[ CAS No. 761446-44-0 ] {[proInfo.proName]}

Name: 761446-44-0|1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole|98%
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SKU: A909767
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Quality Control of [ 761446-44-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 761446-44-0 ]

CAS No. :	761446-44-0	MDL No. :	MFCD03789259
Formula :	C₁₀H₁₇BN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UCNGGGYMLHAMJG-UHFFFAOYSA-N
M.W :	208.07	Pubchem ID :	2773987
Synonyms :		Chemical Name :	1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Calculated chemistry of [ 761446-44-0 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.7
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	59.96
TPSA :	36.28 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 :	No
Log Kp (skin permeation) :	-6.7 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.22
Log Po/w (WLOGP) :	0.72
Log Po/w (MLOGP) :	0.3
Log Po/w (SILICOS-IT) :	0.29
Consensus Log Po/w :	0.51

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.08
Solubility :	1.73 mg/ml ; 0.00833 mol/l
Class :	Soluble
Log S (Ali) :	-1.58
Solubility :	5.48 mg/ml ; 0.0264 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.4
Solubility :	0.823 mg/ml ; 0.00395 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.81

Safety of [ 761446-44-0 ]

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 [ 761446-44-0 ]

* 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 [ 761446-44-0 ]
Downstream synthetic route of [ 761446-44-0 ]

[ 761446-44-0 ] Synthesis Path-Upstream 1~14

1
[ 761446-44-0 ]
[ 78242-20-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	With dihydrogen peroxide; sodium hydroxide In tetrahydrofuran at 0 - 25℃; for 3 h; Inert atmosphere	General procedure: To a cold (0 °C, ice bath) solution of 1-alkyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.0 g, 120.2 mmol) in tetrahydrofuran (600.9 mL, 0.2 M) was slowly added aqueous sodium hydroxide (80.1 mL, 3 M, 240.3 mmol) followed by Hydrogen peroxide (27.3 mL, 240.3 mmol). The reaction mixture was stirred at 0-25 °C for 3 h. The mixture was carefully neutralized with 12N HCl (18.6 mL) and diluted with a mixture of dichloromethane and methanol (90:10, 200 mL). The aqueous layer was extracted with a mixture of dichloromethane and methanol (90:10, 3*200 mL). The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by column chromatography to afford 1-alkyl-1H-pyrazol-4-ol 12.

Reference： [1] Tetrahedron Letters, 2017, vol. 58, # 49, p. 4587 - 4590
[2] Patent: WO2016/11930, 2016, A1, . Location in patent: Page/Page column 138
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1370 - 1387

2
[ 269410-08-4 ]
[ 74-88-4 ]
[ 761446-44-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium hydride In tetrahydrofuran at 0 - 20℃; for 4 h;	To the solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.40 g, 2.06 mmol) in THF (10 mL) was added NaH (0.1.00 g, 4.12 mmol) followed by methyl iodide (0.25 mL, 4.12 mmol) at 0° C and the reaction mixture was stirred at ambient temperature for 4 hr. The reaction was quenched with saturated NH₄Cl solution (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and distilled under reduced pressure to obtain Intermediate 108 (0.40 g, 93.00percent) as yellow viscous liquid.¹H NMR (400 MHz, CDCl3) δ ppm 1.31 (s, 12 H), 3.91 (s, 3 H), 7.65 (s, 1 H), 7.77 (s, 1 H). LCMS (Method-D): retention time 1.58 min, [M+1] 209.1.
90%	With sodium hydride In tetrahydrofuran at 20℃;	To the solution of 4-pinacolatoboron-lH-pyrazole (1.0 g, 5.0 mmol) in THF (30 mL) was added NaH (0.4 g, 10 mmol). After addition of NaH was completed, to the reaction mixture was added CH₃I (1.42 g, 10 mmol) and stirred overnight at room temperature. The reaction was quenched <n="139"/>with MeOH (1 mL). The result mixture was concentrated to give residues, purification by chromatography (EA:PE=l : 10) to give compound l-methyl-4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole (0.9 g, 90percent) as light yellow solid. MS (m/z) (M⁺+Η): 209
72%	With caesium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 3 h;	To a solution of 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H- pyrazole (0. 19g, 1.0 mmol) in 4 ml DMF was added Mel (0. 067 ml, 1.1 eq) and Cs2C03 (0.39g, 1.2 eq). The reaction mixture was stirred at RT for 3h. The solution was taken up into EtOAc, washed with water, brine, dried over Na2SO4 and concentrated. 150mg crude product was obtained (yield 72percent).

Reference： [1] Patent: WO2018/93569, 2018, A1, . Location in patent: Page/Page column 189
[2] Patent: WO2009/155527, 2009, A2, . Location in patent: Page/Page column 137-138
[3] Patent: WO2005/85227, 2005, A1, . Location in patent: Page/Page column 90-91

3
[ 15803-02-8 ]
[ 73183-34-3 ]
[ 761446-44-0 ]

Yield	Reaction Conditions	Operation in experiment
27.1%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 5 h; Inert atmosphere	A suspension of 4-bromo-l -methyl- lH-pyrazole (2 g, 12.42 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (3.47 g, 13.66 mmol), KOAc (2.438 g, 24.84 mmol), PdCl₂(dppf) (0.909 g, 1.242 mmol) in 1,4-dioxane (20 mL) was heated to 100 °C for 5 h under N₂ atmosphere. The mixture was concentrated to give the residue which was extracted with DCM (15 mL x 2). The organic extract was washed with brine (20 mL ), dried over Na₂S0₄, filtered and concentrated, and then the crude product was purified by silica column chromatography (10percent EA: 90percent Petroleum ether, 4 g silica column). All fractions found to contain product by TLC (EA : Petroleum ether = 1 : 1, R_f = 0.3) were combined and concentrated to yield a yellow solid of 1- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (700 mg, 3.36 mmol, 27.1percent yield): NMR (400 MHz, CDC1₃) δ 7.77 (s, 1H), 7.66 (s, 1H), 3.92 (s, 3H), 1.32 (s, 12H). ES- LCMS m/z 209 (M+H).

Reference： [1] Patent: WO2014/141187, 2014, A1, . Location in patent: Page/Page column 163
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 12, p. 5053 - 5074

4
[ 39806-90-1 ]
[ 61676-62-8 ]
[ 761446-44-0 ]

Yield	Reaction Conditions	Operation in experiment
1 g	Stage #1: With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere Stage #2: at 0 - 20℃; for 1.5 h;	To 1-methyl-4-iodopyrazole (1.0 g) and 10 mL of THF,Under the protection of nitrogen, slowly add isopropylmagnesium chloride/lithium chloride solution (3.97mL), the temperature during the dropwise addition does not exceed 0 °C,After the addition, stir for 1 h, then at 0 ° C,Slowly add isopropyl pinacol borate (1.11g) to control the temperature not to exceed 0 ° C, and then stir at room temperature for 1.5 h after the addition.After the reaction was completed, 10 mL of a saturated ammonium chloride solution was added dropwise.Quenched.Then add 50 mL of ethyl acetate and 10 mL of saturated ammonium chloride solution.The organic layer was separated, and the aqueous layer was extracted twice with 50 mL of ethyl acetate. The organic layer was combined and dried over anhydrous Na2SO?Dry under reduced pressure,The title product (1 g) was obtained.

Reference： [1] Patent: CN108484609, 2018, A, . Location in patent: Paragraph 0155; 0156; 0157; 0159

5
[ 76-09-5 ]
[ 847818-55-7 ]
[ 761446-44-0 ]

Reference： [1] Journal of Heterocyclic Chemistry, 2004, vol. 41, # 6, p. 931 - 939

6
[ 930-36-9 ]
[ 76-09-5 ]
[ 761446-44-0 ]

Reference： [1] Organic Process Research and Development, 2010, vol. 14, # 4, p. 849 - 858

7
[ 76-09-5 ]
[ 22038-72-8 ]
[ 761446-44-0 ]

Reference： [1] Patent: CN105440067, 2016, A, . Location in patent: Paragraph 0016

8
[ 35852-81-4 ]
[ 73183-34-3 ]
[ 761446-44-0 ]

Reference： [1] RSC Advances, 2018, vol. 8, # 25, p. 13643 - 13648

9
[ 269410-08-4 ]
[ 74-83-9 ]
[ 761446-44-0 ]

Reference： [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 24, p. 7934 - 7937

10
[ 135034-10-5 ]
[ 761446-44-0 ]
[ 943541-20-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium phosphate; N-benzyl-N,N,N-triethylammonium chloride; triphenylphosphine In tetrahydrofuran; water at 65℃; for 16 h;	Step 5: 3-chloro-6-(1-methyl-1/-/-pyrazol-4-yl)pyridazineWater (253 mL) and THF (842 mL) were put in the reaction balloon. The reagents were added one by one to the stirred reaction mixture: potassium phosphate monohydrate 86,2 g (374 mmol) and BTEAC 2,25g (9,88 mmol). Then 3-chloro-6-iodopyhdazine, 45 g (187,2 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole, 46,73g(224,6 mmol) were added and finally triphenylphosphine, 1 ,96g (7,49 mmol) and palladiumdiacetate, 420 mg (1 ,87 mmol) were added. The reaction mixture was heated at 65°C for 16h . The reaction mixture was allowed to cool to 60⁰C. Then 935 mL water and301 , 5g sodium chloride were added. The mixture was stirred for 15 minutes and allowed <n="74"/>to cool to 45⁰C. The phases were separated and the organic layer was washed with a solution of 45 g sodium chloride in 374 mL water. The organic layer was separated and stirred with magnesium sulphate (225 g) and charcoal (4,5 g). The mixture was filtered and evaporated. The evaporation residue was co-evaporated with toluene twice and evaporated further till a final volume of 200 ml. This residue was stirred for 16 h at room temperature. The resulting solids were collected by filtration. The solids were dried at reduced pressure affording 29,7 g of the title compound (152,6 mmol, yield 82percent).1 H NMR (600 MHz, CHLOROFORM-c/) δ ppm 4.00 (s, 3 H) 7.46 (d, J=8.69 Hz, 1 H) 7.56 (d, J=9.06 Hz, 1 H) 7.98 (s, 1 H) 8.11 (s, 1 H)

Reference： [1] Patent: WO2008/155378, 2008, A1, . Location in patent: Page/Page column 72-73
[2] Patent: US2011/92498, 2011, A1, . Location in patent: Page/Page column 19
[3] Patent: US2011/257181, 2011, A1, . Location in patent: Page/Page column 21

11
[ 141-30-0 ]
[ 761446-44-0 ]
[ 943541-20-6 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate In 1,4-dioxane; water at 80℃; for 4 h;	Example 2 : 6-(l-methyI-li/-pyrazol-4-yl)-[l ,2,4] triazolo [4,3-6] pyridazine-3-thiol; Step 1: 3-Chloro-6-(l-methyl-lH^r-pyrazol-4-yl)-pyridazine; [0345] A mixture of 3,6-dichloropyridazine (20. Ig, 135 mmol), l-methyl-4- pyrazoleboronic acid pinacol ester (22.46 g, 108 mmol) and K₂CO₃ (44.71 g, 324 mmol) in 50OmL of dioxane and 20OmL of H₂O was degassed with nitrogen. To this mixture was added dichloro[l,l '-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (5.28 g, 7.2 mmol) and the resulting mixture was bubbled with nitrogen for another 20 min. The reaction mixture was heated at 8O⁰C for 4h, then concentrated in vacuo. The residue was purified by flash column chromatography with dichloromethane as eluent to provide 21g of 3-chloro-6-(l-methyl-lH-pyrazol-4-yl)-pyridazine (76percent yield): ¹H NMR(CDCl₃) δ 3.99 (s, 3H), 7.45 (d, IH), 7.56 (d, IH), 7.97 (s, IH), 8.11 (s, IH).
75%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ In 1,4-dioxane; water at 90℃; for 5 h;	To a solution of 3,6-dichloropyridazine (500 mg, 3.4 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (560 mg, 2.7 mmol), K2CO3 (1.1 g, 8.1 mmol) in 1,4-dioxane/H2O (2.5:1, 5 mL) was added PdCl2(dppf)2. After stirred at 90 °C for 5 h, the reaction mixture was was extracted with CH2Cl2 (40 mL), and the organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2) afforded 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (494 mg, 75 percent). 3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (1a) ¹HNMR (300 MHz, CDCl3) δ 8.20 (d, J = 7.4 Hz, 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 3.95 (s, 3H).
68%	With sodium carbonate In 1,4-dioxane; water at 80℃;	A flask was charged with 3,6-dichloropyridazine (AJdrich, 23.91 g, 160.5 mmol), l-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2idioxaborolan-2-yl)-lH-pyrazole (20 g, 96 mmol), 2.0 M Na₂Cψ₃ (96 mL) and dioxane (65 mL). Nitrogen was bubbled through the reaction for 60 seconds followed by the addition of Dichlorobis(triphenylphosphine)palladium (0) (6.75 g, 9.6 mmol). The reaction was heated to 80⁰C overnight followed by aqueous work up using AcOEt and a solution of K₂CO₃. After filtration over celite, the organic layer was dried (MgSO₄) and concentrated in vacuo. A first fraction of compound (10.2g) was obtained by crystallization in the solvent (dichoromethane). The filtrate was purified by column chromatography (CH₂Cl₂ 100percent and CH₂Cl₂ZMeOH : 95/5) . The two fractions were gathered and washed with diisopropylether to give the title compound as a yellow solid (12.7 g, 68 percent).

63.1%	With potassium carbonate In 1,4-dioxane; water at 80℃; for 16.3 h; Inert atmosphere	Preparation 1 3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine To a 3000 mL round bottom flask containing a solution of 1-methyl-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (76 g, 365.3 mmol), 3,6-dichloropyridazine (68 g, 456.4 mmol) in 1,4-dioxane (1200 mL) is added a aqueous solution of K₂CO₃ (127 g, 919 mmol) in water (480 mL). After [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (7.5 g, 9.2 mmol) is added, the mixture is purged with N₂ for 20 min and stirred at 80° C. for 16 h. The reaction mixture is poured into water (300 mL) and dichloromethane (2000 mL), and the aqueous layer is extracted with DCM (3*800 mL). The combined organic layers are dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product is purified with silica gel column eluting with DCM/methanol (40:1) to give the title compound as a pale yellow solid (56 g, 63.1percent). MS (m/z): 195.1 (M+H).
47%	With sodium carbonate In 1,4-dioxane; water at 80℃;	A flask was charged with 3,6-dichloropyridzine (Aldrich, 297 mg, 2.0 mmol), l-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (499 mg, 2.4 mmol), 2 M Na₂COs (4 mL) and dioxane (4 mL). Argon was bubbled through the reaction for 60 seconds followed by the addition ofTetrakis(triphenylphosphine)palladium (0) (231 mg, 0.2 mmol). The reaction was heated to 80 ⁰C overnight followed by aqueous work up using EtOAc and brine. The organic layer was dried (MgSO₄) and concentrated in vacuo followed by column chromatography purification (20 percent Ethyl Acetate in Hexanes) resulting in the title compound as a white solid (183 mg, 47 percent). ¹H-NMR (CD₃OD): δ 8.23 (IH, s), 8.08 (IH, s), 7.84 (IH, br s), 7.34 (IH, br s), 4.00 (3H, s).
44%	Stage #1: With sodium hydrogencarbonate In 1,4-dioxane for 0.0166667 h; Stage #2: With bis-triphenylphosphine-palladium(II) chloride In 1,4-dioxane at 80℃; for 15 h;	A solution of 3,6-dichloropyridazine (4.57 g, 0.003 1 mol), (1-methyl-1H-pyrazol-4- yl)boronic acid pinacol ester (3.82 g, 0.0 184 mol) and a solution ofNa2CO3 2M (18.3 mL) in dioxane (18.4 mL) was stirred for 1 minute. PdC12(PPh3)2 (1.29 g, 0.0018 mol) was added and the solution was heated at 80°C for 15 hours. The mixture was cooled to room temperature and poured into water. K2C03 was added and the mixture wasfiltered through a short pad of Celite®. The organic layer was dried (Mg504), filtered and evaporated to dryness. The Celite® was washed with CH2C12, the filtrate was dried (Mg504) and evaporated. The residue was crystallized from CH2C12. The precipitate was filtered and dried to give 1.5 g of a first batch of intermediate 5 (42percent). The filtrate was purified by chromatography over silica gel (30 g of SiOHl5-40jim,mobile phase : gradient from CH2C12 100percent to CH2C12 95percent/CH3OH 5percent). The pure fractions were collected and evaporated until dryness to give 1.58 g of a second batch of intermediate 5 (44percent)

Reference： [1] Patent: WO2008/51808, 2008, A2, . Location in patent: Page/Page column 96
[2] Archives of Pharmacal Research, 2016, vol. 39, # 4, p. 453 - 464
[3] Patent: WO2007/75567, 2007, A1, . Location in patent: Page/Page column 119
[4] Patent: US2012/28984, 2012, A1, . Location in patent: Page/Page column 2
[5] Patent: WO2007/75567, 2007, A1, . Location in patent: Page/Page column 69
[6] Patent: WO2016/87586, 2016, A1, . Location in patent: Page/Page column 17; 18
[7] Patent: WO2013/85957, 2013, A1, . Location in patent: Page/Page column 55

12
[ 89402-43-7 ]
[ 761446-44-0 ]
[ 1151801-90-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl][2-(2-aminoethyl)phenyl]palladium(ll); tetrabutylammomium bromide In 2-methyltetrahydrofuran at 70℃; Inert atmosphere	[00316] 3-fluoro-2-hydrazinyl-5- (i-methyl-i H-pyrazol-4-yl)-pyridine was synthesized according to Scheme 14 by the following procedure. A 60 L jacketed reactor was fitted with a 5 L addition funnel and the jacket temperature was set to 20±5 °C. 36.0 L (15 Vol) of 2- methyltetrahydrofuran was added to the reactor via a 20 tm inline filter with vacuum using polypropylene transfer lines. The solution was sparged by bubbling nitrogen through a dipstick in the solution for 1±0.5 h with agitation. After 1 h the dipstick was removed but the nitrogen sweep continued. 1.55 kg of sparged 2-MeTHF was removed to be used as rinse volumes. 36.7 g of Pd2dba3, 75.6 g X-Phos, 259 g of tetrabutylammonium bromide, and 7397 g of potassium phosphate tribasic were added to the reactor. The manhole was rinsed with 0.125 kg of sparged 2-MeTHF. The reactor was agitated and the nitrogen sweep continued for 1±0.5 h. Then the nitrogen sweep was stopped and the reaction left under a positive pressure of nitrogen.[00317] 3.6 L (1.5 Vol) of sparged water was prepared in advance by bubbling nitrogen through a 4 L bottle of water for 1±0.5 h. The nitrogen sparged water was transferred to the 5 L addition funnel via a 20 tm inline filter with vacuum using polypropylene transfer lines, then slowly added to the reaction while maintaining the internal temperature at 20±5 °C. The 5 L addition funnel was replaced with a 2 L addition funnel. 2412 g of 5-chloro-2,3-difluoropyridine was added to the 2 L addition funnel. The 5-chloro-2,3-difluoropyridine was then added to the reaction through the 2 L addition funnel. The 2L addition funnel was rinsed with 0.060 kg of sparged 2-MeTHF. 83.8 g (1.15 equivalents) of 1-methylpyrazole-4-boronic acid, pinacol ester was added to reactor, the reactor was swept with nitrogen for 1±0.5 h, then left under a positive pressure of nitrogen. The internal temperature of the reactor was adjusted to 70±5 °C. The batch was agitated at 70±5 °C for at least 4 hours after the final reagent was added. A sample was taken from the reaction and the reaction progress assayed for conversion. The progress of the reaction was checked every 2 hours until the reaction was completed (e.g., greater than 99percent conversion). The batch was cooled to 20±5 °C.[00318] A 20percent w/v sodium bisulfite solution (12.0 L, 5 Vol) was prepared by charging 12.0 L of water then 2411 g sodium bisulfite to an appropriate container and agitating until homogeneous. The 20percent sodium bisulfite solution was transferred into the reactor and agitated for 30 minutes. The agitation was stopped, the phases allowed to settle, and the aqueous phase was removed. A 0.5 M potassium fluoride solution (12.0 L, 5 Vol) was prepared by charging 12.0 L of water and 348 g of potassium fluoride to an appropriate container and agitating until homogenous. The 0.5 M potassium fluoride solution was transfened into the reactor and agitated for 30 mm. The agitation was stopped, the phases were allowed to settle, and the aqueous phase was removed. A 25percent w/v sodium chloride solution (12.0 L, 5 Vol) was prepared by charging an appropriate container with 12.0 L of water and 2999 g of sodium chloride and agitating until homogeneous. The 25percent sodium chloride solution was transferred into the reactor and agitated for 30 mm. The agitation was stopped, the phases were allowed to settle, and the aqueous phase was removed from the reactor.[00319] The organic phase was distilled at constant volume (36 L, 15 Vol) while maintaining the internal temperature of the reactor at 50±5 °C by adjusting the vacuum pressure until no more than 0.3percent of water remained. 2-Methyltetrahydrofuran was added to the reactor as needed to maintain constant volume. The batch was cooled to 20 °C and transferred into drums. The batch was transfeffed using a polish filter (using a 5 tm inline filter) into a 60 L jacketed reactor withbatched concentrator attached. 1.2 L of 2-MeTHF was used to rinse the drums. The batch was concentrated to about 9 Vol while maintaining the internal temperature of the vessel at 50±5adjusting the vacuum pressure. The batch was then distilled at constant volume (22.0 L, 9Vol) while maintaining the internal temperature of the vessel at 50±5 °C by adjusting the vacuum pressure. Heptane was added with residual vacuum until a 15percent 2-MeTHF:heptane supernatant mixture was obtained. The pressure was brought to atmospheric pressure under nitrogen. The reactor was cooled to 20±5 °C over 2±2 h. The batch was agitated at 20±5 °C until an assay of the supernatant indicated that the amount of product was 7 mg/mL 2,3-difluoro-1-methyl-i H-pyrazol-4-yl)pyridine.[00320] A 10percent 2-MeTHF:heptane (7.2 L, 3 Vol) wash solution was prepared by mixing 720 mL of 2-MeTHF and 6.5 L of heptane. The batch sluffy was filtered through an Aurora filter fitted with a 25 tm polypropylene filter cloth, resulting in heavy crystals that required pumping with a diaphragm pump using polypropylene transfer lines through the top of the reactor while stirring. The mother liquor was recycled to complete the transfer. The reactor and filter cake were washed with two portions of the 10percent 2-MeTHF:heptane wash solution (3.6 L each). The product cake was dried on a frit under a nitrogen stream at ambient temperature. The 2,3- difluoro-5-(i-methyl-1H-pyrazol-4-yl)pyridine was detennined to be dry when the ‘H NMR assay was 0.05±0.05. 2.635 kg was isolated as an off white crystalline solid (85percent yield).

