[ CAS No. 941685-27-4 ] {[proInfo.proName]}

Name: 941685-27-4|4-(4-Pyrazolyl)-7-[[2-(trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidine|99+%
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Quality Control of [ 941685-27-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 941685-27-4 ]

CAS No. :	941685-27-4	MDL No. :	MFCD11857754
Formula :	C₁₅H₂₁N₅OSi	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AVMLPTWVYQXRSV-UHFFFAOYSA-N
M.W :	315.45	Pubchem ID :	42631346
Synonyms :		Chemical Name :	4-(4-Pyrazolyl)-7-[[2-(trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidine

Safety of [ 941685-27-4 ]

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 [ 941685-27-4 ]

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

Upstream synthesis route of [ 941685-27-4 ]
Downstream synthetic route of [ 941685-27-4 ]

[ 941685-27-4 ] Synthesis Path-Upstream 1~9

1
[ 269410-08-4 ]
[ 941685-26-3 ]
[ 941685-27-4 ]

Yield	Reaction Conditions	Operation in experiment
64%	With potassium carbonate In 1,4-dioxane; water at 90℃; for 2 h; Inert atmosphere	4-(1H-Pyrazol-4-yl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5).; Method A.; To a flask equipped with a reflux condenser, a nitrogen inlet, mechanical stirrer, and a thermowell was added 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 817 g, 2.88 mol) and dioxane (8 L). To this solution was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4, 728 g, 3.75 mol, 1.30 equiv) followed by a solution of potassium carbonate (K₂CO₃, 1196 g, 8.67 mol, 3.0 equiv) in water (4 L). The solution was degassed by passing a stream of nitrogen through the solution for 15 minutes before being treated with tetrakis(triphenylphosphine)palladium(0) (167 g, 0.145 mol, 0.05 equiv) and the resulting reaction mixture was heated at reflux (about 90° C.) for 2 hours. When the reaction was deemed complete by TLC (1:1 heptane/ethyl acetate) and LCMS, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (24 L) and water (4 L). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (4 L). The combined organic layers were washed with water (2.x.2 L), brine (2 L), dried over sodium sulfate (Na₂SO₄), and concentrated under reduced pressure. The residue was suspended in toluene (4 L) and the solvent was removed under reduced pressure. The residue was finally triturated with methyl tert-butyl ether (MTBE, 3 L) and the solids were collected by filtration and washed with MTBE (1 L) to afford 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 581.4 g, 908.5 g theoretical, 64percent yield) as white crystalline solids. For 5: ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 13.41 (bs, 1H), 8.74 (s, 1H), 8.67 (bs, 1H), 8.35 (bs, 1H), 7.72 (d, 1H, J=3.7 Hz), 7.10 (d, 1H, J=3.7 Hz), 5.61 (s, 2H), 3.51 (t, 2H, J=8.2 Hz), 0.81 (t, 2H, J=8.2 Hz), 0.13 (s, 9H); C₁₅H₂₁N₅OSi (MW, 315.45), LCMS (EI) m/e 316 (M⁺+H).
27%	Stage #1: With potassium carbonate In 1,4-dioxane; water at 20℃; for 0.166667 h; Inert atmosphere Stage #2: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In 1,4-dioxane; waterInert atmosphere	At room temperature, 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (12f) (800 mg, 2.82 mmol) and 4-pyrazoleboronic acid pinacol ester (842 mg, 4.34 mmol) were dissolved in dioxane (10 mL), water (2 mL) and potassium carbonate (857 mg, 6.2 mmol) were then added, nitrogen atmosphere protection was applied, and the reaction was stirred at room temperature for 10 min. Under protection of nitrogen, Pd(dppf)Cl₂ (227 mg, 0.31 mmol) was added. The reaction was placed in an oil bath at 95°C, and stirred overnight. TLC indicated starting materials substantially disappeared. The reaction was quenched with water, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate, and purified by preparative flash chromatography (PE:EA=2:3), to afford 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (12g) (240 mg, brown solid), yield: 27percent. MS (ESI, m/z): 316 [M+H]⁺.
166.4 g	Stage #1: With potassium carbonate In water at 25 - 30℃; Inert atmosphere Stage #2: at 78 - 80℃; for 2 h; Inert atmosphere	Nitrogen gas was purged through a mixture of 4-chloro-7- { [2- (0224) (trimemylsilyl)ethoxy]memyl}-7H-pyIτolo[2,3-

Reference： [1] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 75-76
[2] Patent: EP3360878, 2018, A1, . Location in patent: Paragraph 0140; 0145
[3] Patent: WO2016/35014, 2016, A1, . Location in patent: Page/Page column 27

2
[ 941685-41-2 ]
[ 941685-27-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	at 0 - 20℃; Inert atmosphere	4-(1H-Pyrazol-4-yl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5).; Method E.; Into a 22 L four-neck flask equipped with overhead stirring, thermocouple, 2 L addition funnel and nitrogen inlet was charged (3S)-3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile ((S)-10, 491 g, 1.11 mol) and acetonitrile (4.5 L) at room temperature. The mixture was cooled to 0-10° C. before being treated dropwise with a 1M solution of potassium tert-butoxide in THF (KO^tBu, 2.0 L, 2.0 mol, 1.8 equiv) via the addition funnel over 1.5 hours. Following the addition of base the reaction mixture was allowed to return to room temperature and was stirred at room temperature for 12-24 h. When LC/MS showed the reaction was deemed complete, the reaction mixture was diluted with ethyl acetate (EtOAc, 6 L) and 50percent (w/w) aqueous ammonium chloride solution (NH₄Cl, 4 L). The two layers were separated, and the aqueous fraction was back extracted with ethyl acetate (2 L). The combined organic fractions were washed with water (2 L) and brine (3 L), dried over magnesium sulfate (MgSO₄), and concentrated under reduced pressure to afford the crude 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 354 g, 350.1 g theoretical, 101.1percent yield) as an amber oil, which solidified upon standing at room temperature in vacuo. This crude material was subsequently recrystallized in acetonitrile to afford pure compound 5 (308 g, 350.1 g theoretical, 88percent yield) as white crystals (99.5 area percent by HPLC), which was found to be identical in every comparable aspect to the material made from Method A, B, C, and D.

Reference： [1] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 84-85

3
[ 1187595-88-5 ]
[ 941685-27-4 ]

Yield	Reaction Conditions	Operation in experiment
69%	With hydrogenchloride In tetrahydrofuran; water at 20℃;	To a solution of intermediate 3 (8.5 g, 0.022 mol) in THF (80 mL) was added 1.5N aqueous HCI (20 mL)The mixture was stirred at room temperature overnight.The reaction mixture was then concentrated under reduced pressure,Extracted with ethyl acetate,Dried and concentrated,Purification by silica gel column gave intermediate 4(4.8 g, 69percent),As a white solid
3281.7 g	With hydrogenchloride In tetrahydrofuran; water at 16 - 30℃; Large scale	Step 2. 4-(lH-Pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrwlo[2,3- d] pyrimidine (5) To a reactor equipped with the overhead stirrer, a condenser, a thermowell, ' and a nitrogen inlet was charged water (0, 9.0 L), solid potassium carbonate (K₂C0₃, 4461 g, 32.28 mol, 2.42 equiv), 4-chloro-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-cT]pyrimidine (3, 3597 g, 12.67 mol), 1 -( 1 -ethoxyethyl)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-y I)- 1 H-pyrazole (4, 3550 g, 13.34 mol, 1.05 equiv), and 1-butanol (27 L) at room temperature. The resulting reaction mixture was degassed three timed backfilling with nitrogen each time before being treated with tetrakis(triphenylphosphine)palladium(0) (Pd(PPli3)4, 46 g, 0.040 mol, 0.003 equiv) at room temperature. The resulting reaction mixture was heated to gentle reflux (about 90 °C) for 1 - 4 hours. When the reaction was deemed complete determined by HPLC, the reaction mixture was gradually cooled down to room temperature before being filtered through a Ceiite bed. The Ceiite bed was washed with ethyl acetate (2 x 2 L) before the filtrates and washing solution were combined. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (12 L). The combined organic layers were concentrated under reduced pressure to remove solvents, and the crude 4-(l-(l-ethoxyethyl)-lH-pyrazol-4-yl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c/]pynmidine (6) was directly charged back to the reactor with tetrahydrofuran (THF, 4.2 L) for the subsequent acid- promoted de-protection reaction without further purification. To a suspension of crude 4-(l -(l -ethoxyethyl)-lH-pyrazol-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c/]pyrimidine (6), made as described above, in tetrahydrofuran (THF, 4.2 L) in the reactor was charged water (Η₂0, 20.8 L), and a 10percent aqueous HC1 solution (16.2 L, 45.89 mol, 3.44 equiv) at room temperature. The resulting reaction mixture was stirred at 16 - 30 °C for 2 - 5 hours. When the reaction was deemed complete by HPLC analysis, the reaction mixture was treated with a 30percent aqueous sodium hydroxide (NaOH) solution (4 L, 50.42 mol, 3.78 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 - 2 hours. The solids were collected by filtration and washed with water (2 x 5 L). The wet cake was charged back to the reactor with acetonitrile (21.6' L), and resulting suspension was heated to gentle reflux for 1 - 2 hours. The clear solution was then gradually cooled down to room temperature with stirring, and solids were precipitated out from the solution with cooling. The mixture was stirred at room temperature for an additional 1 - 2 hours. The solids were collected by filtration, washed with acetonitrile (2 x 3.5 L), and dried in oven under reduced pressure at 45 - 55 °C to constant weight to afford 4-( 1 H-pyrazol-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-i/]pyrimidine (5, 3281.7 g, 3996.8 g theoretical, 82.1 percent yield) as white crystalline solids (99.5 areapercent by HPLC). For 5: NMR (DMSO-i/₆, 400 MHz) δ 13.41 (br. s, 1 H), 8.74 (s, 1 H), 8.67 (br. s, 1 H), 8.35 (br. s, 1 H), 7.72 (d, l H, J= 3.7 Hz), 7.10 (d, 1 H, J= 3.7 Hz), 5.61 (s, 2H), 3.51 (t, 2H, J= 8.2 Hz), 0.81 (t, 2H, J= 8.2 Hz), 0.13 (s, 9H) ppm; C₁₅H₂iN₅OSi (MW, 315.45), LCMS (El) mle 316 (M⁺ + H).

