[ CAS No. 1003846-21-6 ] {[proInfo.proName]}

Name: 1003846-21-6|1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole|98%
Brand: Ambeed
SKU: A228265
Price: 7.0 USD
Availability: InStock
Rating: 91 (27 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

2D 3D

Structure of 1003846-21-6 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 1003846-21-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1003846-21-6 ]

SDS Specification

Alternatived Products of [ 1003846-21-6 ]

Product Details of [ 1003846-21-6 ]

CAS No. :	1003846-21-6	MDL No. :	MFCD16556148
Formula :	C₁₄H₂₃BN₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YYSLAWXDXHVRHU-UHFFFAOYSA-N
M.W :	278.16	Pubchem ID :	51000384
Synonyms :

Calculated chemistry of [ 1003846-21-6 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.79
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	78.16
TPSA :	45.51 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.59 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.98
Log Po/w (WLOGP) :	1.56
Log Po/w (MLOGP) :	0.98
Log Po/w (SILICOS-IT) :	0.86
Consensus Log Po/w :	1.08

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.86
Solubility :	0.38 mg/ml ; 0.00136 mol/l
Class :	Soluble
Log S (Ali) :	-2.56
Solubility :	0.763 mg/ml ; 0.00274 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.9
Solubility :	0.346 mg/ml ; 0.00124 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.98

Safety of [ 1003846-21-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1003846-21-6 ]

* 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 [ 1003846-21-6 ]
Downstream synthetic route of [ 1003846-21-6 ]

[ 1003846-21-6 ] Synthesis Path-Upstream 1~4

1
[ 110-87-2 ]
[ 269410-08-4 ]
[ 1003846-21-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With trifluoroacetic acid In toluene at 90℃; for 2 h;	3,4-Dihydro-2H-pyran (5.6 g, 67 mmol) and trifluoroacetic acid (1.17 g, 10.3 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (10.0 g, 51.5 mmol) in toluene (200 mL), and the reaction mixture was heated to 90 °C for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonatesolution (100 mL), and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 10percent to 50percent ethyl acetate in petroleum ether) provided the product as a white solid. Yield: 13.4 g, 48.2 mmol, 94percent. ¹H NMR (400 MHz, CDCl3) 7.94 (s, 1H), 7.83 (s, 1H), 5.41 (dd, J=9.5, 2.5 Hz, 1H), 4.01-4.08 (m, 1H), 3.65-3.74(m, 1H), 1.98-2.18 (m, 3H), 1.6-1.76 (m, 3H), 1.32 (s, 12H).
90%	With toluene-4-sulfonic acid In dichloromethane at 20℃; for 4 h;	To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (110.00 g, 566.89 mmol) in DCM (1000 mL) was added dihydropyran (95.37 g, 1.13 mol, 103.66 mL) and TsOH.H₂O (53.92 g, 283.45 mmol). The mixture was stirred at 20 °C for 4 h. TLC (petroleum ether/EtOAc = 5/1) indicated starting material was consumed completely and one main new spot (Rf=0.4) formed. LCMS showed starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove volatiles. The residue was diluted with sat. NaHCCb (350 mL) and the mixture was extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over Na₂S0₄, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography with petroleum ether/ethyl acetate (from 20/1 to 15/1) to afford the title compound (142.00 g, 90percent) as colorless oil. ¹H NMR (400 MHz, DMSO-d₆) 400 MHz δ 8.06 (s, 1H), 7.61 (s, 1H), 5.42 (dd, J= 10.0, 2.0 Hz, 1H), 3.94-3.86 (m, 1H), 3.66-3.54 (m, 1H), 2.17- 2.03 (m, 1H), 1.96- 1.82 (m, 2H), 1.77-1.37 (m, 3H), 1.33-1.18 (m, 12H). MS (ES+) m/e 279 (M+H).
73%	With toluene-4-sulfonic acid In dichloromethane at 30℃; for 4 h;	To a solution of 4-(4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole (10.00 g, 51.54 mmol) in CH2C12 (100.00 mL) was added DHP (8.67 g, 103.08 mmol, 9.42 mL) and TsOHH20 (4.90 g, 25.77 mmol). The mixture was stirred at 30 °C for 4 hour. LCMS showed 4-(4,4, 5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazolewas consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with sat.NaHCO3 (35 mL) and the mixture was extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 20/1 to 1/1) to afford the title compound (10.5 g, 73percent) as colorless oil. ‘H NIVIR (400 MHz, DMSO-d6) ö 8.06 (s, 1H), 7.62 (s, 1H), 5.44-5.41 (m, 1H), 3.94-3.89 (m, 1H), 3.76-3.58 (m, 2H), 3.46-3.41 (m, 1H), 2.15-2.06 (m, 1H), 1.95-1.84 (m, 2H), 1.76-1.40 (m, 9H), 1.26 (s, 12H).

73%	With toluene-4-sulfonic acid In dichloromethane at 30℃; for 4 h;	[0406] To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (10.00 g, 51.54 mmol) in CH₂C1₂ (100.00 mL) was added DHP (8.67 g, 103.08 mmol, 9.42 mL) and TsOH H₂0 (4.90 g, 25.77 mmol). The mixture was stirred at 30 °C for 4 hour. LCMS showed 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazolewas consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with sat.NaHCC (35 mL) and the mixture was extracted with EtOAc (100 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0₂, Petroleum ether/Ethyl acetate = 20/1 to 1/1) to afford the title compound (10.5 g, 73percent) as colorless oil. 1H NMR (400 MHz, DMSO-i/₆) δ 8.06 (s, 1H), 7.62 (s, 1H), 5.44-5.41 (m, 1H), 3.94-3.89 (m, 1H), 3.76-3.58 (m, 2H), 3.46-3.41 (m, 1H), 2.15-2.06 (m, 1H), 1.95-1.84 (m, 2H), 1.76-1.40 (m, 9H), 1.26 (s, 12H).
5.04 g	With toluene-4-sulfonic acid In 1,2-dichloro-ethane at 50℃; for 2 h;	To a stirred solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (5.0 g, 25.76 mmol) in dry dichloroethane (128 ml), 3,4-dihydro-2H-pyran (4.71 ml, 51.52 mmol) was added followed by p-toluenesulfonic acid (490 mg, 2.576 mmol) and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched with aqueous saturated solution of sodium bicarbonate (75 ml) and extracted with ethyl acetate (2 x 150 ml). The combined organic layer was washed with brine (100 ml) and dried over sodium sulphate. The mixture was evaporated under reduced pressure and residue obtained was purified by column chromatography to yield 5.04 g of product as a white solid. 1H NMR (300 MHz, CDCI3): δ I .31 (s, 12H), 1.54-1.70 (m, 3H), 1.98-2.20 (m, 3H), 3.68 (t, / = 10.2 Hz, 1H), 4.04 (d, / = I I .7 Hz, 1H), 5.35-5.45 (m, 1H), 7.82 (s, 1H), 7.93 (s, 1H).

Reference： [1] Patent: WO2014/1973, 2014, A1, . Location in patent: Page/Page column 60; 61; 62
[2] Patent: WO2018/201006, 2018, A1, . Location in patent: Paragraph 0125; 0126
[3] Patent: WO2016/210331, 2016, A1, . Location in patent: Paragraph 0225; 0226
[4] Patent: WO2016/210330, 2016, A1, . Location in patent: Paragraph 0405-0406
[5] Patent: WO2009/71509, 2009, A1, . Location in patent: Page/Page column 80-81
[6] Patent: WO2014/24119, 2014, A1, . Location in patent: Page/Page column 72
[7] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1370 - 1387
[8] Patent: US2017/8889, 2017, A1, . Location in patent: Paragraph 0328; 0329

2
[ 73183-34-3 ]
[ 1003846-21-6 ]

Yield	Reaction Conditions	Operation in experiment
280 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,4-dioxane at 80℃; for 12 h; Inert atmosphere	Step 2. Bis(pinacolato)diboron (247 g, 0.974 mol, 1.5 eq) was added to a solution of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (150 g, 0.65 mol, 1.0 eq) in 1,4-dioxane (1500 ml) at room temperature. Potassium acetate (127 g, 1.30 mol, 2 eq) was then added and the reaction flask was purged with argon for 20 min. PdCl₂(dppf) DCM (26.0 g, 31.8 mmol, 0.05 eq) was added and the mixture was purged with argon for further 10 min followed by stirring at 80° C. for 12 h. After completion of the reaction (monitored by TLC, 10percent ethyl acetate-hexane R_f=0.3), the mixture was cooled to room temperature and filtered through a bed of diatomaceous earth. The bed of diatomaceous earth was washed with ethyl acetate and the combined organic layers were evaporated under reduced pressure to give 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (280 g crude) as a brown oil. LCMS purity: 57.8percent; (ES⁺): m/z 279.18 (M+H⁺); tr=1.95 min. The compound was used without further purification.

