chloromethyl pivalate (pivaloyloxymethyl chloride, POM-Cl, 112 ml, 0.752 mol, 1.1 equiv) was then added drop wise into the reaction mixture over 30 minutes with stirring at 0-5 C. The addition of chloromethyl pivalate was mildly exothermic and the reaction temperature went up to as high as 14 C. After addition of chloromethyl pivalate, the cooling bath was removed and the reaction mixture was allowed to return to room temperature and stirred at room temperature for 90 min. When the reaction was deemed complete after confirmed by HPLC, the reaction mixture was carefully quenched with water (100 mL) and this quenched reaction mixture, which contains crude POM-protected chlorodeazapurine (17), was used directly in the subsequent Suzuki coupling reaction without further work-up and purification.
		4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.651 mmol) was dissolved in tetrahydrofuran (5 mL). After cooling to 0 C, the reaction mixture was added to sodium hydride (60% in mineral oil, 52 mg, 1.30 mmol). 10 minutes later, chloromethyl pivalate (0.19 mL, 1.30 mmol) was added at 0 C. After stirring for 1.5 hours at room temperature, the reaction mixture was added to saturated ammonium chloride aqueous solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, EA:Hx = 1:4) yielded (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (170 mg, 0.635 mmol) as white solid.MS m/z [M+1] 268.01.
		Step 1: (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.651 mmol) was dissolved in tetrahydrofuran (5 mL). After cooling to 0 C., the reaction mixture was added to sodium hydride (60% in mineral oil, 52 mg, 1.30 mmol). 10 minutes later, chloromethyl pivalate (0.19 mL, 1.30 mmol) was added at 0 C. After stirring for 1.5 hours at room temperature, the reaction mixture was added to saturated ammonium chloride aqueous solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, EA:Hx=1:4) yielded (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (170 mg, 0.635 mmol) as white solid. MS m/z [M+1] 268.01.
170 mg		4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.651 mmol) was dissolved in tetrahydrofuran (5 mL). The temperature was lowered to 0 C., and sodium hydride (60% in mineral oil, 52 mg, 1.30 mmol) was added to the reaction solution. After 10 minutes, chloromethyl pivalate (0.19 mL, 1.30 mmol) was added at 0 C. After stirring for 1.5 hours at room temperature, the reaction solution was put into a saturated ammonium chloride aqueous solution. The organic layers were separated and the aqueous solution layer was extracted with ethyl acetate. The collected organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EA:Hx=1:4) to obtain (4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl pivalate (170 mg, 0.635 mmol) as a white solid. MS m/z [M+1] 268.01.
530 g		Under argon protection, 4-chloropyrrolopyridine (308g, 2.0mol, SM-1) was dissolved in 1.5L anhydrous DMAc, cooled to 10C in ice water bath, and added to NaH (104g, 2.6mol, 60%) in batches. The temperature was kept at 10-15 C, and the mixture was stirred for 1 h under the temperature after the dropwise addition was completed. A solution of methyl pivalate in tetrahydrofuran (390g, 2.6mol dissolved in 1.5L anhydrous tetrahydrofuran, SM-2) was slowly added dropwise, and the temperature was maintained below 20C, and the addition was ended after 1h. The reaction solution was warmed to room temperature and reacted for 2h, and the TLC showed the reaction was completed. The reaction was quenched by being added with water drop wise in ice-water bath, and extracted with methyl t-butyl ether. The organic phase was concentrated to obtain white solid 1a (530g).

Reference： [1]Patent: WO2016/88094,2016,A1 .Location in patent: Page/Page column 10
[2]Organic Letters,2009,vol. 11,p. 1999 - 2002
[3]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 73-75
[4]Patent: CN107226814,2017,A .Location in patent: Paragraph 0039-0040; 0042; 0044; 0046; 0048; 0050
[5]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 4089 - 4100
[6]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 67-68
[7]Patent: WO2011/52923,2011,A2 .Location in patent: Page/Page column 42
[8]Patent: US2012/271048,2012,A1 .Location in patent: Page/Page column 21
[9]Patent: US2018/50036,2018,A1 .Location in patent: Paragraph 0111; 0112; 0113; 0114
[10]Russian Journal of Organic Chemistry,2019,vol. 55,p. 1569 - 1574
Zh. Org. Khim.,2019,vol. 55,p. 1569 - 1574,6
[11]Patent: EP3572415,2019,A1 .Location in patent: Paragraph 0096; 0097