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 20, p. 8336 - 8357
[2] Patent: CN106905322, 2017, A, . Location in patent: Paragraph 0052; 0053; 0056
[3] Organic Letters, 2009, vol. 11, # 9, p. 1999 - 2002
[4] Patent: US2009/233903, 2009, A1, . Location in patent: Page/Page column 61-62
[5] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 81-82
[6] Patent: WO2013/36611, 2013, A1, . Location in patent: Page/Page column 25

4
[ 941685-26-3 ]
[ 1029716-44-6 ]
[ 941685-27-4 ]

Reference： [1] Patent: US2011/224190, 2011, A1, . Location in patent: Page/Page column 37-38
[2] Patent: US2015/246046, 2015, A1, . Location in patent: Paragraph 0133

5
[ 941685-39-8 ]
[ 941685-27-4 ]

Reference： [1] Patent: WO2016/35014, 2016, A1, . Location in patent: Page/Page column 27; 28

6
[ 76513-69-4 ]
[ 941685-27-4 ]

Reference： [1] Patent: US2011/224190, 2011, A1,
[2] Patent: WO2013/36611, 2013, A1,
[3] Patent: US2015/246046, 2015, A1,
[4] Patent: CN106905322, 2017, A,
[5] Journal of Medicinal Chemistry, 2017, vol. 60, # 20, p. 8336 - 8357
[6] Patent: EP3360878, 2018, A1,

7
[ 3680-69-1 ]
[ 941685-27-4 ]

8
[ 941685-26-3 ]
[ 941685-27-4 ]

Reference： [1] Patent: WO2013/36611, 2013, A1,
[2] Patent: CN106905322, 2017, A,
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 20, p. 8336 - 8357

9
[ 941685-27-4 ]
[ 1334298-90-6 ]

Reference： [1] Patent: WO2013/36611, 2013, A1,
[2] Patent: US2015/246046, 2015, A1,

[ 941685-27-4 ] Synthesis Path-Downstream 1~88

1
[ 941685-27-4 ]
rac-3-[(1S,3R)-3-hydroxycyclopentyl]acrylonitrile [ No CAS ]
[ 1092974-05-4 ]
[ 1092974-04-3 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 25℃; for 48h;	Step 4. 3-[(1S,3R)-3-hydroxycyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile and 3-[(1R,3S)-3-hydroxycyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-]H-pyrazol-1-yl]propanenitrile; 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.54 mL, 3.6 mmol) was added to a solution of a mixture of (2E)- and (2Z)-3-[(1S,3R)-3-hydroxycyclopentyl]acrylonitrile and (2E)- and (2Z)-3-[(1R,3S)-3-hydroxycyclopentyl]acrylonitrile (0.250 g, 1.82 mmol) and <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (0.57 g, 1.8 mmol) in acetonitrile (5 mL) in a round-bottom flask. The resulting mixture was stirred at 25 C. for 2 days at which time LCMS analysis showed 80% of the starting materials had been consumed. The reaction mixture was purified by chromatography on silica gel using 1:1 EtOAc/hexanes to give the product. 1H NMR(400 MHz, CDCl3): delta 8.90 (d, 1H), 8.39 (m, 2H), 7.46 (m, 1H), 6.86 (m 1H), 5.73 (s, 2H), 4.52 (m, 2H), 3.59 (m, 2H), 3.2 (m, 1H), 3.02 (m, 1H), 2.78 (m, 1H), 2.3 (m, 1H), 1.30-1.90 (m, 6H), 0.99 (m, 2H), 0.08 (s, 9H). LC/MS: 453 (M+H)+.

Reference： [1]Patent: US2008/312258,2008,A1 .Location in patent: Page/Page column 10

2
[ 941685-27-4 ]
[ 118235-51-1 ]
[ 1146629-78-8 ]
(3S)-3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal [ No CAS ]

Reference： [1]Organic Letters,2009,vol. 11,p. 1999 - 2002

3
[ 1187595-88-5 ]
[ 941685-27-4 ]

Yield	Reaction Conditions	Operation in experiment
69%	With hydrogenchloride; In tetrahydrofuran; water; at 20℃;	To a solution of intermediate 3 (8.5 g, 0.022 mol) in THF (80 mL) was added 1.5N aqueous HCI (20 mL)The mixture was stirred at room temperature overnight.The reaction mixture was then concentrated under reduced pressure,Extracted with ethyl acetate,Dried and concentrated,Purification by silica gel column gave intermediate 4(4.8 g, 69%),As a white solid
		To a suspension of crude 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (6), made as described above, in tetrahydrofuran (THF, 4.2 L) in the reactor was charged water (H2O, 20.8 L), and a 10% aqueous HCl solution (16.2 L, 45.89 mol, 3.44 equiv) at room temperature. The resulting reaction mixture was stirred at 16-30 C. for 2-5 h. When the reaction was deemed complete by HPLC analysis, the reaction mixture was treated with a 30% aqueous sodium hydroxide (NaOH) solution (4 L, 50.42 mol, 3.78 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 1-2 h. The solids were collected by filtration and washed with water (2×5 L). The wet cake was charged back to the reactor with acetonitrile (21.6 L), and resulting suspension was heated to gentle reflux for 1-2 h. The clear solution was then gradually cooled down to room temperature with stirring, and solids were precipitated out from the solution with cooling. The mixture was stirred at room temperature for an additional 1-2 h. The solids were collected by filtration, washed with acetonitrile (2×3.5 L), and dried in oven under reduced pressure at 45-55 C. to constant weight to afford 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 3281.7 g, 3996.8 g theoretical, 82.1% yield) as white crystalline solids (99.5 area % by HPLC). For 5: 1H NMR (DMSO-d6, 400 MHz) delta 13.41 (br. s, 1H), 8.74 (s, 1H), 8.67 (br. s, 1H), 8.35 (br. s, 1H), 7.72 (d, 1H, J=3.7 Hz), 7.10 (d, 1H, J=3.7 Hz), 5.61 (s, 2H), 3.51 (t, 2H, J=8.2 Hz), 0.81 (t, 2H, J=8.2 Hz), 0.13 (s, 9H) ppm; C15H21N5OSi (MW, 315.45), LCMS (EI) m/e 316 (M++H).
		To a reactor equipped with overhead stirring, condenser, thermowell, and nitrogen inlet was charged crude 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (15, 1030.9 g based on 100% conversion, 2.66 mol), tetrahydrofuran (THF, 0.9 L), water (H2O, 4.4 L), and a 10% aqueous HCl solution (2.7 L, 10.64 mol, 3.44 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 2-5 h. When the reaction was deemed complete by HPLC analysis, the reaction mixture was treated with a 30% aqueous sodium hydroxide (NaOH) solution (940 mL, 11.70 mol, 3.78 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 1-2 h. The solids were collected by filtration, washed with water (2×0.75 L), and dried in a vacuum oven at 45-55 C. to constant weight to afford the crude 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 826.8 g, 839.1 g theoretical, 98.5% yield) as off-white solids (94.2 area % pure by HPLC). This crude material was subsequently recrystallized in acetonitrile to afford pure compound 5 (738.4 g, 839.1 g theoretical, 88% yield) as white crystals (99.5 area % by HPLC), which was found to be identical in every comparable aspect to the material made from Method A.

3281.7 g

With hydrogenchloride; In tetrahydrofuran; water; at 16 - 30℃;Large scale;

Step 2. 4-(lH-Pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrwlo[2,3- d] pyrimidine (5) To a reactor equipped with the overhead stirrer, a condenser, a thermowell, ' and a nitrogen inlet was charged water (0, 9.0 L), solid potassium carbonate (K2C03, 4461 g, 32.28 mol, 2.42 equiv), 4-chloro-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-cT]pyrimidine (3, 3597 g, 12.67 mol), 1 -( 1 -ethoxyethyl)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-y I)- 1 H-pyrazole (4, 3550 g, 13.34 mol, 1.05 equiv), and 1-butanol (27 L) at room temperature. The resulting reaction mixture was degassed three timed backfilling with nitrogen each time before being treated with tetrakis(triphenylphosphine)palladium(0) (Pd(PPli3)4, 46 g, 0.040 mol, 0.003 equiv) at room temperature. The resulting reaction mixture was heated to gentle reflux (about 90 C) for 1 - 4 hours. When the reaction was deemed complete determined by HPLC, the reaction mixture was gradually cooled down to room temperature before being filtered through a Ceiite bed. The Ceiite bed was washed with ethyl acetate (2 x 2 L) before the filtrates and washing solution were combined. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (12 L). The combined organic layers were concentrated under reduced pressure to remove solvents, and the crude 4-(l-(l-ethoxyethyl)-lH-pyrazol-4-yl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c/]pynmidine (6) was directly charged back to the reactor with tetrahydrofuran (THF, 4.2 L) for the subsequent acid- promoted de-protection reaction without further purification. To a suspension of crude 4-(l -(l -ethoxyethyl)-lH-pyrazol-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c/]pyrimidine (6), made as described above, in tetrahydrofuran (THF, 4.2 L) in the reactor was charged water (Eta20, 20.8 L), and a 10% aqueous HC1 solution (16.2 L, 45.89 mol, 3.44 equiv) at room temperature. The resulting reaction mixture was stirred at 16 - 30 C for 2 - 5 hours. When the reaction was deemed complete by HPLC analysis, the reaction mixture was treated with a 30% aqueous sodium hydroxide (NaOH) solution (4 L, 50.42 mol, 3.78 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 - 2 hours. The solids were collected by filtration and washed with water (2 x 5 L). The wet cake was charged back to the reactor with acetonitrile (21.6' L), and resulting suspension was heated to gentle reflux for 1 - 2 hours. The clear solution was then gradually cooled down to room temperature with stirring, and solids were precipitated out from the solution with cooling. The mixture was stirred at room temperature for an additional 1 - 2 hours. The solids were collected by filtration, washed with acetonitrile (2 x 3.5 L), and dried in oven under reduced pressure at 45 - 55 C to constant weight to afford 4-( 1 H-pyrazol-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-i/]pyrimidine (5, 3281.7 g, 3996.8 g theoretical, 82.1 % yield) as white crystalline solids (99.5 area% by HPLC). For 5: NMR (DMSO-i/6, 400 MHz) delta 13.41 (br. s, 1 H), 8.74 (s, 1 H), 8.67 (br. s, 1 H), 8.35 (br. s, 1 H), 7.72 (d, l H, J= 3.7 Hz), 7.10 (d, 1 H, J= 3.7 Hz), 5.61 (s, 2H), 3.51 (t, 2H, J= 8.2 Hz), 0.81 (t, 2H, J= 8.2 Hz), 0.13 (s, 9H) ppm; C15H2iN5OSi (MW, 315.45), LCMS (El) mle 316 (M+ + H).

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 8336 - 8357
[2]Patent: CN106905322,2017,A .Location in patent: Paragraph 0052; 0053; 0056
[3]Organic Letters,2009,vol. 11,p. 1999 - 2002
[4]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 61-62
[5]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 81-82
[6]Patent: WO2013/36611,2013,A1 .Location in patent: Page/Page column 25

4
[ 941685-27-4 ]
[ 1187595-85-2 ]
[ 1187594-13-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;	At room temperature, acetonitrile (10 mL) was added to a mixture of 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (9a) (214 mg) and <strong>[1187595-85-2]2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile</strong> (126 mg) to obtain a reaction solution. DBU (120 mg) was then added, and the reaction was stirred at room temperature overnight. The reaction was concentrated, and purified on a preparative silica gel plate, to afford 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (9b) (327 mg, solid), yield: 77%. MS m/z: 502 [M+1]+.
	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 15 - 25℃;Product distribution / selectivity;	To a suspension of 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 440 g, 1.395 mol) and <strong>[1187595-85-2]2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile</strong> (11, 312.4 g, 1.68 mol, 1.2 equiv) in acetonitrile (4.4 L) was added DBU (249.8 mL, 1.67 mol, 1.2 equiv) drop wise to keep the reaction temperature between 15-25 C. After adding DBU, the reaction mixture became homogeneous, but a precipitate appeared in 30 min. The reaction mixture was stirred for 3 h at room temperature. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (11 L). The resulting mixture was stirred at room temperature for additional 30 min and then filtered. The solid cake was washed with water (4 L), MTBE (2 L) and dried in vacuum oven at 35 C. for 24 h to afford crude 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (12, 681 g, 699.8 g theoretical, 97.3% yield) as white solids, which was found to be sufficiently pure for the subsequent reaction without further purification. For 12: 1HNMR (CDCl3, 300 MHz), 6 8.86 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 7.43 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.65 (d, 2H), 4.27 (d, 2H), 3.55 (s, 2H), 3.4 (t, 2H), 3.07 (m, 2H), 1.42 (m, 3H), 0.92 (m, 2H), -0.05 (s, 9H) ppm; C22H31N7O3SSi (MW, 501.68), LCMS (EI) m/e 502 (M++H).