Reference： [1] Patent: WO2014/210042, 2014, A2, . Location in patent: Paragraph 00316-00320
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2328 - 2342

13
[ 761446-44-0 ]
[ 1151801-90-9 ]

Yield	Reaction Conditions	Operation in experiment
57.4%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In N,N-dimethyl-formamide at 80℃; for 10.16 h; Inert atmosphere	A mixture of 5-bromo-2,3-difluoropyridine (1.9 g, 9.79 mmol) and 1-methyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (2.038 g, 9.79 mmol), Na₂C0₃ (2.076 g, 19.59 mmol) and Pd(PPh₃)₄ (1 .131 g, 0.979 mmol) in DMF (8 ml) was bubbled with N₂ for 10 min and was then heated to 80°C for 10 h. After being cooled to rt, the mixture was filtered and the filtrate was diluted with EA,washed with water and brine, dried over anhydrous MgS0₄. Filtered and concentrated. The residue was purified by silica gel chromatography eluted with Hex/EA (from 100percent to 20percent) to afford the title compound as a white solid (1 .5 g, 57.4percent yield). ¹ H-NMR (400 MHz, DMSO-d₆) δ ppm 8.29 (d, 3H), 7.99 (d, 1 H), 3.87 (s, 3H). LCMS (method B): [M+H]⁺ = 196, t_R = 1 .91 min.
57.4%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In N,N-dimethyl-formamide at 80℃; for 10 h; Inert atmosphere	A mixture of 5-bromo-2,3-difluoropyridine (1.9 g, 9.79 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole (2.038 g, 9.79 mmol), Na₂CO₃(2.076 g, 19.59 mmol) and Pd(PPh₃)₄(1.131 g, 0.979 mmol) in DMF (8 ml) was bubbled with N₂for 10 min and was then heated to 80° C. for 10 h. After being cooled to rt, the mixture was filtered and the filtrate was diluted with EA, washed with water and brine, dried over anhydrous MgSO₄. Filtered and concentrated. The residue was purified by silica gel chromatography eluted with Hex/EA (from 100percent to 20percent) to afford the title compound as a white solid (1.5 g, 57.4percent yield). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.29 (d, 3H), 7.99 (d, 1H), 3.87 (s, 3H). LCMS (method B): [M+H]⁺=196, t_R=1.91 min.

Reference： [1] Patent: WO2013/38362, 2013, A1, . Location in patent: Page/Page column 78; 79
[2] Patent: US2013/245002, 2013, A1, . Location in patent: Paragraph 0719

14
[ 106-37-6 ]
[ 761446-44-0 ]
[ 1191616-45-1 ]

Yield	Reaction Conditions	Operation in experiment
75%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,4-dioxane; water at 80℃; for 3 h; Inert atmosphere	Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 1-methyl-4-(tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (2.00 g, 9.61 mmol), 1 ,4-dibromobenzene (2.30 g, 9.75 mmol), Pd(PPh3)4 (550 mg, 0.48 mmol), potassium carbonate (2.60 g, 18.8 mmol), dioxane (40 ml_) and water (10 ml_). The resulting solution was stirred for 3 h at 80°C. The resulting mixture was evaporated to dryness. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 1.70 g (75percent) of 4-(4- bromophenyl)-1-methyl-1 H-pyrazole as a yellow solid.

Reference： [1] Patent: WO2016/41618, 2016, A1, . Location in patent: Page/Page column 69

[ 761446-44-0 ] Synthesis Path-Downstream 1~88

1
[ 872624-52-7 ]
[ 761446-44-0 ]
2-amino-5-(1-methyl-1H-pyrazol-4yl)-4-trifluoromethyl-benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate;triphenylphosphine; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 90℃; for 18h;	Example 31:; N-[6-(l-methyI-lH-pyrazol-4-yl)-2,4-dioxo-7-trifluoromethyI-l,4-dihydro-2H-quHiazoHn-3-yl]-methanesulfonamide; 2-Amino-5-(l-methyl-lH-pyrazol-4-yl)-4-trifluoromethyl-benzoic acid methyl ester; 2-Amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (300 mg, 0.87 mmol) and l-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)lH-pyrazole (181 mg, 1.0 equiv), K2CO3 ( 303 mg, 2.5 equiv.) and triphenylphosphine (45 mg. 0.2 equiv) were weighed in air and added in a flame-dried flask. Bis(dibenzylidenacetone)palladium (25 mg, 0.05 equiv) was added and the flask was closed by a septum. Dioxane (6 mL) was added and the mixture was stirred for 18 h (TLC control) at 900C. The catalyst was filtered off and washed with EtOAc, the filtrate was evaporated to dryness. The crude product was purified by column chromatography (silica gel 60, EtOAc/hexanes 1/3 to 1/2) to give 2-amino-5-(l- methyl-lEta-pyrazol-4yl)-4-trifluoromethyl-benzoic acid methyl ester (0.57 mmol, 66%) as a white solid. ESI-MS: m/z 300 [M+H]+, rt: 4.97min.

Reference： [1]Patent: WO2006/108591,2006,A1 .Location in patent: Page/Page column 95-96

2
[ 1013-83-8 ]
[ 761446-44-0 ]
[ 917909-70-7 ]

Yield	Reaction Conditions	Operation in experiment
59%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; for 22.0h;Heating / reflux;	A mixture of 5-bromo-2-:naphthoic acid (2,12g, 8.44mmol), 1-methyl-4-(4,4,5,5- tetramethy1-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.84g, 8.86mmol), and tetrakis(triphenylphosphine p)alladium (0) (502mg, 0.435mmol) in a 250mL round bottomed flask was evacuated and purged with nitrogen (in three cycles). Acetonitrile (40mL) and 2M aqueous sodium carbonate (10mL) were added to the mixture via syringe, and the mixture was heated under reflux under nitrogen for 22 hours. The reaction mixture was allowed to cool before the addition of IM aqueous hydrochloric acid (30mL) and it was then extracted with ethyl acetate (3 x 50mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo to provide a crude product (2.98g after air drying). This crude material was dissolved in hot ethanol (150mL) and filtered while hot to remove a yellow impurity (120mg). The filtrate was concentrated in vacuo and the residue was recrystallised from dichloromethane (30mL) to provide S-(1-methyl-1H-pyrazol-4-yl)-2-naphthoic acid as a white solid (724mg, 34percent). A second crop of 5-(1-methyil-1H-pyrazol-4-yl)-2-naphthoic acid (527mg, 25percent) was obtained from the concentrated mother liquors by recrystallisation from dichloromethane (2OmL).
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In acetonitrile; for 22.0h;Inert atmosphere; Reflux;	[0099] A mixture of <strong>[1013-83-8]5-bromo-2-naphthoic acid</strong> (2.12g, 8.44mmol), 1-methyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 7/-/-pyrazole (1.84g, 8.86mmol), and (0127) tetrakis(triphenylphosphine)palladium(0) (502mg, 0.435mmol) in a 250ml_ round bottomed flask was evacuated and purged with nitrogen (in three cycles). Acetonitrile (40ml_) and 2M aqueous sodium carbonate (10ml_) were added to the mixture via syringe, and the mixture was heated under reflux under nitrogen for 22 hours. The reaction mixture was allowed to cool before the addition of 1 M aqueous hydrochloric acid (30ml_) and it was then extracted with ethyl acetate (3 x 50ml_). The combined organic layers were dried (MgSCU), filtered, and concentrated in vacuo to provide a crude product (2.98g after air drying). This crude material was dissolved in hot ethanol (150ml_) and filtered while hot to remove a yellow impurity (120mg). The filtrate was concentrated in vacuo and the residue was recrystallised from dichloromethane (30ml_) to provide 5-(1-methyl-1 /--pyrazol-4-yl)-2-naphthoic acid as a white solid (724mg, 34percent). A second crop of 5-(1-methyl-1 /--pyrazol-4-yl)-2-naphthoic acid (527mg, 25percent) was obtained from the concentrated mother liquors by recrystallisation from (0128) dichloromethane (20ml_).

Reference： [1]Patent: WO2006/135978,2006,A1 .Location in patent: Page/Page column 26
[2]Patent: WO2018/145148,2018,A1 .Location in patent: Paragraph 0099

3
[ 141-30-0 ]
[ 761446-44-0 ]
[ 943541-20-6 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80℃; for 4h;	Example 2 : 6-(l-methyI-li/-pyrazol-4-yl)-[l ,2,4] triazolo [4,3-6] pyridazine-3-thiol; Step 1: 3-Chloro-6-(l-methyl-lHr-pyrazol-4-yl)-pyridazine; [0345] A mixture of 3,6-dichloropyridazine (20. Ig, 135 mmol), l-methyl-4- pyrazoleboronic acid pinacol ester (22.46 g, 108 mmol) and K2CO3 (44.71 g, 324 mmol) in 50OmL of dioxane and 20OmL of H2O was degassed with nitrogen. To this mixture was added dichloro[l,l '-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (5.28 g, 7.2 mmol) and the resulting mixture was bubbled with nitrogen for another 20 min. The reaction mixture was heated at 8O0C for 4h, then concentrated in vacuo. The residue was purified by flash column chromatography with dichloromethane as eluent to provide 21g of 3-chloro-6-(l-methyl-lH-pyrazol-4-yl)-pyridazine (76% yield): 1H NMR(CDCl3) delta 3.99 (s, 3H), 7.45 (d, IH), 7.56 (d, IH), 7.97 (s, IH), 8.11 (s, IH).
75%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 90℃; for 5h;	To a solution of 3,6-dichloropyridazine (500 mg, 3.4 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (560 mg, 2.7 mmol), K2CO3 (1.1 g, 8.1 mmol) in 1,4-dioxane/H2O (2.5:1, 5 mL) was added PdCl2(dppf)2. After stirred at 90 C for 5 h, the reaction mixture was was extracted with CH2Cl2 (40 mL), and the organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2) afforded 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (494 mg, 75 %). 3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (1a) 1HNMR (300 MHz, CDCl3) delta 8.20 (d, J = 7.4 Hz, 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 3.95 (s, 3H).
68%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 80℃;Product distribution / selectivity;	A flask was charged with 3,6-dichloropyridazine (AJdrich, 23.91 g, 160.5 mmol), l-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2idioxaborolan-2-yl)-lH-pyrazole (20 g, 96 mmol), 2.0 M Na2Ctheta3 (96 mL) and dioxane (65 mL). Nitrogen was bubbled through the reaction for 60 seconds followed by the addition of Dichlorobis(triphenylphosphine)palladium (0) (6.75 g, 9.6 mmol). The reaction was heated to 800C overnight followed by aqueous work up using AcOEt and a solution of K2CO3. After filtration over celite, the organic layer was dried (MgSO4) and concentrated in vacuo. A first fraction of compound (10.2g) was obtained by crystallization in the solvent (dichoromethane). The filtrate was purified by column chromatography (CH2Cl2 100% and CH2Cl2ZMeOH : 95/5) . The two fractions were gathered and washed with diisopropylether to give the title compound as a yellow solid (12.7 g, 68 %).

63.1%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80℃; for 16.3h;Inert atmosphere;	Preparation 1 3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine To a 3000 mL round bottom flask containing a solution of 1-methyl-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (76 g, 365.3 mmol), 3,6-dichloropyridazine (68 g, 456.4 mmol) in 1,4-dioxane (1200 mL) is added a aqueous solution of K2CO3 (127 g, 919 mmol) in water (480 mL). After [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (7.5 g, 9.2 mmol) is added, the mixture is purged with N2 for 20 min and stirred at 80 C. for 16 h. The reaction mixture is poured into water (300 mL) and dichloromethane (2000 mL), and the aqueous layer is extracted with DCM (3*800 mL). The combined organic layers are dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product is purified with silica gel column eluting with DCM/methanol (40:1) to give the title compound as a pale yellow solid (56 g, 63.1%). MS (m/z): 195.1 (M+H).
47%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃;Product distribution / selectivity;	A flask was charged with 3,6-dichloropyridzine (Aldrich, 297 mg, 2.0 mmol), l-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (499 mg, 2.4 mmol), 2 M Na2COs (4 mL) and dioxane (4 mL). Argon was bubbled through the reaction for 60 seconds followed by the addition ofTetrakis(triphenylphosphine)palladium (0) (231 mg, 0.2 mmol). The reaction was heated to 80 0C overnight followed by aqueous work up using EtOAc and brine. The organic layer was dried (MgSO4) and concentrated in vacuo followed by column chromatography purification (20 % Ethyl Acetate in Hexanes) resulting in the title compound as a white solid (183 mg, 47 %). 1H-NMR (CD3OD): delta 8.23 (IH, s), 8.08 (IH, s), 7.84 (IH, br s), 7.34 (IH, br s), 4.00 (3H, s).
44%		A solution of 3,6-dichloropyridazine (4.57 g, 0.003 1 mol), (1-methyl-1H-pyrazol-4- yl)boronic acid pinacol ester (3.82 g, 0.0 184 mol) and a solution ofNa2CO3 2M (18.3 mL) in dioxane (18.4 mL) was stirred for 1 minute. PdC12(PPh3)2 (1.29 g, 0.0018 mol) was added and the solution was heated at 80C for 15 hours. The mixture was cooled to room temperature and poured into water. K2C03 was added and the mixture wasfiltered through a short pad of Celite. The organic layer was dried (Mg504), filtered and evaporated to dryness. The Celite was washed with CH2C12, the filtrate was dried (Mg504) and evaporated. The residue was crystallized from CH2C12. The precipitate was filtered and dried to give 1.5 g of a first batch of intermediate 5 (42%). The filtrate was purified by chromatography over silica gel (30 g of SiOHl5-40jim,mobile phase : gradient from CH2C12 100% to CH2C12 95%/CH3OH 5%). The pure fractions were collected and evaporated until dryness to give 1.58 g of a second batch of intermediate 5 (44%)
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 5h;Inert atmosphere;	STEP 1 : 3-chloro-6-(1 -methyl-1 H-pyrazol-4-yl)pyridazine In a two-neck flask was placed 3,6-dichloropyridazine (1 .49 g, 10 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (1 .04 g, 5 mmol), K2CO3 (1.38 g, 10 mmol), and Pd(PPh3)4 (289 mg, 0.25 mmol). The resulting mixture was degassed and refilled with N2 (3 times). 1 ,4-Dioxane/H20 (9 mL/2 mL) was added and the resulting mixture was heated at 100C for 5 h. The resulting mixture was poured into EtOAc/H20 (30 mL/30 mL). The organic layer was washed with brine (30 mL), dried (Na2S04), and filtered. The solvent was removed and the resulting residue was purified by column using 90-100% EtOAc/hexane as the eluent to yield 3-chloro-6-(1-methyl-1 H-pyrazol-4- yl)pyridazine.

Reference： [1]Patent: WO2008/51808,2008,A2 .Location in patent: Page/Page column 96
[2]Archives of Pharmacal Research,2016,vol. 39,p. 453 - 464
[3]Patent: WO2007/75567,2007,A1 .Location in patent: Page/Page column 119
[4]Patent: US2012/28984,2012,A1 .Location in patent: Page/Page column 2
[5]Patent: WO2007/75567,2007,A1 .Location in patent: Page/Page column 69
[6]Patent: WO2016/87586,2016,A1 .Location in patent: Page/Page column 17; 18
[7]Patent: WO2013/85957,2013,A1 .Location in patent: Page/Page column 55

4
[ 905590-33-2 ]
[ 905590-61-6 ]
aqueous potassium carbonate [ No CAS ]
[ 247940-06-3 ]
[ 761446-44-0 ]
4-(3,4-diethoxyphenyl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyridin-2-yl]-4-oxobutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	tris-(dibenzylideneacetone)dipalladium(0); In 1,2-dimethoxyethane; water;	Example 119 4-(3,4-diethoxyphenyl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyridin-2-yl]-4-oxobutanamide To a solution of N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg) and biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg) in DME (1 mL) were added 1N aqueous potassium carbonate solution (0.1 mL) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (26.0 mg), and the mixture was reacted using microwave (250 W) at 150C for 5 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure. The obtained residue was subject to a reversed-phase preparative high performance liquid chromatography (Gilson, UniPoint System, Column Capcellpak C18 UG120 20 x 50 mm, manufactured by SHISEIDO), and the fraction eluted with acetonitrile (containing 0.1% formic acid)-water (20:80, v/v) was concentrated under reduced pressure to give 4-(3,4-diethoxyphenyl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyridin-2-yl]-4-oxobutanamide (6.9 mg). HPLC (220 nm) purity 97% (retention time 1.75 min) MS (ESI+, m/e) 499 (M+H)

Reference： [1]Patent: EP1845081,2007,A1

5
[ 905590-58-1 ]
aqueous potassium carbonate [ No CAS ]
[ 247940-06-3 ]
[ 761446-44-0 ]
4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyridin-2-yl]-4-oxobutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	tris-(dibenzylideneacetone)dipalladium(0);	Example 153 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (26.0 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyridin-2-yl]-4-oxobutanamide (2.2 mg) was obtained. HPLC (220 nm) purity 100% (retention time 1.87 min) MS (ESI+, m/e) 453 (M+H)

Reference： [1]Patent: EP1845081,2007,A1

6
[ 136866-30-3 ]
[ 761446-44-0 ]
[ 1048389-43-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;palladium(0)bis(tricyclohexylphosphine); In water; toluene; at 100℃;	l-Methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.0955 g, 0.459 mmol), <strong>[136866-30-3]3,5-dichloro-2-iodopyrazine</strong> (0.1042 g, 0.379 mmol), potassium phosphate, tribasic (0.275 ml, 1.295 mmol), and bis(tricyclohexylphosphine)palladium(0) (0.0186 g, 0.028 mmol) were combined. The mixture was purged with argon. Toluene was added (1.8 ml). Water (0.09 ml) was added. The reaction was allowed to heat in an oil bath at 1000C overnight. The reaction was filtered over celite washing with ethyl acetate and methanol. The filtrate was concentrated. The resulting residue was purified by column chromatography. MS[M+eta]+229.0 (calcd 230.1).