Reference： [1] Patent: US2015/252051, 2015, A1, . Location in patent: Paragraph 0165; 0167
[2] Patent: US2015/252022, 2015, A1, . Location in patent: Paragraph 0207; 0209
[3] Patent: WO2016/14913, 2016, A1, . Location in patent: Paragraph 109
[4] Patent: WO2016/14916, 2016, A1, . Location in patent: Paragraph 109
[5] Patent: WO2016/14918, 2016, A1, . Location in patent: Paragraph 107
[6] Patent: US2017/298060, 2017, A1, . Location in patent: Paragraph 0082; 0084
[7] Patent: US2016/24056, 2016, A1, . Location in patent: Paragraph 0201

3
[ 1040377-02-3 ]
[ 73183-34-3 ]
[ 1003846-21-6 ]

Reference： [1] Patent: WO2014/86032, 2014, A1, . Location in patent: Page/Page column 43

4
[ 110-87-2 ]
[ 1003846-21-6 ]

Reference： [1] Patent: US2015/252022, 2015, A1,
[2] Patent: WO2016/14916, 2016, A1,
[3] Patent: US2017/298060, 2017, A1,
[4] Patent: WO2016/14913, 2016, A1,
[5] Patent: WO2016/14918, 2016, A1,
[6] Patent: US2016/24056, 2016, A1,

[ 1003846-21-6 ] Synthesis Path-Downstream 1~88

1
(2S,4R,6R)-4-[(5-bromo-pyrimidin-2-yl)-(3-chloro-5-trifluoromethyl-benzyl)-amino]-2,6-dimethyl-piperidine-1-carboxylic acid isopropyl ester [ No CAS ]
[ 1003846-21-6 ]
C₃₁H₃₈ClF₃N₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 6h;	Example 35: Synthesis of (2R,4R,6S)-4-{(3-chloro-5-trifluoromethyl-benzyl)-[5-(1H- pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-dimethyl-piperidine-1-carboxylic acid isopropyl ester; A mixture of (2R,4R,6S)-4-[(5-bromo-pyrimidin-2-yl)-(3-chloro-5-trifluoromethyl- benzyl)-amino]-2,6-dimethyl-piperidine-1-carboxylic acid isopropyl ester (54 mg, 0.0958 mmol), 1-(tetrahydro-pyran-2-yl)-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (0.144 mmol), tetrakis(triphenylphosphine)palladium(0) (0.01 mmol, 11 mg) and sodium hydrogen carbonate (0.2 mmol, 20 mg) in 1 ,2-dimethoxy-ethane (1 ml_) and water (0.2 mL) <n="111"/>is allowed to warm to 90 0C and stirred for 6 hours. The mixture is cooled to room temperature and then added 2M HCI in methanol. After stirred for 1 hour, the mixture is basified with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layer is washed with brine, dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by PTLC (eluent: hexane / EtOAc) to give (2R,4R,6S)-4-{(3-chloro-5-trifluoromethyl-benzyl)-[5-(1H-pyrazol-4-yl)-pyrimidin-2-yl]- amino}-2,6-dimethyl-piperidine-1-carboxylic acid isopropyl ester (6 mg); ESI-MS m/z: 551 [M+ 1]+, Retention time 2.29 min (condition A).

Reference： [1]Patent: WO2008/9435,2008,A1 .Location in patent: Page/Page column 108-109

2
[ 1003846-21-6 ]
[ 1148129-84-3 ]
[ 1148129-91-2 ]

Yield	Reaction Conditions	Operation in experiment
69.4%		Example 8 Synthesis of [trans-4-(cis-4-[3,5-bis(trifluoromethyl)benzyl]-[5-(1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carbonyl)-cyclohexyl]-acetic acid ethyl ester (trans-4-{cis-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2,6-diethylpiperidine-1-carbonyl}-cyclohexyl)-acetic acid ethyl ester (205 mg, 0.419 mmol), 1-(tetrahydro-pyran-2-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (116 mg, 0.419 mmol), tetrakis(triphenylphosphine)palladium(0) (32.2 mg, 0.0279 mmol), and sodium carbonate (59.1 mg, 0.558 mmol) are dissolved in H2O (0.54 ml) and DME (2.7 ml). The mixture is stirred at 95 C. for 2 hours and cooled to room temperature. To the mixture is added 1M HCl in EtOH (6 mL), and the solution is stirred at room temperature for 2 hours. To the mixture is added 4M HCl in dioxane (6 mL), and the solution is stirred at room temperature for 2 hours. Saturated aqueous NaHCO3 is added to the mixture, and the solution is extracted with dichloromethane. The solvent is removed under reduced pressure, and the obtained residue is purified by silica gel column chromatography to give [trans-4-(cis-4-{(3,5-bis(trifluoromethyl)benzyl)-[5-(1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carbonyl)-cyclohexyl]-acetic acid ethyl ester (140 mg 69.4%); ESI-MS m/z 723 [M+1]+, Retention time 2.29 min (condition A).

Reference： [1]Patent: US2009/118287,2009,A1 .Location in patent: Page/Page column 41

3
[ 110-87-2 ]
[ 269410-08-4 ]
[ 1003846-21-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With trifluoroacetic acid; In toluene; at 90℃; for 2h;	3,4-Dihydro-2H-pyran (5.6 g, 67 mmol) and trifluoroacetic acid (1.17 g, 10.3 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (10.0 g, 51.5 mmol) in toluene (200 mL), and the reaction mixture was heated to 90 C for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonatesolution (100 mL), and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 10% to 50% ethyl acetate in petroleum ether) provided the product as a white solid. Yield: 13.4 g, 48.2 mmol, 94%. 1H NMR (400 MHz, CDCl3) 7.94 (s, 1H), 7.83 (s, 1H), 5.41 (dd, J=9.5, 2.5 Hz, 1H), 4.01-4.08 (m, 1H), 3.65-3.74(m, 1H), 1.98-2.18 (m, 3H), 1.6-1.76 (m, 3H), 1.32 (s, 12H).
90%	With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 4h;	To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (110.00 g, 566.89 mmol) in DCM (1000 mL) was added dihydropyran (95.37 g, 1.13 mol, 103.66 mL) and TsOH .H2O (53.92 g, 283.45 mmol). The mixture was stirred at 20 C for 4 h. TLC (petroleum ether/EtOAc = 5/1) indicated starting material was consumed completely and one main new spot (Rf=0.4) formed. LCMS showed starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove volatiles. The residue was diluted with sat. NaHCCb (350 mL) and the mixture was extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography with petroleum ether/ethyl acetate (from 20/1 to 15/1) to afford the title compound (142.00 g, 90%) as colorless oil. 1H NMR (400 MHz, DMSO-d6) 400 MHz delta 8.06 (s, 1H), 7.61 (s, 1H), 5.42 (dd, J= 10.0, 2.0 Hz, 1H), 3.94-3.86 (m, 1H), 3.66-3.54 (m, 1H), 2.17- 2.03 (m, 1H), 1.96- 1.82 (m, 2H), 1.77-1.37 (m, 3H), 1.33-1.18 (m, 12H). MS (ES+) m/e 279 (M+H).
73%	With toluene-4-sulfonic acid; In dichloromethane; at 30℃; for 4h;	To a solution of 4-(4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole (10.00 g, 51.54 mmol) in CH2C12 (100.00 mL) was added DHP (8.67 g, 103.08 mmol, 9.42 mL) and TsOHH20 (4.90 g, 25.77 mmol). The mixture was stirred at 30 C for 4 hour. LCMS showed 4-(4,4, 5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazolewas consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with sat.NaHCO3 (35 mL) and the mixture was extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 20/1 to 1/1) to afford the title compound (10.5 g, 73%) as colorless oil. ?H NIVIR (400 MHz, DMSO-d6) oe 8.06 (s, 1H), 7.62 (s, 1H), 5.44-5.41 (m, 1H), 3.94-3.89 (m, 1H), 3.76-3.58 (m, 2H), 3.46-3.41 (m, 1H), 2.15-2.06 (m, 1H), 1.95-1.84 (m, 2H), 1.76-1.40 (m, 9H), 1.26 (s, 12H).

73%	With toluene-4-sulfonic acid; In dichloromethane; at 30℃; for 4h;	[0406] To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (10.00 g, 51.54 mmol) in CH2C12 (100.00 mL) was added DHP (8.67 g, 103.08 mmol, 9.42 mL) and TsOH H20 (4.90 g, 25.77 mmol). The mixture was stirred at 30 C for 4 hour. LCMS showed 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazolewas consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with sat.NaHCC (35 mL) and the mixture was extracted with EtOAc (100 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 20/1 to 1/1) to afford the title compound (10.5 g, 73%) as colorless oil. 1H NMR (400 MHz, DMSO-i/6) delta 8.06 (s, 1H), 7.62 (s, 1H), 5.44-5.41 (m, 1H), 3.94-3.89 (m, 1H), 3.76-3.58 (m, 2H), 3.46-3.41 (m, 1H), 2.15-2.06 (m, 1H), 1.95-1.84 (m, 2H), 1.76-1.40 (m, 9H), 1.26 (s, 12H).
		Example 14: Synthesis of (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1H-pyrazol-4- yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester; A solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (5 mmol; 970 mg) and 3,4-dihydro-2H-pyran (10 mmol; 841 mg) and p-toluenesulfonic acid monohydrate (0.5 mmol; 95 mg) in 1 ,2-dichloroethane (25 ml_) is stirred at 40 0C for 2 hours. The reaction mixture is cooled to ambient temperature, and then quenched with saturated aqueous NaHCO3 solution. The product is extracted with dichloromethane. The organic layer is <n="82"/>washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The resulting material is used in the next step without further purification.
5.04 g	With toluene-4-sulfonic acid; In 1,2-dichloro-ethane; at 50℃; for 2h;	To a stirred solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (5.0 g, 25.76 mmol) in dry dichloroethane (128 ml), 3,4-dihydro-2H-pyran (4.71 ml, 51.52 mmol) was added followed by p-toluenesulfonic acid (490 mg, 2.576 mmol) and the reaction mixture was stirred at 50 C for 2 h. The reaction mixture was quenched with aqueous saturated solution of sodium bicarbonate (75 ml) and extracted with ethyl acetate (2 x 150 ml). The combined organic layer was washed with brine (100 ml) and dried over sodium sulphate. The mixture was evaporated under reduced pressure and residue obtained was purified by column chromatography to yield 5.04 g of product as a white solid. 1H NMR (300 MHz, CDCI3): delta I .31 (s, 12H), 1.54-1.70 (m, 3H), 1.98-2.20 (m, 3H), 3.68 (t, / = 10.2 Hz, 1H), 4.04 (d, / = I I .7 Hz, 1H), 5.35-5.45 (m, 1H), 7.82 (s, 1H), 7.93 (s, 1H).
	With toluene-4-sulfonic acid; In dichloromethane; at 40℃; for 2h;Inert atmosphere;	step 1: DTSA (463 mg, 2.6 mmol) was added to a solution of compound 101-1 (5.0 g, 25.8 mmol) and 2,3-dihydropyran (4.33 g, 51.5 mmol) in dichloromethane (100 ml) with stirring, and the reaction mixture was stirred at 40 C. for 2 h. After completion of the reaction, the reaction solution was washed with water, extracted with EA, and concentrated under reduced pressure to give the crude product 102-2 (7.0 g, 60%) which was used for the next step without purification, MS m/z (ESI): 279 [M+H]+.
	With toluene-4-sulfonic acid; In dichloromethane; at 60℃; for 1h;	A solution of 4-(4,4,5, 5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H-pyrazole (10 g, 51.5 mmol), 3,4- dihydro-2H-pyran (9.40 ml, 103 mmol), and p-toluenesulfonic acid monohydrate (1.274 g, 6.70 mmol) in DCM (100 ml) was stirred at 60 C for 1 hour to see complete conversion of the startmaterial, by LCMS. It was quenched with saturated NaHCO3, and extracted with DCM. The organic phase was purified with a silica gel column, eluting with 30 % EtOAc in hexanes, to get the desired product as a white solid. MS (M+1): 279
5.49 g	With toluene-4-sulfonic acid; In chloroform; at 50℃; for 3.5h;	(1) 3,4-Dihydro-2H-pyran (4.00 mL) and p-toluenesulfonic acid monohydrate (421 mg) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.29 g) in chloroform (44.2 mL), and the mixture was stirred at 50C for 3.5 hours. The mixture was cooled to room temperature, diluted with chloroform, and then washed sequentially with an aqueous solution of saturated sodium hydrogen carbonate and brine. The organic layer was separated by a phase separator and concentrated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane/ethyl acetate = 19:1 to ethyl acetate only) to give 1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (5.49 g) as a light brown oily substance.