Reference： [1]Patent: EP3360878,2018,A1 .Location in patent: Paragraph 0125; 0126
[2]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 64

5
[ 941685-27-4 ]
[ 1153949-98-4 ]
[ 1187595-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;	3-(Cyanomethylene)cyclobutanecarbonitrile (120 mg, 0.0010 mol) was combined with <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (0.1 g, 0.0003 mol) in acetonitrile (2 mL, 0.04 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (6 muL, 0.00004 mol) under nitrogen. The mixture was stirred at room temperature over the weekend. After evaporation to dryness, the crude mixture was purified by flash column, eluding with 0 to 10% MeOH in dichloromethane, to give the desired product. LCMS (M+H) 434.4.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 52

6
[ 941685-27-4 ]
[ 1153949-11-1 ]
[ 1187594-11-1 ]

Yield	Reaction Conditions	Operation in experiment
97.6%	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 3h;Product distribution / selectivity;	To a suspension of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9, 417.2 g, 2.15 mol, 1.05 equiv) and <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine</strong> (5, 645 g, 2.04 mol) in acetonitrile (4.9 L) was added DBU (30.5 mL, 0.204 mol, 0.1 equiv) drop wise at room temperature. The resulting reaction mixture was then stirred at room temperature for 3 h. After about 1 h, a clear, brown solution was obtained. When LCMS showed that no starting material remained, silica gel (SiO2, 1 Kg) was added and the mixture was concentrated to dryness under reduced pressure. This material, which contains the crude desired product (15), was then loaded onto a pre-packed silica column (SiO2, 2.5 Kg) and the column was eluted with 60-80% of ethyl acetate/heptane. The fractions containing the pure desired product (15) were combined and concentrated under reduced pressure to give the desired product as thick oil which was then stirred in heptane at room temperature until crystallization occurred. The solids were collected by filtration and washed with heptane to afford tert-butyl 3-(cyanomethyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (15, 1014.9 g, 1039.7 g theoretical, 97.6% yield) as white solids. For 15: 1H NMR (DMSO-d6, 300 MHz) delta 8.93 (s, 1H), 8.77 (s, 1H), 8.47 (s, 1H), 7.80 (d, 1H, J=3.8 Hz), 7.20 (d, 1H, J=3.7 Hz), 5.63 (s, 2H), 4.50 (d, 2H, J=9.3 Hz), 4.21 (d, 2H, J=9.3 Hz), 3.66 (s, 2H), 3.52 (t, 2H, J=7.8 Hz), 1.40 (s, 9H), 0.82 (t, 2H, J=8.1 Hz), -0.12 (s, 9H) ppm; C25H35N7O3Si (MW, 509.68), LCMS (EI) m/e 510 (M-+H) and 532 (M++Na).
94.0%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 10 - 20℃; for 3.4h;Large scale;	Step 1. tert-But l 3-(cyanomethyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)azetidine-l-carboxylate (19) In a dried 30 L reactor equipped with a mechanic stirrer, a thermometer, an addition funnel and a vacuum outlet were placed 4-(lH-pyrazol-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-i/]pyrimidine (5, 4.50 kg, 14.28 mol), terf-butyl 3-(cyanomethylene)azetidine-l -carboxylate (13, 3.12 kg, 16.08 mol, 1.126 equiv) in acetonitrile (9 L) at 20 ± 5 C. To the resultant pink suspension was added l ,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 225 mL, 1.48 mol, 0.10 equiv) over 40 minutes. The batch temperature was kept between 10 C and 20 C during addition. The brown solution obtained was stirred at 20 C for 3 hours. After the reaction was complete, water (18 L) was added with stirring over 80 minutes at 20 C. The mixture was seeded and the seeded mixture was stirred at room temperature for 12 hours. The solids were collected by filtration and the filter cake was washed with a mixture of acetonitrile and water (1 : 2, 9 L) and dried in a vacuum oven with nitrogen purge for 12 hours at 60 C to provide the crude product (19, 7.34 kg) as a light yellow powder. The crude product obtained above was dissolved in methyl teri-butyl ether (MTBE, 22 L) at 60 C in a 50 L reactor equipped with a mechanic stirrer, a thermometer, an addition funnel and a septum. Hexanes (22 L) was added over 1 hour at 60 C. The solution was then seeded, cooled to 20 C over 3 hours and stirred at 20 C for 12 hours. The precipitation was collected by filtration. The resultant cake was washed with a mixture of MTBE and hexane (1 : 15, 3 L) and dried in a vacuum oven for 10 hours at 50 C to provide the compound 19 (6.83 kg, 13.42 mol, 94.0%) as a white powder. For 19: NMR (400 MHz, CDCI3) delta 8.87 (s, 1 H), 8.46 (d, J = 0.6 Hz, 1 H), 8.36 (d, J= 0.7 Hz, 1 H), 7.44 (d, J= 3.7 Hz, 1 H), 6.82 (d, J = 3.7 Hz, I H), 5.69 (s, 2H), 4.57 (d, J= 9.6 Hz, 2Eta), 4.32 (d, J= 9.5 Hz, 2H), 3.59 - 3.49 (m, 2H), 3.35 (s, 2H), 1.49 (s, 9H), 0.96 - 0.87 (m, 2H), -0.03 - -0.10 (s, 9H) ppm; 13C NMR (101 MHz, CDC13) delta 157.22, 153.67, 153.24, 151.62, 142.13, 130.16, 129.67, 124.47, 1 16.72, 1 15.79, 102.12, 82.54, 74.23, 68.01, 60.25, 58.23, 29.65, 29.52, 19.15, -0.26 ppm; C25H35N7O3S1 (MW, 509.68), LCMS (EI) mle 510.1 (M+ + H).
88%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 3h;Inert atmosphere;	A 2 L round bottom flask fitted with overhead stirring, septa and nitrogen inlet was charged with tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9.17 g, 0.0472 mol), <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine</strong> (14.9 g, 0.0472 mol) and acetonitrile (300 mL). The resulting solution was heterogeneous. To the solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.48 mL, 0.0567 mol) portionwise via syringe over 3 min at room temperature. The solution slowly became homogeneous and yellow in color. The reaction was allowed to stir at room temperature for 3 h. The reaction was complete by HPLC and LC/MS and was concentrated by rotary evaporation to remove acetonitrile (150 mL). EtOAc (100 mL) was added followed by 100 ml of 20% brine. The two phases were partitioned. The aqueous phase was extracted with 150 mL of EtOAC. The combine organic phases were dried over MgSO4, filtered and concentrated to yield an orange oil. Purification by flash chromatography (150 grams silica, 60% EtOAc/hexanes, loaded with CH2Cl2) yielded the title compound tert-butyl 3-(cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate as a yellow oil (21.1 g, 88% yield). LC-MS: [M+H]+=510.3.

88%

With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 3.05h;

Step E: tert-Butyl 3-(Cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate A 2 L round bottom flask fitted with overhead stirring, septa and nitrogen inlet was charged with tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9.17 g, 0.0472 mol 1), <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine</strong> (14.9 g, 0.0472 mol) and acetonitrile (300 mL). The resulting solution was heterogeneous. To the solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.48 mL, 0.0567 mol) portionwise via syringe over 3 min at room temperature. The solution slowly became homogeneous and yellow in color. The reaction was allowed to stir at room temperature for 3 h. The reaction was complete by HPLC and LC/MS and was concentrated by rotary evaporation to remove acetonitrile (?150 mL). EtOAc (100 mL) was added followed by 100 ml of 20% brine. The two phases were partitioned. The aqueous phase was extracted with 150 mL of EtOAC. The combine organic phases were dried over MgSO4, filtered and concentrated to yield an orange oil. Purification by flash chromatography (150 grams silica, 60% EtOAc/hexanes, loaded with CH2Cl2) yielded the title compound tert-butyl 3-(cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate as a yellow oil (21.1 g, 88% yield). LC-MS: [M+H]+=510.3.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 65-66
[2]Patent: WO2013/36611,2013,A1 .Location in patent: Page/Page column 33; 34
[3]Patent: US2011/224190,2011,A1 .Location in patent: Page/Page column 38
[4]Patent: US2015/246046,2015,A1 .Location in patent: Paragraph 0134

7
[ 941685-27-4 ]
[ 1187594-27-9 ]
[ 1187594-28-0 ]

Yield	Reaction Conditions	Operation in experiment
77%	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; for 1.5h;	To a solution of <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (0.108 g, 0.344 mmol) and 1-[(1-methylcyclopropyl)sulfonyl]azetidin-3-ylideneacetonitrile (71 mg, 0.33 mmol) in acetonitrile (3 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (51 muL, 0.34 mmol). After a reaction time of 1.5 hours, the acetonitrile was removed in vacuo and the residue was partitioned between ethyl acetate and IN HCl. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Flash column chromatography, eluding with a gradient of 0-80% ethyl acetate in hexanes afforded product (135 mg, 77%). 1H NMR (300 MHz, CDCl3): delta 8.86 (s, 1H), 8.46 (s, 1H), 8.35 (s, 1H), 7.42 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.62 (d, 2H), 4.22 (d, 2H), 3.59-3.50 (m, 2H), 3.42 (s, 2H), 1.55 (s, 3H), 1.42-1.36 (m, 2H), 0.96-0.89 (m, 2H), 0.85 (dt, 2H), -0.06 (s, 9H); LCMS (M+H)+: 528.1.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 31

8
[ 941685-27-4 ]
[ 1187595-00-1 ]
C₂₄H₂₉N₇O₂Si [ No CAS ]
C₂₄H₂₉N₇O₂Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; for 72h;	To a solution of (3-isoxazol-3-ylcyclobutylidene)acetonitrile (prepared in Step 8) in acetonitrile (8 mL) was added <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (0.59 g, 1.9 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (280 muL, 1.9 mmol). The reaction was stirred for 72 hours. The acetonitrile was removed in vacuo. Flash column chromatography, eluting with a gradient of 50-100% ethyl acetate in hexanes, afforded a mixture of cis- and trans-isomers. The mixture was stirred with 20% TFA/DCM (8 mL/32 mL) for 3 hours, and the excess solvents were removed in vacuo. The residue was stirred with ethylenediamine (2 mL) in MeOH (40 mL) for 16 hours. Solvents were again removed in vacuo. The mixture was purified by preparative-HPLC/MS (XBridge C18 column, mobile phases 20.5-25.5% of MeCN/H2O containing 0.1% NH40H). Peak 1, cis-3-isoxazol-3-yl-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylac (185 mg, 28%), Peak 2, trans-3-isoxazol-3-yl-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (85 mg, 13%).Peak 1, (cis-): 1H NMR (400 MHz, d6-dmso): delta 12.13 (br s, 1H), 8.85 (d, 1H), 8.76 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.60 (d, 1H), 7.07 (d, 1H), 6.67 (d, 1H), 3.85 (p, 1H), 3.67 (s, 2H), 3.04-2.95 (m, 2H), 2.89-2.81 (m, 2H); LCMS (M+H)+: 346.1.Peak 2, (trans-): 1H NMR (400 MHz, d6-dmso): delta 12.14 (br s, 1H), 8.94 (s, 1H), 8.89 (d, 1H), 8.71 (s, 1H), 8.47 (s, 1H), 7.62 (dd, 1H), 7.11 (dd, 1H), 6.73 (d, 1H), 3.71 (p, 1H), 3.46 (s, 2H), 3.34-3.27 (m, 2H), 2.80-2.71 (m, 2H); LCMS (M+H)+: 346.1.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 42-43