Reference： [1]Patent: WO2008/99210,2008,A2 .Location in patent: Page/Page column 63

7
[ 135034-10-5 ]
[ 761446-44-0 ]
[ 943541-20-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium phosphate; N-benzyl-N,N,N-triethylammonium chloride; triphenylphosphine;palladium diacetate; In tetrahydrofuran; water; at 65℃; for 16h;	Step 5: 3-chloro-6-(1-methyl-1/-/-pyrazol-4-yl)pyridazineWater (253 mL) and THF (842 mL) were put in the reaction balloon. The reagents were added one by one to the stirred reaction mixture: potassium phosphate monohydrate 86,2 g (374 mmol) and BTEAC 2,25g (9,88 mmol). Then 3-chloro-6-iodopyhdazine, 45 g (187,2 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole, 46,73g(224,6 mmol) were added and finally triphenylphosphine, 1 ,96g (7,49 mmol) and palladiumdiacetate, 420 mg (1 ,87 mmol) were added. The reaction mixture was heated at 65C for 16h . The reaction mixture was allowed to cool to 600C. Then 935 mL water and301 , 5g sodium chloride were added. The mixture was stirred for 15 minutes and allowed <n="74"/>to cool to 450C. The phases were separated and the organic layer was washed with a solution of 45 g sodium chloride in 374 mL water. The organic layer was separated and stirred with magnesium sulphate (225 g) and charcoal (4,5 g). The mixture was filtered and evaporated. The evaporation residue was co-evaporated with toluene twice and evaporated further till a final volume of 200 ml. This residue was stirred for 16 h at room temperature. The resulting solids were collected by filtration. The solids were dried at reduced pressure affording 29,7 g of the title compound (152,6 mmol, yield 82%).1 H NMR (600 MHz, CHLOROFORM-c/) delta ppm 4.00 (s, 3 H) 7.46 (d, J=8.69 Hz, 1 H) 7.56 (d, J=9.06 Hz, 1 H) 7.98 (s, 1 H) 8.11 (s, 1 H)
	With potassium phosphate tribasic trihydrate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; at 80℃; for 3h;Inert atmosphere; Industry scale;	1.2 705 g (3.39 mol) of pinacolyl 1-methyl-1H-pyrazole-4-boronate and 1.44 kg of tripotassium phosphate trihydrate are added to a solution of 815 g (3.39 mol) of 3-chloro-6-iodopyridazine in 3.8 l of 1,2-dimethoxy-ethane. The resultant suspension is heated to 80 C. under nitrogen and with stirring, and 59.5 g (85 mmol) of bis(triphenylphosphine)palladium(II)-chloride are added. The reaction mixture is stirred at 80 C. for 3 hours. The mixture is allowed to cool to room temperature, and 9 l of water are added. The resultant precipitate is filtered off with suction, washed with water and dried in vacuo: 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine as brown crystals; ESI 195.
	With potassium phosphate tribasic trihydrate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; at 80℃; for 3h;Inert atmosphere;	705 g (3.39 mol) of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 1.44 kg of tripotassium phosphate trihydrate are added to a solution of 815 g (3.39 mol) of 3-chloro-6-iodopyridazine in 3.8 l of 1,2-dimethoxy-ethane. The resultant suspension is heated to 80 C. under nitrogen and with stirring, and 59.5 g (85 mmol) of bis(triphenylphosphine)palladium(II) chloride are added. The reaction mixture is stirred at 80 C. for 3 hours. The mixture is allowed to cool to room temperature, and 9 l of water are added. The resultant precipitate is filtered off with suction, washed with water and dried in vacuo: 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine as brown crystals; ESI 195.

Reference： [1]Patent: WO2008/155378,2008,A1 .Location in patent: Page/Page column 72-73
[2]Patent: US2011/92498,2011,A1 .Location in patent: Page/Page column 19
[3]Patent: US2011/257181,2011,A1 .Location in patent: Page/Page column 21

8
[ 23003-30-7 ]
[ 761446-44-0 ]
[ 1117686-40-4 ]

Yield	Reaction Conditions	Operation in experiment
49%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 0.75h;	2-Iodo-6-methyl-pyridin-3-ol (0.79 g), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (0.7 g), Cs2CO3 (2.74 g) and Pd(PPh3)4 (0.195 g) were combined with 1,4-dioxane (8 mL) and water (2 mL) and the mixture was heated to 100 C. for 0.75 h. The mixture was then concentrated in vacuo and the resulting aqueous residue was taken to pH 7 with 10% aqueous HCl. The resulting mixture was partitioned between water and EtOAc and the phases were separated. The aqueous portion was extracted with EtOAc and the combined organic portions were dried (MgSO4) and concentrated in vacuo. Purification by FCC using a gradient of 0-15% MeOH in DCM afforded the title compound as a yellow solid; (0.313 g, 49%)

Reference： [1]Patent: US2009/48269,2009,A1 .Location in patent: Page/Page column 61

9
[ 333408-31-4 ]
[ 7709-13-9 ]
[ 761446-44-0 ]
[ 1167546-76-0 ]

Yield	Reaction Conditions	Operation in experiment
16%		To a solution of (2-chloro-8-methylquinolin-3-yl)methanol (150 mg, 0.72 mmol) in 1 ,4-dioxane/water (4 mL/1 mL) was added l-methyl-4-(4,4,5,5-tetramethyl-[ 1,3,2]- dioxaborolan-2-yl)-lH-pyrazole (181 mg, 0.87 mmol), K2CO3 (199 mg, 1.44 mmol) and Pd(PPh3)4 (83 mg, 0.07 mmol). The mixture was degassed and heated in a microwave at 1500C for 1 h. The solvent was removed in vacuo and the residue dissolved in DCM (50 mL) and washed with water (2 x 10 mL). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo. Purification by column chromatography (SiO2, 0-20% EtOAc in Et2O) afforded the desired intermediate. This was dissolved in 1,4-dioxane (6 mL) under nitrogen and to it was added NaH (55 mg, 1.36 mmol, 60% in mineral oil). The solution was stirred at r.t for 5 minutes before 4- chloro-l,3,5-triazin-2-amine (106 mg, 0.82 mmol) was added and the mixture heated at 800C for 48 h. The mixture was poured into EtOAc (50 mL) and washed with water (3 x 10 mL). Purification by column chromatography (SiO2, 2-6% MeOH in DCM) yielded the title compound (38 mg, 16%) as a white solid. deltaH (DMSO-J6) 8.42 (s, IH), 8.37 (s, IH), 8.34 (s, IH), 8.04 (s, IH), 7.83 (d, J 8.1 Hz, IH), 7.57-7.69 (m, 3H), 7.47 (t, J7.6 Hz, IH), 5.69 (s, 2H), 3.99 (s, 3H), 2.78 (s, 3H). LCMS (ES+) 348 (M+H)+, RT 2.75 minutes (Method T).

Reference： [1]Patent: WO2009/81105,2009,A2 .Location in patent: Page/Page column 109

10
[ 78686-83-6 ]
[ 913836-14-3 ]
[ 761446-44-0 ]
[ 1112849-95-2 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 2 5-(3-Chloro-5-methvIphenyl)-2-(l -methyl- 1H-pyrazol-4-vQ nicotinic acid (2-2)To a solution of methyl 2-chloro-5-iodonicotonate {2?_, 1.00 g, 3.36 mmol) in dimethylformamide (15 mL) at 25 C was added 3-chloro-5-methylboronic acid (0.573 g, 3.36 mmol; synthesized via procedures found in Org. Lett. 2007, P, 757-760), PdCl2dppf (0.246 g, 0.336 mmol) followed by IM aqueous cesium carbonate (13.5 mL, 13.5 mmol) and the system was stirred for 4h at 25 C. The system was partitioned between water and EtOAc, and dried over magnesium sulfate. Filtration and concentration yielded a brown solid which upon tritiration with ether afforded a tan solid. To this tan solid (0.05 g, 0.169 mmol) in dimethylformamide (0.8 mL) at 25 C was added l-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H pyrazole (0.038 g, 0.186 mmol), PdCl2dppf (0.012 g, 0.017 mmol) followed by 4M aqueous cesium carbonate (0.67 mL, 0.675 mmol) and the system was stirred for 15 minutes at 135 C in the microwave. The system was partitioned between water and EtOAc. The aqueous layer was then acidified using 25% citric acid to a pH of 3, extracted with EtOAc and the organic layer was dried over magnesium sulfate. Filtration and concentration afforded the title compound (2-2) as a cream solid. ESI+ MS [M+H]+ C17H14ClN3O2 = 328.0.

Reference： [1]Patent: WO2009/20642,2009,A1 .Location in patent: Page/Page column 47-48

11
[ 116632-23-6 ]
[ 761446-44-0 ]
[ 1036756-65-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 80℃; for 1.5h;	The product from step 1 (1.0 eq) was dissolved in THF to make a 0.30 M solution. A 2.0 M aqueous solution of sodium carbonate (3.5 eq) was added. The mixture was degassed by bubbling argon through the solution for 10 min. 1 - Methylpyrazole-4-boronic acid, pinacol ester (1.2 eq) and (dppf)Pd(II)Cl2-CH2C12 (0.060 eq) were added. The mixture was stirred at 80 C for 90 min and then returned to ambient temperature. The mixture was diluted with ethyl acetate. Dilute aqueous hydrochloric acid was added until the pH of the aqueous layer was 5-6. The layers were separated. The aqueous phase was extracted with additional ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (ethyl acetate then 92:8 ethyl acetate: methanol) to give the desired product as a yellow-brown solid. ES/MS m/z 220.0 (MH+).

Reference： [1]Patent: WO2009/153313,2009,A1 .Location in patent: Page/Page column 181

12
[ 139194-79-9 ]
[ 761446-44-0 ]
[ 1202036-25-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; at 90℃; for 16h;	To a solution of <strong>[139194-79-9](3-bromo-5-nitrophenyl)methanol</strong> in THF/ water was added 1- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2eq) and sodium carbonate ( 3eq) and the mixture was degassed for 15min. To it was added Pd(dppfhCl2 (0.05eq) and the mixture was heated to 90C for 16h. Complete conversion to the product was observed on LC/MS. The mixture was portioned between ethyl acetate and water and the organic layer was washed with brine and dried with sodium sulfate to give (3-(l-methyl-1H-pyrazol-4-yl)-5-nitrophenyl)methanol. ES/MS m/z 234 (MH+).

Reference： [1]Patent: WO2009/153313,2009,A1 .Location in patent: Page/Page column 193

13
[ 1001070-33-2 ]
[ 761446-44-0 ]
[ 1147998-19-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 2h;	Step 2: 5-(l-methyl-lH-rhoyrazol-4-yl)-l-(phenylsulfonvn-lH-pyrrolor2,3-felpyridine; To a degassed (sparging with argon for 5 minutes), stirred solution of 1 -methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-leta-pyrazole (0.617 g, 2.97 mmol) and 5-bromo-l- (phenylsulfonyl)-lH-pyrrolo[2,3-6]pyridine (1.00 g, 2.97 mmol) in dioxane (12.0 ml) was added Pd(Ph3P)4 (0.171 g, 0.148 mmol), followed by a degassed aqueous solution of sodium carbonate (4.45 ml, 8.90 mmol). The reaction mixture was stirred under nitrogen at 100 0C for 2 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (25 mL) and saturated aqueous ammonium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to a crude residue. The residue was purified by silica gel chromatography (EtOAc/etaexanes gradient) to afford 5-(l-methyl-l//-pyrazol-4-yl)-l- (rhohenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine as a white solid. LRMS (ESI) calculated for Ci7Hi4N4O2S [M+H]+, 339.1 ; found 339.1.

Reference： [1]Patent: WO2009/54941,2009,A1 .Location in patent: Page/Page column 45

14
[ 1187449-01-9 ]
[ 761446-44-0 ]
[ 1226795-88-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2552 - 2555

15
[ 77337-82-7 ]
[ 761446-44-0 ]
[ 1079178-14-5 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 150℃; for 18h;	[1,1' ~Bis(dirhohenylrhohosrhohino)ferrocene] -dichloropalladiuni(II)(1:1 complex with dichloromethane, 7.0 g, 8.62 mmol) was added to a degassed mixture of l-bromo-2-methoxy-4-nitrobenzene (20 g, 86.2 mmol), l-methyl-4- (4,4,5,5-tetramethyl-l,3s2-dioxaborolan-2~yl)-lH-pyrazole (23,3 g, 112 mmol), and potassium carbonate (23.6 g, 122 mmol) in DMF (200 mL). The mixture was heated at 150 C for 18 h. The crude reaction mixture was cooled to it and filtered through diatomaceous earth (Celite ). The reaction mixture was diluted with EtOAc (200 mL) and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (EtOAc/hexane) to afford 4-(2-methoxy-4-nitrophenyl)-l- methyl- 1 H-pyrazole (14 g, 70 % yield).

Reference： [1]Patent: WO2010/83141,2010,A1 .Location in patent: Page/Page column 47

16
[ 71759-89-2 ]
[ 76513-69-4 ]
[ 761446-44-0 ]
1-methyl-5-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-1H-pyrazole [ No CAS ]
[ 1254162-31-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 91 -Methyl-4-[1 -(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-4-yl]-1 H-p yrazol e (as a mixture with the 5-regioisomer) By following General procedure A (SEM Protection), <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (500 mg, 2.58 mmol) was used to prepare 4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H- imidazole product (462 mg and 305 mg) (as a mixture with the 5-regioisomer). In a three separate tubes, a suspension of 4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)- 1H-imidazole (100 mg, 0.308 mmol), 1-benzyl-4-(4,4,5,5-tetramethyl)-1,3,2- dioxaborolan-2-yl-1H-pyrazole (97 mg, 0.463 mmol) Pd2(dba)3 (3.0 mg, 0.003 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (5.0 mg, 0.012 mmol) in 2M aqueous K3PO4 (2 mol. eq.; 0.30 ml.) and 1,4-dioxane (0.6 ml.) was degassed with nitrogen. Each tube was heated in a microwave reactor at 80 0C for 1 hour. The combined reactions were diluted with H2O and CHCI3, filtered and extracted into CHCI3 (x3). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The product was purified by SiO2 chromatography providing the title compound (as a mixture with the 5-regioisomer) (88 mg).

Reference： [1]Patent: WO2010/125402,2010,A1 .Location in patent: Page/Page column 112-113

17
[ 71759-89-2 ]
[ 1254163-00-2 ]
[ 76513-69-4 ]
[ 761446-44-0 ]
[2-(2,6-difluoro-phenyl)-pyridin-4-yl]-[4-(1-methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol [ No CAS ]
[ 1254163-08-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 48[2-(2,6-Difluoro-phenyl)-pyridin-4-yl]-[5-(1 -methyl-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl]- methanoneStep 1 : To a stirred solution of Example 9 (84 mg, 0.302 mmol; as a mixture of two regioisomers) in THF (2 ml.) at -78 0C was added n-BuLi (2.5M in hexanes; 0.262 ml_, 0.654 mmol) dropwise. The mixture was stirred at -78 0C for 1 hour before a solution of 2-(2,6-difluoro-phenyl)-pyridine-4-carbaldehyde (Example 42) (70 mg, 2.52 mmol) in THF (1 ml.) was added and the reaction was allowed to warm to room temperature overnight. The reaction was quenched with water and the mixture extracted with CHCI3 (x3). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by SiC>;2 chromatography providing [2-(2,6-difluoro-phenyl)-pyridin-4-yl]-[5- (1 -methyl-1 H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl]- methanol (78 mg, as a mixture with the 4-regioisomer).

Reference： [1]Patent: WO2010/125402,2010,A1 .Location in patent: Page/Page column 133

18
[ 71759-89-2 ]
[ 1254163-00-2 ]
[ 76513-69-4 ]
[ 761446-44-0 ]
[2-(2,6-difluoro-phenyl)-pyridin-4-yl]-[4-(1-methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanone [ No CAS ]
[ 1254163-10-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 48[2-(2,6-Difluoro-phenyl)-pyridin-4-yl]-[5-(1 -methyl-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl]- methanoneStep 1 : To a stirred solution of Example 9 (84 mg, 0.302 mmol; as a mixture of two regioisomers) in THF (2 ml.) at -78 0C was added n-BuLi (2.5M in hexanes; 0.262 ml_, 0.654 mmol) dropwise. The mixture was stirred at -78 0C for 1 hour before a solution of 2-(2,6-difluoro-phenyl)-pyridine-4-carbaldehyde (Example 42) (70 mg, 2.52 mmol) in THF (1 ml.) was added and the reaction was allowed to warm to room temperature overnight. The reaction was quenched with water and the mixture extracted with CHCI3 (x3). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by SiC>;2 chromatography providing [2-(2,6-difluoro-phenyl)-pyridin-4-yl]-[5- (1 -methyl-1 H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl]- methanol (78 mg, as a mixture with the 4-regioisomer).

Reference： [1]Patent: WO2010/125402,2010,A1 .Location in patent: Page/Page column 133-134

19
[ 71759-89-2 ]
[ 1254163-00-2 ]
[ 761446-44-0 ]
[ 1254160-35-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 48[2-(2,6-Difluoro-phenyl)-pyridin-4-yl]-[5-(1 -methyl-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl]- methanoneStep 1 : To a stirred solution of Example 9 (84 mg, 0.302 mmol; as a mixture of two regioisomers) in THF (2 ml.) at -78 0C was added n-BuLi (2.5M in hexanes; 0.262 ml_, 0.654 mmol) dropwise. The mixture was stirred at -78 0C for 1 hour before a solution of 2-(2,6-difluoro-phenyl)-pyridine-4-carbaldehyde (Example 42) (70 mg, 2.52 mmol) in THF (1 ml.) was added and the reaction was allowed to warm to room temperature overnight. The reaction was quenched with water and the mixture extracted with CHCI3 (x3). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by SiC>;2 chromatography providing [2-(2,6-difluoro-phenyl)-pyridin-4-yl]-[5- (1 -methyl-1 H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl]- methanol (78 mg, as a mixture with the 4-regioisomer).