Reference： [1]Patent: WO2014/1973,2014,A1 .Location in patent: Page/Page column 60; 61; 62
[2]Patent: WO2018/201006,2018,A1 .Location in patent: Paragraph 0125; 0126
[3]Patent: WO2016/210331,2016,A1 .Location in patent: Paragraph 0225; 0226
[4]Patent: WO2016/210330,2016,A1 .Location in patent: Paragraph 0405-0406
[5]Patent: WO2009/71509,2009,A1 .Location in patent: Page/Page column 80-81
[6]Patent: WO2014/24119,2014,A1 .Location in patent: Page/Page column 72
[7]Journal of Medicinal Chemistry,2016,vol. 59,p. 1370 - 1387
[8]Patent: US2017/8889,2017,A1 .Location in patent: Paragraph 0328; 0329
[9]Patent: WO2019/5588,2019,A1 .Location in patent: Page/Page column 36
[10]Patent: EP3418276,2018,A1 .Location in patent: Paragraph 0733; 0734

4
[ 1003846-21-6 ]
[ 1160065-25-7 ]
[ 1160065-26-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example 25: Synthesis of 1-[4-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1H- pyrazol-4-y.)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-chloro-pyrimidin-2-yl]- piperidin-4-ol; A 25 ml round-bottom flask is charged with 1-(tetrahydro-pyran-2-yl)-4-(4,4,5,5-tetramethyl- [1 ,3,2]diotaoxaborolan-2-yl)-1 H-pyrazole (56 mg, 0 2 mmol), 1-(4-{(2R,4S)-4-[(3,5-biotas- triotafluoromethyl-benzyl)-(5-bromo-pyriotamiotadiotan-2-yl)-amiotano]-2-ethyl-pyrroliotadiotan-1 -yl}-5-chloro- py?miotadiotan-2-yl)-piotaperiotadiotan-4-ol (110 mg, 0 15 mmmol) under N2 Pd(PPh3)4 (34 mg, 0 03 mmol) is added promptly and the flask is recharged with N2 Then DME (0 5 ml), Na2CO3 ( 1 M in H2O, 0 3 ml, 0 3 mmol) are added The mixture is then heated to 95 degree for 2 hours After cooling down to rt, NaIO4 (103 mg, 0 48 mmol) is added into reaction mixture Stirring is continued for 1 h to give white suspension H2O and dichloromethane are added, then organic layer is collected with phase separator Removal of solvent gave 1-{4-[(2R,4S)-4- <n="100"/>((3,5-bis-trifluoromethyl-benzyl)-{5-[1-(tetrahydro-pyran-2-yl)-1 H-pyrazol-4-yl]-pyrimidin-2-yl}- amino)-2-ethyl-pyrrolidin-1-yl]-5-chloro-pyrimidin-2-yl}-piperidin-4-ol which is used without further purification.

Reference： [1]Patent: WO2009/71509,2009,A1 .Location in patent: Page/Page column 98-99

5
[ 1003846-21-6 ]
[ 1160065-28-0 ]
[ 1160065-29-1 ]

Yield	Reaction Conditions	Operation in experiment
		Example 26: Synthesis of 1-[4-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1 H- pyrazol^-ylJ-pyrimidin-?-yll-amino^-ethyl-pyrrolidin-i-ylJ-delta-chloro-pyrimidin^-yl]- piperidine-4-carboxylic acid; A 25 ml round-bottom flask is charged with 1 -(tetrahydro-pyran-2-yl)-4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (83 mg, 0.3 mmol), 1-(4-{(2R,4S)-4-[(3,5-bis- trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidin-1 -yl}-5-chloro- <n="101"/>pyrimidin-2-yl)-piperidine-4-carboxylic acid ethyl ester (178 mg, 0.23 mmmol) under N2. Pd(PPh3)4 (57 mg, 0.05 mmol) is added promptly and the flask is recharged with N2. Then DME (1 ml), Na2CO3 (1 M in H2O, 0.45 ml, 0.45 mmol) are added. The mixture is then heated to 95 degree for 2 hrs. After cooling down to rt, NaIO4 (140 mg, 0.72 mmol) is added into reaction mixture. Stirring is continued for 1 h to give white suspension. H2O and dichloromethane are added, and then organic layer is collected. Removal of solvent give 1- {4-[(2R,4S)-4-((3,5-bis-trifluoromethyl-benzyl)-{5-[1-(tetrahydro-pyran-2-yl)-1 H-pyrazol-4-yl]- pyrimidin-2-yl}-amino)-2-ethyl-pyrrolidin-1-yl]-5-chloro-pyrimidin-2-yl}-piperidine-4-carboxylic acid ethyl ester which is used without further purification.

Reference： [1]Patent: WO2009/71509,2009,A1 .Location in patent: Page/Page column 99-100

6
[ 1003846-21-6 ]
[ 1160064-91-4 ]
[ 1160064-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 20 - 90℃; for 13h;	The obtained 1-(tetrahydro-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H- pyrazole (ca. 0.269 mmol; 112 mg), (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo- pyrimidin-2-yl)-amino]-2-ethyI-pyrrolidine-1-carboxylic acid isopropyl ester (0.192 mmol; 112 mg), tetrakis(triphenylphosphine) palladium (0.019 mmol; 21.9 mg), and aqueous 2M sodium carbonate (0.2 ml_) are dissolved in 1 ,2-dimethoxyethane (1 ml_) at room temperature. The mixture is stirred at 90 0C for 13 hours, and then cooled to ambient temperature. To the mixture is added brine and the solution is extracted three times with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is subjected to column chromatography on silica gel (eluent: /7-hexane/EtOAc) to give a diastereomeric mixture of (2R,4S)-4-((3,5-bis-trifluoromethyl- benzyl)-{5-[1-(tetrahydro-pyran-2-yl)-1 H-pyrazol-4-yl]-pyrimidin-2-yl}-amino)-2-ethyl- pyrrolidine-1-carboxylic acid isopropyl ester (99 mg).

Reference： [1]Patent: WO2009/71509,2009,A1 .Location in patent: Page/Page column 80-81

7
[ 89891-65-6 ]
[ 1003846-21-6 ]
[ 1346245-22-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; for 20h;Inert atmosphere; Reflux;Product distribution / selectivity;	7-Bromo-2-chloroquinoxaline (1 Og, 41.1 mmol), 1 -(tetrahydro-2H-pyran-2-yl)-4-(4, 4,5,5- tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1 H-pyrazole (1 1.42g, 41 .1 mmol), sodium carbonate 2M (20.5ml_, 41.1 mmol) in ethylene glycol dimethyl ether (100ml_) were degassed with N2 for 15 minutes, Pd(PPh3)4 (1 .4g, 1.2mmol) was added and heated at reflux for 20 hours. The reaction mixture was cooled to room temperature, poured into H20 and EtOAc. The precipitate was filtered and dried under vacuum to give 12 g (84%) of intermediate 21 .
60%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water;Inert atmosphere; Reflux;	7-bromo-2-chloroquinoxaline (87 g, 312.8 mmo 1), 1 -(tetrahydro-2H-pyran-2-yl)-4-(4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole (76.6 g, 312.8 mmol), 2Maqueous sodium carbonate (156.4 mL, 318.8 mmo 1) in ethylene glyco 1 dimethyl ether(1.5 L) were degassed with N2 for 10 minutes. Then,tetrakis(trisphenylphosphine)palladium(O) (8.6 g, 7.6 mmo 1) was added and the reaction mixture was heated at reflux overnight. The mixture was poured into H20 and EtOAc. The precipitate was filtered and dried to give 68 g (60%) of intermediate 7.

Reference： [1]Patent: WO2011/135376,2011,A1 .Location in patent: Page/Page column 203
[2]Patent: WO2017/50864,2017,A1 .Location in patent: Page/Page column 72; 73

8
[ 1003846-21-6 ]
[ 1431873-00-5 ]
[ 1431873-12-9 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water;Inert atmosphere; Reflux;	A mixture of intermediate 5a (7.5 g; 30.68 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-4- (4>4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (CAS 1003846-21-6) (9.39 g; 33.75 mmol) in a 2M aqueous solution of sodium carbonate (76 mL; 153.39 mmol) and DME (310 mL) was degassed with N2 for 15 minutes, then Pd(Ph3)4 (1.77 g; 1.53 mmol) was added. The reaction mixture was refluxed overnight, poured into a saturated solution of NaHC03 and extracted with AcOEt. The organic layer was washed with brine, dried over MgS04, filtered and evaporated to dryness. The residue was crystallized from ACN. The precipitate was filtered, washed with Et20 and dried yielding 3.06 g (32%) of intermediate 27 . The filtrate was purified by chromatography over silica gel (irregular SiOH, 15-45muiotatauiota, 120g; mobile phase : gradient from 100% DCM, 0% MeOH to 99%DCM, 1 % MeOH). The fractions were collected and evaporated to dryness yielding 4.21 g (43%) of intermediate 27 . (overall yield: 75%).