9
[ 941685-27-4 ]
[ 1187595-05-6 ]
[ 1187595-06-7 ]

Yield	Reaction Conditions	Operation in experiment
	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 136h;	Step 5. ethyl 3-(cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarboxylate To a solution of <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (5.23 g, 16.6 mmol) and ethyl 3-(cyanomethylene)cyclobutanecarboxylate (prepared in Step 4) in acetonitrile (40 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.48 mL, 16.6 mmol). The mixture was stirred for 136 hours at room temperature. The solvent was removed in vacuo. Flash column chromatography, eluding with a gradient of 50-90% ethyl acetate in hexanes afforded product as a mixture of cis- and trans-isomers (4.53 g, 52% over the two steps). 1H NMR (400 MHz, CDCl3): delta 8.85 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 8.31 (s, 1H), 7.41 (d, 1H), 7.40 (d, 1H), 6.81 (d, 1H), 6.80 (d, 1H), 5.68 (s, 4H), 4.17 (q, 2H), 4.12 (q, 2H), 3.54 (t, 4H), 3.27 (s, 2H), 3.28-2.80 (m, 10H), 3.19 (s, 2H), 1.26 (t, 3H), 1.25 (t, 3H), 0.92 (t, 4H), -0.06 (s, 18H); LCMS (M+H)+: 481.1.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 45

10
[ 941685-27-4 ]
[ 27784-69-6 ]
[ 1187595-62-5 ]

Yield	Reaction Conditions	Operation in experiment
	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;	To a solution of <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (0.030 g, 0.000095 mol) in acetonitrile (0.60 mL, 0.011 mol) was added cyclobutylideneacetonitrile (0.0177 g, 0.000190 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.0142 mL, 0.0000951 mol). The resulting mixture was stirred at rt overnight. After evaporation to dryness, the residue was purified on silica gel to give the desired Micheal addition product. LCMS (M+H) 409.1.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 45-46

11
[ 941685-27-4 ]
[ 206445-57-0 ]
cis-methyl 3-(cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarboxylate [ No CAS ]
trans-methyl 3-(cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 50℃;	To a solution of <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (2.01 g, 0.00637 mol) in acetonitrile (4.0E1 mL, 0.77 mol) was added methyl 3-(cyanomethylene)cyclobutanecarboxylate (1.93 g, 0.0127 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.953 mL, 0.00637 mol). The resulting mixture was stirred at 50 C. overnight. After evaporation to dryness, the residue was purified on silica gel, eluding with 0 to 100% EtOAc in hexane, to give the desired Micheal addition product as a mixture of cis- and trans-isomers (2.12 g, 71.3%). LCMS calculated for C23H31N6O3Si(M+H)+: 467.2; Found: 467.4.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 46

12
[ 941685-27-4 ]
[ 1187595-30-7 ]
[ 1297358-20-3 ]

Yield	Reaction Conditions	Operation in experiment
	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;	To a solution of <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (0.030 g, 0.000095 mol) in acetonitrile (0.5 mL, 0.01 mol) was added 3-(cyanomethylene)-1-methylcyclobutanecarbonitrile (0.0126 g, 0.0000951 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.0142 mL, 0.0000951 mol). The resulting mixture was stirred at rt overnight, then evaporated to dryness. LCMS (M+H) 448.4.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 49

13
[ 941685-27-4 ]
[ 1187595-35-2 ]
[ 1297359-39-7 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide;1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;	To a solution of <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (0.256 g, 0.000812 mol) in acetonitrile (5 mL, 0.1 mol) was added 3-(cyanomethylene)-1-(methoxymethyl)cyclobutanecarbonitrile (0.166 g, 0.00102 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.153 mL, 0.00102 mol). The resulting mixture was stirred at rt overnight, and evaporated to dryness. LCMS (M+H) 478.4.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 50

14
[ 941685-27-4 ]
[ 1187595-41-0 ]
[ 1187595-87-4 ]

Yield	Reaction Conditions	Operation in experiment
	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;	To a solution of <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (0.256 g, 0.000812 mol) in acetonitrile (5 mL, 0.1 mol) was added 3-(cyanomethylene)-1-(fluoromethyl)cyclobutanecarbonitrile (0.153 g, 0. 00102 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.153 mL, 0.00102 mol). The resulting mixture was stirred at rt overnight, evaporated to dry. LCMS (M+H) 465.4.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 50

15
[ 941685-27-4 ]
[ 1187595-47-6 ]
[ 1187596-01-5 ]

Yield	Reaction Conditions	Operation in experiment
	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;	To a solution of 4-(1 H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.256 g, 0.000812 mol) in acetonitrile (5 mL, 0.1 mol) was added 1-(cyanomethyl)-3-(cyanomethylene)cyclobutanecarbonitrile (0.161 g, 0.00102 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.153 mL, 0.00102 mol). The resulting mixture was stirred at rt overnight, evaporated to dry. LCMS (M+H) 473.4.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 51

16
[ 941685-27-4 ]
[ 1187595-52-3 ]
[ 1187595-53-4 ]

Yield	Reaction Conditions	Operation in experiment
	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 50℃;	Diisopropyl 3-(cyanomethylene)cyclobutane-1,1-dicarboxylate (2.65 g, 0.00999 mol) was combined with <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (1 g, 0.003 mol) in acetonitrile (10 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL, 0.003 mol) was added under N2. The mixture was heated at 50 C. overnight. The reaction was concentrated and purified with Combiflash (silica gel, 0-50% EtOAc/Hex) to give the desired product (0.3 g) as colorless oil. LCMS calculated for C29H41N6O5Si(M+H): 581.3; Found: 581.4.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 53

17
[ 941685-27-4 ]
[ 1187595-69-2 ]
[ 1187595-71-6 ]

Yield	Reaction Conditions	Operation in experiment
	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 50℃;	(3-[tert-Butyl(diphenyl)silyl]oxycyclobutylidene)acetonitrile (0.15 g, 0.00043 mol) was combined with <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (0.14 g, 0.00043 mol) in acetonitrile (5 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.064 mL, 0.00043 mol) was added under nitrogen. The mixture was heated to 50 C. over night. LCMS showed a peak with m/z of 425.4, indicating a de-silyl reaction occurred simultaneously during the Micheal addition. The reaction was concentrated and purified on combiflash (silica gel, 0-100% EtOAc/Hex) to yield the desired produt. LCMS (M+H) 425.4.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 55-56

18
[ 941685-27-4 ]
[ 1187595-82-9 ]
cis-3-(benzyloxy)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile [ No CAS ]
trans-3-(benzyloxy)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 50℃;	To a mixture of [3-(benzyloxy)cyclobutylidene]acetonitrile (0.1 g, 0.0005 mol) and <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (0.1 g, 0.0003 mol) in acetonitrile (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL, 0.0003 mol) under nitrogen. The mixture was heated at 50 C. overnight, then concentrated under reduced pressure. The residue was purified with combiflash (silica gel, 0-55% EtOAc/Hex) to give the desired product as cis- and trans-isomer mixture. LCMS calculated for C28H35N6O2Si(M+H)+: 515.3; Found: 515.4.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 58

19
[ 941685-27-4 ]
[ 1187595-97-6 ]
[ 1187595-98-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 3h;	A mixture of <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine</strong> (0.40 g, 1.3 mmol), tert-butyl 3-[fluoro(phenylsulfonyl)methylene]azetidine-1-carboxylate (0.56 g, 1.7 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.182 mL, 1.22 mmol) in acetonitrile (6 mL, 100 mmol) was stirred at rt for 3 h. After evaporation to dryness, the residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexane, to give the desired product (820 mg, 100%). LCMS calculated for C30H40FN6O5SSi(M+H)+: m/z=643.3; Found: 643.4. 1H NMR (CDCl3, 300 MHz) delta 8.92 (1H, s), 8.55 (1H, s), 8.32 (1H, s), 7.87 (2H, m), 7.68 (1H, m), 7.55 (2H, m), 7.47 (1H, d, J=3.6 Hz), 6.84 (1H, d, J=3.6 Hz), 5.77 (1H, d, J=45.6 Hz), 5.74 (2H, s), 4.93 (1H, d, J=10.2 Hz), 4.734.58 (3H, m), 3.60 (2H, t, J=8.1 Hz), 1.51 (9H, s), 0.98 (3H, t, J=8.1 Hz), 0.07 (9H, s) ppm. 19F NMR (CDCl3, 300 MHz) delta -181.84 (1F, d, J=48.6 Hz) ppm.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 72-73

20
[ 941685-27-4 ]
[ 1187594-92-8 ]
C₂₃H₃₃N₇O₃SSi [ No CAS ]
C₂₃H₃₃N₇O₃SSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; for 16h;	To a solution of 4-(1 H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (7.09 g, 22.5 mmol) and crude 3-(cyanomethylene)-N,N-dimethylcyclobutanesulfonamide (prepared above) in acetonitrile (200 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.36 mL, 22.5 mmol). The reaction was stirred for 16 hours. The crude product was purified by flash column chromatography, eluting with a gradient of 0-10% MeOH in DCM (dichloromethane). The product collected from this pre-purification was further purified using preparative-HPLC/MS (XBridge C18 column, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford a mixture of isomers. The cis- and trans-isomers were separated using a portion of this mixture by the following method: Chiral Technologies Chiralcel OJ column, 30×250 mm, 5 mu packing material, eluting with 60% ethanol in hexanes at a flow rate of 14.5 mL/min and column loading of 65 mg/injection. Peak 1 so obtained was deprotected by stirring with 20% TFA/DCM for 2 hours, followed by evaporation and dissolving the residue in 4 mL MeOH to which 0.25 mL of ethylenediamine was then added. After stirring for 1 hour, the solvents were removed in vacuo, the crude product reconstituted and purified by preparative-HPLC/MS (XBridge C18 column, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford cis-3-(cyanomethyl)-N,N-dimethyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanesulfonamide.1H NMR (500 MHz, d6-dmso): delta 12.10 (br s, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.60 (d, 1H), 7.06 (d, 1H), 4.25 (p, 1H), 3.59 (s, 2H), 3.14-3.07 (m, 2H), 2.85-2.79 (m, 2H), 3.80 (s, 6H); LCMS: 386.1.Peak 2 obtained from the separation of isomers was deprotected and purified by the same method as for Peak 1 to afford trans-3-(cyanomethyl)-N,N-dimethyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1-yl]cyclobutanesulfonamide.1H NMR (500 MHz, d6-dmso): delta 12.10 (br s, 1H), 8.90 (s, 1H), 8.70 (s, 1H), 8.45 (s, 1H), 7.60 (d, 1H), 7.09 (d, 1H), 4.18 (p, 1H), 3.46 (s, 2H), 3.35-3.28 (m, 2H), 2.89-2.82 (m, 2H), 2.79 (s, 6H); LCMS: 386.0.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 40