3
[ 1153949-38-2 ]
[ 1146629-75-5 ]
[ 1236033-05-8 ]

Yield	Reaction Conditions	Operation in experiment
88.6%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 20 - 82℃;Inert atmosphere;	Racemic (4-(1-(2-Cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20).; Method B.; Into a 50 ml round bottom flask equipped with a stir bar, condenser and 3-way valve connected to nitrogen and vacuum was charged <strong>[1146629-75-5](4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate</strong> (3f, 700 mg, 2.61 mmol), 3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (23, 935 mg, 2.97 mmol, 1.13 equiv), 1,2-dimethoxyethane (DME, 10 mL, 96 mmol), water (5 mL, 0.28 mol) and potassium carbonate (K2CO3, 1.82 g, 7.84 mmol, 3.0 equiv) at room temperature. The resulting reaction mixture was degassed three times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol, 0.010 equiv). The resulting reaction mixture was degassed four times back filling with nitrogen each time and then warmed to 82 C. The reaction mixture was stirred at 82 C. for 6 hours. When the reaction was deemed complete, the reaction mixture was cooled to room temperature before being diluted with ethyl acetate (45 mL) and water (10 mL). The resulting mixture was stirred until the majority of solids had gone into solution. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic fractions were washed with aqueous brine (2×25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-50% ethyl acetate/hexane gradient elution) to afford racemic 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 0.97 g, 1.1 g theoretical, 88.6% yield) as colorless oil, which solidified upon standing at room temperature in vacuo. For 20: 1H NMR (CDCl3, 300 MHz) delta 8.85 (s, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 7.45 (d, 1H, J=3.8 Hz), 6.73 (d, 1H, J=3.8 Hz), 6.22 (s, 2H), 4.23 (ddd, 1H, J=10.0, 8.6, 4.0 Hz), 3.10 (dd, 1H, J=17.0, 8.6 Hz), 2.92 (dd, 1H, J=17.0, 4.0 Hz), 2.56 (m, 1H), 2.0-1.25 (m, 8H), 1.12 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421 (M++H).

Reference： [1]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 92-93

4
[ 1146629-75-5 ]
[ 1298084-47-5 ]

Reference： [1]Patent: WO2011/52923,2011,A2
[2]Patent: US2012/271048,2012,A1
[3]Patent: US2018/50036,2018,A1

5
[ 1146629-75-5 ]
[ 1298084-29-3 ]

Reference： [1]Patent: WO2011/52923,2011,A2
[2]Patent: US2012/271048,2012,A1
[3]Patent: US2018/50036,2018,A1

6
[ 1146629-75-5 ]
[ 1298084-30-6 ]