Reference： [1]Patent: WO2013/61080,2013,A1 .Location in patent: Page/Page column 150; 151

9
[ 757978-19-1 ]
[ 1003846-21-6 ]
1-(benzenesulfonyl)-5-bromo-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyrrolo[2,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; water; at 95℃;Inert atmosphere;	[0254] Step 1 : l-(Benzenesulfonyl)-5-bromo-3-(l-tetrahydropyran-2-ylpyrazol-4- yl)pyrrolo[2,3-b]pyridine. A solution of l-(benzenesulfonyl)-5-bromo-3-iodo-pyrrolo[2,3- b]pyridine (2.0 g, 4.3 mmol), l-tetrahydropyran-2-yl-4-(4,4, 5,5 -tetramethyl- 1,3,2- dioxaborolan-2-yl)pyrazole (1.8 g, 6.4 mmol) and NaHC03 ( 0.72 g, 8.6 mmol) in dioxane/water (3: 1, 32 mL) was sparged with N2 (g) for 5 min. Tetrakis palladium triphenylphosphine (0.05 g, 0.43 mmol) was added and the reaction mixture heated to 90 C overnight. The reaction was cooled to rt, water (5 mL) and EtOAc (25 mL) were added, the layers separated and the aq. layer extracted with EtOAc (2 x 50 mL). The organic layers were combined, dried, filtered and evaporated. Purification of the residue by column chromatography (EtOAc/Hexanes) afforded the desired product (1.5 g, 71%). 1H NMR (DMSO-de) delta 8.65 (d, IH), 8.62 (s, IH), 8.52 (d, IH), 8.34 (s, IH), 8.15 (d, IH), 8.11-8.08 (m, 2H), 7.73 (dt, IH), 7.63 (dt, 2H), 5.43 (dd, IH), 3.96 (d, IH), 3.68-3.62 (m, IH), 2.33- 2.16 (m, IH), 1.95 (t, 2H), 1.76-1.65 (m, IH), 1.59-1.53 (m, 2H). LC-MS [M+H]+ 489.1.

Reference： [1]Patent: WO2014/4863,2014,A2 .Location in patent: Paragraph 0254

10
[ 757978-19-1 ]
[ 1003846-21-6 ]
1-(benzenesulfonyl)-5-(3,4-dimethoxyphenyl)-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyrrolo[2,3-b]pyridine [ No CAS ]

Reference： [1]Patent: WO2014/4863,2014,A2

11
[ 1003846-21-6 ]
[ 1207543-30-3 ]
[ 1527475-92-8 ]

Yield	Reaction Conditions	Operation in experiment
1.33 g	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); at 130℃; for 1.5h;Inert atmosphere; Microwave irradiation;	A mixture of 4-chloro-5-iodo-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3- d]pyrimidine (Cl) (2.0 g, 4.9 mmol), 1 -(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1H-pyrazole (C17) (1 .91 g, 6.87 mmol), potassium phosphate (4.0 g, 19 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.10 g, 87 pmol) was degassed several times with nitrogen and irradiated in a microwave synthesizer at 130C for 1.5 hours. The reaction mixture was partitioned between ethyl acetate (400 mL) and water (60 mL), and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Chromatography on silica gel (Gradient: 10% to 80% ethyl acetate inpetroleum ether) afforded the product as a brown oil. Yield: 1.33 g, 3.06 mmol, 62%. 1HNMR (400 MHz, CDCl3) 8.67 (s, 1H), 7.87 (s, 1H), 7.76 (s, 1H), 7.38 (s, 1H), 5.68 (s,2H), 5.46 (dd, J=9.4, 2.9 Hz, 1H), 4.08-4.15 (m, 1H), 3.71-3.79 (m, 1H), 3.57 (dd, J=8.3,8.0 Hz, 2H), 2.04-2.24 (m, 3H), 1.61-1.79 (m, 3H), 0.94 (dd, J=8.3, 8.3 Hz, 2H), -0.03(s, 9H).

Reference： [1]Patent: WO2014/1973,2014,A1 .Location in patent: Page/Page column 60; 61; 62

12
[ 1003846-21-6 ]
[ 1207543-30-3 ]
[ 1527475-93-9 ]

Reference： [1]Patent: WO2014/1973,2014,A1

13
[ 1040377-02-3 ]
[ 73183-34-3 ]
[ 1003846-21-6 ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 24h;	To a solution of 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (745 mg, 3,21 mmol) in dioxane (15 mL) was added KOAc (944 mg, 9.63 mmol), PdCl2(dppf) (352mg, 0,48 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1,22 g, 4.82 mmol). The mixture was stirred at 80 C for 24 hours, then was filtered and concentrated to give crude product, which was used for next step directly. MS (m/z): 279 (M + H)+,

Reference： [1]Patent: WO2014/86032,2014,A1 .Location in patent: Page/Page column 43

14
[ 1003846-21-6 ]
[ 51554-95-1 ]
[ 1620400-82-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 110 - 120℃; for 0.333333h;Inert atmosphere; Microwave irradiation;	K3PO4 (0:33 g, 1:54 mmol) was dissolved in 5 mL dmf and 5 mL water, and the solution was saturated with argon. A mixture of Pd(PPh3)4 (0:06 g, 0:05 mmol), 3a(THP) (0:14 g, 0:51 mmol), and 4-pentylbromobenzene (0:12 g, 92 mL, 0:51 mmol) was added to the K3PO4 solution. Theresulting suspension was saturated with argon. After microwave irradiation at 120 °C for 20 min, the reaction mixture was treated with a saturated aqueous NaHCO3 solution (30 mL). The product was extracted into ethyl acetate (3 x 30 mL). The combined organic layers were washed three times with 30 mL of a saturated aqueous NaCl solution and dried over anhydrous MgSO4. After removal of the solvent in vacuo, the THP-protected product remained as a pale-yellow oil (0:12 g, 82percent). Treatment with a solution of HCl in MeOH (10 mL, AcCl in MeOH) and stirring for 30 min yielded the hydrochloride of 6(pentyl) [13]. When the hydrochloride was treated with NEt3 (1 mL), the pyrazole 6(pentyl) [13] was obtained quantitatively. After evaporation of the solvent, the crude product was purified by column chromatography (hexane/ethyl acetate 2 : 1). Colorless solid (yield: 0:07 g, 68percent).

Reference： [1]Zeitschrift fur Naturforschung, B: Chemical Sciences,2014,vol. 69,p. 83 - 97

15
[ 1003846-21-6 ]
[ 23703-22-2 ]
C₂₀H₂₈N₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 110 - 120℃; for 0.333333h;Inert atmosphere; Microwave irradiation;	General procedure: K3PO4 (0:33 g, 1:54 mmol) was dissolved in 5 mL dmf and 5 mL water, and the solution was saturated with argon. A mixture of Pd(PPh3)4 (0:06 g, 0:05 mmol), 3a(THP) (0:14 g, 0:51 mmol), and 4-pentylbromobenzene (0:12 g, 92 mL, 0:51 mmol) was added to the K3PO4 solution. Theresulting suspension was saturated with argon. After microwave irradiation at 120 C for 20 min, the reaction mixture was treated with a saturated aqueous NaHCO3 solution (30 mL). The product was extracted into ethyl acetate (3 x 30 mL). The combined organic layers were washed three times with 30 mL of a saturated aqueous NaCl solution and dried over anhydrous MgSO4. After removal of the solvent in vacuo, the THP-protected product remained as a pale-yellow oil (0:12 g, 82%). Treatment with a solution of HCl in MeOH (10 mL, AcCl in MeOH) and stirring for 30 min yielded the hydrochloride of 6(pentyl) [13]. When the hydrochloride was treated with NEt3 (1 mL), the pyrazole 6(pentyl) [13] was obtained quantitatively. After evaporation of the solvent, the crude product was purified by column chromatography (hexane/ethyl acetate 2 : 1). Colorless solid (yield: 0:07 g, 68%).

Reference： [1]Zeitschrift fur Naturforschung, B: Chemical Sciences,2014,vol. 69,p. 83 - 97

16
1-bromo-4-(2'-ethylhexyl)benzene [ No CAS ]
[ 1003846-21-6 ]
C₂₂H₃₂N₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 110 - 120℃; for 0.333333h;Inert atmosphere; Microwave irradiation;	General procedure: K3PO4 (0:33 g, 1:54 mmol) was dissolved in 5 mL dmf and 5 mL water, and the solution was saturated with argon. A mixture of Pd(PPh3)4 (0:06 g, 0:05 mmol), 3a(THP) (0:14 g, 0:51 mmol), and 4-pentylbromobenzene (0:12 g, 92 mL, 0:51 mmol) was added to the K3PO4 solution. Theresulting suspension was saturated with argon. After microwave irradiation at 120 C for 20 min, the reaction mixture was treated with a saturated aqueous NaHCO3 solution (30 mL). The product was extracted into ethyl acetate (3 x 30 mL). The combined organic layers were washed three times with 30 mL of a saturated aqueous NaCl solution and dried over anhydrous MgSO4. After removal of the solvent in vacuo, the THP-protected product remained as a pale-yellow oil (0:12 g, 82%). Treatment with a solution of HCl in MeOH (10 mL, AcCl in MeOH) and stirring for 30 min yielded the hydrochloride of 6(pentyl) [13]. When the hydrochloride was treated with NEt3 (1 mL), the pyrazole 6(pentyl) [13] was obtained quantitatively. After evaporation of the solvent, the crude product was purified by column chromatography (hexane/ethyl acetate 2 : 1). Colorless solid (yield: 0:07 g, 68%).