21
[ 941685-27-4 ]
2,2',2"-cyclobutane-1,1-diyl-3-ylidenetriacetonitrile [ No CAS ]
[ 1187595-60-3 ]

Yield	Reaction Conditions	Operation in experiment
	1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 50℃;	The crude 2,2',2"-cyclobutane-1,1-diyl-3-ylidenetriacetonitrile (1 g, 0.006 mol) was combined with <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (0.2 g, 0.0006 mol) in acetonitrile (10 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL, 0.001 mol) was added under nitrogen. The mixture was heated at 50 C. over night. The reaction was concentrated and purified with Combiflash (silica gel, 0-100% EtOAc/Hex) to give the desired product as light brown oil. LCMS calculated for C25H31N8OSi(M+H)+: 487.2; Found: 487.4.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 54

22
[ 269410-08-4 ]
[ 941685-26-3 ]
[ 941685-27-4 ]

Yield	Reaction Conditions	Operation in experiment
64%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere;	4-(1H-Pyrazol-4-yl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5).; Method A.; To a flask equipped with a reflux condenser, a nitrogen inlet, mechanical stirrer, and a thermowell was added 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 817 g, 2.88 mol) and dioxane (8 L). To this solution was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4, 728 g, 3.75 mol, 1.30 equiv) followed by a solution of potassium carbonate (K2CO3, 1196 g, 8.67 mol, 3.0 equiv) in water (4 L). The solution was degassed by passing a stream of nitrogen through the solution for 15 minutes before being treated with tetrakis(triphenylphosphine)palladium(0) (167 g, 0.145 mol, 0.05 equiv) and the resulting reaction mixture was heated at reflux (about 90 C.) for 2 hours. When the reaction was deemed complete by TLC (1:1 heptane/ethyl acetate) and LCMS, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (24 L) and water (4 L). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (4 L). The combined organic layers were washed with water (2×2 L), brine (2 L), dried over sodium sulfate (Na2SO4), and concentrated under reduced pressure. The residue was suspended in toluene (4 L) and the solvent was removed under reduced pressure. The residue was finally triturated with methyl tert-butyl ether (MTBE, 3 L) and the solids were collected by filtration and washed with MTBE (1 L) to afford 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 581.4 g, 908.5 g theoretical, 64% yield) as white crystalline solids. For 5: 1H NMR (DMSO-d6, 400 MHz) delta ppm 13.41 (bs, 1H), 8.74 (s, 1H), 8.67 (bs, 1H), 8.35 (bs, 1H), 7.72 (d, 1H, J=3.7 Hz), 7.10 (d, 1H, J=3.7 Hz), 5.61 (s, 2H), 3.51 (t, 2H, J=8.2 Hz), 0.81 (t, 2H, J=8.2 Hz), 0.13 (s, 9H); C15H21N5OSi (MW, 315.45), LCMS (EI) m/e 316 (M++H).
27%		At room temperature, <strong>[941685-26-3]4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine</strong> (12f) (800 mg, 2.82 mmol) and 4-pyrazoleboronic acid pinacol ester (842 mg, 4.34 mmol) were dissolved in dioxane (10 mL), water (2 mL) and potassium carbonate (857 mg, 6.2 mmol) were then added, nitrogen atmosphere protection was applied, and the reaction was stirred at room temperature for 10 min. Under protection of nitrogen, Pd(dppf)Cl2 (227 mg, 0.31 mmol) was added. The reaction was placed in an oil bath at 95C, and stirred overnight. TLC indicated starting materials substantially disappeared. The reaction was quenched with water, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate, and purified by preparative flash chromatography (PE:EA=2:3), to afford 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (12g) (240 mg, brown solid), yield: 27%. MS (ESI, m/z): 316 [M+H]+.
166.4 g		Nitrogen gas was purged through a mixture of 4-chloro-7- { [2- (0224) (trimemylsilyl)ethoxy]memyl}-7H-pyItauolo[2,3-<f]pyrm^ (as prepared in Step a), denaturated spirit (DNS) (1.85 L) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (176.96 g) for 15 minutes to 20 minutes. Aqueous potassium carbonate solution (269.96 g of potassium carbonate dissolved in 925 mL of DI water) was added to the mixture under nitrogen at 25C to 30C. Purging of nitrogen gas was continued for 20 minutes to 30 minutes at 25C to 30C. Tetrakis-triphenyl phosphine palladium (0) (15 g) was added to the reaction mixture under nitrogen atmosphere and the temperature of the reaction mixture was raised to 50C to 60C. Nitrogen purging was stopped and the reaction mixture was refluxed at 78C to 80C for 14 hours to 15 hours. The reaction mixture was cooled to room temperature and DI water (3700 mL) was added slowly at 25 C to 30C. The reaction mixture was stirred for 1 hour and the solid obtained was filtered and dried in an air oven at 55C to 60C. Methyl fert-butyl ether (370 mL) was added to the dried solid (230 g) and the mixture was stirred at 25 C to 30C for 30 minutes. The solid obtained was filtered, washed with methyl fert-butyl ether (2 chi 92.5 mL), and then dried under vacuum at 40C to 45C for 10 hours to 12 hours to obtain title compound.Yield: 166.4 g

Reference： [1]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 75-76
[2]Patent: EP3360878,2018,A1 .Location in patent: Paragraph 0140; 0145
[3]Patent: WO2016/35014,2016,A1 .Location in patent: Page/Page column 27

23
[ 941685-27-4 ]
[ 941685-68-3 ]
[ 941685-69-4 ]

Yield	Reaction Conditions	Operation in experiment
82.6%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 0.5h;	(Z)-3-Cyclopentyl-3-(4-(7-((2-(trimethylsily)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylonitrile (19).; To a stirred solution of <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine</strong> (17, 7.260 g, 23.01 mmol) and 3-cyclopentylprop-2-ynenitrile (8, 6.140 g, 34.52 mmol, 1.5 equiv) in N,N-Dimethylformamide (DMF, 40.0 mL, 516 mmol) at room temperature was added solid potassium carbonate (K2CO3, 318 mg, 2.30 mmol, 0.1 equiv). The resulting reaction mixture was stirred at room temperature for 30 min. When LCMS showed the reaction was deemed complete, the reaction mixture was quenched with water (80 mL), extracted with EtOAc (2×150 mL). The combined organic layers were washed with water (80 mL) and brine (50 mL), dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-30% EtOAc/hexane gradient elution) to give (Z)-3-cyclopentyl-3-(4-(7((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylonitrile (19, 8.256 g, 10.0 g theoretical, 82.6% yield) as a colorless syrup. For 19: 1H NMR (CDCl3, 300 MHz) delta ppm 9.15 (bs, 1H), 8.96 (s, 1H), 8.56 (s, 1H), 7.51 (d, 1H, J=3.5 Hz), 6.93 (d, 1H, J=3.5 Hz), 5.75 (s, 2H), 5.29 (s, 1H), 3.62 (m, 1H), 3.60 (t, 2H, J=8.2 Hz), 2.16 (m, 2H), 1.81 (m, 4H), 1.59 (m, 2H), 0.98 (t, 2H, J=8.2 Hz), 0.00 (s, 9H); C23H30N6OSi (MW, 434.61), LCMS (EI) m/e 435.2 (M++H).

Reference： [1]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 60-61

24
[ 941685-41-2 ]
[ 941685-27-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	potassium tert-butylate; In tetrahydrofuran; acetonitrile; at 0 - 20℃;Inert atmosphere;	4-(1H-Pyrazol-4-yl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5).; Method E.; Into a 22 L four-neck flask equipped with overhead stirring, thermocouple, 2 L addition funnel and nitrogen inlet was charged (3S)-3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile ((S)-10, 491 g, 1.11 mol) and acetonitrile (4.5 L) at room temperature. The mixture was cooled to 0-10 C. before being treated dropwise with a 1M solution of potassium tert-butoxide in THF (KOtBu, 2.0 L, 2.0 mol, 1.8 equiv) via the addition funnel over 1.5 hours. Following the addition of base the reaction mixture was allowed to return to room temperature and was stirred at room temperature for 12-24 h. When LC/MS showed the reaction was deemed complete, the reaction mixture was diluted with ethyl acetate (EtOAc, 6 L) and 50% (w/w) aqueous ammonium chloride solution (NH4Cl, 4 L). The two layers were separated, and the aqueous fraction was back extracted with ethyl acetate (2 L). The combined organic fractions were washed with water (2 L) and brine (3 L), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure to afford the crude 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 354 g, 350.1 g theoretical, 101.1% yield) as an amber oil, which solidified upon standing at room temperature in vacuo. This crude material was subsequently recrystallized in acetonitrile to afford pure compound 5 (308 g, 350.1 g theoretical, 88% yield) as white crystals (99.5 area % by HPLC), which was found to be identical in every comparable aspect to the material made from Method A, B, C, and D.

Reference： [1]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 84-85

25
[ 406-86-0 ]
[ 941685-27-4 ]
[ 941685-95-6 ]

Yield	Reaction Conditions	Operation in experiment
91.3%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 0.5h;Inert atmosphere;	Racemic 4,4,4-Trifluoro-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butanenitrile (33, Racemic SEM-protected compound).; To a flask equipped with a mechanical stirrer, nitrogen inlet and thermowell was added compound <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine</strong> (5, 1424 g, 4.52 mol) and acetonitrile (14 L). The resulting suspension was added 4,4,4-trifluorocrotonitrile (32, 601.6 g, 4.97 mol, 1.1 equiv) followed by 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU, 67 mL, 0.452 mol, 0.1 equiv). A slight exotherm (5 C.) was noted upon the addition of the DBU. The reaction mixture was stirred at room temperature for 30 minutes when TLC and LCMS showed the reaction was deemed complete. The reaction mixture was then concentrated under reduced pressure to remove most of the solvent and the residue was purified by two silica gel columns (3 Kg each) for chromatography purification. The column was eluting with 2:1 heptane/ethyl acetate (30 L) followed by 1:1 heptane/ethyl acetate (30 L). The fractions containing pure desired product (33) were combined and concentrated under reduced pressure to afford racemic 4,4,4-trifluoro-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butanenitrile (33, Racemic SEM-protected compound, 1802 g, 1973 g theoretical, 91.3% yield) as a thick oil, which was directly used in subsequent chiral column separation without further purification. For 33: 1H NMR (DMSO-d6, 400 MHz) delta ppm 8.99 (s, 1H), 8.79 (s, 1H), 8.56 (s, 1H), 7.80 (d, 1H, J=3.7 Hz), 7.09 (d, 1H, J=3.7 Hz), 6.05 (m, 1H), 5.63 (s, 2H), 3.82 (dd, 1H, J=17.5, 10.6 Hz), 3.66 (dd, 1H, J=17.0, 4.9 Hz), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.2 Hz), -0.145 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) delta ppm 151.7, 151.3, 149.5, 140.8, 132.9, 130.4, 123.2 (JCF=282 Hz), 121.9, 116.2, 113.5, 100.2, 72.3, 65.7, 57.8 (JCF=32.4 Hz), 17.1, -1.46; C19H23F3N6OSi (MW, 436.51), LCMS (EI) m/e 437 (M++H).