Reference： [1]Patent: WO2011/52923,2011,A2
[2]Patent: US2012/271048,2012,A1

7
[ 1146629-75-5 ]
[ 1266726-40-2 ]
[ 1298084-48-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane; at 120℃; for 2h;In a sealed reactor;	6-(3-Nitrophenyl)-1H-indole (100 mg, 0.42 mmol) and <strong>[1146629-75-5](4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate</strong> (112 mg, 0.42 mmol) were dissolved in 1,4-dioxane (5 mL) in a sealed reactor and then Cs2CO3 (270 mg, 0.83 mmol) was added. After removing the gas included in the solution using ultrasonic wave and sequentially adding Xantphos (CAS No. 161265-03-8; 49 mg, 0.084 mmol) and Pd(OAc)2 (9.4 mg, 0.042 mmol), the reaction mixture was stirred at 120 C for 2 hours. After cooling to room temperature and adding ethyl acetate and water, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, methylene chloride 100%) yielded (4-(6-(3-nitrophenyl)-1H-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (177 mg, 0.377 mmol) as white solid.MS m/z [M+1] 470.03; 1H NMR (400 MHz, DMSO-d 6) d 8.91 (s, 1H), 8.89 (s, 1H), 8.45 (s, 1H), 8.26 (d, J = 3.53 Hz, 1H), 8.20 (d, J = 8.23 Hz, 1H), 8.17 (d, J = 7.30 Hz, 1H), 7.85 (d, J = 7.65 Hz, 1H), 7.82 (d, J = 3.62 Hz, 1H), 7.78 (t, J = 7.97 Hz, 1H), 7.66 (dd, J = 5.8, 6.71 Hz, 1H), 7.03 (d, J = 3.79 Hz, 1H), 6.97 (d, J = 3.50 Hz, 1H), 6.30 (s, 2H), 1.10 (s, 9H).
	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 2h;Inert atmosphere; Sealed tube;	Step 2: (4-(6-(3-nitrophenyl)-1H-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate 6-(3-Nitrophenyl)-1H-indole (100 mg, 0.42 mmol) and <strong>[1146629-75-5](4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate</strong> (112 mg, 0.42 mmol) were dissolved in 1,4-dioxane (5 mL) in a sealed reactor and then Cs2CO3 (270 mg, 0.83 mmol) was added. After removing the gas included in the solution using ultrasonic wave and sequentially adding Xantphos (CAS No. 161265-03-8; 49 mg, 0.084 mmol) and Pd(OAc)2 (9.4 mg, 0.042 mmol), the reaction mixture was stirred at 120 C. for 2 hours. After cooling to room temperature and adding ethyl acetate and water, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, methylene chloride 100%) yielded (4-(6-(3-nitrophenyl)-1H-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (177 mg, 0.377 mmol) as white solid. MS m/z [M+1] 470.03; 1H NMR (400 MHz, DMSO-d6) d 8.91 (s, 1H), 8.89 (s, 1H), 8.45 (s, 1H), 8.26 (d, J=3.53 Hz, 1H), 8.20 (d, J=8.23 Hz, 1H), 8.17 (d, J=7.30 Hz, 1H), 7.85 (d, J=7.65 Hz, 1H), 7.82 (d, J=3.62 Hz, 1H), 7.78 (t, J=7.97 Hz, 1H), 7.66 (dd, J=5.8, 6.71 Hz, 1H), 7.03 (d, J=3.79 Hz, 1H), 6.97 (d, J=3.50 Hz, 1H), 6.30 (s, 2H), 1.10 (s, 9H).
177 mg	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 2h;	In an airtight container, 6-(3-nitrophenyl)-1H-indole (100 mg, 0.42 mmol) and <strong>[1146629-75-5](4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl pivalate</strong> (112 mg, 0.42 mmol) were dissolved in 1,4-dioxane (5 mL), and then Cs2CO3 (270 mg, 0.83 mmol) was added. After removing the gas of solution using ultrasonic waves, Xantphos (CAS No. 161265-03-8; 49 mg, 0.084 mmol) and Pd (OAc)2 (9.4 mg, 0.042 mmol) were added continuously, and then the reaction solution was stirred at 120 C. for 2 hours. After cooling it to room temperature, ethyl acetate and water were added, and the water layers were extracted with ethyl acetate. The collected organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100% methylene chloride) to obtain (4-(6-(3-nitrophenyl)-1H-indole-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl pivalate (177 mg, 0.377 mmol) as a white solid. MS m/z [M+1] 470.03; 1H NMR (400 MHz, DMSO-d6) delta 8.91 (s, 1H), 8.89 (s, 1H), 8.45 (s, 1H), 8.26 (d, J=3.53 Hz, 1H), 8.20 (d, J=8.23 Hz, 1H), 8.17 (d, J=7.30 Hz, 1H), 7.85 (d, J=7.65 Hz, 1H), 7.82 (d, J=3.62 Hz, 1H), 7.78 (t, J=7.97 Hz, 1H), 7.66 (dd, J=5.8, 6.71 Hz, 1H), 7.03 (d, J=3.79 Hz, 1H), 6.97 (d, J=3.50 Hz, 1H), 6.30 (s, 2H), 1.10 (s, 9H).