Reference： [1]Zeitschrift fur Naturforschung, B: Chemical Sciences,2014,vol. 69,p. 83 - 97

17
[ 1003846-21-6 ]
6-bromo-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methylisoindolin-1-one [ No CAS ]
2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-(tetrahydropyran-2-yl)pyrazol-4-yl)isoindolin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 70 - 85℃; for 18h;Inert atmosphere;	Combine 6-bromo-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-isoindolin-1-one (64 g, 177 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (67g, 295 mmol), potassium carbonate (70 g, 506 mmol), (l,l'-bis(diphenylphosphino)ferrocene)palladium(II) chloride (9 g, 11 mmol), dioxane (800 mL), and water (212 mL) under nitrogen and heat to 70-75 C for 16 hours. Add 1- (tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (15 g, 54 mmol) and heat to 80-85 C for 2 hours. Concentrate under reduced pressure to 200 mL, add ethyl acetate (500 mL) and water (500 mL), stir for 30 minutes, and filter the solids. Combine the solids and the organic layer and evaporate under reduced pressure. Dissolve the residue in dichloromethane and filter through a pad of silica gel. Wash the silica gel pad with dichloromethane/ethyl acetate (1:0) and then (2:1) and evaporate to dryness under reduced pressure. Slurry the solid in a 2:1 mixture of petroleum ether/ethyl acetate (600 mL) for 30 minutes at 25-30 C and filter to collect the solid to give the title compound as an off-white solid (68 g, 89%). ES/MS m/z: 432 (M+H)

Reference： [1]Patent: WO2014/143601,2014,A1 .Location in patent: Page/Page column 12; 13

18
[ 1003846-21-6 ]
3-(6-chloro-5-fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-(tetrahydropyran-2-yl)pyrazol-4-yl)isoindolin-1-one [ No CAS ]

Reference： [1]Patent: WO2014/143601,2014,A1

19
[ 1003846-21-6 ]
3-(5-fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-(tetrahydropyran-2-yl)pyrazol-4-yl)isoindolin-1-one [ No CAS ]

Reference： [1]Patent: WO2014/143601,2014,A1

20
[ 1003846-21-6 ]
1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine [ No CAS ]
1-benzyl-5-chloro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; for 1.5h;Reflux; Inert atmosphere;	Step 1. 1-benzyl-5-chloro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridine A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.120 g, 0.373 mmol, from Example 62, Step 2), <strong>[1003846-21-6]1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (0.11 g, 0.41 mmol, Aldrich) and Na2CO3 (0.20 g, 1.9 mmol) in 1,2-dimethoxyethane (4 mL) and water (0.7 mL) was degassed by a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.037 mmol) was added, and the reaction was heated to reflux for 1.5 hours. Upon cooling to room temperature, the mixture was partitioned between water and EtOAc, and the aqueous layer was extracted a total of three times. The combined extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes afforded product. Yield: (0.106 g, 72%). 1H NMR (400 MHz, CDCl3) delta 7.70 (d, J=0.7 Hz, 1H), 7.58 (d, J=0.7 Hz, 1H), 7.40 (dd, J=8.5, 0.8 Hz, 1H), 7.34-7.26 (m, 3H), 7.03 (d, J=8.5 Hz, 1H), 6.99-6.94 (m, 2H), 6.73 (d, J=0.8 Hz, 1H), 5.40 (s, 2H), 5.38 (dd, J=6.6, 5.5 Hz, 1H), 4.09-4.02 (m, 1H), 3.74-3.65 (m, 1H), 2.13-1.95 (m, 3H), 1.77-1.58 (m, 3H). LCMS (M+H)+: 393.1.

Reference： [1]Patent: US2015/175604,2015,A1 .Location in patent: Paragraph 0517; 0518; 0519; 0520

21
[ 1003846-21-6 ]
[ 7511-49-1 ]
1,3,5-tri[4-(1H-pyrazol-4-yl)phenyl]benzene [ No CAS ]

Reference： [1]CrystEngComm,2015,vol. 17,p. 4992 - 5001

22
[ 1003846-21-6 ]
4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine [ No CAS ]
4-(6-nitro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43.35%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; sodium iodide; In 1,2-dimethoxyethane; water; at 95℃;Inert atmosphere;	Step 1: Preparation of 4-(6-nitro-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4- yl)thiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in step 7 of example 1, 4-(5-chloro-6- nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of step 4 of example 20) (250mg, 0.833 mmol) was coupled with l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (579mg, 2.083 mmol) using sodium iodide (375mg, 2.5 mmol), potassium carbonate (345mg, 2.5 mmol) and Pd(dppf)Cl2 (304mg, 0.4166 mmol) in 1,2- dimethoxyethane/water (5/lmL) to get the title compound (150mg, 43.35%). LCMS: m/z = 417.15 (M+l)+.

Reference： [1]Patent: WO2015/104688,2015,A1 .Location in patent: Page/Page column 147

23
[ 26218-75-7 ]
[ 1003846-21-6 ]
methyl 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 95℃;Sealed tube; Inert atmosphere;	In a sealed tube methyl 6-bromopicolinate (900mg, 4.l66mmol) was coupled with 1- (tetrahydro-2H-pyran-2-yl)-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole (1 .39g,5mmol) using sodium carbonate (1.324g, 12.49mmol) and Pd(PPh3)2C12 (339mg, 0.4l6mmol) in1,2-dimethoxyethane (l0mL) and water (2mL) and purged argon for 10 mm, and heated at 95C overnight to get the crude product. The obtained crude was purified by 60-120 silica gel column chromatography using 30% ethyl acetate in hexane as eluent to obtain the title compound (450mg, 38%). LCMS: mlz: 288.1 (M+1).
38%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere; Sealed tube;	In a sealed tube methyl 6-bromopicolinate (900 mg, 4.166 mmol) was coupled with <strong>[1003846-21-6]1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (1.39 g, 5 mmol) using sodium carbonate (1.324 g, 12.49 mmol) and Pd(PPh3)2Cl2 (339 mg, 0.416 mmol) in 1,2-dimethoxyethane (10 mL) and water (2 mL) and purged argon for 10 min, and heated at 95 C. overnight to get the crude product. The obtained crude was purified by 60-120 silica gel column chromatography using 30% ethyl acetate in hexane as eluent to obtain the title compound (450 mg, 38%). LCMS: m/z: 288.1 (M+1)+.

Reference： [1]Patent: WO2015/104662,2015,A1 .Location in patent: Page/Page column 25
[2]Patent: US2016/326151,2016,A1 .Location in patent: Paragraph 0136

24
[ 1003846-21-6 ]
N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide [ No CAS ]

Reference： [1]Patent: WO2015/104662,2015,A1
[2]Patent: WO2015/104662,2015,A1
[3]Patent: US2016/326151,2016,A1

25
[ 1003846-21-6 ]
N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide [ No CAS ]

Reference： [1]Patent: WO2015/104662,2015,A1
[2]Patent: US2016/326151,2016,A1

26
[ 1003846-21-6 ]
6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid [ No CAS ]

Reference： [1]Patent: WO2015/104662,2015,A1
[2]Patent: US2016/326151,2016,A1

27
[ 1003846-21-6 ]
6-bromo-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)picolinamide [ No CAS ]
N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; tricyclohexylphosphine; In 1,2-dimethoxyethane; water; at 85℃; for 6h;Sealed tube; Inert atmosphere;	A solution of 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (0.300 g, 0.967 mmol) (product of step 3 in example 5) in toluene:H20 (12 mL, 3:1), cyclopropyl boronic acid (0.124 g, 1.45 mmol), Pd2(dba)3 (10 mg, 0.009 mmol), potassium carbonate (0.300 g, 2.901 mmol) andtricyclohexyl phosphine (16 mg, 0.058 mmol) were taken in a sealed tube under nitrogen atmosphere. The contents were heated at 90 C for 12 h, cooled to room temperature and filtered through Celite. The filtrate was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane:EtOAc;7:3) to give the title compound (0.160 g, 61 %) as a light brown solid.?H NMR (400 MHz, DMSO-d6):oe8.69 (s, 1H), 8.43 (s, 1H), 7.50 (s, 1H), 5.12-5.05 (m, 1H), 2.33-2.20 (m, 3H), 2.19-2.01 (m, 2H), 1.93-1.83 (m, 2H), 1.75-1.65 (m, 2H), 0.94-0.79 (m, 2H),0.73-0.69 (m, 2H). LCMS: mlz: 272 (M+1).Using the same reagents and conditions as described in step 1 of example 6, 6-bromo-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)picolinamide (150mg, 0.4043 mmol) was coupled with1 -(tetrahydro-2H-pyran-2-yl)-4-(4,4,5 , 5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole(135mg, 0.4851 mmol) using Pd(dppf)Cl2 (15 mg, 0.0202 mmol) and sodium carbonate (128mg,1.212 mmol) in DME/H20 (5/1 mL) at 85C for 6h to obtain title product (148mg, 83%).LCMS: 100%,mlz=443.1 (M+1).
83%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 58℃; for 6h;	2-methyl-5-nitro-6-(piperidin-1-yl)-2H-indazole (0.39 g, 1.5 mmol) was dissolved in ethanol (15 mL) To this solution, Fe powder (0.42 g, 7.5 mmol) and 0.4 mL of HCl were added at 0 C. and the reaction mixture was refluxed for 1 h. After completion of reaction, reaction mixture was cooled to room temperature and diluted with ethyl acetate and filtered through Celite. The filtrate was basified with sodium bicarbonate solution, extracted with ethyl acetate and the organic layer washed with water followed by brine solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The crude residue was purified by column chromatography (n-hexane:EtOAc; 1:4) to give the title compound (0.2 g, 58%) as a light brown liquid.Using the same reagents and conditions as described in step 1 of example 6, 6-bromo-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)picolinamide (150 mg, 0.4043 mmol) was coupled with <strong>[1003846-21-6]1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (135 mg, 0.4851 mmol) using Pd(dppf)Cl2 (15 mg, 0.0202 mmol) and sodium carbonate (128 mg, 1.212 mmol) in DME/H2O (5/1 mL) at 85 C. for 6 h to obtain title product (148 mg, 83%). LCMS: 100%, m/z=443.1 (M+1)+.