Reference： [1]Patent: WO2010/125402,2010,A1 .Location in patent: Page/Page column 133-134

20
[ 1211533-83-3 ]
[ 761446-44-0 ]
[ 1239719-83-5 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In water; acetonitrile; for 1h;Reflux;Product distribution / selectivity;	Example 2a6-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-ylamine Method 1:To MeCN (20 mL) and water (10.0 mL) were added <strong>[1211533-83-3]5-bromo-6-methoxypyridin-2-amine</strong> (CAS 1211533-83-3, 2.2 g, 10.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H pyrazole (CAS 761446-44-0, 2.93 g, 14.1 mmol) and Suzuki mix s-phos [(dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (329 mg, 0.8 mmol), potassium carbonate (3025 mg, 21.9 mmol) and palladium(II) acetate (123 mg, 0.55 mmol)]. The reaction was heated to reflux for 1 h. The mixture was cooled to r.t. and the solvents were evaporated. DCM (10 mL) was added and a precipitate was formed. 1.5 g of product was filtered off and washed with ether. Another 80 mg of product precipitated o.n. in DCM. The remaining product in the mother-liquor was purified using flash chromatography, 0-100% EtOAc in heptane yielding in total 1.67 g (76%) of the title compound. 1H NMR (400 MHz, DMSO-d6) delta ppm 3.82 (s, 3H) 3.84 (s, 3H) 5.85 (s, 2H) 6.05 (d, 1H) 7.59 (d, 1H) 7.70 (d, 1H) 7.86 (s, 1H). MS m/z 205.6 [M+H]+.
60%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; potassium carbonate; In water; acetonitrile; for 1h;Inert atmosphere; Reflux;	To a stirred solution of <strong>[1211533-83-3]5-bromo-6-methoxypyridin-2-amine</strong> (2 g, 9.85 mmol) in CH3CN: water (2: 1, 30 mL) under an argon atmosphere were added potassium carbonate (2.7 g, 19.70 mmol), S-phos (404 mg, 0.98 mmol), Pd(OAc)2 (332 mg, 0.49 mmol) and degassed for 30 min at room temperature. Then (1-methyl-4-(4, 4, 5, 5-tetramethyl-1, 3, 2- dioxaborolan-2-yl)-1H-pyrazole (6 g, 23.90 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at reflux for 1 h. After consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was recrystallized with CH2Cl2 (2 x 30 mL) to obtain 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl) pyridin-2-amine (1.2 g, 60%) as a pale yellow solid. 1H-NMR (DMSO-d6, 400 MHz): delta 7.82 (s, 1H), 7.69 (s, 1H), 7.55 (d, 1H), 6.03 (d, 1H), 5.80 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H); LCMS: 205 (M+1); (column; X-Select CSH C-18 (50 × 3.0 mm, 3.5 mum); RT 2.19 min 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 50% EtOAc:hexanes (Rf: 0.2).
60%		Synthesis of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine To a stirred solution of <strong>[1211533-83-3]5-bromo-6-methoxypyridin-2-amine</strong> (2 g, 9.85 mmol) in CH3CN: water (2:1, 30 mL) under an argon atmosphere were added potassium carbonate (2.7 g, 19.70 mmol), S-phos (404 mg, 0.98 mmol), Pd(OAc)2 (332 mg, 0.49 mmol) and degassed for 30 min at room temperature. Then (1-methyl-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole (6 g, 23.90 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at reflux for 1 h. After consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was recrystallized with CH2Cl2 (230 mL) to obtain 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (1.2 g, 60%) as a pale yellow solid. 1H-NMR (DMSO-d6, 400 MHz): delta 7.82 (s, 1H), 7.69 (s, 1H), 7.55 (d, 1H), 6.03 (d, 1H), 5.80 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H); LCMS: 205 (M+1); (column; X-Select CSH C-18 (50*3.0 mm, 3.5 mum); RT 2.19 min 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 50% EtOAc:hexanes (Rf: 0.2).

59%

With water; potassium carbonate;acetato(2'-di-tert-butylphosphino-1,1'-biphenyl-2-yl)-palladium; In 1,4-dioxane; at 110℃; for 0.75h;Microwave oven;

Example 50 b. 6-methoxy-5-(l-methyl-lH-pyrazol-4-yl)pyridin-2-aminel-Methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (205 mg, 0.99 mmol), potassium carbonate (340 mg, 2.46 mmol) and Pd 118 (32.1 mg, 0.05 mmol) were added to <strong>[1211533-83-3]5-bromo-6-methoxypyridin-2-amine</strong> (200 mg, 0.99 mmol) in dioxane (3 mL). Water (0.5 mL) was added and the reaction was heated to 1100C for 45 min in the microwave oven. The solids were filtered off and washed with DCM. The solvent was evaporated and the crude product was purified on silica column chromatography using a gradient of 0-10% MeOH in DCM yielding 118 mg of the title compound (59 % Yield). 1H NMR (500 MHz, DMSO-J6) delta ppm 7.87 (s, 1 H) 7.71 (s, 1 H) 7.59 (d, 1 H) 6.06 (d, 1 H) 5.84 (s, 2 H) 3.86 (s, 3 H) 3.83 (s, 3 H). MS m/z 205 [M+H] +.

Reference： [1]Patent: US2012/122843,2012,A1 .Location in patent: Page/Page column 12-13
[2]Patent: WO2015/109109,2015,A1 .Location in patent: Paragraph 0712
[3]Patent: US2017/44182,2017,A1 .Location in patent: Paragraph 0984
[4]Patent: WO2010/132015,2010,A1 .Location in patent: Page/Page column 134-135

21
[ 233770-01-9 ]
[ 761446-44-0 ]
[ 944718-17-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate tribasic trihydrate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; at 80℃; for 16h;Inert atmosphere;	EXAMPLE 7: Synthesis of 2-(5-chloro-2-fIuoro-phenyl)-4-[5-(1-methyl-1 H-pyrazol-4-yl)- pyridin-3-yl]-[1 ,8]naphthyridine (no. 7)A slurry of 4.33 g (15.3 mmol) <strong>[233770-01-9]3-bromo-5-iodo-pyridine</strong>, 3.49 g (16.8 mmol) 1-methyl-4- (4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazol and 6.48 g (30.5 mmol) tri- potassium-phosphate-trihydrate in 30 ml 1 ,2-dimethoxyethane was heated to 80C under nitrogen. Then 321 mg (0.46 mmol) bis-(triphenylphosphine)-palladium(ll)-chloride were added. The reaction mixture was stirred for 16 hours at 80C. The reaction mixture was evaporated. The residue was chromatographed on a silica gel column withdichloromethane/methanol as eluent yielding 3-bromo-5-(1-methyl-1 H-pyrazol-4-yl)-pyridine als slightly yellow crystals; HPLC-MS: [M+H] 238/234.
	With potassium phosphate tribasic trihydrate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; at 80℃; for 16h;Inert atmosphere;	A suspension of 5.68 g (20.0 mmol) <strong>[233770-01-9]3-bromo-5-iodo-pyridine</strong>, 4.37 g (21.0 mmol) 1-methyl-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazol and 8.49 g (40.0 mmol) tri-potassium-phosphate-trihydrate in 40 ml 1 ,2- dimethoxyethane was heated to 80 C under nitrogen. Then 281 mg (0.40 mmol) bis-(triphenylphosphine)-palladium(ll)-chloride were added. The reaction mixture was stirred for 16 hours at 80 C. The reaction mixture was cooled to room temperature and partitioned between water. and dichloromethane. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 3-bromo-5-(1-methyl-1 H-pyrazol-4-yl)-pyridine as colourless crystals; HPLC/MS (A): 1.77 min, [M+H] 238/240.
	With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate tribasic trihydrate; In 1,2-dimethoxyethane; at 80℃; for 16h;Inert atmosphere;	A slurry of 4.33 g (15.3 mmol) <strong>[233770-01-9]3-bromo-5-iodo-pyridine</strong>, 3.49 g (16.8 mmol) 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazol and 6.48 g (30.5 mmol) tri-potassium-phosphate-trihydrate in 30 ml 1,2-dimethoxyethane was heated to 80 C. under nitrogen. Then 321 mg (0.46 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The reaction mixture was stirred for 16 hours at 80 C. The reaction mixture was evaporated. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)-pyridine als slightly yellow crystals; HPLC-MS: [M+H] 238/234

Reference： [1]Patent: WO2011/95196,2011,A1 .Location in patent: Page/Page column 88
[2]Patent: WO2012/119690,2012,A1 .Location in patent: Page/Page column 59; 60
[3]Patent: US2012/295902,2012,A1 .Location in patent: Paragraph 0279; 0280

22
[ 1337962-47-6 ]
[ 761446-44-0 ]
[ 1337963-50-4 ]

Yield	Reaction Conditions	Operation in experiment
45.3%	With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 140℃; for 0.5h;Microwave irradiation;	A mixture of 0.1 g (0.33 mmol) of 5-bromo-2,6-di(lH-pyrazol-l-yl)pyrimidin-4-amine (Example 1), 0.10 g (0.49 mmol) of l-methylpyrazole-4-boronic acid pinacol ester, 0.23 (0.72 mmol) of cesium carbonate and 5 mg (6.5 mu?iotaomicron) of [l ,l '-Bis(diphenylphosphino) ferrocenejdichloropaladium (II) dichloromethane complex in 3 ml dioxane and 0.5 ml of water were irradiated with microwaves at 140C for 30 min. After cooling to room temperature ethyl acetate was added and filtered by celite. The solution was extracted two times with 10 ml of saturated solution of NaHC03 and Brine. The organic layer was separated, dried with MgS04 and concentrated. The residue was purified by column chromatography with silica gel and methylene chloride and methanol as eluent to give 45.5 mg (45.3 %) of the desired product. 1H-RMN (300 MHz, DMSO-d6): delta = 4.05 (s, 3H), 6.56 (dd, 1H), 6.59 (dd, 1H), 7.25 (s, 1H), 7.45 (s, 1H), 7.52 (s, 1H), 7.80 (d, 1H), 7.86 (d, 1H), 8.40 (s, 1H), 8.51 (d, 1H), 8.59 (d, 1H).

Reference： [1]Patent: WO2011/121418,2011,A1 .Location in patent: Page/Page column 40-41

23
[ 1350643-72-9 ]
[ 761446-44-0 ]
[ 1350643-65-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; ruphos;palladium diacetate; In 1,4-dioxane; water; at 125℃; for 3h;Inert atmosphere; microwave heating;	Compound 73 was prepared in two steps from compound 1 according to the following procedures: Compound 1 (860 mg, 2.9 mmol, 1 eq.), l-methylpyrazole-4-boronic acid pinacol ester (1.8 g, 3 eq.), sodium carbonate (1.6 g, 5 eq.), palladium diacetate (100 mg, 0.15 eq.) and RuPhos (400 mg, 0.30 eq) were combined in a 20 mL septum-sealed microwave reaction tube with stir bar. The tube was purged with vacuum and refilled with dry argon three times, then charged with 1,4-dioxane (16 mL) and water (4 mL), and subjected to microwave heating at 125 C for 3h. The reaction mixture was then purified using flash silica gel chromatography (30g of silica gel packed using a solution of 1 % triethylamine in methylene chloride, mobile phase was a gradient of 1-4% methanol:methylene chloride) NMR analysis revealed this material to be a mixture of the amine 63 and 2.6 eq. of pinacol; this mixture was taken forward without further purification.

Reference： [1]Patent: WO2011/146882,2011,A1 .Location in patent: Page/Page column 139

24
[ 1207625-18-0 ]
[ 761446-44-0 ]
[ 1349723-36-9 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 13h;Inert atmosphere;	3-(1 -Methyl-1 H-pyrazol-4-yl)-7/-/-pyrrolo[2,3-c]pyridazineThrough a well stirred suspension of 3-chloro-7/-/-pyrrolo[2,3-c]pyridazine (200 mg, 1.3 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (324 mg, 1 .55 mmol, 1.2 eq) and cesium carbonate (848 mg, 2.6 mmol, 2 eq) in 20 % aqueous dioxane (40 mL) was bubbled N2 gas for 15 min. at room temp. To the resulting solution was then added Pd(PPh3)4 (72 mg, 0.06 mmol) and heated at 100 C for 13 h. The reaction mixture was cooled to RT and solvent was removed under reduced pressure. The residue was partitioned between DCM and water (50 mL each), and the aqueous layer was extracted with methylene chloride (3 x 100 mL). The combined organic layers were washed with water (20 mL) followed by brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a brown solid, which was purified by column chromatography on silica gel using 5 to 10% MeOH in DCM as eluent to yield the title compound as brown solid. 1H NMR (300 MHz, CDCI3): delta = 4.01 (s, 3H), 6.52 (d, J = 3.3 Hz, 1 H), 7.71 (d, J = 3.3 Hz, 1 H), 7.88 (s, 1 H), 8.03 (s, 1 H), 8.09 (s, 1 H).

Reference： [1]Patent: WO2011/143646,2011,A1 .Location in patent: Page/Page column 58

25
[ 62968-37-0 ]
[ 761446-44-0 ]
[ 1351933-96-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; lithium hydroxide; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;	General procedure: To a solution of 2-chloroheteroaryl compound 1 (0.50 mmol) in 1,4-dioxane (4.0 mL) were added pinacol boronate 3, 5, or 7 (0.60 mmol), Pd(OAc)2 (1.1 mg, 5.0 mumol), S-Phos (4.1 mg, 10.0 mumol), and 2 M LiOH solution (1.0 mL, 2.0 mmol) at room temperature, and the mixture was stirred for 30 min at 80 C under N2 atmosphere. The reaction was quenched by adding water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by silica-gel column chromatography. The solvent was removed in vacuo, and the residue was triturated with Et2O to give biaryl compounds.

Reference： [1]Tetrahedron,2012,vol. 68,p. 272 - 279

26
[ 81045-39-8 ]
[ 761446-44-0 ]
[ 1353970-23-6 ]
[ 1353970-21-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate tribasic trihydrate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; at 80℃; for 18h;Inert atmosphere;	A suspension of 573 mg (2.0 mmol) <strong>[81045-39-8]5,8-dibromoisoquinoline</strong>, 458 mg (2.2 mmol) 1- methyM^^.S.S-tetramethyl-fl .S^ldioxaborolan^-y -I H-pyrazole, 849 mg (4.0 mmol) tri-potassium-phosphate trihydrate and 140 mg (0.20 mmol) bis- (triphenylphosphine)-palladium(ll)-chloride in 4 ml 1 ,2-dimethoxyethane were stirred for 18 hours at 80 C under nitrogen. The reaction mixture was cooled to room temperature, diluted with THF and filtered. The filtrate was evaporated and the residue was chromatographed on a silica gel column with ethylacetate/methanol as eluent. The two isomers were obtained separately.First eluted isomer: 8-bromo-5-(1-methyl-1 H-pyrazol-4-yl)-isoquinoline as colourless crystals; HPLC/MS 1.90 min, [M+H] = 288/290.Second eluted isomer: 5-bromo-8-(1-methyl-1 H-pyrazol-4-yl)-isoquinoline as yellow crystals; HPLC/MS (A) 2.02 min, [M+H] = 288/290.
	With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate tribasic trihydrate; In 1,2-dimethoxyethane; at 80℃; for 18h;Inert atmosphere;	1. A suspension of 573 mg (2.0 mmol) <strong>[81045-39-8]5,8-dibromoisoquinoline</strong>, 458 mg (2.2 mmol) 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole, 849 mg (4.0 mmol) tri-potassium-phosphate trihydrate and 140 mg (0.20 mmol) bis-(triphenylphosphine)-palladium(II)-chloride in 4 ml 1,2-dimethoxyethane were stirred for 18 hours at 80 C. under nitrogen. The reaction mixture was cooled to room temperature, diluted with THF and filtered. The filtrate was evaporated and the residue was chromatographed on a silica gel column with ethylacetate/methanol as eluent. The two isomers were obtained separately.[0446]First eluted isomer: 8-bromo-5-(1-methyl-1H-pyrazol-4-yl)-isoquinoline as colourless crystals; HPLC/MS 1.90 min, [M+H]=288/290.[0447]Second eluted isomer: 5-bromo-8-(1-methyl-1H-pyrazol-4-yl)-isoquinoline as yellow crystals; HPLC/MS (A) 2.02 min, [M+H]=288/290.

Reference： [1]Patent: WO2012/595,2012,A1 .Location in patent: Page/Page column 102-103
[2]Patent: US2013/102603,2013,A1 .Location in patent: Paragraph 0444; 0445; 0446; 0447

27
[ 81045-39-8 ]
[ 1323919-50-1 ]
[ 761446-44-0 ]
[ 1353967-97-1 ]
[ 1353968-20-3 ]

Yield	Reaction Conditions	Operation in experiment
		A suspension of 573 mg (2.0 mmol) <strong>[81045-39-8]5,8-dibromoisoquinoline</strong>, 458 mg (2.2 mmol) 1- methyM^^.S.S-tetramethyl-fl .S^ldioxaborolan^-y -I H-pyrazole, 849 mg (4.0 mmol) tri-potassium-phosphate trihydrate and 140 mg (0.20 mmol) bis- (triphenylphosphine)-palladium(ll)-chloride in 4 ml 1 ,2-dimethoxyethane were stirred for 18 hours at 80 C under nitrogen. The reaction mixture was cooled to room temperature, diluted with THF and filtered. The filtrate was evaporated and the residue was chromatographed on a silica gel column with ethylacetate/methanol as eluent. The two isomers were obtained separately.First eluted isomer: 8-bromo-5-(1-methyl-1 H-pyrazol-4-yl)-isoquinoline as colourless crystals; HPLC/MS 1.90 min, [M+H] = 288/290.Second eluted isomer: 5-bromo-8-(1-methyl-1 H-pyrazol-4-yl)-isoquinoline as yellow crystals; HPLC/MS (A) 2.02 min, [M+H] = 288/290.; A suspension of 135 mg (0.47 mmol) 8-bromo-5-(1-methyl-1H-pyrazol-4-yl)- isoquinoline, 126 mg (0.47 mmol) 2-(2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid and 47.4 mg (0.56 mmol) sodium hydrogen carbonate in 1.2 ml DMF and 0.6 ml water was heated to 80 C under nitrogen. Then 6.6 mg (0.009 mmol) bis- (triphenylphosphine)-palladium(ll)-chloride were added. The reaction mixture was stirred for 18 hours at 80 C. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with ethyl acetate/methanol as eluent yielding 2-(2-fluoro-phenyl)-4-[5- (1-methyl-1H-pyrazol-4-yl)-isoquinolin-8-yl]-[1,8]naphthyridine as colourless solid; HPLC/MS (A): 1.87 min, [M+H] 432.1H NMR (400 MHz, DMSO) delta = 9.19 (dd, J=4.1, 1.9, 1H), 8.83 (d, J=0.9, 1H), 8.60 (d, J=6.0, 1H), 8.27 (s, 1H), 8.23 (td, J=7.9, 1.8, 1H), 8.17 (dd, J=6.0, 0.9, 1H), 8.11 (d, J=2A, 1H), 7.95 (d, J=7.4, 1H), 7.91 (m, 2H), 7.80 (d, J=7A, 1H), 7.62 (m, 1H), 7.57 (dd, J=8.4, 4.1, 1H), 7.47 (td, J=7.6, 1.1, 1H), 7.41 (ddd, J=11.6, 8.3, 1.0, 1H), 4.01 (s, 3H). Similarly was prepared: 2-(2-Fluoro-phenyl)-4-[8-(1-methyl-1H-pyrazol-4-yl)- isoquinolin-5-yl]-[1,8]naphthyridine as yellow solid; HPLC/MS (A): 1.84 min, [M+H] 432.1H NMR (400 MHz, DMSO) delta = 9.66 (d, J=0.9, 1H), 9.18 (dd, J=4.1, 1.9, 1H), 8.45 (d, J=5.9, 1H), 8.33 (s, 1H), 8.22 (td, J=7.9, 1.8, 1H), 8.06 (d, J=2.3, 1H), 7.95 (d, J=0.8, 1H), 7.93 (d, J=7.4, 1H), 7.87 (dd, J=8.4, 1.9, 1H), 7.83 (d, J=7.4, 1H), 7.62 (dddd, J=8.2, 7.2, 5.1, 1.9, 1H), 7.56 (dd, J=8A, 4.1, 1H), 7.47 (td, J=7.6, 1.1, 1H), 7.41 (ddd, .7=11.7, 8.3, 1.0, 1H), 7.29 (dd, .7=5.9, 0.9, 1H), 4.02 (s, 3H).

Reference： [1]Patent: WO2012/595,2012,A1 .Location in patent: Page/Page column 102-103

28
[ 112253-70-0 ]
[ 761446-44-0 ]
[ 1362910-84-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; at 160℃; for 0.333333h;Microwave irradiation; Inert atmosphere;	To bis(triphenylphosphine)palladium(II) dichloride (98 mg, 0.14 mmol), <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (600 mg, 2.79 mmol), and l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (754 mg, 3.62 mmol) were added acetonitrile (9 mL) and 1M aq Na2CC>3 (9 mL, 9 mmol). The reaction vessel was evacuated and flushed with argon (3X). The mixture was heated in a microwave reactor at 160 C for 20 min. The mixture was allowed to cool to rt, the organic layer was decanted, and the aqueous layer was retained. The organic layer was concentrated under reduced pressure and the residue was diluted with water. The resulting solid was collected by filtration washing with water and acetonitrile. The retained aqueous layer from above was filtered, and the collected solid was washed with water and acetonitrile. The collected solids were combined to afford 2-amino-4-(l -methyl- 1H- pyrazol-4-yl)benzamide (520 mg, 86%). LCMS (ESI) m/z 217 (M + H)+.