Reference： [1]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 97

26
[ 4786-20-3 ]
[ 941685-27-4 ]
[ 1236033-14-9 ]

Yield	Reaction Conditions	Operation in experiment
97.5%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20 - 55℃;Inert atmosphere;	3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (37).; Into a 250 mL three-neck round bottom flask equipped with a stir bar, condenser, thermocouple and nitrogen inlet was charged <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine</strong> (5, 10.3 g, 0.033 mol), 2-butenenitrile (36, 3.0 mL, 0.037 mmol, 1.12 equiv) and acetonitrile (100 mL, 2.0 mol) at room temperature. The resulting mixture was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.0 mL, 0.013 mol, 0.4 equiv) and was subsequently warmed to 55 C. The reaction mixture was stirred at 55 C. for 15-20 h. When LC/MS showed the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure to yield an orange oil. The crude product was then purified by flash column chromatography (SiO2, 40-80% ethyl acetate/hexane gradient elution) to afford 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (37, 12.3 g, 12.62 g theoretical, 97.5% yield) as a colorless oil, which solidified upon standing at room temperature in vacuo. For 37: 1H NMR (CDCl3, 400 MHz) delta ppm 8.84 (s, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.39 (d, 1H, J=3.8 Hz), 6.79 (d, 1H, J=3.8 Hz), 5.67 (s, 2H), 4.77 (m, 1H), 3.53 (t, 2H, J=8.2 Hz), 3.05 (dd, 1H, J=16.8, 6.2 Hz), 2.98 (dd, 1H, J=16.8, 6.3 Hz), 1.79 (d, 3H, J=6.5 Hz), 0.91 (t, 2H, J=8.3 Hz), -0.068 (s, 9H); C19H26N6OSi (MW, 382.53), LCMS (EI) m/e 383 (M++H).

Reference： [1]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 98-99

27
[ 941685-27-4 ]
[ 591769-05-0 ]
[ 941685-39-8 ]

Yield	Reaction Conditions	Operation in experiment
97.7%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20 - 80℃; for 25h;	Racemic 3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (9, racemic SEM-protected compound).; Method A.; 3-Cyclopentylacrylonitrile (8, 273.5 g, 2.257 mol, 1.20 equiv) and DBU (28 mL, 0.187 mol, 0.10 equiv) was added to a suspension of 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 591.8 g, 1.876 mol) in acetonitrile (4.7 L) at room temperature. The resulting reaction mixture was heated to 50-60° C. for 17 hours (a clear solution developed midway through heating) then to 70-80° C. for 8 hours. When LCMS analysis showed the reaction was deemed complete, the reaction mixture was cooled to room temperature. The cooled solution was then concentrated under reduced pressure to give the crude product (9) as a thick amber oil. The crude product was dissolved in dichloromethane (DCM) and absorbed onto silica gel then dry-loaded onto a silica column (3 Kg) packed in 33percent EtOAc/heptanes. The column was eluted with 33percent EtOAc/heptanes (21 L), 50percent EtOAc/heptanes (28 L), 60percent EtOAc/heptanes (12 L) and 75percent EtOAc/heptanes (8 L). The fractions containing the desired product (9) were combined and concentrated under reduced pressure to generate a yellow oil, which was transferred to a 3 L flask with EtOAc. The solvent was removed under reduced pressure and the residual EtOAc by co-evaporating with heptanes. The residue was further dried under high vacuum for overnight to afford racemic 3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (9, racemic SEM-protected compound, 800 g, 819.1 g theoretical, 97.7percent yield) as an extremely viscous yellow oil. For 9: 1H NMR (DMSO-d6, 400 MHz) delta ppm 8.83 (s, 1H), 8.75 (s, 1H), 8.39 (s, 1H), 7.77 (d, 1H, J=3.7 Hz), 7.09 (d, 1H, J=3.7 Hz), 5.63 (s, 2H), 4.53 (td, 1H, J=19.4, 4.0 Hz), 3.51 (t, 2H, J=8.1 Hz), 3.23 (dq, 2H, J=9.3, 4.3 Hz), 2.41 (m, 1H), 1.79 (m, 1H), 1.66-1.13 (m, 7H), 0.81 (t, 2H, J=8.2 Hz), 0.124 (s, 9H); C23H32N6OSi (MW, 436.63), LCMS (EI) m/e 437 (M++H) and 459 (M++Na).
93%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;	To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]-pyrimidine (15.0 g, 0.0476 mol) in ACN (300 mL) was added 3- cyclopentylacrylonitrile (15 g, 0.12 mol) (as a mixture of cis and trans isomers), followed by DBU (15 mL, 0.10 mol). The resulting mixture was stirred at room temperature overnight. The ACN was evaporated. The mixture was diluted with ethyl acetate, and the solution was washed with 1.0 N HC1. The aqueous layer was back- extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (gradient of ethyl acetate/hexanes) to yield a viscous clear syrup, which was dissolved in ethanol and evaporated several times to remove ethyl acetate, to afford 19.4 g of racemic adduct (93percent).
93%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;	Step 2. (3R)- and (3S)-3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile. To a solution of 4-(1H-pyrazol- 4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (15.0 g, 0.0476 mol) in ACN (300 mL) was added <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (15 g, 0.12 mol) (as a mixture of cis and trans isomers), followed by DBU (15 mL, 0.10 mol). The resulting mixture was stirred at room temperature overnight. The ACN was evaporated. The mixture was diluted with ethyl acetate, and the solution was washed with 1.0 N HCl. The aqueous layer was back-extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (gradient of ethyl acetate/hexanes) to yield a viscous clear syrup, which was dissolved in ethanol and evaporated several times to remove ethyl acetate, to afford 19.4 g of racemic adduct (93percent). The enantiomers were separated by preparative-HPLC, (OD-H column, 15percent ethanol/hexanes) and used separately in the next step to generate their corresponding final product. The final products (see Step 3) stemming from each of the separated enantiomers were found to be active JAK inhibitors; however, the final product stemming from the second peak to elute from the preparative-HPLC was more active than its enantiomer. The products may be isolated by preparative HPLC or other means known to those of skill in the art for use in Step 3 below. 1H NMR (300 MHz, CDCl3): delta 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 1H), 2.03- 1.88 (m, 1H), 1.80-1.15 (m, 7H), 0.92 (t, 2H),?0.06 (s, 9H); MS(ES): 437 (M+1).

93%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;	Step 2. (3R)- and (3S)-3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile. To a solution of 4-(1H-pyrazol- 4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (15.0 g, 0.0476 mol) in ACN (300 mL) was added <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (15 g, 0.12 mol) (as a mixture of cis and trans isomers), followed by DBU (15 mL, 0.10 mol). The resulting mixture was stirred at room temperature overnight. The ACN was evaporated. The mixture was diluted with ethyl acetate, and the solution was washed with 1.0 N HCl. The aqueous layer was back-extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (gradient of ethyl acetate/hexanes) to yield a viscous clear syrup, which was dissolved in ethanol and evaporated several times to remove ethyl acetate, to afford 19.4 g of racemic adduct (93percent). The enantiomers were separated by preparative-HPLC, (OD-H column, 15percent ethanol/hexanes) and used separately in the next step to generate their corresponding final product. The final products (see Step 3) stemming from each of the separated enantiomers were found to be active JAK inhibitors; however, the final product stemming from the second peak to elute from the preparative-HPLC was more active than its enantiomer. The products may be isolated by preparative HPLC or other means known to those of skill in the art for use in Step 3 below. 1H NMR (300 MHz, CDCl3): delta 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 1H), 2.03- 1.88 (m, 1H), 1.80-1.15 (m, 7H), 0.92 (t, 2H), 0.06 (s, 9H); MS(ES): 437 (M+1).
93%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃;	To a solution of 4-(1 H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (15.0 g,0.0476 mol) mACN (300 mE) was added 3-cyclopentylacry-lonitrile (15 g, 0.12 mol) (as a mixture of cis and trans isomers), followed by DBU (15 mE, 0.10 mol). The resultingmixture was stirred at room temperature overnight. The ACNwas evaporated. The mixture was diluted with ethyl acetate,and the solution was washed with 1.0 N HC1. The aqueouslayer was back-extracted with three portions of ethyl acetate.The combined organic extracts were washed with brine, driedover sodium sulfate, filtered and concentrated. The crudeproduct was purified by silica gel chromatography (gradientof ethyl acetate/hexanes) to yield a viscous clear syrup, whichwas dissolved in ethanol and evaporated several times toremove ethyl acetate, to afford 19.4 g of racemic adduct(93percent). The enantiomers were separated by preparativeHPEC, (OD-H, 15percent ethanol/hexanes) and used separately inthe next step to generate their corresponding final product.The final products (see Step 3) stemming from each of theseparated enantiomers were found to be active JAK inhibitors; however, the final product stemming from the secondpeak to elute from the preparative-HPEC was more activethan its enantiomer.?H NMR (300 MHz, CDC13): oe 8.85 (s, 1H), 8.32 (s, 2H),7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H), 3.54 (t,2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 1H), 2.03-1.88 (m, 1H), 1.80-1.15 (m, 7H), 0.92 (t, 2H), ?0.06 (s, 9H);MS (ES): 437 (M+1).
	With potassium carbonate; In dimethyl sulfoxide; at 43 - 45℃; for 24h;	3-Cyclopentylacrylonitrile (76.06 g) (prepared as per the procedure disclosed in U.S. Patent No. 7,598,257) was added to a mixture of 4-(lH-pyrazol-4-yl)-7-[2- (trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-£/]pyrimidine (165 g, as prepared in Step b) in dimethylsulfoxide (825 mL). Powdered potassium carbonate (16.58 g) was added to the reaction mixture and the temperature of the reaction mixture was raised to 43 °C to 45 °C. The reaction mixture was stirred for 24 hours. The reaction mixture was cooled to 20°C to 25°C and DI water (3300 mL) was added to the reaction mixture at 10°C to 25°C. The aqueous layer was extracted with ethyl acetate (825 mL) and the organic layer was collected. The aqueous layer was again extracted with ethyl acetate (825 mL) and the organic layer was collected. The combined organic layers were washed with DI water (825 mL) and concentrated under reduced pressure at 45°C to 50°C to obtain title compound, which was used as such for next step.
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 60 - 80℃; for 26h;Inert atmosphere;	231.67 g (1.90 mol) 3-Cyclopentyl-acrylonitrile and 23.70 ml ( 0.16 mol) 1,8- Diazabicyclo[5.4.0]undec-7-en (DBU) were added to a suspension of the starting material (1) (500 g, 1.56 mol) in 4000 ml acetonitrile (MeCN) at room temperature under stirring and nitrogen atmosphere. The reaction mixture was heated to 60°C for -22 hours, then to 80°C for 4 hours. The reaction mixture was cooled to room temperature. The cooled reaction mixture was evaporated under reduced pressure at 42°C to yield a viscous black oil. The oil was dissolved in 1300 ml dichloromethane (DCM) and 650 g silica (63-200 tim) were added. The suspension was evaporated under reduced pressure at 44°C. The obtained crude product on silica was dry loaded on a silica column (1.25 kg (2.5 1) silica 63-200 jim, diameter of column 7 cm length 92 cm). The whole separation was accomplished via flash system (companion ?combi flash?) with a solvent flow of 100 ml/min. (pressure 5-15 bar). Elution was accomplished with EtOAc (ethylacetate)/n-hexane 1/2. The solvent was evaporated at 50°C to yield the product as highly viscous yellow oil.