Reference： [1]Patent: WO2015/104662,2015,A1 .Location in patent: Page/Page column 46; 80
[2]Patent: US2016/326151,2016,A1 .Location in patent: Paragraph 0215; 0428

28
[ 1003846-21-6 ]
6-bromo-N-(6-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)picolinamide [ No CAS ]
N-(6-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39.44%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; tricyclohexylphosphine; In 1,2-dimethoxyethane; water; at 90℃; for 2h;Sealed tube; Inert atmosphere;	A solution of 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (0.300 g, 0.967 mmol) (product of step 3 in example 5) in toluene:H20 (12 mL, 3:1), cyclopropyl boronic acid (0.124 g, 1.45 mmol), Pd2(dba)3 (10 mg, 0.009 mmol), potassium carbonate (0.300 g, 2.901 mmol) andtricyclohexyl phosphine (16 mg, 0.058 mmol) were taken in a sealed tube under nitrogen atmosphere. The contents were heated at 90 C for 12 h, cooled to room temperature and filtered through Celite. The filtrate was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane:EtOAc;7:3) to give the title compound (0.160 g, 61 %) as a light brown solid.?H NMR (400 MHz, DMSO-d6):oe8.69 (s, 1H), 8.43 (s, 1H), 7.50 (s, 1H), 5.12-5.05 (m, 1H), 2.33-2.20 (m, 3H), 2.19-2.01 (m, 2H), 1.93-1.83 (m, 2H), 1.75-1.65 (m, 2H), 0.94-0.79 (m, 2H),0.73-0.69 (m, 2H). LCMS: mlz: 272 (M+1).Using the same reagents and conditions as described in step 1 of example 6, 6-bromo-N- (6-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin- 1 -yl)-2-methyl-2H-indazol-5 -yl)picolinamide (450mg, 0. 82Ommol) was coupled with 1 -(tetrahydro-2H-pyran-2-yl)-4-(4,4,5 ,5 - tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole (330mg, 1.1 87mmol) using Pd(dppf)Cl2 (60mg, 0.O82mmol) and sodium carbonate (249mg, 2.349mmo1) in DMEIH2O (5/1 mL) at 90C for 2h to obtain title product (200mg, 39.44%). LCMS: mlz = 630.5 (M+1) .
39.44%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 2h;Sealed tube; Inert atmosphere;	A solution of 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (0.300 g, 0.967 mmol) (product of step 3 in example 5) in toluene:H2O (12 mL, 3:1), cyclopropyl boronic acid (0.124 g, 1.45 mmol), Pd2(dba)3 (10 mg, 0.009 mmol), potassium carbonate (0.300 g, 2.901 mmol) and tricyclohexyl phosphine (16 mg, 0.058 mmol) were taken in a sealed tube under nitrogen atmosphere. The contents were heated at 90 C. for 12 h, cooled to room temperature and filtered through Celite. The filtrate was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane:EtOAc; 7:3) to give the title compound (0.160 g, 61%) as a light brown solid.; Using the same reagents and conditions as described in step 1 of example 6, 6-bromo-N-(6-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)picolinamide (450 mg, 0.820 mmol) was coupled with <strong>[1003846-21-6]1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (330 mg, 1.187 mmol) using Pd(dppf)Cl2 (60 mg, 0.082 mmol) and sodium carbonate (249 mg, 2.349 mmol) in DME/H2O (5/1 mL) at 90 C. for 2 h to obtain title product (200 mg, 39.44%). LCMS: m/z=630.5 (M+1)+.

Reference： [1]Patent: WO2015/104662,2015,A1 .Location in patent: Page/Page column 46; 132
[2]Patent: US2016/326151,2016,A1 .Location in patent: Paragraph 0251; 0252; 0672

29
[ 1003846-21-6 ]
1-(7-azabicyclo[2.2.1]heptan-2-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indole [ No CAS ]

Reference： [1]Patent: US2015/252051,2015,A1

30
[ 1003846-21-6 ]
phenyl(2-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone [ No CAS ]

Reference： [1]Patent: US2015/252051,2015,A1

31
[ 110-87-2 ]
[ 1003846-21-6 ]

Reference： [1]Patent: US2015/252022,2015,A1
[2]Patent: WO2016/14913,2016,A1
[3]Patent: WO2016/14918,2016,A1
[4]Patent: US2016/24056,2016,A1

32
[ 1075-34-9 ]
[ 1003846-21-6 ]
2-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere;	Synthesis of 2-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indole 1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.9 g, 36 mmol) was added to a solution of 5-bromo-2-methyl-1H-indole (5.0 g, 23.8 mmol) in a mixture of DMF and water (9:1, 50 mL) at room temperature. Potassium carbonate (6.5 g, 48 mmol, 2.0 eq) was then added and the reaction mixture was purged with argon for 20 min. PdCl2(dppf)·dichloromethane (1.9 g, 2.38 mmol, 0.1 eq) was added, argon was passed through the solution for further 10 min and the mixture was heated at 80° C. for 16 h. After completion of the reaction (monitored by TLC, 50percent ethyl acetate-hexanes Rf=0.3), the reaction mixture was cooled to room temperature and filtered through a bed of diatomaceous earth. washing with ethyl acetate. The combined filtrate was washed with water followed by brine, the organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh, eluting with a 40-50percent gradient of ethyl acetate in hexanes to afford 2-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indole (2.0 g, 30percent) as a pale yellow sticky solid. LCMS purity: 93.89percent; (ES+): m/z 282.5 (M+H+); tr=1.99 min.

Reference： [1]Patent: US2015/252022,2015,A1 .Location in patent: Paragraph 0257; 0258

33
[ 1003846-21-6 ]
2-methyl-1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indole [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

34
[ 1003846-21-6 ]
benzyl 4-((2-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

35
[ 1003846-21-6 ]
1-((1-benzyl-5-methylpyrrolidin-3-yl)methyl)-2-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indole [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

36
[ 1003846-21-6 ]
2-methyl-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indole [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

37
[ 1003846-21-6 ]
1-(pyrrolidin-3-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indole [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

38
[ 1003846-21-6 ]
phenyl(3-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)pyrrolidin-1-yl)methanone [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

39
[ 1003846-21-6 ]
1-(azepan-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indole [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

40
[ 1003846-21-6 ]
phenyl(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)azepan-1-yl)methanone [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

41
[ 1003846-21-6 ]
1-(piperidin-4-ylmethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

42
[ 1003846-21-6 ]
3-phenyl-1-(4-((6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidin-1-yl)propan-1-one [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

43
[ 1003846-21-6 ]
2-phenyl-1-(4-((6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidin-1-yl)ethanone [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

44
[ 1003846-21-6 ]
1-(2-methyl-4-((2-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)pyrrolidin-1-yl)-3-phenylpropan-1-one [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

45
[ 1003846-21-6 ]
1-(4-((2-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)piperidin-1-yl)-3-phenylpropan-1-one [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

46
[ 1003846-21-6 ]
1-(4-((2-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)piperidin-1-yl)-2-phenylethanone [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

47
4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole [ No CAS ]
[ 73183-34-3 ]
[ 1003846-21-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; dichloromethane; at 20 - 80℃; for 12.5h;Inert atmosphere;	Step 2. Bis(pinacolato)diboron (247 g, 0.974 mol, 1.5 eq) was added to a solution of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (150 g, 0.65 mol, 1.0 eq) in 1,4-dioxane (1500 ml) at room temperature. Potassium acetate (127 g, 1.30 mol, 2 eq) was then added and the reaction flask was purged with argon for 20 min. PdCl2(dppf).DCM (26.0 g, 31.8 mmol, 0.05 eq) was added and the mixture was purged with argon for further 10 min followed by stirring at 80 C. for 12 h. After completion of the reaction (monitored by TLC, 10% ethyl acetate-hexane Rf=0.3), the mixture was cooled to room temperature and filtered through a bed of diatomaceous earth. The bed of diatomaceous earth was washed with ethyl acetate and the combined organic layers were evaporated under reduced pressure to give 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (280 g crude) as a brown oil. LCMS purity: 57.8%; (ES+): m/z 279.18 (M+H+); tr=1.95 min. The compound was used without further purification.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 12h;Inert atmosphere;	Step 2. Bis(pinacolato)diboron (247 g, 0.974 mol, 1.5 eq) was added to a solution of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (150 g, 0.65 mol, 1.0 eq) in 1,4-dioxane (1500 ml) at room temperature. Potassium acetate (127 g, 1.30 mol, 2 eq) was then added and the reaction flask was purged with argon for 20 min. PdCl2(dppf)·DCM (26.0 g, 31.8 mmol, 0.05 eq) was added and the mixture was purged with argon for further 10 min followed by stirring at 80 C. for 12 h. After completion of the reaction (monitored by TLC, 10% ethyl acetate-hexane Rf=0.3), the mixture was cooled to room temperature and filtered through a bed of diatomaceous earth. The bed of diatomaceous earth was washed with ethyl acetate and the combined organic layers were evaporated under reduced pressure to give 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (280 g crude) as a brown oil. LCMS purity: 57.8%; (ES+): m/z 279.18 (M+H+); tr=1.95 min. The compound was used without further purification.
		Bis(pinacolato)diboron (247 g, 0.974 mol, 1.5 eq) was added to a solution of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (150 g, 0.65 mol, 1.0 eq) in 1,4-dioxane (1500 ml) at room temperature. Potassium acetate (127 g, 1.30 mol, 2 eq) was then added and the reaction flask was purged with argon for 20 min. PdCl2(dppf).DCM (26.0 g, 31.8 mmol, 0.05 eq) was added and the mixture was purged with argon for further 10 min followed by stirring at 80 C for 12 h. After completion of the reaction (monitored by TLC, 10% ethyl acetate-hexane, Rf = 0.3), the mixture was cooled to room temperature and filtered through a bed of diatomaceous earth washing with ethyl acetate and the combined organic layers were evaporated under reduced pressure to give 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (280 g crude) as a brown oil. LCMS purity: 57.8 %; (ES+): m/z 279.18 (M+H+); tr = 1.95 min. The compound was used without further purification.