Reference： [1]Patent: WO2012/30912,2012,A1 .Location in patent: Page/Page column 91

29
[ 38762-41-3 ]
[ 761446-44-0 ]
[ 1400287-20-8 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water;Reflux;	Preparation 83: 2-Chloro-4-(1 -methyl-1 H-pyrazol-4-yl)aniline; Method B[00253] PdCI2(dppf).CH2CI2 (0.040g, 0.049mmol) was added to a solution of 4-bromo-2- chloroaniline (0.102g, 0.494mmol), 1 -methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-pyrazole (0.134g, 0.642mmol) and sodium carbonate (0.1 15g, 1 .087mmol) in THF/H20 (3/1 , 2.157ml_). The reaction mixture was refluxed overnight. It was then diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2S04), filtered and concentrated under reduced pressure. The crude mixture was purified via Biotage silica gel column chromatography eluting with (Cyclohexane/EtOAc 80/20 to 60/40) to give the title product as a white solid (62mg, 60%). 1 H NMR (500 MHz, CDCI3): delta 3.92 (s, 3H), 4.05 (br s, 2H), 6.76 (d, J = 8.2Hz, 1 H), 7.17 (dd, J = 8.2, 2.0Hz, 1 H), 7.36 (d, J = 2.0Hz, 1 H), 7.49 (s, 1 H), 7.65 (s, 1 H); LC (Method B)-MS (ESI, m/z) fR 2.23 min, 208 [(M+H+), 100%].
60%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In tetrahydrofuran; water;Reflux;	Method B PdCl2(dppf).CH2Cl2 (0.040 g, 0.049 mmol) was added to a solution of 4-bromo-2-chloroaniline (0.102 g, 0.494 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.134 g, 0.642 mmol) and sodium carbonate (0.115 g, 1.087 mmol) in THF/H2O (3/1, 2.157 mL). The reaction mixture was refluxed overnight. It was then diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude mixture was purified via Biotage silica gel column chromatography eluting with (Cyclohexane/EtOAc 80/20 to 60/40) to give the title product as a white solid (62 mg, 60%). 1H NMR (500 MHz, CDCl3): delta 3.92 (s, 3H), 4.05 (br s, 2H), 6.76 (d, J=8.2 Hz, 1H), 7.17 (dd, J=8.2, 2.0 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.49 (s, 1H), 7.65 (s, 1H); LC (Method B)-MS (ESI, m/z) tR 2.23 min, 208 [(M+H+), 100%].
	With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In tetrahydrofuran; at 100℃; for 1h;Microwave irradiation;	The following Preparations were prepared according to Method 11 (Preparation 17) above using the appropriate aniline and heterocyclic cross-coupling partner as described. [0019] The Preparations were purified according to the method described or as described below: Method A: Biotage silica gel column chromatography eluting with 40% EtOAc in cyclohexane. Method B: The reaction mixture was diluted with EtOAc and filtered. The organic layer was extracted with 2M HCI. The combined aqueous layers were washed with EtOAc and basified with solid NaHC03. The resulting aqueous solution was extracted with EtOAc, dried with Na2S04 and concentrated in vacuo to afford the title compound with no further purification. Method C: Method B followed by Biotage silica gel column chromatography eluting with between 25-40% EtOAc in cyclohexane. Method D: Biotage silica gel column chromatography eluting with 1 -5% MeOH in DCM. 21 2-chloro-4-(1 -methyl-1 -/-pyrazol-4- NMR (500 MHz, CDCI3): delta 7.66 (s, 1 H), yl)aniline 7.50 (s, 1 H), 7.37 (d, J = 2.0 Hz, 1 H), 7.18 NH2 (dd, J = 8.2, 2.0 Hz, 1 H), 6.77 (d, J = 8.2 Hz, 1 H), 4.04 (s, 2H), 3.93 (s, 3H). LCMS (ESI) Rt = 1 .91 minutes MS m/z 208 [M+H]+ Using 4-bromo-2-chloroaniline and 1 -methyl- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-pyrazole at 100C in THF and N-N purification method B.

Reference： [1]Patent: WO2012/123745,2012,A1 .Location in patent: Page/Page column 90-91
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 10045 - 10065
[3]Patent: US2013/345181,2013,A1 .Location in patent: Paragraph 0689
[4]Patent: WO2014/37750,2014,A1 .Location in patent: Paragraph 0018; 0019

30
[ 1226878-98-3 ]
[ 761446-44-0 ]
[ 1404095-47-1 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In acetonitrile; at 100℃; for 0.25h;Microwave irradiation; Inert atmosphere;	General procedure: The appropriate 5-iodo-2-chloropyridine Intermediate I-8, or I-9 (1 eq) was dissolved in acetonitrile (7 ml. solvent per 1 mmol of compound). 1 -Methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1 eq), tetrakis - (triphenylphosphine)palladium(O) (5 mol%) and sodium carbonate (1 .5 eq) were added and the mixture was heated in a microwave reactor at 100C for 30 minutes (Intermediate I-8) or 15 minutes (Intermediate I-9). The reaction mixture was concentrated in vacuo onto silica gel. Gradient chromatography (1-5% MeOH:CH2CI over 15 column volume and 5-10% over 8 column volume) gave the required 5-substituted product.

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10229 - 10240
[2]Patent: WO2013/68755,2013,A1 .Location in patent: Page/Page column 64; 73

31
5-bromo-2,3-difluoropyridine [ No CAS ]
[ 761446-44-0 ]
[ 1151801-90-9 ]

Yield	Reaction Conditions	Operation in experiment
57.4%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In N,N-dimethyl-formamide; at 80℃; for 10.16h;Inert atmosphere;	A mixture of 5-bromo-2,3-difluoropyridine (1.9 g, 9.79 mmol) and 1-methyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (2.038 g, 9.79 mmol), Na2C03 (2.076 g, 19.59 mmol) and Pd(PPh3)4 (1 .131 g, 0.979 mmol) in DMF (8 ml) was bubbled with N2 for 10 min and was then heated to 80C for 10 h. After being cooled to rt, the mixture was filtered and the filtrate was diluted with EA,washed with water and brine, dried over anhydrous MgS04. Filtered and concentrated. The residue was purified by silica gel chromatography eluted with Hex/EA (from 100% to 20%) to afford the title compound as a white solid (1 .5 g, 57.4% yield). 1 H-NMR (400 MHz, DMSO-d6) delta ppm 8.29 (d, 3H), 7.99 (d, 1 H), 3.87 (s, 3H). LCMS (method B): [M+H]+ = 196, tR = 1 .91 min.
57.4%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In N,N-dimethyl-formamide; at 80℃; for 10.0h;Inert atmosphere;	A mixture of 5-bromo-2,3-difluoropyridine (1.9 g, 9.79 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole (2.038 g, 9.79 mmol), Na2CO3 (2.076 g, 19.59 mmol) and Pd(PPh3)4 (1.131 g, 0.979 mmol) in DMF (8 ml) was bubbled with N2 for 10 min and was then heated to 80 C. for 10 h. After being cooled to rt, the mixture was filtered and the filtrate was diluted with EA, washed with water and brine, dried over anhydrous MgSO4. Filtered and concentrated. The residue was purified by silica gel chromatography eluted with Hex/EA (from 100% to 20%) to afford the title compound as a white solid (1.5 g, 57.4% yield). 1H-NMR (400 MHz, DMSO-d6) delta ppm 8.29 (d, 3H), 7.99 (d, 1H), 3.87 (s, 3H). LCMS (method B): [M+H]+=196, tR=1.91 min.

Reference： [1]Patent: WO2013/38362,2013,A1 .Location in patent: Page/Page column 78; 79
[2]Patent: US2013/245002,2013,A1 .Location in patent: Paragraph 0719

32
[ 1017789-38-6 ]
[ 761446-44-0 ]
[ 1429777-47-8 ]

Yield	Reaction Conditions	Operation in experiment
		1017789-38-6) (200 mg, 0.760 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (348 mg, 1.67 mmol), [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (62 mg, 0.076 mmol), and potassium phosphate tribasic (484 mg, 2.28 mmol) in a flask was evacuated and backfilled with argon three times. Dioxane (3 mL) and water (0.33 mL) were added, and the reaction mixture was heated to 100C for 5 hours. The mixture was allowed to cool to room temperature. Hydrochloric acid (4.0 N in dioxane, 3.80 mL, 15 mmol) was added to the mixture, and the suspension was stirred vigorously for 14 hours at room temperature. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in DMSO and purified via reverse phase HPLC (15-50% acetonitrile/water with 0.1% TFA, linear gradient) to give 4,6-bis(l -methyl- lH-pyrazol-4-yl)pyridin-2-amine. MS ESI calc'd. for C13H15N6 [M + H]+ 255, found 255. 1H NMR (500 MHz, DMSO-d6) delta 8.46 (s, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.70-7.59 (m, 2H), 7.40 (s, 1H), 6.80 (s, 1H), 3.93 (s, 3H), 3.90 (s, 3H).

Reference： [1]Patent: WO2013/52393,2013,A1 .Location in patent: Paragraph 00175

33
[ 33332-28-4 ]
[ 761446-44-0 ]
[ 1454654-39-7 ]

Yield	Reaction Conditions	Operation in experiment
75.44%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In ethanol; toluene; at 130℃; for 1h;Microwave irradiation;	17.1 6-(1- pyrazin-2-ylamine To a solution of 2-amino-6-chloro pyrazine (0.5 g, 3.86 mmol) in toluene / ethanol (9:1 , 10 ml), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (0.8 g, 4.24 mmol), tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol) and cesium carbonate (2.5 g, 7.72 mmol) are added, degassed briefly and irradiated in microwave at 130 °C for an hour. The reaction mixture is passed through celite, washed with dichloromethane/methanol (1:1, 25 ml), the filtrate is concentrated and purified by silica column using (230-400) mesh to get the product as yellow solid (0.51 g, 75.44 percent); TLC: chloroform/methanol (9.5/0.5) R - 0.3; 1H NMR: 400 MHz, DMSO-d6: delta [ppm] 8.16 (s, 1H), 8.00 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 6.32 (br s, 2H), 3.86 (s, 3H); LCMS: Mass found (M+, 176.0) Method: A-0.1percent TFA in H20, B-0.1percent TFA in ACN: Flow - 0.6 ml/min. Column: XBridge C8 (50 X 4.6 mm, 3.5 pm), +ve mode Rt (min): 1.09 area percent -96.86 (Max).

Reference： [1]Patent: WO2013/131609,2013,A1 .Location in patent: Page/Page column 123

34
[ 31928-46-8 ]
[ 761446-44-0 ]
4-(3-bromo-4-chlorophenyl)-1-methyl-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;Microwave irradiation;	4-(3-bromo-4-chlorophenyl)-1-methyl-1H-pyrazole (2) (0156) To a stirred solution of 1 (1 mmol, 1 equivalent (eq.)) and 1-methyl-4-tetramethyldioxaborolanyl-pyrazole (1 eq.) in dioxane/water (10:1) (3 mL) was added PdCl2(Ph3P)2 (0.1 eq.), K2CO3 (2 eq.). The mixture was heated in microwave at 90 C. for 4 hr. The crude product was then extracted with DCM, and purified with column chromatography on silica gel to provide pure 4-(3-bromo-4-chlorophenyl)-1-methyl-1H-pyrazole (2) in 80% yield.
2.1 g	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 2h;Microwave irradiation;	[00124] A mixture of 2-bromo-l-chloro-4-iodo benzene (10 mmol), 1-methyl-4- tetramethyldioxaborolanyl-pyrazole (10 mmol), bis(triphenylphosphine)-palladium(II)dichloride (0.4 mmol), and K2CO3 (10 mmol) in dioxane/water (10:1, 20 ml) was heated in microwave at 90C for 2 hr., the reaction mixture was poured over water, the crude product was extracted with DCM, and purified with silica gel column to give pure 4-(3-bromo-4-chlorophenyl)-1-methyl-1H-pyrazole (2.1g).

Reference： [1]Patent: US9604978,2017,B2 .Location in patent: Page/Page column 144-145
[2]Patent: WO2013/63385,2013,A1 .Location in patent: Paragraph 00124

35
[ 598-39-0 ]
[ 761446-44-0 ]
[ 1049730-40-6 ]

Yield	Reaction Conditions	Operation in experiment
50%		Preparation 112: 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 -/-pyrazole NaH (60%, 128 mg) was added to a solution of 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 -/-pyrazole (313 mg, 1 .61 mmol) in DMF (4 mL). After stirring for 15 minutes, 1 ,1 -difluoro-2-iodoethane (372 mg, 1 .94 mmol) in DMF (1 mL) was added. The resulting solution was stirred at 80C under microwave irradiation for 60 minutes. The reaction mixture was diluted with brine and extracted with EtOAc. The combined organic layers were washed with water, dried with Na2S04 and concentrated in vacuo to afford the title compound as a yellow oil that was used directly in the next step (21 0 mg, 50%). 1 H NMR (500 MHz, CDCI3): delta 7.84 (d, J = 0.7 Hz, 1 H), 7.77 (d, J = 0.7 Hz, 1 H), 6.25 - 5.93 (m, 1 H), 4.57 - 4.39 (m, 2H), 1 .33 (s, 12H). LCMS (ESI) Rt = 2.64 minutes MS m/z 259 [M+H]+

Reference： [1]Patent: WO2014/37750,2014,A1 .Location in patent: Paragraph 00297-00299

36
[ 116557-46-1 ]
[ 761446-44-0 ]
[ 1609531-35-2 ]

Yield	Reaction Conditions	Operation in experiment
77%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 110℃; for 2h;Inert atmosphere;	[00238j To a reaction vial charged with <strong>[116557-46-1]3-bromo-2-methoxyaniline</strong> (1.12 g, 5.54mmol), 1 -methyl-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole (1.499 g,7.21 mmol) in dioxane (6 mL) was added aqueous potassium phosphate (2.0 M) (5.54 ml,11.09 mmol). The resulting mixture was deoxygenated by bubbling argon through themixture for 5 minutes. [1,1 ?-Bis(diphenylphosphino)ferrocene] dichloropalladium(II)(PdC12(dppf), 0.122 g, 0.166 mmol) was then added and the mixture was heated at 110 Cfor 2 hours. The reaction was cooled, diluted with ethyl acetate (200 mL), washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford tan oil as the crude product mixture. This material was purified by silica gel flash chromatography using hexanes/ethyl acetate mixtures as the eluent. Fractions containingthe desired product were collected, combined, and concentrated under vacuum to afford0.87 g (77%) of the desired product as an oil which solidified upon standing. HPLC (Method N) = 0.89 minutes. LCMS MH+ 204.1.
77%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 110℃; for 2h;Inert atmosphere;	Preparation 10 To a reaction vial charged with <strong>[116557-46-1]3-bromo-2-methoxyaniline</strong> (from Step 4 of Preparation 9, 1.12 g, 5.54 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyrazole (1.499 g, 7.21 mmol) in dioxane (6 mL) was added aqueous potassium phosphate (2.0 M) (5.54 ml, 11.09 mmol). The resulting mixture was deoxygenated by bubbling argon through the mixture for ~5 min. PdCl2(dppf) (0.122 g, 0.166 mmol) was then added and the mixture was heated at 110 C for 2h. The reaction was cooled, diluted with EtOAc (200 mL), washed with water, brine, dried over anhyd sodium sulfate, filtered and concentrated to afford tan oil as the crude product mixture. This material was purified by silica gel flash chromatography using hexanes/ethyl acetate mixtures as the eluant. Fractions containing the desired product were collected, combined, and concentrated under vacuum to afford 0.87 g (77%) of the desired product (Preparation 10) as an oil which solidified upon standing. HPLC (method N) = 0.89 min. LCMS MH+ 204.1.
77%	In 1,4-dioxane; at 110℃; for 2h;Inert atmosphere;	To a solution containing dioxane (6 mL)<strong>[116557-46-1]3-bromo-2-methoxyaniline</strong> (from Step 4 of Preparation 9, 1.12 g, 5.54 mmol), 1-methyl-4- (4,4,5,5-tetramethyl- ,2-Dioxaborolan-2-yl) -lH-pyrazole (1.499 g, 7.21 mmol)(2.0 M) (5.54 ml, 11.09 mmol) was added to the reaction vial.The mixture was removed by bubbling argon through the resulting mixture for about 5 min.PdCl2 (dppf) (0.122 g, 0.166 mmol) was then added and the mixture was heated at 110 & lt; 0 & gt; C for 2 h.The reaction was cooled, diluted with EtOAc (200 mL), washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford a crude product mixture as a tan oil. The material was purified by flash chromatography using silica gel using a hexane / ethyl acetate mixture as a solvate. The fractions containing the desired product were collected, combined and concentrated in vacuo to afford 0.87 g (77%) of the desired product in the form of an oil (Preparation 10)It solidifies after standing.

Reference： [1]Patent: WO2014/74660,2014,A1 .Location in patent: Paragraph 00238
[2]Patent: WO2015/69310,2015,A1 .Location in patent: Paragraph 00178
[3]Patent: TWI582077,2017,B .Location in patent: Page/Page column 84

37
[ 630125-49-4 ]
[ 761446-44-0 ]
1-methyl-4-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29.9%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 0.333333h;Inert atmosphere;	A suspension of l-bromo-3 -nitro-5 -(trifluoromethyl)benzene (1 g, 3.70 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was added to a solution of l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (0.771 g, 3.70 mmol) in 1,4-dioxane (12 mL) and water (4 mL). PdCl2(dppf) (0.271 g, 0.370 mmol) and CS2CO3 (2.413 g, 7.41 mmol) were added and the mixture was heated at 100 C for 20 min. The mixture was then cooled to rt. Then the solution was concentrated and distributed between EA and saturated NaHC03 solution. The combined organic extracts were washed with brine, dried over MgSO/i, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA = 1 : 1). All fractions found to contain product by TLC (PE/EA = 5: 1, Rf = 0.3) were combined and concentrated to yield a light yellow solid of l-methyl-4-(3-nitro-5-(trifluoromethyl)phenyl)-lH-pyrazole (300 mg, 1.106 mmol, 29.9% yield): 1H NMR (400 MHz, CDC13) delta 8.47 (s, 1H), 8.31 (s, 1H), 7.99 (s, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 4.01 (s, 3H). ES-LCMS m/z 272 (M+H).

Reference： [1]Patent: WO2014/141187,2014,A1 .Location in patent: Page/Page column 164

38
[ 1111638-02-8 ]
[ 761446-44-0 ]
2-methyl-5-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 18h;Inert atmosphere;	A solution of 3.18 g (30.0 mmol) of sodium carbonate in 15 ml of water is added to a solution, kept under nitrogen, of 2.11 g (10.0 mmol) of <strong>[1111638-02-8]5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine</strong> and 3.54 g (17.0 mmol) of pinacolyl 1-methyl-1H-pyrazole-4-boronate in 30 ml of DMF. The mixture is heated to 80 C., 462 mg (0.40 mmol) of tetrakis(triphenylphosphine)palladium are added, and the mixture is stirred at 80 C. for 18 hours. The reaction mixture is cooled to room temperature, and 50 ml of water are added. The precipitate formed is filtered off with suction, washed with water and dried in vacuo: 2-methyl-5-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3-b]-pyridine as grey solid; HPLC/MS (A): 1.68 min, [M+H] 213.