Reference： [1]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 75-76
[2]Patent: WO2013/23119,2013,A1 .Location in patent: Page/Page column 31; 32
[3]Patent: WO2016/24232,2016,A1 .Location in patent: Paragraph 00674
[4]Patent: WO2016/24230,2016,A1 .Location in patent: Paragraph 00649
[5]Patent: US9358229,2016,B2 .Location in patent: Page/Page column 22; 23
[6]Patent: WO2016/35014,2016,A1 .Location in patent: Page/Page column 27
[7]Patent: WO2016/26975,2016,A1 .Location in patent: Page/Page column 12

28
[ 941685-27-4 ]
[ 1236033-19-4 ]
[ 1236033-20-7 ]

Yield	Reaction Conditions	Operation in experiment
38%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 2h;	(E)-Methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21).; To a stirred suspension of <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine</strong> (17, 12.08 g, 38.31 mmol) and methyl 3-cyclopentylprop-2-ynoate (18, 8.970 g, 45.97 mmol, 1.2 equiv) in acetonitrile (76 mL, 1400 mmol) at room temperature was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.92 mL, 19.2 mmol, 0.5 equiv). The resulting reaction mixture was stirred at room temperature for 2 h. When LCMS showed the reaction was deemed complete, the reaction mixture was quenched with water (50 mL) and 1 N aqueous HCl solution (20 mL). The quenched reaction mixture was adjusted to pH 4 after treatment with 1 N aqueous HCl solution. The mixture was then extracted with EtOAc (2×100 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by Combiflash (SiO2, 0-50% EtOAc/hexane gradient elution) to afford (E)-methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21, 6.838 g, 17.92 g theoretical, 38% in yield) as a colorless, very viscous oil. For 19: 1H NMR (CDCl3, 400 MHz) delta ppm 8.93 (s, 1H), 8.55 (bs, 1H), 8.44 (s, 1H), 7.49 (d, 1H, J=3.5 Hz), 6.86 (d, 1H, J=3.5 Hz), 6.34 (s, 1H), 5.74 (s, 2H), 4.56 (m, 1H), 3.84 (s, 3H), 3.60 (t, 2H, J=8.2 Hz), 2.01 (m, 2H), 1.96 (m, 4H), 1.77 (m, 2H), 0.98 (t, 2H, J=8.2 Hz), 0.00 (s, 9H); C24H33N5O3Si (MW, 467.64), LCMS (EI) m/e 468.2 (M++H).

Reference： [1]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 62-63

29
[ 941685-27-4 ]
[ 118235-51-1 ]
[ 1146629-78-8 ]

Yield	Reaction Conditions	Operation in experiment
83.8%	With (2R)-2-(bis[3,5-bis(trifluoromethyl)phenyl][(triethylsilyl)oxy]methyl)pyrrolidine; 4-nitro-benzoic acid; In toluene; at 20℃; for 24.16h;	(3R)-3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal ((R)-38).; A solution of (2E)-3-cyclopentylacrylaldehyde (28, 327 mg, 2.50 mmol, 5.0 equiv), (2R)-2-bis[3,5-bis(trifluoromethyl)phenyl][(triethylsilyl)oxy]methylpyrrolidine ((R)-35, 32 mg, 0.050 mmol, 0.10 equiv) and 4-nitrobenzoic acid (8.5 mg, 0.050 mmol, 0.10 equiv) in anhydrous toluene (5.0 mL, 47 mmol) was stirred at room temperature for 10 min before <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (17, 158 mg, 0.50 mmol) was added. The resulting reaction mixture was stirred at room temperature for 24 h. When LCMS showed that the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residue was directly purified by Combiflash (SiO2) with 0-70% EtOAc/hexane gradient elution to give (3R)-3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal ((R)-38, 184.1 mg, 219.8 mg theoretical, 83.8% yield) as a pale yellow viscous oil. For (R)-38: C23H33N5O2Si (MW, 439.63), LCMS (EI) m/e 440 (M +H).

Reference： [1]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 70

30
[ 941685-27-4 ]
[ 5687-79-6 ]
[ 1236033-08-1 ]

Yield	Reaction Conditions	Operation in experiment
90.6%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; for 18h;Reflux;	Racemic 3-Cyclopropyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (28, Racemic SEM-protected compound).; To a suspension of 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 1.115 Kg, 3.54 mol, 1.0 equiv) in acetonitrile (11 L) was added 3-cyclopropylacrylonitrile (27, 428.7 g, 4.60 mol, 1.3 equiv) and 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU, 55 mL, 0.37 mol, 0.105 equiv). The resulting reaction mixture was heated to gentle reflux for approximate 18 hours. When HPLC and TLC showed the reaction was deemed complete, the reaction micture, which was a clear solution, was cooled to room temperature before being concentrated under reduced pressure to give the crude Michael addition product (28) as a dark red oil. The crude product was then diluted with dichloromethane, divided into three portions and absorbed onto silica gel (3×2 Kg). The crude product absorbed on silica gel was purified by column chromatography on three 2 Kg silica gel columns (packed in 87.5:12.5 heptanes/EtOAc and eluted with 87.5:12.5 to 25:75 heptanes/EtOAc). The fractions containing the pure desired product (28) were combined and concentrated under reduced pressure, transferred to afford racemic 3-cyclopropyl-3-{4-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrazol-1-yl}-propionitrile (28, racemic SEM-protected compound, 1.310 Kg, 1.446 Kg theoretical, 90.6% yield) as a amber syrup, which was used for chiral column separation without further purification. For 28: C21H28N5OSi (MW, 408.57), LCMS (EI) m/e 409 (M++H).

Reference： [1]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 94-95

31
[ 63909-21-7 ]
[ 941685-27-4 ]
C₂₃H₃₄N₆OSi [ No CAS ]
C₂₃H₃₄N₆OSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;	A mixture of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3- d]pyrimidine (prepared substantially as described in Example 65 of U.S. Pat. App. Pub. No. 2007/0135461 or International App. No. PCT/US2006/047369 (published as WO 2007/070514); 12 g, 0.038 mol), oct-2-enenitrile (6.0 g, 0.049 mol) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 4.6 niL, 0.030 mol) in acetonitrile (120 mL, 2.3 mol) was stirred at room temperature overnight. After being concentrated in vacuo, the resultant residue was purified on silica gel (eluting with 0 to 40% EtOAc in hexanes) to give the desired product (15 g, 89.89%). The enantiomers (first peak retention time 11.02 min, second peak retention time 14.10 min) were separated on a ChiralCel OD-H column (30x250 mm, 5muM), eluting with mobile phase of 15% ethanol and 85% hexane at 25 mL/min. MS calculated for C23H35N6OSi(IVHH)+: m/z = 439.264; Found: 439.4. 1H NMR (300 MHz, CDCl3) delta 8.91 (IH, s), 8.38 (IH, s), 8.37 (IH, s), 7.46 (IH, d, J = 3.8 Hz), 6.86 (IH, d, J = 3.8 Hz), 5.73 (2H, s), 4.59 (IH, m), 3.60 (2H, t, J = 8.3 Hz), 3.06 (2H, td, J = 16.8 and 7.5 Hz), 2.21 (IH, m), 2.01 (IH, m), 1.40-1.21 (6H, m), 0.98 (2H, t, J = 8.3 Hz), 0.91 (3H, t, J = 6.3 Hz), 0.00 (9H, s) ppm.

Reference： [1]Patent: WO2010/135621,2010,A1 .Location in patent: Page/Page column 31-32

32
[ 22031-56-7 ]
[ 941685-27-4 ]
[ 1256446-05-5 ]

Yield	Reaction Conditions	Operation in experiment
84%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;	To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7H- pyrrolo[2,3-d]pyrimidine (6.1 g, 19 mmol) in acetonitrile (58 mL) was added crude hept-2- enenitrile (2.6 g, 23 mmol), followed by l,8-diazabicyclo[5.4.0]undec-7-ene (3.49 mL, 23.4 mmol). The resulting mixture was stirred at room temperature over the weekend and then evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 50% of ethyl acetate in hexane, to give the desired product (6.90 g, 84%). LCMS calculated for C22H33N6OSi(M-HH)+: m/z = 425.2; Found: 425.4. The racemic mixture was applied on an OD- H column (3x25cm, 5 muM), eluting with 15% ethanol and 85% hexane mixture at a flow rate of 28 mL/min to give the two desired enantiomers. First peak retention time of 9.46 min; second peak (3.45 g) retention time of 12.35 min.

Reference： [1]Patent: WO2010/135621,2010,A1 .Location in patent: Page/Page column 34

33
[ 941685-27-4 ]
tert-butyl 3-[(E)-2-cyanoethenyl]pyrrolidine-1-carboxylate [ No CAS ]
[ 1257069-36-5 ]

Yield	Reaction Conditions	Operation in experiment
18%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; for 72h;	Step 2. tert-butyl 3-{2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidine-1-carboxylateTo a solution of tert-butyl 3-[2-cyanovinyl]pyrrolidine-1-carboxylate (39 g, 180 mmol) and <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine</strong> (55 g, 180 mmol, prepared as described in WO 2007/070514, Ex. 65) in acetonitrile (500 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (26 mL) and the reaction was stirred for three days. The majority of the solvent was removed by rotary evaporation prior to partition of the reaction mixture between saturated sodium bicarbonate solution and ethyl acetate. The product was extracted with a further two portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted and concentrated. Flash column chromatography (on 2.5 Kg silica gel) using 7.5% isopropanol/25% ethyl acetate/67.5% hexanes as eluent afforded 27.73 g of pure diastereomer 1 (first to elute). Recolumn of mixed fractions, eluting with a gradient from 5% isopropanol/5% ethyl acetate/90% hexanes to 10% isopropanol/50% ethyl aceate/40% hexanes afforded 9.84 g additional product (diastereomer 1). The enantiomers were separated by chiral HPLC (Chiral Technologies Chiralcel OD-H, 5mu, 30×250 mm, 20% EtOH/Hexanes, 22 mL/min) Desired enantiomer 2 (second to elute, retention time 22.9 min) was collected (17.3 g, 18%). 1H NMR (300 MHz, CDCl3): delta 8.84 (s, 1H), 8.34 (s, 1H), 8.33 (s, 1H), 7.40 (d, 1H), 6.78 (d, 1H), 5.67 (s, 2H), 4.37 (dt, 1H), 3.76-2.80 (m, 9H), 1.85-1.52 (m, 2H), 1.45 (s, 9H), 0.95-0.87 (m, 2H), -0.07 (s, 9H); LCMS (M+H)+: 538.1.

Reference： [1]Patent: US2010/298334,2010,A1 .Location in patent: Page/Page column 43

34
[ 852655-64-2 ]
[ 941685-27-4 ]
benzyl 3-{2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidine-1-carboxylate [ No CAS ]
benzyl 3-{2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;	Step 1. benzyl 3-{2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidine-1-carboxylateBenzyl 3-[2-cyanovinyl]pyrrolidine-1-carboxylate (4.3 g, 0.017 mol, mixture of E and Z isomers prepared as described in WO 2007/070514 Ex. 742) was dissolved in acetonitrile (270 mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (5.02 mL, 0.0336 mol) was added, followed by <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine</strong> (5.6 g, 0.017 mol, prepared as described in WO 2007/070514, Ex. 65). The mixture was stirred at RT overnight. The solvent was removed by rotary evaporation, and the residue was redissolved in ethyl acetate. The solution was washed successively with 1N HCl, water, saturated sodium bicarbonate, and brine, dried over sodium sulfate and concentrated in vacuo. The product was purified by flash column chromatography on silica gel, eluting with a gradient of 0-100% ethyl acetate in hexanes to afford diastereomer 1 (first to elute) (3.5 g, 36%) and diastereomer 2 (second to elute) (2.5 g, 25%). LCMS (M+H)+: 572.2.