Reference： [1]Patent: WO2011/52923,2011,A2 .Location in patent: Page/Page column 42-43
[2]Patent: US2012/271048,2012,A1 .Location in patent: Page/Page column 21-22
[3]Patent: US2018/50036,2018,A1 .Location in patent: Paragraph 0111; 0115; 0116; 0117

8
[ 1146629-75-5 ]
C₃₄H₃₂N₆O₄ [ No CAS ]

Reference： [1]Patent: US2012/271048,2012,A1

9
[ 1146629-75-5 ]
[ 1553981-84-2 ]
[ 1553977-77-7 ]

Yield	Reaction Conditions	Operation in experiment
		Step 16: tert-Butyl 4-(6-aminopyrimidin-4-yI)-2-(5-chloro-2-methylphenyl)-1 H-pyrrole-1 -carboxylate (XXI) The crude tert-butyl 2-(5-chloro-2-methylphenyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrole-1 -carboxylate (392 mg, 0.94 mmol), Na2003 (250 mg, 2.36 mmol), PdC2(dppf) (77 mg, 0.094 mmol) and 6-iodopyrimidin-4-amine (311 mg, 1.41 mmol) were degassed and purged with argon and suspended in degassed 1,4-dioxane (3 mL) and water (1 mL). The reaction mixture was heated to 110 00 (oil bath temperature) for 2 h. Thesolution was diluted with EtOAc and washed with water. After drying over anhydrous Na2SO4, the organic layer was evaporated. The crude was purified by chromatography on silica gel (hexane/EtOAc 8:2) providing the title compound (220 mg, 58%).1H NMR (600 MHz, DMSQ-d6) 8.55 (s, 1 H), 7.79 (s, 1H), 7.41 (d, 1H), 7.29 (d, 1H), 7.16 (m, 1H), 6.98 (s, 1H),6.66 (s, 1H), 2.30 (s, 3H), 1.44 (s, 9H).According to this procedure, but starting from tert-butyl 2-(5-chloro-2-ethyl phenyl)-4-iodo-1 H-pyrrole-1 -carboxylate, using 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate instead of 6-iodopyrimidin-4-amine in the step 16 and removing the 2,2-dimethylpropanoyl protecting group with LiOH.H20 in THE/water at roomtemperature, the following compound was prepared:2-(5-Chloro-2-ethylphenyl)-N-methyl-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-1 H-pyrrole-1 -carboxamide (compd185)ESI (+) MS: m/z 380 (MW).

Reference： [1]Patent: WO2014/19908,2014,A2 .Location in patent: Page/Page column 77

10
[ 1146629-75-5 ]
[ 1553981-91-1 ]
[ 1553977-87-9 ]

Yield	Reaction Conditions	Operation in experiment
		Step 16: tert-Butyl 4-(6-aminopyrimidin-4-yI)-2-(5-chloro-2-methylphenyl)-1 H-pyrrole-1 -carboxylate (XXI) The crude tert-butyl 2-(5-chloro-2-methylphenyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrole-1 -carboxylate (392 mg, 0.94 mmol), Na2003 (250 mg, 2.36 mmol), PdC2(dppf) (77 mg, 0.094 mmol) and 6-iodopyrimidin-4-amine (311 mg, 1.41 mmol) were degassed and purged with argon and suspended in degassed 1,4-dioxane (3 mL) and water (1 mL). The reaction mixture was heated to 110 00 (oil bath temperature) for 2 h. Thesolution was diluted with EtOAc and washed with water. After drying over anhydrous Na2SO4, the organic layer was evaporated. The crude was purified by chromatography on silica gel (hexane/EtOAc 8:2) providing the title compound (220 mg, 58%).1H NMR (600 MHz, DMSQ-d6) 8.55 (s, 1 H), 7.79 (s, 1H), 7.41 (d, 1H), 7.29 (d, 1H), 7.16 (m, 1H), 6.98 (s, 1H),6.66 (s, 1H), 2.30 (s, 3H), 1.44 (s, 9H).According to this procedure, but starting from tert-butyl 2-(5-chloro-2-ethyl phenyl)-4-iodo-1 H-pyrrole-1 -carboxylate, using 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate instead of 6-iodopyrimidin-4-amine in the step 16 and removing the 2,2-dimethylpropanoyl protecting group with LiOH.H20 in THE/water at roomtemperature, the following compound was prepared:2-(5-Chloro-2-ethylphenyl)-N-methyl-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-1 H-pyrrole-1 -carboxamide (compd185)ESI (+) MS: m/z 380 (MW).