Reference： [1]Patent: US2014/323481,2014,A1 .Location in patent: Paragraph 0330-0331

39
[ 6945-68-2 ]
[ 761446-44-0 ]
5-(1-methyl-1H-pyrazol-4-yl)-3-nitropyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 16h;Inert atmosphere;	Intermediate Example 7. 5-(l -Methyl-1H-pyrazol-4-yl)-3-nitropyridin-2-amine A solution of <strong>[6945-68-2]5-bromo-3-nitropyridin-2-amine</strong> (5 g, 23 mmol) in 1, 2-dimethoxy- ethane (50 ml) was degassed by N2 bubbling for 5 mm. l-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.2 g, 37 mmol, 1.5 eq) was added and the mixture was degassed for another 5 mm. Pd(dppf)C12 (1.88 g, 2.3 mmol, 0.1 eq) and aqueous sodium carbonate (6.1 g, 52 mmol, 2.5 eq) were added sequentially using the procedure of Intermediate Example 1 and the mixture was heated at 90 C for 16 h. The reaction mixture was quenched and extracted as in Intermediate Example 1. The solventwas distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 70% ethyl acetate in hex ahe) to afford the title product in 50 % yield (2.5 g) LC-MS (ESI: Caluelated mass: 219.08; Observed mass:220.1 [M+HJ + (rt: 0.22 mm).

Reference： [1]Patent: WO2014/162039,2014,A1 .Location in patent: Page/Page column 34; 35

40
[ 89402-43-7 ]
[ 761446-44-0 ]
[ 1151801-90-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2?,4?,6?-triisopropyl-1,1?-biphenyl][2-(2-aminoethyl)phenyl]palladium(ll); tetrabutylammomium bromide; In 2-methyltetrahydrofuran; at 70℃;Inert atmosphere;	[00316] 3-fluoro-2-hydrazinyl-5- (i-methyl-i H-pyrazol-4-yl)-pyridine was synthesized according to Scheme 14 by the following procedure. A 60 L jacketed reactor was fitted with a 5 L addition funnel and the jacket temperature was set to 20±5 °C. 36.0 L (15 Vol) of 2- methyltetrahydrofuran was added to the reactor via a 20 tm inline filter with vacuum using polypropylene transfer lines. The solution was sparged by bubbling nitrogen through a dipstick in the solution for 1±0.5 h with agitation. After 1 h the dipstick was removed but the nitrogen sweep continued. 1.55 kg of sparged 2-MeTHF was removed to be used as rinse volumes. 36.7 g of Pd2dba3, 75.6 g X-Phos, 259 g of tetrabutylammonium bromide, and 7397 g of potassium phosphate tribasic were added to the reactor. The manhole was rinsed with 0.125 kg of sparged 2-MeTHF. The reactor was agitated and the nitrogen sweep continued for 1±0.5 h. Then the nitrogen sweep was stopped and the reaction left under a positive pressure of nitrogen.[00317] 3.6 L (1.5 Vol) of sparged water was prepared in advance by bubbling nitrogen through a 4 L bottle of water for 1±0.5 h. The nitrogen sparged water was transferred to the 5 L addition funnel via a 20 tm inline filter with vacuum using polypropylene transfer lines, then slowly added to the reaction while maintaining the internal temperature at 20±5 °C. The 5 L addition funnel was replaced with a 2 L addition funnel. 2412 g of <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> was added to the 2 L addition funnel. The <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> was then added to the reaction through the 2 L addition funnel. The 2L addition funnel was rinsed with 0.060 kg of sparged 2-MeTHF. 83.8 g (1.15 equivalents) of 1-methylpyrazole-4-boronic acid, pinacol ester was added to reactor, the reactor was swept with nitrogen for 1±0.5 h, then left under a positive pressure of nitrogen. The internal temperature of the reactor was adjusted to 70±5 °C. The batch was agitated at 70±5 °C for at least 4 hours after the final reagent was added. A sample was taken from the reaction and the reaction progress assayed for conversion. The progress of the reaction was checked every 2 hours until the reaction was completed (e.g., greater than 99percent conversion). The batch was cooled to 20±5 °C.[00318] A 20percent w/v sodium bisulfite solution (12.0 L, 5 Vol) was prepared by charging 12.0 L of water then 2411 g sodium bisulfite to an appropriate container and agitating until homogeneous. The 20percent sodium bisulfite solution was transferred into the reactor and agitated for 30 minutes. The agitation was stopped, the phases allowed to settle, and the aqueous phase was removed. A 0.5 M potassium fluoride solution (12.0 L, 5 Vol) was prepared by charging 12.0 L of water and 348 g of potassium fluoride to an appropriate container and agitating until homogenous. The 0.5 M potassium fluoride solution was transfened into the reactor and agitated for 30 mm. The agitation was stopped, the phases were allowed to settle, and the aqueous phase was removed. A 25percent w/v sodium chloride solution (12.0 L, 5 Vol) was prepared by charging an appropriate container with 12.0 L of water and 2999 g of sodium chloride and agitating until homogeneous. The 25percent sodium chloride solution was transferred into the reactor and agitated for 30 mm. The agitation was stopped, the phases were allowed to settle, and the aqueous phase was removed from the reactor.[00319] The organic phase was distilled at constant volume (36 L, 15 Vol) while maintaining the internal temperature of the reactor at 50±5 °C by adjusting the vacuum pressure until no more than 0.3percent of water remained. 2-Methyltetrahydrofuran was added to the reactor as needed to maintain constant volume. The batch was cooled to 20 °C and transferred into drums. The batch was transfeffed using a polish filter (using a 5 tm inline filter) into a 60 L jacketed reactor withbatched concentrator attached. 1.2 L of 2-MeTHF was used to rinse the drums. The batch was concentrated to about 9 Vol while maintaining the internal temperature of the vessel at 50±5adjusting the vacuum pressure. The batch was then distilled at constant volume (22.0 L, 9Vol) while maintaining the internal temperature of the vessel at 50±5 °C by adjusting the vacuum pressure. Heptane was added with residual vacuum until a 15percent 2-MeTHF:heptane supernatant mixture was obtained. The pressure was brought to atmospheric pressure under nitrogen. The reactor was cooled to 20±5 °C over 2±2 h. The batch was agitated at 20±5 °C until an assay of the supernatant indicated that the amount of product was 7 mg/mL 2,3-difluoro-1-methyl-i H-pyrazol-4-yl)pyridine.[00320] A 10percent 2-MeTHF:heptane (7.2 L, 3 Vol) wash solution was prepared by mixing 720 mL of 2-MeTHF and 6.5 L of heptane. The batch sluffy was filtered through an Aurora filter fitted with a 25 tm polypropylene filter cloth, resulting in heavy crystals that required pumping with a diaphragm pump using polypropy...

Reference： [1]Patent: WO2014/210042,2014,A2 .Location in patent: Paragraph 00316-00320
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 2328 - 2342

41
[ 1150617-54-1 ]
[ 761446-44-0 ]
6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; ethanol; water; at 120℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation;	Into a microwave reaction tube, 300 mg compound a, 473 mg 1-methyl-1H-pyrazolo-4-borate pinacol ester and 628 mg potassium carbonate were disposed, 5 ml dioxane, 2.5 ml ethanol and 2.5 ml water were added into the microwave reaction tube, air was displaced for three times, under a nitrogen atmosphere, 62 mg complex of 1,1?-bis(diphenylphosphino) ferrocene palladium (II) dichloride and dichloromethane was added into the microwave tube, then the microwave tube was sealed, The microwave tube was placed into a microwave reactor, reaction was conducted at a temperature of 120 C. for 30 minutes, till the reaction was completed. The aforementioned reactant liquid was poured into 15 ml water, extracted three times with dichloromethane, the organic layer was dried over anhydrous sodium sulfate then concentrated, isolated by flash preparative chromatography to obtain compound n (m=275 mg, yield: 91%). (0192) 1H NMR (300 MHz, DMSO-d6) delta 13.29 (s, 1H), 8.80 (s, 1H), 8.36 (s, 1H), 8.24 (s, 1H), 8.07 (s, 2H), 3.90 (s, 3H).
86%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere; Sealed tube;	A solution of <strong>[1150617-54-1]6-bromo-1H-pyrazolo[4,3-b]pyridine</strong> (29) (330mg, 1.52 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (30) (378 mg, 1.82 mmol), PdCl2(dppf)-CH2Cl2 (61.9 mg, 80 mol) and K2CO3 (628mg, 4.54 mmol) in 1,4-dioxane:water (15 mL, 2:1, v) in a microwave tube was flushed with N2 for 5min then sealed. The tube was heated at 80 C for 2 h. Then the reaction mixture was evaporated todryness. The residue was purified by flash chromatography to give 31 (260 mg, 86% yield); LC-MSm/z (ESI) found (M + H)+ 200.0 (M + H)+; 1H-NMR (400 MHz, DMSO-d6) delta13.29 (s, 1H), 8.80 (s, 1H),8.36 (s, 1H), 8.24 (s, 1H), 8.07 (s, 2H), 3.90 (s, 3 H).
82%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;	<strong>[1150617-54-1]6-bromo-1H-pyrazolo[4,3-b]pyridine</strong> (400 mg, 2.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.4 mmol), K2CO3 (828 mg, 6 mmol), and Pd(dppf)Cl2(81.7 mg, 0.1 mmol) were dissolved in the solvent of 1,4-dioxane/H2O (v/v = 3:1, 20 mL). The resultingmixture was stirred at 80 C under Ar for 2 h. Then, the reaction mixture was evaporated to dryness.The residue was purified by flash chromatography to give compound 39 as a yellow hairy solidwith the yield of 82%. 1H-NMR (300 MHz, DMSO-d6, ppm) 13.29 (s, 1H), 8.80 (s, 1H), 8.36 (s, 1H),8.24 (s, 1H), 8.07 (s, 2H), 3.90 (s, 3H). ESI-MS: C10H10N7O2S, Exact Mass: 199.09, m/z 200.0 (M + 1)+.Retention time 2.51 min, >95% purity.

Reference： [1]Patent: US2016/137640,2016,A1 .Location in patent: Paragraph 0190; 0191
[2]Molecules,2017,vol. 22
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 2513 - 2529
[4]Molecules,2018,vol. 23

42
[ 6329-74-4 ]
[ 761446-44-0 ]
2-hydroxy-5-(1-methyl-1H-pyrazol-4-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 26h;Inert atmosphere;	Preparation 1632-hydroxy-5-(1 -methyl-i H-pyrazol-4-yl) benzamide A solution of <strong>[6329-74-4]5-bromo-2-hydroxybenzamide</strong> (50 g, 23i mmol), i-methyl-4-(4,4,5,5-tetramethyl- i,3,2-dioxaborolan-2-yl)-1H-pyrazole (57.78 g, 277 mmol) and sodium carbonate (78.59 g, 740 mmol) in dioxane/water (400 mLI250 mL) was degassed with nitrogen. 1,1- bis(diphenylphosphino)ferrocene palladium (II) dichloride (14.19 g, 17.3 mmol) was added and the reaction heated to 100C for 26 hours. The reaction was cooled, concentrated in vacuo andpurified using silica gel column chromatography eluting with 10% MeOH in DCM to afford thetitle compound (40 g, 67%).1H NMR (400 MHz, DMSO-d6): O ppm 3.80 (5, 3H), 6.80 (d, 1H), 7.50 (m, 1H), 7.80 (5, 1H), 7.90(m, 1H), 8.00 (5, 1H), 8.00 (d, 2H), 8.40 (5, 1H).MS mlz 216 [M-H]

Reference： [1]Patent: WO2015/92610,2015,A1 .Location in patent: Page/Page column 181

43
[ 75711-00-1 ]
[ 761446-44-0 ]
3-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; potassium carbonate; In water; acetonitrile; at 20℃; for 1h;Inert atmosphere; Reflux;	A stirred solution of Pd(OAc)2 (89 mg, 0.13 mmol) and S-phos (273 mg, 0.66 mmol) in CH3CN: H2O (2: 1, 60 mL) was purged under an argon atmosphere for 15 min. Then <strong>[75711-00-1]2-chloro-3-methoxy-5-nitropyridine</strong> (2.5 g, 13.29 mmol), 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.6 g, 17.30 mmol) and potassium carbonate (3.67 g, 26.59 mmol) was added at room temperature. The reaction mixture and stirred at reflux for 1 h. After consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 30-80% EtOAc:hexanes to afford 3-methoxy-2-(1-methyl-1H-pyrazol- 4-yl)-5-nitropyridine (2.6 g, 84%) as a yellow solid. 1H-NMR (DMSO-d6, 400 MHz): delta 8.95 (d, 1H), 8.50 (s, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 4.10 (s, 3H), 3.93 (s, 3H); LCMS: 234.9 (M+1); (column; X-Select CSH C-18 (50 × 3.0 mm, 3.5 mum); RT 2.94 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity BEH C-18 2.1 X 50 mm, 1.7 mum); RT 1.87 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 50% EtOAc:hexane (Rf: 0.3).
84%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; potassium carbonate; In water; acetonitrile; for 1h;Inert atmosphere; Reflux;	Synthesis of 3-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-5-nitropyridine A stirred solution of Pd(OAc)2 (89 mg, 0.13 mmol) and S-phos (273 mg, 0.66 mmol) in CH3CN: H2O (2:1, 60 mL) was purged under an argon atmosphere for 15 min. Then <strong>[75711-00-1]2-chloro-3-methoxy-5-nitropyridine</strong> (2.5 g, 13.29 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.6 g, 17.30 mmol) and potassium carbonate (3.67 g, 26.59 mmol) was added at room temperature. The reaction mixture and stirred at reflux for 1 h. After consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2100 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 30-80% EtOAc:hexanes to afford 3-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-5-nitropyridine (2.6 g, 84%) as a yellow solid. 1H-NMR (DMSO-d6, 400 MHz): delta 8.95 (d, 1H), 8.50 (s, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 4.10 (s, 3H), 3.93 (s, 3H); LCMS: 234.9 (M+1); (column; X-Select CSH C-18 (503.0 mm, 3.5 mum); RT 2.94 min 0.05% Aq TFA:ACN; 0.80 mL/min); UPLC (column; Acquity BEH C-18 2.1*50 mm, 1.7 mum); RT 1.87 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 50% EtOAc:hexane (Rf: 0.3).

Reference： [1]Patent: WO2015/109109,2015,A1 .Location in patent: Paragraph 0736
[2]Patent: US2017/44182,2017,A1 .Location in patent: Paragraph 1017

44
[ 68819-84-1 ]
[ 761446-44-0 ]
(4-(1-methyl-1H-pyrazol-4-yl)phenyl)methanamine dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9.18 g		A mixed solution of tert-butyl 4-bromobenzylcarbamate (12.0 g), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.4 g), sodium carbonate (6.64 g) and tetrakis(triphenylphosphine)palladium(0) (2.42 g) in 1,2-dimethoxyethane (120 mL)-water (40 mL) was stirred under an argon atmosphere at 90C overnight. The reaction solution was concentrated, and the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was solidified with diisopropyl ether to give a crudely purified product. The crudely purified product was dissolved in ethyl acetate (90 mL), 4N hydrochloric acid (ethyl acetate solution) (50 mL) was added, and the mixture was stirred at room temperature for 3 hr. The precipitate was collected by filtration to give the title compound (9.18 g). 1H NMR (300 MHz, DMSO-d6) delta 3.86 (3H, s), 3.98 (2H, q, J = 5.7 Hz), 7.45-7.50 (2H, m), 7.56-7.64 (3H, m), 7.90 (1H, d, J = 0.8 Hz), 8.18 (1H, s), 8.46 (3H, brs).

Reference： [1]Patent: EP2921480,2015,A1 .Location in patent: Paragraph 0319; 0320

45
[ 105884-19-3 ]
C₇H₉BNO₄ [ No CAS ]
[ 761446-44-0 ]
(Z)-1-(2-(1-methyl-1H-pyrazol-4-yl)-5-(prop-1-en-1-yl)phenyl)ethan-1-one [ No CAS ]
(E)-1-(2-(1-methyl-1H-pyrazol-4-yl)-5-(prop-1-en-1-yl)phenyl)ethan-1-one [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2015,vol. 54,p. 9976 - 9979
Angew. Chem.,2015,vol. 127,p. 10114 - 10117,4

46
[ 944401-69-8 ]
[ 761446-44-0 ]
4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 120℃; for 0.2h;Microwave irradiation;	Step 2. 4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine To the reaction mixture of <strong>[944401-69-8]5-bromo-4-fluoropyridin-2-amine</strong> (369 mg, 1.932 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (603 mg, 2.90 mmol), PdCl2(dppf)DCM (141 mg, 0.193 mmol) and DME (9.660 muL), 2M Na2CO3 (3.220 mL) was added. The reaction mixture was heated at microwave synthesizer (120 C., 12 min). To the reaction mixture, anhydrous sodium sulfate was added, filtered, and concentrated. The crude product was purified by flash chromatography eluting with 0-100% EtOAc (containing 10% of MeOH/heptane to provide 280 mg of desired product in 75% yield. LCMS (m/z): 193.1 (MH+), 0.35 min.

Reference： [1]Patent: US9242996,2016,B2 .Location in patent: Page/Page column 92; 93

47
[ 54932-72-8 ]
[ 761446-44-0 ]
4-(4-chloro-3-methylphenyl)-1-methyl-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In tetrahydrofuran; water; at 120℃; for 1h;Microwave irradiation;	a. 4-(4-chloro-3-methylphenyl)-1-methyl-1H-pyrazole A mixture of <strong>[54932-72-8]2-chloro-5-bromotoluene</strong> (305 mg, 1.48 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (315 mg, 1.51 mmol), Pd(dppf)Cl2 (130 mg, 0.16 mmol), and K2CO3 (400 mg, 2.89 mmol) in a mixture of THF (4 mL) and water (1.2 mL) was heated at 120 C. for 1 h under microwave irradiation. The reaction mixture was concentrated in vacuo and purified by Biotage (SNAP 25 g column, cyclohexane/EtOAc 90/10->50/50) to give the title compound as a brown oil (215 mg, 70%).

Reference： [1]Patent: US2016/16951,2016,A1 .Location in patent: Paragraph 0267; 0268

48
[ 761446-44-0 ]
[ 78242-20-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	With dihydrogen peroxide; sodium hydroxide; In tetrahydrofuran; at 0 - 25℃; for 3h;Inert atmosphere;	General procedure: To a cold (0 C, ice bath) solution of 1-alkyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.0 g, 120.2 mmol) in tetrahydrofuran (600.9 mL, 0.2 M) was slowly added aqueous sodium hydroxide (80.1 mL, 3 M, 240.3 mmol) followed by Hydrogen peroxide (27.3 mL, 240.3 mmol). The reaction mixture was stirred at 0-25 C for 3 h. The mixture was carefully neutralized with 12N HCl (18.6 mL) and diluted with a mixture of dichloromethane and methanol (90:10, 200 mL). The aqueous layer was extracted with a mixture of dichloromethane and methanol (90:10, 3*200 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography to afford 1-alkyl-1H-pyrazol-4-ol 12.
	With dihydrogen peroxide; sodium hydroxide; In tetrahydrofuran; at 20℃; for 2h;	At 20°C., hydrogen peroxide (599.71 mg, 5.29 mmol, 508.23 muL, 30percent purity, 1.10 eq) and sodium hydroxide (211.64 mg, 5.29 mmol, 1.10 eq) was added into a solution of Compound 48-a (1.00 g, 4.81 mmol, 1.00 eq) in tetrahydrofuran (30.00 mL). The mixture was stirred at 20°C. for 2 h. The reaction mixture was quenched by adding a saturated solution of sodium sulfite (10 mL), and extracted with ethyl acetate (5 mL3). The combined organic phase was washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 48-b . 1H NMR (400 MHz, CDCl3) delta ppm 7.13 (s, 1H) 7.03 (s, 1H) 3.78 (s, 3H) 1.25 (s, 8H).