	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 12h;Inert atmosphere;	Intermediate 1Synthesis of 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazoleStep 2Bis(pinacolato)diboron (247 g, 0.974 mol, 1.5 eq) was added to a solution of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (150 g, 0.65 mol, 1.0 eq) in 1,4-dioxane (1500 ml) at room temperature. Potassium acetate (127 g, 1.30 mol, 2 eq) was then added and the reaction flask was purged with argon for 20 min. PdCl2(dppf).DCM (26.0 g, 31.8 mmol, 0.05 eq) was added and the mixture was purged with argon for further 10 min followed by stirring at 80 C for 12 h. After completion of the reaction (monitored by TLC, 10% ethyl acetate-hexane, Rf = 0.3), the mixture was cooled to room temperature and filtered through a bed of diatomaceous earth washing with ethyl acetate and the combined organic layers were evaporated under reduced pressure to give 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (280 g crude) as a brown oil. LCMS purity: 57.8 %; (ES+): m/z 279.18 (M+H+); tr = 1.95 min. The compound was used without further purification.
		Step 2. Bis(pinacolato)diboron (247 g, 0.974 mol, 1.5 eq) was added to a solution of 4-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole (150 g, 0.65 mol, 1.0 eq) in 1,4-dioxane (1500 ml) at room temperature. Potassium acetate (127 g, 1.30 mol, 2 eq) was then added and the reaction flask was purged with argon for 20 min. PdCl2(dppf)DCM (26.0 g, 31.8 mmol, 0.05 eq) was added and the mixture was purged with argon for further 10 min followed by stirring at 80 C for 12 h. After completion of the reaction (monitored by TLC, 10% ethyl acetate-hexane, R/ = 0.3), the mixture was cooled to room temperature and filtered through a bed of diatomaceous earth washing with ethyl acetate and the combined organic layers were evaporated under reduced pressure to give l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole (280 g crude) as a brown oil. LCMS purity: 57.8 %; (ES+): m/z 279.18 (M+H+); tr = 1.95 min. The compound was used without further purification.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 12h;Inert atmosphere;	Step 2. Bis(pinacolato)diboron (247 g, 0.974 mol, 1.5 eq) was added to a solution of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (150 g, 0.65 mol, 1.0 eq) in 1,4-dioxane (1500 ml) at room temperature. Potassium acetate (127 g, 1.30 mol, 2 eq) was then added and the reaction flask was purged with argon for 20 min. PdCl2(dppf) DCM (26.0 g, 31.8 mmol, 0.05 eq) was added and the mixture was purged with argon for further 10 min followed by stirring at 80 C. for 12 hr. After completion of the reaction (monitored by TLC, 10% ethyl acetate-hexane Rf=0.3), the mixture was cooled to room temperature and filtered through a bed of diatomaceous earth. The bed of diatomaceous earth was washed with ethyl acetate and the combined organic layers were evaporated under reduced pressure to give 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (280 g crude) as a brown oil. LCMS purity: 57.8%; (ES+): m/z 279.18 (M+H+); tr=1.95 min. The compound was used as such without further purification.
280 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 12h;Inert atmosphere;	Step 2. Bis(pinacolato)diboron (247 g, 0.974 mol, 1.5 eq) was added to a solution of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (150 g, 0.65 mol, 1.0 eq) in 1,4-dioxane (1500 ml) at room temperature. Potassium acetate (127 g, 1.30 mol, 2 eq) was then added and the reaction flask was purged with argon for 20 min. PdCl2(dppf) DCM (26.0 g, 31.8 mmol, 0.05 eq) was added and the mixture was purged with argon for further 10 min followed by stirring at 80 C. for 12 h. After completion of the reaction (monitored by TLC, 10% ethyl acetate-hexane Rf=0.3), the mixture was cooled to room temperature and filtered through a bed of diatomaceous earth. The bed of diatomaceous earth was washed with ethyl acetate and the combined organic layers were evaporated under reduced pressure to give 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (280 g crude) as a brown oil. LCMS purity: 57.8%; (ES+): m/z 279.18 (M+H+); tr=1.95 min. The compound was used without further purification.

Reference： [1]Patent: US2015/252051,2015,A1 .Location in patent: Paragraph 0165; 0167
[2]Patent: US2015/252022,2015,A1 .Location in patent: Paragraph 0207; 0209
[3]Patent: WO2016/14913,2016,A1 .Location in patent: Paragraph 109
[4]Patent: WO2016/14916,2016,A1 .Location in patent: Paragraph 109
[5]Patent: WO2016/14918,2016,A1 .Location in patent: Paragraph 107
[6]Patent: US2017/298060,2017,A1 .Location in patent: Paragraph 0082; 0084
[7]Patent: US2016/24056,2016,A1 .Location in patent: Paragraph 0201

48
[ 1003846-21-6 ]
benzyl 2-((5-bromo-1H-indol-1-yl)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate [ No CAS ]
benzyl 2-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In water; N,N-dimethyl-formamide; at 20℃; for 6.33h;Inert atmosphere;	Reaction Step 9. Synthesis of benzyl 2-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylateTo a mixture of <strong>[1003846-21-6]1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (14.2 g, 51.2 mmol, 1.5 eq), benzyl 2-((5-bromo-1H-indol-1-yl)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (15.0 g, 34.1 mmol, 1.0 eq) in DMF: water (4:1, 150 mL) at room temperature was added Cs2CO3 (22.0 g, 68.2 mmol, 2.0 eq) and the reaction mixture was purged with argon for 10 min. PdCl2(dppf)dichloromethane adduct (1.39 g, 0.17 mmol, 0.05 eq) was added to the reaction mixture and purging with argon was continued for another 10 min. The mixture was heated at 100 C. for 6 h. After completion of the reaction (monitored by TLC, 30% ethyl acetate-hexane Rf=0.35), the mixture was cooled to room temperature and diluted with water. The product was extracted with ethyl acetate and the extracts were dried over anhydrous sodium sulfate, then concentrated The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with 20% ethyl acetate in hexanes to afford benzyl 2-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (6.0 g, 35%) as a light brown sticky mass. LCMS m/z=511.6 (M+1).
35%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 6h;Inert atmosphere;	Reaction Step 9 Synthesis of benzyl 2-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate To a mixture of <strong>[1003846-21-6]1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (14.2 g, 51.2 mmol, 1.5 eq), benzyl 2-((5-bromo-1H-indol-1-yl)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (15.0 g, 34.1 mmol, 1.0 eq) in DMF:water (4:1, 150 mL) at room temperature was added Cs2CO3 (22.0 g, 68.2 mmol, 2.0 eq) and the reaction mixture was purged with argon for 10 min. PdCl2(dppf)dichloromethane adduct (1.39 g, 0.17 mmol, 0.05 eq) was added to the reaction mixture and purging with argon was continued for another 10 min. The mixture was heated at 100 C. for 6 h. After completion of the reaction (monitored by TLC, 30% ethyl acetate-hexane, Rf=0.35), the mixture was cooled to room temperature and diluted with water. The aqueous mixture was extracted with ethyl acetate and the combined extracts were dried over anhydrous sodium sulfate, then concentrated The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with 20% ethyl acetate in hexanes to afford benzyl 2-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (6.0 g, 35%) as a light brown sticky mass. LCMS m/z=511.6 (M+1).

Reference： [1]Patent: US2015/252051,2015,A1 .Location in patent: Paragraph 0185; 0186
[2]Patent: US2016/24056,2016,A1 .Location in patent: Paragraph 0240

49
[ 1003846-21-6 ]
benzyl 3-((5-bromo-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate [ No CAS ]
benzyl 3-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 5h;Inert atmosphere;	Reaction step 3. Synthesis of benzyl 3-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate <strong>[1003846-21-6]1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (4.00 g, 14.5 mmol, 1.5 eq) was added to a solution of benzyl 4-((5-bromo-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate (4.00 g, 9.68 mmol, 1 eq) in DMF: H2O (10:1, 40 mL) at room temperature. Cesium carbonate (6.3 g, 19.36 mmol, 2 eq) was then added and the mixture was purged with argon. After 10 min, Pd(dppf)Cl)2 (0.79 g, 0.968 mmol, 0.1 eq) was added and the mixture was purged with argon for a further 10 min, after which period the mixture was heated to 80 C. for 5 h. After completion of the reaction (monitored by TLC, 50% ethyl acetate-hexane Rf=0.4), the reaction was cooled to room temperature and filtered through a bed of diatomaceous earth, washing the bed of diatomaceous earth with ethyl acetate. The combined filtrate and the washings were washed with water followed by brine and dried over anhydrous sodium sulfate. Removal of the solvents under reduced pressure gave a crude product that was purified by chromatography on neutral alumina, eluting with 0-20% gradient of ethyl acetate in hexanes to afford benzyl 3-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate as brown sticky solid. Yield=2.82 g; 60%; LCMS m/z=485 (M+1; purity=91%.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 6h;Inert atmosphere;	Reaction step 3. Synthesis of benzyl 3-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate A mixture of <strong>[1003846-21-6]1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (10.0 g, 36.3 mmol), benzyl 3-((5-bromo-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate (10.00 g, 24.2 mmol) and potassium carbonate (6.70 g, 48.4 mmol, 2 eq) in a mixture of DMF and water (9:1, 100 mL) at room temperature was purged with argon for 10 min. PdCl2(dppf)·dichloromethane (2.0 g, 2.4 mmol, 0.1 eq) was added and argon was passed through the solution for a further 10 min. The mixture was heated at 80 C. for 6 h. After completion of the reaction (monitored by TLC, 30% ethyl acetate-hexanes Rf=0.40), the reaction mixture was cooled to room temperature and filtered through a bed of diatomaceous earth washing with ethyl acetate. The mixture of filtrate and washings was washed with water followed by brine, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on neutral alumina, eluting with a 50-55% gradient of ethyl acetate in hexanes to afford benzyl 3-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate (6.20 g, 53%) as a colorless sticky mass. LCMS purity: 90.6%; (ES+): m/z 485.21 (M+H+); tr=2.34 min.
2.82 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 5h;Inert atmosphere;	Reaction Step 3 Synthesis of benzyl 3-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate <strong>[1003846-21-6]1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (4.00 g, 14.5 mmol, 1.5 eq) was added to a solution of benzyl 4-((5-bromo-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate (4.00 g, 9.68 mmol, 1 eq) in DMF: H2O (10:1, 40 mL) at room temperature. Cesium carbonate (6.3 g, 19.4 mmol, 2 eq) was then added and the mixture was purged with argon. After 10 min, Pd(dppf)Cl)2 (0.79 g, 0.968 mmol, 0.1 eq) was added and the mixture was purged with argon for a further 10 min, after which period the mixture was heated to 80 C. for 5 h. After completion of the reaction (monitored by TLC, 50% ethyl acetate-hexane, Rf=0.4), the reaction mixture was cooled to room temperature and filtered through a bed of diatomaceous earth, washing with ethyl acetate. The combined filtrate was washed with water followed by brine and dried over anhydrous sodium sulfate. Removal of the solvents under reduced pressure gave a crude product that was purified by chromatography on neutral alumina, eluting with a 0-20% gradient of ethyl acetate in hexanes to afford benzyl 3-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate as a brown sticky solid. Yield=2.82 g; 60%; LCMS m/z=485 (M+1; purity=91%.