Reference： [1]Patent: WO2014/19908,2014,A2 .Location in patent: Page/Page column 77

11
[ 1146629-75-5 ]
[ 1553982-56-1 ]
[ 1553977-69-7 ]

Yield	Reaction Conditions	Operation in experiment
		Step 16: tert-Butyl 4-(6-aminopyrimidin-4-yI)-2-(5-chloro-2-methylphenyl)-1 H-pyrrole-1 -carboxylate (XXI) The crude tert-butyl 2-(5-chloro-2-methylphenyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrole-1 -carboxylate (392 mg, 0.94 mmol), Na2003 (250 mg, 2.36 mmol), PdC2(dppf) (77 mg, 0.094 mmol) and 6-iodopyrimidin-4-amine (311 mg, 1.41 mmol) were degassed and purged with argon and suspended in degassed 1,4-dioxane (3 mL) and water (1 mL). The reaction mixture was heated to 110 00 (oil bath temperature) for 2 h. Thesolution was diluted with EtOAc and washed with water. After drying over anhydrous Na2SO4, the organic layer was evaporated. The crude was purified by chromatography on silica gel (hexane/EtOAc 8:2) providing the title compound (220 mg, 58%).1H NMR (600 MHz, DMSQ-d6) 8.55 (s, 1 H), 7.79 (s, 1H), 7.41 (d, 1H), 7.29 (d, 1H), 7.16 (m, 1H), 6.98 (s, 1H),6.66 (s, 1H), 2.30 (s, 3H), 1.44 (s, 9H).According to this procedure, but using 4-chloro-7H-pyrrolo[2,3-djpyrimidin-7-yI)methyl 2,2-dimethyipropanoateinstead of 6-iodopyrimidin-4-amine in the step 16 and removing the 2,2-dimethyipropanoyl protecting group withLiOH.H20 in THE/water at room temperature, the following compound was prepared:2-(5-Chloro-2-methylphenyl)-N-methyl-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-1 H-pyrrole-1 -carboxamide (compd

Reference： [1]Patent: WO2014/19908,2014,A2 .Location in patent: Page/Page column 77

12
[ 269410-08-4 ]
[ 1146629-75-5 ]
[ 1146629-77-7 ]

Yield	Reaction Conditions	Operation in experiment
82.27%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; for 14h;Heating;	(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate (10 g; Formula V), water (50 mL), and potassium carbonate (15.5 g) were added into a reaction vessel at ambient temperature. 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (8.7 g; Formula VIII), 1,4-dioxane (100 mL), and tetrakis(triphenylphosphine)palladium(0) (0.08 g) were added to the reaction mixture. The reaction mixture was heated to a temperature of 80C to 85C, and then stirred at the same temperature for 14 hours. The progress of the reaction was monitored by thin layer chromatography. On completion, ethyl acetate (100 mL) was added to the reaction mixture. The contents were stirred for 1 hour,then filtered through a Hyflo, and then washed with ethyl acetate (40 mL). The organic layer was separated, and then concentrated under reduced pressure to obtain [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl]methyl pivalate. Yield: 82.27%

Reference： [1]Patent: WO2016/88094,2016,A1 .Location in patent: Page/Page column 10