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 4587 - 4590
[2]Patent: WO2016/11930,2016,A1 .Location in patent: Page/Page column 138
[3]Journal of Medicinal Chemistry,2016,vol. 59,p. 1370 - 1387
[4]Patent: US2019/225597,2019,A1 .Location in patent: Paragraph 0596-0598

49
[ 16732-69-7 ]
[ 761446-44-0 ]
ethyl 7-(1-methyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium phosphate; methanesulfonic acid(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II); In 1,4-dioxane; water; at 20 - 100℃; for 1h;Inert atmosphere;	To a solution of <strong>[16732-69-7]ethyl 7-bromo-1H-indole-2-carboxylate</strong> (100 mg, 0.37 mmol) in dioxane (3 mL) and H20 (0.5 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (93 mg, 0.45 mmol), K3P04 (198 mg, 0.93 mmol) andXPhos- G2-Pd-preCat (14.7 mg, 0.0 19 mmol) at rt. The reaction was stirred under N2 at100 C for 1 h. The reaction was cooled to rt. The solvent was removed. Purification by normal phase chromatography provided Intermediate 136 (94 mg, 94%) as a white solid. ?H NMR (400MHz, CDC13) oe 8.92 (br. s., 1H), 7.82 (s, 1H), 7.69 (s, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.31 (dd,J=7.3, 1.1 Hz, 1H), 7.27 (d,J2.2 Hz, 1H), 7.18 (dd,J7.9, 7.3 Hz,1H), 4.41 (q, J=7.2 Hz, 2H), 4.03 (s, 3H), 1.42 (t, J=7.2 Hz, 3H). LC-MS(ESI) m/z: 270.1 [M+H].

Reference： [1]Patent: WO2016/10950,2016,A1 .Location in patent: Page/Page column 238; 239

50
[ 669066-91-5 ]
4-((aR)-6-aminospiro[3.3]heptan-2-yl)phthalazin-1-(2H)-one trifluoroacetate [ No CAS ]
[ 761446-44-0 ]
3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%		To a solution of Intermediate 2 (20 mg, 0.078 mmol) in DMF (1 mL) were added 5- bromo-3-fluoropicolinic acid (17.2 mg, 0.078 mmol), HATU (32.8 mg, 0.086 mmol) and DIEA (0.068 mL, 0.39 mmol) at rt. The reaction was stirred under N2 at rt for 1 h. To thereaction were added 1 -methyl-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H- pyrazole (24.5 mg, 0.12 mmol), K3P04 (50 mg, 0.24 mmol), water (0.2 mL), and XPhosG2-Pd-preCat (6.2 mg, 7.8 jimol). The reaction was heated at 90 C for 2 h, and then it was cooled to rt. It was filtered. Purification by reverse phase chromatography provided Example 463 (7.4 mg, 21%). ?H NMR (500MHz, DMSO-d6) oe 12.46 (s, 1H), 8.73 (d,J7.9Hz, 1H), 8.71 (br. s., 1H), 8.42(s, 1H), 8.25 (d,J7.6Hz, 1H), 8.11 (s, 1H), 8.04(d, J12.2 Hz, 1H), 7.95 - 7.80 (m, 3H), 4.40 - 4.26 (m, 1H), 3.89 (s, 3H), 3.95 - 3.82 (m,1H), 2.57 (d, J=9.5 Hz, 2H), 2.45 - 2.33 (m, 3H), 2.32 - 2.25 (m, 1H), 2.22 (br. s., 1H),2.15 - 2.04 (m, 1H). LC-MS(ESI) m/z: 459.1 [M+H]. Analytical HPLC RT = 1.44 mm(Method E), 1.48 mm (Method F).

Reference： [1]Patent: WO2016/10950,2016,A1 .Location in patent: Page/Page column 534; 535

51
[ 16461-94-2 ]
[ 824-94-2 ]
[ 761446-44-0 ]
[ 930286-90-1 ]
C₃₁H₃₃N₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		3-Amino-4-bromopyrazole (5 g, 30.9 mmol) and 4-methoxybenzyl chloride (21 g, 134 mmol, 4.3 equiv.) werecombined in anhydrous DMF (25 mL) and added dropwise to a stirred suspension of sodium hydride (60% dispersionin mineral oil, 6.25 g, 156 mmol, 5 equiv.) in anhydrous DMF (50 mL). The presuming suspension was stirred 2 days atroom temperature. Water (300 mL) was added slowly and the resulting mixture was extracted with ether (4 x 350 mL).The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude product was dissolved in dichloromethane and purified by silica gel chromatography using a gradient from 10% to 20% ethyl acetate-hexanes. The product, a white solid, is obtained as a 60:40 mixture of the 1-benzylated-1 H product and the 2-benzylated-2H product (14.96 g total, 93% yield). The compound from Preparative Example 100-C (10 g, 19.15 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.95 g, 57.42 mmol, 3.0 equiv.) were combined in 120 mL dimethoxyethane. 2M sodiumcarbonate solution (30 mL, 60 mmol, 3.1 equiv.) was added followed by tetrakis(triphenylphosphine) palladium(0) (2.36g, 2.04 mmol, 0.11 equiv.). The mixture was stirred 16 hours at 90 C. After cooling to room temperature, water (200mL) and brine (50 mL) were added and the mixture was extracted with ethyl acetate (2 x 200 mL). The extracts werecombined, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Thecrude product was dissolved in dichloromethane and purified by silica gel chromatography using a gradient from 33%to 66% ethyl acetate-hexanes. The 1-benzylated-1 H product (Rf = 0.27 in 66% ethyl acetate-hexanes) elutes first,followed by the 2-benzylated-2H-product (Rf= 0.19 in 66% ethyl acetate-hexanes). The product is obtained as a yellowsolid (5.60 g total, 56% yield) with an isomeric ratio of 62:38.

Reference： [1]Patent: EP2069350,2016,B1 .Location in patent: Paragraph 0087-0090

52
[ 16461-94-2 ]
[ 824-94-2 ]
[ 761446-44-0 ]
[ 930286-91-2 ]

Yield	Reaction Conditions	Operation in experiment
77%		3-Amino-4-bromopyrazole (5 g, 30.9 mmol) and 4-methoxybenzyl chloride (21 g, 134 mmol, 4.3 equiv.) werecombined in anhydrous DMF (25 mL) and added dropwise to a stirred suspension of sodium hydride (60% dispersionin mineral oil, 6.25 g, 156 mmol, 5 equiv.) in anhydrous DMF (50 mL). The presuming suspension was stirred 2 days atroom temperature. Water (300 mL) was added slowly and the resulting mixture was extracted with ether (4 x 350 mL).The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude product was dissolved in dichloromethane and purified by silica gel chromatography using a gradient from 10% to 20% ethyl acetate-hexanes. The product, a white solid, is obtained as a 60:40 mixture of the 1-benzylated-1 H product and the 2-benzylated-2H product (14.96 g total, 93% yield). The compound from Preparative Example 100-C (10 g, 19.15 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.95 g, 57.42 mmol, 3.0 equiv.) were combined in 120 mL dimethoxyethane. 2M sodiumcarbonate solution (30 mL, 60 mmol, 3.1 equiv.) was added followed by tetrakis(triphenylphosphine) palladium(0) (2.36g, 2.04 mmol, 0.11 equiv.). The mixture was stirred 16 hours at 90 C. After cooling to room temperature, water (200mL) and brine (50 mL) were added and the mixture was extracted with ethyl acetate (2 x 200 mL). The extracts werecombined, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Thecrude product was dissolved in dichloromethane and purified by silica gel chromatography using a gradient from 33%to 66% ethyl acetate-hexanes. The 1-benzylated-1 H product (Rf = 0.27 in 66% ethyl acetate-hexanes) elutes first,followed by the 2-benzylated-2H-product (Rf= 0.19 in 66% ethyl acetate-hexanes). The product is obtained as a yellowsolid (5.60 g total, 56% yield) with an isomeric ratio of 62:38. The compound from Preparative Example 110-C (4.3 g, 8.22 mmol) was dissolved in trifluoroacetic acid (70mL) and stirred 17 hours at reflux. After cooling, the trifluoroacetic acid was removed under reduced pressure. Theresulting residue was dissolved in tetrahydrofuran (100 mL), methanol (50 mL) and 4N aqueous sodium hydroxidesolution (25 mL, 100 mmol, 12 equiv.). The mixture was stirred 4 hours at 70 C then cooled to room temperature. Themixture was concentrated and the residue was suspended in brine (100 mL) and water (40 mL). This mixture wasextracted with 20% isopropanol in ethyl acetate (8 x 100 mL). The extracts were combined, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The crude product was dissolved in 10% methanol in dichloromethaneand purified by silica gel, chromatography using 10% methanol-dichloromethane followed by 10% 7N ammoniain methanol-dichloromethane. The product is obtained as a tan to brown solid (1.03 g, 77% yield).

Reference： [1]Patent: EP2069350,2016,B1 .Location in patent: Paragraph 0087-0092

53
[ 877264-77-2 ]
[ 76-05-1 ]
[ 761446-44-0 ]
[ 1448429-59-1 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of tert-butyl 6-bromo-lH-indazole-l-carboxylate (400 mg, 1.34 mmol), 1- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (420 mg, 2.02 mmol), bis(tri-t-butylphosphine)palladium(0) (220 mg, 0.27 mmol) and K2C03 (372 mg, 2.69 mmol) in 1,4-dioxane (6 mL) and H20 (200 mu) was micro waved at 110 °C for lh and at 130 °C for lh. The filtration removed the solid and washed with DCM. The combined filtrate was concentrated in vacuo. The residue was treated with TFA (5 ml), stirred at rt for 30 min), concentrated in vacuo, basified by addition of 7N NH3 in MeOH (10 ml) and purified by ISCO flash chromatography (eluted with 0-100percent EtOAc / hexane) to provide 6-(l -methyl- lH-pyrazol-4-yl)- lH-indazole as the yellow solid.

Reference： [1]Patent: WO2016/36586,2016,A1 .Location in patent: Page/Page column 31

54
[ 106-37-6 ]
[ 761446-44-0 ]
[ 1191616-45-1 ]

Yield	Reaction Conditions	Operation in experiment
75%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere;	Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 1-methyl-4-(tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (2.00 g, 9.61 mmol), 1 ,4-dibromobenzene (2.30 g, 9.75 mmol), Pd(PPh3)4 (550 mg, 0.48 mmol), potassium carbonate (2.60 g, 18.8 mmol), dioxane (40 ml_) and water (10 ml_). The resulting solution was stirred for 3 h at 80C. The resulting mixture was evaporated to dryness. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 1.70 g (75%) of 4-(4- bromophenyl)-1-methyl-1 H-pyrazole as a yellow solid.
47%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 18h;Inert atmosphere; Sealed tube;	1-methylpyrazole-4-boronic acid pinacol ester (300 mg, 1.44 mmol) 1,4-dibromobenzene (0.2 mL, 1.6 mmol) and potassium carbonate (399 mg, 20 2.9 mmol) were mixed in water (1 mL) and 1,4-dioxane (4 mL) and the mixture degassed with N2. tetrakis(triphenylphosphine)palladium(0) (167 mg, 0.14 mmol) was added and the tube sealed and heated at 80 C for 18h. The reaction mixture was reduced in vacuo directly onto silica and purified by silica column chromatography, eluting with 5-40% EtOAc in Pet. Ether to afford 4-(4-bromophenyl)-1-methyl-pyrazole (160 mg, 0.67 mmol, 47% yield) as a white solid. LC-MS (ES+, 25 Method A): 1.66 min, m/z 237.1 [M+H]+.

Reference： [1]Patent: WO2016/41618,2016,A1 .Location in patent: Page/Page column 69
[2]Patent: WO2019/145729,2019,A1 .Location in patent: Page/Page column 261

55
[ 22190-35-8 ]
[ 761446-44-0 ]
6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 120℃; for 16h;Inert atmosphere;	A mixture of <strong>[22190-35-8]6-bromo-1,2,3,4-tetrahydroquinoline</strong> (17.0 g, 80.16 mmol), 1-methyl-4-(4,4,5,5- tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole (25.0 g, 120.23 mmol), K2C03 (33.2 g,240.47 mmol) and [1,1 ?-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (5.8 g, 8.02 mmol) in dioxane/H20 (5:1, 150 mL) was heated to 120 C for 16 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc = 1/1) to give the title product (8.0 g, 47%) as a yellow solid. ?HNMR (400 MHz, CD3OD) oe 7.71 (s, 1H), 7.62 (s, 1H), 7.08 -7.06 (m, 2H), 6.50 (d, J= 8.4 Hz, 1H), 3.87 (s, 3H), 3.23 (t, J= 5.2 Hz, 1H), 2.75 (t, J= 6.4 Hz, 1H), 1.94 - 1.88 (m, 2H).
47%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 120℃; for 16h;Inert atmosphere;	To a solution of <strong>[22190-35-8]6-bromo-1,2,3,4-tetrahydroquinoline</strong> (17.0 g, 80.16 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-IH-pyrazole (25.0 g, 120.23 mmol) and K2C03 (33.2 g, 240.47 mmol) in dioxane / 1120 (5:1, 150 mL) was added [1,1?- bis(diphenylphosphino)ferrocene]diehloropalladium(11) (5.8 g, 8.02 mmol). The mixture was heated to 120 C for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude the title compound (8.0 g, 47%) as a yellow solid. ?11 NMR (400 MHz, CD3OD) 13 7.71 (s, 111), 7.62 (s, IH), 7.07 (d,J= 6.0 Hz, 2H), 6.50 (d,J= 8.4 Hz, IH), 3.87 (s, 311), 3.23 (t,J5.2 Hz, 2H), 2.75 (t, Jr 6.4 Hz, 2H), 1.94 - 1.88 (m, 2H).

Reference： [1]Patent: WO2016/55028,2016,A1 .Location in patent: Page/Page column 259
[2]Patent: WO2016/86200,2016,A1 .Location in patent: Page/Page column 199; 200
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 9162 - 9183

56
[ 63839-24-7 ]
[ 761446-44-0 ]
6-(1-methyl-1H-pyrazol-4-yl)indoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 12h;Inert atmosphere;	To a solution of <strong>[63839-24-7]6-bromoindoline</strong> (5 g, 25.1 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1fI-pyrazole (6.3 g, 30.3 mmol) in dioxane (80 mL) and water (20mL) was added Na2CO3 (8.03 g, 75.7 mmol) and [1,1?- bis(diphenylphosphino)ferrocenejdichloropalladium(II) (1.83 g, 2.51 mniol). The mixtue was heated to 100 °C for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (200 mL) was added and the mixture was extracted with EtOAc (200 mLx 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether / EtOAc = 1: 1) to give the title compound (1.8 g, 36percent) as a yellow solid. ?H NMR (400 MHz, CDC13) 67.70 (s, 1H), 7.54 (s, IH), 7.10 (d,.J= 8.0 Hz, IH), 6.83 (d,J8.0 lIz, 1H), 6.77 (s, lH), 3.93 (s, 3H), 3.59 (t, J 8.4 Hz, 2H), 3.04 (t,J 8.4 Hz, 2H).

Reference： [1]Patent: WO2016/86200,2016,A1 .Location in patent: Page/Page column 296

57
[ 1191028-50-8 ]
[ 761446-44-0 ]
5-chloro-6-(1-methyl-1H-pyrazol-4-yl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 12.0h;Inert atmosphere;	To a solution of <strong>[1191028-50-8]6-bromo-5-chloro-1H-indole</strong> (500 mg, 2.17 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-IH-pyrazole (0.54 g, 2.60 rnrnol) and Na2CO3 (0.69 g, 6.51 mmol) in DME/1120 (10 mL, 4: 1) was added bis(triphenylphosphine)palladium(II) dichloride (140 mg, 0.22 mmol). The mixture was heated to 120 C for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL x 3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether / EtOAc3: 1) to give the title compound (0.38 g, 76%) as a light yellow solid.

Reference： [1]Patent: WO2016/86200,2016,A1 .Location in patent: Page/Page column 328

58
[ 885519-01-7 ]
[ 761446-44-0 ]
4-chloro-6-(1-methyl-1H-pyrazol-4-yl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 12h;Inert atmosphere;	To a solution of <strong>[885519-01-7]6-bromo-4-chloro-1H-indole</strong> (500 mg, 2.17 mmol), 1-methyl-4-(4,4,5,5-tetramcthyl-I ,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.54 g, 2.60 mmol) and Na2CO3 (0.69 g,6.51 minol) in DME/T-120 (10 mL, 4: 1) was added bis(triphenylphosphine)palladium(II) dichloride (140 mg, 0.22 mmol). The mixture was heated to 120 C for 12 h under a nitrogen the mixture was extracted with EtOAc (10 mL x3). The combined organic layers werewashed with sat. aq. NaHCO3 (10 mL x 3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether EtOAc= 3: 1) to give the title compound (0.38 g, 76%) as a light yellow solid.

Reference： [1]Patent: WO2016/86200,2016,A1 .Location in patent: Page/Page column 330; 331

59
[ 885520-59-2 ]
[ 761446-44-0 ]
4-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 120℃; for 12h;Inert atmosphere;	To a solution of 6-bromo-4-fluoro-lH-indole (500 mg, 2.34 mmol), 1-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-IH-pyrazole (0.63 g, 3.04 mmol) and K2C03 (0.97g.7.01 mmol) in dioxane/H20 (10.0 mL, 4: 1) was added j1,1?- bis(diphenylphosphino)ferrocenejdichloropalladium(II) (171 mg, 0.24 mmol). The mixture was heated to 120 C for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL x 3), driedover anhydrous Na2SO4, filtered and concentrated in vacuo. The emde residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3 : 1) to give the title compound (0.33 g, 66%) as a light yellow solid.

Reference： [1]Patent: WO2016/86200,2016,A1 .Location in patent: Page/Page column 333

60
[ 3993-78-0 ]
[ 761446-44-0 ]
4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.5%	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 15h;	To a degassed solution of 4-chloropyrimidin-2-amine (800 mg, 6.18 mmol), solid 1- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1927 mg, 9.26 mmol) and K3P04 (3932 mg, 18.53 mmol) in 1,4-Dioxane (20 mL),Water (5.00 mL) stirred under at room temp. Then added PdCl2(dppf)-CH2Cl2 adduct (756 mg, 0.926 mmol)and degassed for 5 min. Then reaction mixture was stirred at 80 C for 15h 30min.The reaction mixture was monitored by TLC. The reaction was cooled to RT. The organic phase was evaporated and added water 50 mL and Extracted with Ethyl acetate (3x 70 ml) and washed with saturated brine 50 mL dried over Na2S04 and evaporated in vacuum to give the crude product. The crude compound was purified by flash column chromatography (Neutral alumina, eluent: 90% EtOAc in Pet ether) to afford 4-(l-methyl- lH-pyrazol-4-yl)pyrimidin-2-amine (600 mg, 3.42 mmol, 55.5 % yield) as an off white solid, LCMS (m/z): 176.1 [M+H]+.

Reference： [1]Patent: WO2016/79709,2016,A1 .Location in patent: Page/Page column 259-260

61
[ 2302-25-2 ]
[ 76513-69-4 ]
[ 761446-44-0 ]
[ 1254162-31-6 ]
1-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: To a stirred mixture of DMF (15 mL) and NaH (60% dispersion in mineral oil, 539 mg, 21 mmol) at 0C under argon was added <strong>[2302-25-2]4-bromo-1H-imidazole</strong> (3 g, 20 mmol) in one portion. The mixture was stirred for 5 min at 0C. A solution of 2-(trimethylsilyl)ethoxymethyl chloride (4.3 mL, 24 mmol) in DMF (3 mL) was added dropwise. Afterstirring at 0 C for 1 h, the mixture was warmed slowly to rt and stirred for 6 h. The mixture was then partitioned betweenEtOAc (100 mL) and water (50 mL). The EtOAc layer was separated and washed with brine, dried over Na2SO4, filtered,and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel flash chromatography(eluting with a gradient of 100% hexanes to 100% EtOAc) to afford a regioisomeric mixture of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole as an oil (2.9 g, 53%). Step 2: To a mixture of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (345 mg, 1.3 mmol) from Step 1 of this Example, and 1-methylpyrazole-4-boronicacid pinacol ester (390 mg, 1.9 mmol) in DME (3 mL) was added K2CO3 (691, 5 mmol). Argon was bubbled into themixture for 5 min followed by the addition of Pd(PPh3)2Cl2 (44 mg, 0.06 mmol). Argon was bubbled into the mixture foran additional 5 min. Then the reaction vessel was sealed and the mixture was heated at 100 C for 15 h. The mixturewas cooled to rt, then partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was separated andwashed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified viasilica gel flash chromatography eluting with a gradient of 100% CH2Cl2 to 10% MeOH in CH2Cl2 to afford a regioisomericmixture of 1-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-1H-pyrazole and 1-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-1H-pyrazole as an oil (280 mg, 82%). LCMS (ESI) m/z 280 (M+H)+.