Reference： [1]Patent: US2015/252022,2015,A1 .Location in patent: Paragraph 0273
[2]Patent: US2015/252022,2015,A1 .Location in patent: Paragraph 0324; 0327
[3]Patent: US2016/24056,2016,A1 .Location in patent: Paragraph 0205

50
[ 1003846-21-6 ]
benzyl 4-((5-bromo-1H-indol-1-yl)methyl)piperidine-1-carboxylate [ No CAS ]
benzyl 4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-indol-1-yl)methyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 6h;Inert atmosphere;	Reaction step 3. Synthesis of 1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indole 1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (117 g, 421 mmol, 1.5 eq) was added to a solution of benzyl 4-((5-bromo-1H-indol-1-yl)methyl)piperidine-1-carboxylate (120 g, 281.0 mmol, 1.0 eq) in a mixture of DMF and water (9:1, 1200 mL) at room temperature. Potassium carbonate (77.0 g, 562 mmol, 2 eq) was then added and the reaction mixture was purged with argon for 20 min. PdCl2(dppf)*dichloromethane (23.0 g, 28.1 mmol, 0.1 eq) was added, argon was passed through the solution for a further 10 min and the mixture was heated at 80 C. for 6 h. After completion of the reaction (monitored by TLC, 50% ethyl acetate-hexanes Rf=0.40), the reaction mixture was cooled to room temperature and filtered through a bed of diatomaceous earth. The bed of diatomaceous earth was washed with ethyl acetate and the washings were mixed with the filtrate. The mixture of filtrate and washings was washed with water followed by brine, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography over neutral alumina, eluting with a 40-50% gradient of ethyl acetate in hexanes to afford benzyl 4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-indol-1-yl)methyl)piperidine-1-carboxylate (80.0 g, 57%) as colorless oil. LCMS purity: 86.4%; (ES+): m/z 499.5 (M+H+); tr=2.42 min.

Reference： [1]Patent: US2015/252022,2015,A1 .Location in patent: Paragraph 0298

51
[ 1003846-21-6 ]
benzyl 4-((5-bromo-1H-indol-1-yl)methyl)azepane-1-carboxylate [ No CAS ]
benzyl 4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)azepane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 5h;Inert atmosphere;	Reaction step 7. Synthesis of benzyl 4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)azepane-1-carboxylate To a solution of benzyl 4-((5-bromo-1H-indol-1-yl)methyl)azepane-1-carboxylate (2.00 g, 4.54 mmol, 1.0 eq) in DMF: water (10:1, 20 mL) at room temperature was added <strong>[1003846-21-6]1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (1.50 g, 5.44 mmol, 1.5 eq) and Cs2CO3 (3.0 g, 9.1 mmol, 2.0 eq). The mixture was purged with argon for 10 min and Pd(dppf)Cl2.CH2Cl2 (0.370 g, 0.454 mmol, 0.1 eq) was added to the reaction mixture followed by purging with argon for another 10 min. The resulting reaction mixture was heated at 90 C. for 5 h. After completion of the reaction (monitored by TLC, 30% ethyl acetate-hexane Rf=0.35), the reaction mixture was allowed to cool and was poured into ice-cold water. The mixture was extracted with ethyl acetate and the organic phase was washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with a 0-20% gradient of ethyl acetate in hexanes to afford benzyl 4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)azepane-1-carboxylate (1.50 g, 60%) as an off white solid. LCMS m/z=513.6 (M+1); purity=85%.
1.5 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 5h;Inert atmosphere;	Reaction Step 7 Synthesis of benzyl 4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)azepane-1-carboxylate To a solution of benzyl 4-((5-bromo-1H-indol-1-yl)methyl)azepane-1-carboxylate (2.00 g, 4.54 mmol, 1.0 eq) in DMF:water (10:1, 20 mL) at room temperature was added <strong>[1003846-21-6]1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (1.50 g, 5.44 mmol, 1.5 eq) and Cs2CO3 (3.0 g, 9.1 mmol, 2.0 eq). The mixture was purged with argon for 10 min and Pd(dppf)Cl2.CH2Cl2 (0.370 g, 0.454 mmol, 0.1 eq) was added to the reaction mixture followed by purging with argon for another 10 min. The resulting reaction mixture was heated at 90 C. for 5 h. After completion of the reaction (monitored by TLC, 30% ethyl acetate-hexane Rf=0.35), the reaction mixture was allowed to cool and was poured into ice-cold water. The mixture was extracted with ethyl acetate and the organic phase was washed with water followed by brine. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with a 0-20% gradient of ethyl acetate in hexanes to afford benzyl 4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)azepane-1-carboxylate (1.50 g, 60%) as an off white solid. LCMS m/z=513.6 (M+1); purity=85%.

Reference： [1]Patent: US2015/252022,2015,A1 .Location in patent: Paragraph 0313
[2]Patent: US2016/24056,2016,A1 .Location in patent: Paragraph 0227

52
[ 1003846-21-6 ]
benzyl 4-((6-bromo-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidine-1-carboxylate [ No CAS ]
benzyl 4-((6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.5 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere;	Reaction step 4: Synthesis of benzyl 4-((6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidine-1-carboxylate To a stirred solution of <strong>[1003846-21-6]1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (7.5 g, 27.1 mmol, 1.5 eq) and benzyl 4-((6-bromo-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidine-1-carboxylate (8.0 g, 18 mmol, 1.0 eq) in a mixture of DMF and water (9:1, 100 mL) potassium carbonate (4.9 g, 36.1 mmol, 2.0 eq) was added and the mixture was purged with argon for 20 min. PdCl2(dppf)·dichloromethane (2.6 g, 3.26 mmol, 0.1 eq) was added, purging with argon was continued for a further 10 min and the mixture was then heated at 90 C. for 12 h. After completion of reaction (monitored by TLC, 30% ethyl acetate-hexane Rf=0.30), the mixture was cooled to room temperature and poured into ice cold water. The aqueous mixture was extracted with ethyl acetate, the extract was washed with water followed by brine and was dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on neutral alumina, eluting with a 20-30% gradient of ethyl acetate in hexanes to afford benzyl 4-((6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidine-1-carboxylate (1.5 g, 16%) as a colourless viscous liquid LCMS: purity 97.1%; (ES+): m/z 515.34 (M+H+); tr=2.57 min.
1.5 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere;	Reaction Step 4 Synthesis of benzyl 4-((6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidine-1-carboxylate To a stirred solution of <strong>[1003846-21-6]1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (7.5 g, 27.1 mmol, 1.5 eq) and benzyl 4-((6-bromo-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidine-1-carboxylate (8.0 g, 18 mmol, 1.0 eq) in a mixture of DMF and water (9:1, 100 mL). Potassium carbonate (4.9 g, 36.1 mmol, 2.0 eq) was added and the mixture was purged with argon for 20 min. PdCl2(dppf).dichloromethane (2.6 g, 3.26 mmol, 0.1 eq) was added, purging with argon continued for a further 10 min and the mixture was then heated at 90 C. for 12 h. After completion of the reaction (monitored by TLC, 30% ethyl acetate-hexane, Rf=0.30), the mixture was cooled to room temperature and poured into ice cold water. The aqueous mixture was extracted with ethyl acetate, the extract was washed with water followed by brine and was dried over anhydrous sodium sulfate The solution was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on neutral alumina, eluting with a 20-30% gradient of ethyl acetate in hexanes to afford benzyl 4-((6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidine-1-carboxylate (1.5 g, 16%) as a colourless viscous liquid LCMS: purity 97.1%; (ES+): m/z 515.34 (M+H+); tr=2.57 min.

Reference： [1]Patent: US2015/252022,2015,A1 .Location in patent: Paragraph 0377
[2]Patent: US2016/24056,2016,A1 .Location in patent: Paragraph 0246

53
[ 1003846-21-6 ]
N-benzyl-3-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxamide [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

54
[ 1003846-21-6 ]
N-isobutyl-3-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxamide [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

55
[ 1003846-21-6 ]
isobutyl 3-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2015/252022,2015,A1

56
[ 16234-14-3 ]
[ 1003846-21-6 ]
C₁₄H₁₃ClN₄OS [ No CAS ]