13
[ 1146629-75-5 ]
[ 1298084-34-0 ]
(4-(6-(2-methyl-5-nitrophenyl)-1H-indole-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl pivalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 2h;	6-(2-methyl-5-nitrophenyl)-1H-indole (1 g, 4.2 mmol) was dissolved in 1,4-dioxane solution (28 mL). <strong>[1146629-75-5](4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl pivalate</strong> (1.35 g, 5.04 mmol) and potassium carbonate (1.74 g, 12.6 mmol) were added, and then a nitrogen gas was injected for 5 minutes to remove the gas included in the mixture solution. Then, the reaction vessel was placed in an oil bath heated to 120 C., and Pd(OAc)2 (95 mg, 0.42 mmol) and Xantphos (365 mg, 0.63 mmol) were added and stirred for 2 hours. After the reaction was completed, it was extracted with ethyl acetate and water. The collected organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by MPLC to obtain the target compound (3.53 g, 72%) as a yellow solid. 1H NMR (400 MHz, CDCl3-d6) delta 8.84 (s, 1H), 8.56 (s, 1H), 8.20 (d, J=2.4 Hz, 1H), 8.11 (dd, J=2.4 Hz, 8.4 Hz, 1H), 7.95 (d, J=3.6 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.21 (dd, J=1.6 Hz, 8.0 Hz, 1H), 6.87 (d, J=3.6 Hz, 1H), 6.79 (d, J=4.0 Hz, 1H), 6.28 (s, 2H), 2.42 (s, 3H), 1.17 (s, 9H)

Reference： [1]Patent: US2018/50036,2018,A1 .Location in patent: Paragraph 0125; 0126; 0127; 0128; 0129

14
[ 1146629-75-5 ]
[ 1298084-34-0 ]
(4-(6-(5-amino-2-methylphenyl)-1H-indole-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl pivalate [ No CAS ]

Reference： [1]Patent: US2018/50036,2018,A1

15
[ 18997-19-8 ]
[ 55052-28-3 ]
[ 1146629-75-5 ]

Yield	Reaction Conditions	Operation in experiment
8.47 g	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of 3 4-chloro-1H-pyrrolo[2,3-b]pyridine (5.0 g, 32.56 mmol) in 4 dimethylformamide (DMF) (20 mL), 5 K2CO3 (5.4 g, 39.07 mmol) was added. The solution was stirred at room temperature, and 6 chloromethyl pivalate (5.5 g, 36.52 mmol) was added dropwise into the solution at room temperature. The reaction mixture was stirred at room temperature for 16 hours. 7 Water (50 mL) was added to the resulting solution, and the resulting suspension was stirred at room temperature for 2 hours. The solids were collected by filtration, washed with water (10 mL×2), and dried under vacuum to give 8 (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (8.47 g) as an off-white solid.

Reference： [1]Patent: US2019/202834,2019,A1 .Location in patent: Paragraph 0059; 0060

16
[ 1146629-75-5 ]
[ 1146629-77-7 ]

Reference： [1]Patent: US2019/202834,2019,A1
[2]Patent: EP3572415,2019,A1
[3]Russian Journal of Organic Chemistry,2019,vol. 55,p. 1569 - 1574
Zh. Org. Khim.,2019,vol. 55,p. 1569 - 1574,6

17
[ 1003846-21-6 ]
[ 1146629-75-5 ]
(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10.83 g	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,4-dioxane; water; at 72℃; for 3h;Inert atmosphere;	To a suspension of (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (5 g, 18.68 mmol) in 1,4-dioxane (50 mL), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-boronic acid pinacol ester (denoted as TAPE hereinafter) (6.23 g, 22.40 mmol) and K2CO3 (5.16 g, 37.34 mmol)/H2O (15 mL) were added at room temperature under nitrogen atmosphere. Pd(PPh3)2Cl2 (0.262 g, 0.02 mmol) was added and the resulting mixture was heated to reflux (about 72 C.) for 3 hours. When the reaction was deemed to complete, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (80 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (80 mL). The combined organic phase was dried over MgSO4 and the residue was evaporated under vacuum to give (4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (10.83 g) as a red oil.

Reference： [1]Patent: US2019/202834,2019,A1 .Location in patent: Paragraph 0061; 0062; 0063; 0064

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[ 1187595-90-9 ]

Reference： [1]Patent: US2019/202834,2019,A1
[2]Patent: US2019/202834,2019,A1
[3]Russian Journal of Organic Chemistry,2019,vol. 55,p. 1569 - 1574
Zh. Org. Khim.,2019,vol. 55,p. 1569 - 1574,6

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(4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate [ No CAS ]