Reference： [1]Patent: US2010/298334,2010,A1 .Location in patent: Page/Page column 35-36

35
[ 941685-27-4 ]
[ 1257069-60-5 ]
tert-butyl 3-{2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-3-fluoropyrrolidine-1-carboxylate [ No CAS ]
tert-butyl 3-{2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-3-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 0.5h;	Step 2. tert-butyl 3-{2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-3-fluoropyrrolidine-1-carboxylatetert-Butyl 3-[2-cyanovinyl]-3-fluoropyrrolidine-1-carboxylate (0.95 g, 4.0 mmol) (as a mixture of olefin isomers) and <strong>[941685-27-4]4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine</strong> (1.2 g, 4.0 mmol, prepared as described in WO 2007/070514, Ex. 65, or US2007/135461) in acetonitrile (10 mL) were treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.59 mL, 4.0 mmol) and stirred at RT for 30 min. Solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel, eluting with a gradient of 5% IPA/5% ethyl acetate/90% hexanes to 10% IPA/50% ethyl acetate/40% hexanes. Diastereomer 1 (first to elute) (0.92 g, 42%), and diastereomer 2 (second to elute) (0.91 g, 41%). 1H NMR diastereomer 1 (400 MHz, CDCl3): delta 8.86 (s, 1H), 8.39 (s, 1H), 8.34 (s, 1H), 7.42 (d, 1H), 6.81-6.78 (m, 1H), 5.68 (s, 2H), 4.93-4.81 (m, 1H), 3.84-3.34 (m, 7H), 3.08 (dt, 1H), 2.37-2.13 (m, 1H), 1.93 (dt, 1H), 1.45 (s, 9H), 0.95-0.89 (m, 2H), -0.06 (s, 9H); 19F NMR diastereomer 1 (400 MHz, CDCl3): -158.8 (m, 1F); LCMS (M+H)+: 556.2. 1H NMR diastereomer 2 (400 MHz, CDCl3): delta 8.86 (s, 0.5H), 8.85 (s, 0.5H), 8.39 (s, 0.5H), 8.37 (s, 0.5H), 8.35 (s, 0.5H), 8.30 (s, 0.5H), 7.44-7.40 (m, 1H), 6.81-6.77 (m, 1H), 5.68 (s, 2H), 4.87 (ddd, 1H), 3.83-3.38 (m, 6H), 3.34 (dd, 1H), 3.17 (dd, 1H), 2.34-2.18 (m, 1H), 2.07-1.79 (m, 1H), 1.42 (s, 9H), 0.96-0.88 (m, 2H), -0.06 (s, 9H); 19F NMR diastereomer 2 (400 MHz, CDCl3): 6-157.6 (m, 1F); LCMS (M+H)+: 556.2.

Reference： [1]Patent: US2010/298334,2010,A1 .Location in patent: Page/Page column 52

36
[ 941685-27-4 ]
[ 1270981-29-7 ]
[ 89501-90-6 ]
[ 1270982-49-4 ]
[ 1270981-34-4 ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7H- pyrrolo[2,3-d]pyrimidine (prepared as described in WO 2007/070514 Example 65; 0.248 g, 0.785 mmol) in 1,4-dioxane (4 mL)was added 1.0 M of potassium tert-butoxide in tert-butyl alcohol (0.822 mL, 0.822 mmol). The reaction was stirred at RT for 10 min. To the resulting mixture was added benzyl 4-{3-fluoro-2-[(methylsulfonyl)oxy]propyl}piperazine-l- carboxylate (0.280 g, 0.748 mmol). The reaction was stirred at 95 C for 2 h, quenched with aqueous ammonium chloride, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried and evaporated to dryness. The residue was purified on silica gel column, eluting with 0 to 80% EtOAc in hexanes, to provide the desired product and (+/-)- benzyl 4-(2-fluoro-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-lH-pyrazol-l-yl]methyl}ethyl)piperazine-l-carboxylate (128 mg, 28.8%). LCMS calculated for C3oH4iF 703Si(M+H)+: m/z = 594.3; Found: 594.3. A mixture of (+/-)-benzyl 4-{3-fluoro-2-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propyl}piperazine-l-carboxylate (0.064 g, 0.11 mmol) and (+/-)-benzyl 4-(2-fluoro-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl}ethyl)piperazine-l-carboxylate (0.064 g, 0.11 mmol) in 5 mL of methanol was hydrogenated in the presence of 5% Pd/C, under balloon pressure of hydrogen, for 2 h. After filtering off the catalyst, the filtrate was concentrated and used directly in next step. LCMS calculated for C22H35F 70Si(M+H)+: m/z = 460.3; Found: 460.4. To a mixture of (+/-)-4-{ l-[2-fluoro-l-(piperazin-l-ylmethyl)ethyl]-lH-pyrazol-4-yl}- 7- [2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.050 g, 0.11 mmol) and (+/-)-4- [ 1 -(3 -fluoro-2-piperazin- 1 -ylpropyl)- 1 H-pyrazol-4-yl]-7- { [2- (trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.050 g, 0.11 mmol) in acetonitrile (2 mL) was added triethylamine (0.0606 mL, 0.435 mmol) followed by 1-methyl- lH-pyrazole-3-sulfonyl chloride (0.0491 g, 0.272 mmol). The reaction was stirred at RT for 1 h and evaporated to dryness. LCMS calculated for C26H39F 903SSi(M+H)+: m/z = 604.3; Found: 604.4. The crude mixture from above was treated with 2 mL of TFA at RT for 1 h, evaporated to dryness. The residue was dissolved in 3 mL of methanol and treated with 100 muL ethylenediamine at RT for 1 h. The reaction mixture was purified on RP-HPLC (XBridge C-18 Column, eluting with a gradient of acetonitrile/water containing 0.1% TFA to give the desired products as TFA salts. First peak, with retention time 0.844 min at Waters SunFire HPLC column (CI 8, 2.1x50 mm, 5 muMu, injection volume 2 muL, flow rate 3 mL/min, eluting with a gradient from 2 to 80% of acetonitrile/water with 0.025% TFA, was found to be titled compound, LCMS calculated for C2oH25F 902S(M+H)+: m/z = 474.2; Found: 474.1. Second peak with retention time 0.961 min at the same analytical HPLC conditions was isomer (+/-)-4- ( 1 -(3 -fluoro-2-(4-( 1 -methyl- 1 H-pyrazol-3 -ylsulfonyl)piperazin- 1 -yl)propyl)- 1 H-pyrazol-4- yl)-7H-pyrrolo[2,3-d]pyrimidine, LCMS calculated for C2oH25F 902S(M+H)+: m/z = 474.2; Found: 474.1.

Reference： [1]Patent: WO2011/28685,2011,A1 .Location in patent: Page/Page column 65; 66

37
[ 941685-27-4 ]
[ 1270981-29-7 ]
[ 89501-90-6 ]
[ 1270982-51-8 ]
[ 1270982-53-0 ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7H- pyrrolo[2,3-d]pyrimidine (prepared as described in WO 2007/070514 Example 65; 0.248 g, 0.785 mmol) in 1,4-dioxane (4 mL)was added 1.0 M of potassium tert-butoxide in tert-butyl alcohol (0.822 mL, 0.822 mmol). The reaction was stirred at RT for 10 min. To the resulting mixture was added benzyl 4-{3-fluoro-2-[(methylsulfonyl)oxy]propyl}piperazine-l- carboxylate (0.280 g, 0.748 mmol). The reaction was stirred at 95 C for 2 h, quenched with aqueous ammonium chloride, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried and evaporated to dryness. The residue was purified on silica gel column, eluting with 0 to 80% EtOAc in hexanes, to provide the desired product and (+/-)- benzyl 4-(2-fluoro-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-lH-pyrazol-l-yl]methyl}ethyl)piperazine-l-carboxylate (128 mg, 28.8%). LCMS calculated for C3oH4iF 703Si(M+H)+: m/z = 594.3; Found: 594.3. A mixture of (+/-)-benzyl 4-{3-fluoro-2-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propyl}piperazine-l-carboxylate (0.064 g, 0.11 mmol) and (+/-)-benzyl 4-(2-fluoro-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl}ethyl)piperazine-l-carboxylate (0.064 g, 0.11 mmol) in 5 mL of methanol was hydrogenated in the presence of 5% Pd/C, under balloon pressure of hydrogen, for 2 h. After filtering off the catalyst, the filtrate was concentrated and used directly in next step. LCMS calculated for C22H35F 70Si(M+H)+: m/z = 460.3; Found: 460.4. To a mixture of (+/-)-4-{ l-[2-fluoro-l-(piperazin-l-ylmethyl)ethyl]-lH-pyrazol-4-yl}- 7- [2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.050 g, 0.11 mmol) and (+/-)-4- [ 1 -(3 -fluoro-2-piperazin- 1 -ylpropyl)- 1 H-pyrazol-4-yl]-7- { [2- (trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.050 g, 0.11 mmol) in acetonitrile (2 mL) was added triethylamine (0.0606 mL, 0.435 mmol) followed by 1-methyl- lH-pyrazole-3-sulfonyl chloride (0.0491 g, 0.272 mmol). The reaction was stirred at RT for 1 h and evaporated to dryness. LCMS calculated for C26H39F 903SSi(M+H)+: m/z = 604.3; Found: 604.4.

Reference： [1]Patent: WO2011/28685,2011,A1 .Location in patent: Page/Page column 65; 66

38
[ 941685-27-4 ]
[ 533-68-6 ]
[ 1270981-82-2 ]

Yield	Reaction Conditions	Operation in experiment
100%		To a O C solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl}-7H- pyrrolo[2,3-d]pyrimidine (2.0 g, 0.0063 mol) in N,N-dimethylformamide (40 mL, 0.5 mol) was added sodium hydride (0.30 g, 0.0076 mol). After 15 minutes, ethyl 2-bromobutyrate (1.4 mL, 0.0095 mol) was added. After 4.5 hours, ethyl acetate and water were added. The organic phase was washed with water twice and saturated NaCl. The organic phase was then and the solvent was removed by rotary evaporation to give 3.02 g of a thick orange oil (110% yield). 'H NMR (400 MHz, CDC13): delta 8.92 (1H, s); 8.49 (1H, s); 8.35 (1H, s); 7.45 (1H, d); 6.85 (1H, d); 6.75 (2H, s); 5.0 (1H, t); 4.35 (2H,m); 3.6(2H, t); 2.35 (2H, m); 1.35 (6H, m); (1.0 (3H, m); 0 (9H, s). LCMS (M+l): 430.

Reference： [1]Patent: WO2011/28685,2011,A1 .Location in patent: Page/Page column 118; 119

39
[ 1270981-07-1 ]
[ 941685-27-4 ]
tert-butyl 4-{3-cyano-2-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperidine-1-carboxylate [ No CAS ]