Reference： [1]Patent: EP2766359,2016,B1 .Location in patent: Paragraph 0415; 0416

62
[ 2302-25-2 ]
[ 761446-44-0 ]
4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
248 mg		Step 1: To a stirred mixture of DMF (15 mL) and NaH (60% dispersion in mineral oil, 539 mg, 21 mmol) at 0C under argon was added <strong>[2302-25-2]4-bromo-1H-imidazole</strong> (3 g, 20 mmol) in one portion. The mixture was stirred for 5 min at 0C. A solution of 2-(trimethylsilyl)ethoxymethyl chloride (4.3 mL, 24 mmol) in DMF (3 mL) was added dropwise. Afterstirring at 0 C for 1 h, the mixture was warmed slowly to rt and stirred for 6 h. The mixture was then partitioned betweenEtOAc (100 mL) and water (50 mL). The EtOAc layer was separated and washed with brine, dried over Na2SO4, filtered,and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel flash chromatography(eluting with a gradient of 100% hexanes to 100% EtOAc) to afford a regioisomeric mixture of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole as an oil (2.9 g, 53%). Step 2: To a mixture of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (345 mg, 1.3 mmol) from Step 1 of this Example, and 1-methylpyrazole-4-boronicacid pinacol ester (390 mg, 1.9 mmol) in DME (3 mL) was added K2CO3 (691, 5 mmol). Argon was bubbled into themixture for 5 min followed by the addition of Pd(PPh3)2Cl2 (44 mg, 0.06 mmol). Argon was bubbled into the mixture foran additional 5 min. Then the reaction vessel was sealed and the mixture was heated at 100 C for 15 h. The mixturewas cooled to rt, then partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was separated andwashed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified viasilica gel flash chromatography eluting with a gradient of 100% CH2Cl2 to 10% MeOH in CH2Cl2 to afford a regioisomericmixture of 1-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-1H-pyrazole and 1-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-1H-pyrazole as an oil (280 mg, 82%). LCMS (ESI) m/z 280 (M+H)+. Step 3: A mixture of 1-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-1-pyrazole and 1-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-1H-pyrazole (170 mg, 0.7 mmol) from Step 2 of this Examplewere stirred in a 1:1 mixture of TFA and CH2Cl2 (5 mL) for 15 h. The mixture was then concentrated under reducedpressure to afford 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole (248 mg) as an oil and was used in the next step withoutfurther purification. LCMS (ESI) m/z 149 (M+H)+.

Reference： [1]Patent: EP2766359,2016,B1 .Location in patent: Paragraph 0415; 0416; 0417

63
[ 1015610-31-7 ]
[ 761446-44-0 ]
4-chloro-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; at 100℃; for 13h;	[0289] 1,4-Dioxane (15 mL), a 2 M aqueous solution of sodium carbonate (3 mL) and PdCl2(dppf)CH2Cl2 (122 mg)were added to <strong>[1015610-31-7]4-chloro-5-iodo-1H-pyrrolo[2,3-b]pyridine</strong> (835 mg) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (749 mg), and the temperature of the obtained mixture was then increased to 100C, followed bystirring for 13 hours. Thereafter, water was added to the reaction mixture for dilution, and the obtained mixture was thenextracted with ethyl acetate. The gathered organic layer was washed with a saturated saline, dried over anhydroussodium sulfate, and then concentrated under a reduced pressure. The obtained residue was purified by silica gel chromatography(chloroform : methanol) to obtain a product of interest (573 mg, yield: 82%).ESI-MS m/z 233 (MH+)

Reference： [1]Patent: EP3070086,2016,A1 .Location in patent: Paragraph 0289

64
[ 179692-08-1 ]
[ 761446-44-0 ]
ethyl 4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With bis-triphenylphosphine-palladium(II) chloride; cesium fluoride; In water; acetonitrile; at 70℃;Sealed tube; Microwave irradiation;	General procedure: Aryl Halide, tetrakis (triphenylphosphine)palladium or Palladium (II)bis(triphenylphosphine) dichloride (0.05eq) and boronic acid or pinnacol ester (1.2eq) were weighed out into a microwave vessel or sealed tube. Acetonitrile (3mL/mmol) and a 1M aqueous solution of Sodium Carbonate (3eq) were added. The vessel was capped and heated thermally 3-18hrs at 100C. Upon completion, the reaction was cooled and crude product was either triterated via addition of water and collection by filtration or extracted with sat ammonium chloride and DCM. If the crude product was an intermediate, it was taken into the next step in most cases w/o further purification or alternatively submitted for reverse phase HPLC purification when it was a final product.Similar to the procedure as described in General Procedure M, ethyl 4-iodo-lH- pyrazole-3-carboxylate was reacted with l-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)-lH-pyrazole to give the title compound (352 mg, 18%) as a yellow solid. LCMS was confirmed. LC-MS (ES, m/z): 221 [M+H]+.

Reference： [1]Patent: WO2016/135163,2016,A1 .Location in patent: Paragraph 0192; 0330

65
[ 19230-27-4 ]
[ 761446-44-0 ]
4-(3-bromo-2-chlorophenyl)-1-methyl-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 95℃; for 1h;Inert atmosphere;	To a flask containing I ,3 dibromo2-chorobenzene (2.0 g, 7.4 mmo), 1 methy-4-(4,4,5,5-tetramethy-1 3,2-(1.5 g, 7.4 mmo), and potassium phosphate (3.1 g, 15 mmo) were added dioxane (32 mL) and water (8 mL). After purging with nitrogen for 10 minutes, PdC2(dppfCH2C2 (541 mg, 0.74 mmo) was added at once. The reaction mixture was heated at 95 00 for I h. After coohng to rt, the mixture was diuted with water and extracted with DOM (x2). The combined organic extracts were dried over Na2SO4,fiftered, and concentrated in vacuo. The crude residue was purified by FCC (5i02 020%EtOAc/hexanes) to afford the desired product (870 mg, 43% yied). MS (ESD: mass cacd.for C10H8BrCN2, 270.0; m/z found, 270.9 [M+Hj. I H NMR (400 MHz, DM50): 5 8.23 --8.14 (m, IH), 7.83 (d, J= 0.9 Hz, IH), 7.66 (dd, J= 8.0, 1.5 Hz, IH), 7.57 (dd, J= 7.8, 1.5Hz, 1 H), 7.28 (t, J = 7.9 Hz, I H), 3.90 (5, 3H).

Reference： [1]Patent: WO2016/176449,2016,A1 .Location in patent: Page/Page column 198

66
[ 74877-08-0 ]
[ 761446-44-0 ]
(S)-1-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-ethylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; acetonitrile; at 100℃; for 0.5h;Inert atmosphere; Sealed tube;	A sealed tube is charged with (S)-1-(3-Bromo-phenyl)-ethylamine (100.00mg; 0.50 mmol; 1.00 eq.), I-methyl-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (109.19 mg; 0.52 mmol; 1.05 eq.),Na2CO3 (52.97 mg; 0.5 mmol; 1.0 eq.), CH3CN (1.5 mL) and water (0.5 mL).The suspension is purged with argon and then Pd(PPh3)4 (28.88 mg; 0.02mmol; 0.05 eq.) is added. The tube is sealed and reaction is carried out inMW reactor at 100C for 30 mm. After this time, the mixture is filtered through a Celite pad and the filtrate is diluted with EtOAc and extracted with water. Organic phase is washed with brine, dried over Na2SO4 and then solvent isevaporated. Crude (S)-1 -[3-( 1-methyl-I H-pyrazol-4-yl)-phenyl]-ethylamine (80 mg, yield 80 %, 96 % by U PLC) is used in the next step.

Reference： [1]Patent: WO2016/180536,2016,A1 .Location in patent: Page/Page column 222

67
[ 1207557-36-5 ]
[ 761446-44-0 ]
4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;Inert atmosphere; Sealed tube;	To a solution of 6-bromo-4-methoxypyrazolo[i,5-a]pyridine (Intermediate P1; 2.00g, 227.1 mmol) and 1 -methyl-4- (4,4, 5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H-pyrazole (2.02 g, 208.1 mmol) in dioxane (10 mL) was added 2 M Na2CO3(aq) (8.1 mL, 17.6 mmol) and Pd(PPh3)4 (4.584 g, 3.967 mmol). The reaction mixture was purged with nitrogen for 2 mm, sealed and heated at 90 C for 4 h. After cooling to ambient temperature, the reaction mixture was diluted with water (50 mL) and stirred for 30 mm. The resulting suspension was vacuum filtered, rinsed sequentially with water (2 x 20 mL) and Et20 (2 x 10 mL) to yield the crude title compound, which was used in the next step without further purification. MS (apci), m/z = 229.1 (M+H).

Reference： [1]Patent: WO2017/11776,2017,A1 .Location in patent: Paragraph 00652; 00653

68
[ 944937-53-5 ]
[ 761446-44-0 ]
6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; Sealed tube;	A solution of <strong>[944937-53-5]6-bromo-1H-pyrrolo[3,2-b]pyridine</strong> (32) (100 mg, 0.51 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrazole(30) (116 mg, 0.56 mmol), PdCl2(dppf)-CH2Cl2 (37 mg, 50 mol) and K2CO3 (140 mg, 1.01mmol) in 1,4-dioxane:water(6 mL, 2:1, v) in a microwave tube was flushed with N2 for 5 mins thensealed. The tube was heated at 80 C for 3 h. Then the reaction mixture was evaporated to dryness.The residue was purified by flash chromatography to give 34 (90 mg, 89% yield); LC-MS m/z (ESI)found (M + H)+ 199.1 (M + H)+; 1H-NMR (400 MHz, DMSO-d6) delta 11.31 (brs, 1H), 8.59 (s, 1H), 8.21 (s,1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.60 (t, J = 2.8 Hz, 1H), 6.53 (t, J = 2.8 Hz, 1H), 3.88 (s, 3H).

Reference： [1]Molecules,2017,vol. 22

69
[ 13669-57-3 ]
[ 761446-44-0 ]
[ 1022151-48-9 ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 120℃;Inert atmosphere;	The compound <strong>[13669-57-3]3-bromo-6-hydroxyquinoline</strong> (2.24 g, 10 mmol)1-methyl-1H-pyrazole-4-boronic acid glycol ester (2.20 g, 10.5 mmol)Pd (dppf) Cl2 (365 mg, 0.5 mmol)And potassium carbonate (4.14 g, 30 mmol) were placed in a bottle,Add 1,4-dioxane,Nitrogen replacement protection, reaction at 120 C overnight,The 1,4-dioxane was distilled off, diluted with water,Dichloromethane extraction, drying. The organic phase was distilled off,Column chromatography gave the compound3- (1-methyl-1H-pyrazol-4-yl) -quinolin-6-phenol.

Reference： [1]Patent: CN104250252,2017,B .Location in patent: Paragraph 0147; 0156; 0157; 0158

70
[ 1134327-98-2 ]
[ 761446-44-0 ]
ethyl 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium dihydrogenphosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;	To a solution of ethyl 7-bromoirnidazo[ 1 ,2-a]pyridine-3-carboxyiate (100 rng,0.372 rnrnol) in dioxane (3 rnL) and water (0.5 rnL) were added 1-rnethyi4-(4,4,5,5-tetrarnethvl-1,3.2-dioxaboroian-2-yi)-IH-pvrazoie (93 mg, 0.45 rnrnoi), K3P04 (197 mg, 0.929 rnmoi) and XPhosPdG2 (14.6 rng, 0.019 rnmol) at rt. The reaction was stirred under N2 at 100 C for I h, The reaction was cooled to it. The solvent was removed and the crude product was purified by flash chromatography (0% to 15% MeOH/DCM gradient) to afford ethyl 7-(1 -methyi 1Hpyrazoi-4-yi)irnidazo[1 ,2ajpyridine-3-carboxylate (98 mg. 98 % yield), as a white solid. MS (ESI) m??: 271.0 (M-HH). ?H NMR(400MHz. CDCI3) d ppm ).2i (dd, J:::73, 07 FIz. 1FI). 825 (s. IFI). 75(s. 1FI). 774 (s.2H), 7.13 (dd, J=7.3, 1.8 Hz, 1H). 4.40 (q, J=7.0 Hz, 2H), 3.97 (s, 3H), 1.41 (t, J=7.0 Hz,3H).

Reference： [1]Patent: WO2017/123860,2017,A1 .Location in patent: Page/Page column 183; 184

71
[ 1035235-27-8 ]
[ 761446-44-0 ]
tert-butyl 4-(1-methyl-1H-pyrazol-4-yl)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.121 g	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 85℃; for 0.5h;	Step a. To a stirred solution of <strong>[1035235-27-8]tert-butyl 4-bromoisoindoline-2-carboxylate</strong> (Intermediate 1, 0.2 g, 0.671 mmol) in l,4-dioxane:water (4.1; 5 ml) were added Cs2C03 (0.44 g, 1.342 mmol) and 1-methyl- lH-pyrazole-4-boronic acid pinacol ester (CAS Number 761446-44-0; available from Combi Blocks) (0.17 g, 0.805 mmol) at rt. The reaction mixture was degassed for 20 min. Pd(PPh3)4 (0.077 g, 0.067 mmol) was added to the reaction mixture at rt. The reaction mixture was heated at 85C for 30 min. The resulting reaction mixture was cooled to rt, diluted with water (100 ml) and extracted with EtOAc (3 x 80 ml). The combined organic phase was separated, dried over Na2S04, filtered and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (30% EtOAc in hexane) yielding tert-butyl 4-(1 -methyl- lH-pyrazol-4-yl)isoindoline-2-carboxylate (0.121 g, 0.404 mmol). LCMS: Method A, 2.335 min, MS: ES+ 300.53; NMR (400 MHz, DMSO-d6) delta ppm 8.03 (d, J=11.2 Hz, 1H), 7.78 (d, J=20.4 Hz, 1H), 7.43 - 7.49 (m, 1H), 7.31 (t, J=7.2 Hz, 1H), 7.19 (t, J=7.6 Hz, 1H), 4.69 (s, 2 H), 4.62 (d, J=11.2 Hz, 2 H), 3.90 (s, 3 H), 1.48 (s, 9 H).

Reference： [1]Patent: WO2017/158388,2017,A1 .Location in patent: Page/Page column 70

72
[ 35852-81-4 ]
[ 73183-34-3 ]
[ 761446-44-0 ]

Reference： [1]RSC Advances,2018,vol. 8,p. 13643 - 13648

73
[ 52833-94-0 ]
[ 761446-44-0 ]
2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;	To a mixture of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (23 g, 100 mmol) and 1- methylpyrazole-4-boronic acid pinacol ester (27 g, 130 mmol) in 400 mL of 1,4-dioxane/ water (3/1) was added K2CO3 (27.6 g, 200 mmol) followed by Pd(PPh3)4 (8.1 g, 7 mmol). The reaction mixture was heated at 100 C for 3 h, cooled to room temperature, and partitioned between water and ethyl acetate. Water layer was separated and adjusted to pH value around 5. The precipitate was collected by filtration and triturated in mixture of methanol and water. The precipitate was filtered. The wet cake was dried to afford 17.5g of the title compound. The crude product was used for the next step without further purification.1H NMR (600 MHz, DIMETHYL SULFOXIDE-d6) delta ppm 3.82 (s, 3H), 5.73(s, 2H), 7.77 (s, 1H), 8.05 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.42 (d, J = 2.4 Hz, 1H); MS (ESI, m/z): 219.1 [M+H]+

Reference： [1]Patent: WO2018/71343,2018,A1 .Location in patent: Paragraph 1128
[2]Patent: WO2017/39331,2017,A1 .Location in patent: Paragraph 719; 721; 725-726

74
[ 18740-39-1 ]
[ 761446-44-0 ]
2-chloro-4-(1-methyl-1H-pyrazol-4-yl)thieno[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With toluene-4-sulfonic acid; In butan-1-ol; at 170℃; for 2h;Microwave irradiation;	Weigh 11-a (125 mg, 1 eq) and methyl p-aminobenzoate (67 mg, 1.2 eq). Butanol was added to dissolve, then p-toluenesulfonic acid (7 mg, 0.1 eq) was added, and the reaction was carried out at 170° C. for 2 hours in the microwave. Cool and filter to obtain crude compound 12-a crude (168 mg, 99percent).

Reference： [1]Patent: CN104177363,2018,B .Location in patent: Paragraph 0234; 0235; 0237; 0238; 0387; 0389; 0390; 0391

75
[ 21594-52-5 ]
[ 761446-44-0 ]
C₁₀H₈N₄O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 6779 - 6800

76
[ 87941-55-7 ]
[ 761446-44-0 ]
4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole dihydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 531 - 551

77
[ 923595-58-8 ]
[ 1035690-24-4 ]
[ 761446-44-0 ]
3-(3-cyclopropoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 1062 - 1066
Angew. Chem.,2019,vol. 131,p. 1074 - 1078,5

78
[ 923595-58-8 ]
[ 32316-92-0 ]
[ 761446-44-0 ]
5-(1-methyl-1H-pyrazol-4-yl)-3-(naphthalen-2-yl)pyrazolo[1,5-a]pyrimidine [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 1062 - 1066
Angew. Chem.,2019,vol. 131,p. 1074 - 1078,5

79
[ 891785-28-7 ]
[ 761446-44-0 ]
6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 90℃; for 16h;Sealed tube; Inert atmosphere;	In a sealed tube, <strong>[891785-28-7]6-bromoisoquinolin-3-amine</strong> (XV) (10.0 g, 45.01 mmol) was added to 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (XLIII) (10.58 g, 50.85 mmol), 12 M aqueous solution of K3PO4 (9.52 mL, 114.95 mmol), Pd(dppf)Cl2 (1.95 g, 2.39 mmol) in dioxane (240 mL) and water (59.4 mL). This mixture was degassed with Argon, sealed and heated to 90 C. for 16 h. The mixture was poured into water (500 mL), the solid was filtered and rinsed with MeOH to yield 6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine (XLIV) (5.69 g, 25.37 mmol, 56.4% yield). The product was used for the next step without further purification. ESIMS found for C13H12N4 m/z 225.0 (M+H).

Reference： [1]Patent: US2019/125741,2019,A1 .Location in patent: Paragraph 0632-0633

80
[ 64067-99-8 ]
[ 761446-44-0 ]
ethyl 6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere;	To a stirred solution of ethyl 6-chloroimidazo[l,2-b]pyridazine-2-carboxylate (A50, 1 g, 4.43 mmol) in l,4-dioxane(20 mL) and DMF(1 mL) and 1- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole(A41, 1.38 g, 6.64 mmol) was added Na2C03(1.40 g, 13.29 mmol) dissolved in H20(2 mL). The reaction mixture was purged with N2 gas for 20 min. To the above reaction mixture was added[l,l '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(dppf)(0.32 g, 0.44 mmol), and the resulting solution was further purged with N2 gas for 10 min then stirred for 16 h at 80C. The reaction mixture was filtered over celite bed and washed with ethylacetate/water mixture. The filtrate was washed with water, brine solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The compound was purified by column chromatography using 0-10% methanol/dichloromethane as the eluent to afford ethyl 6-(l-methyl-lH-pyrazol-4-yl)imidazo[l,2-b]pyridazine-2-carboxylate 1-67 as a brown solid. Yield: 0.70 g(59%) LC-MS(ES) m/z : 272.26[M+H]+.

Reference： [1]Patent: WO2019/102494,2019,A1 .Location in patent: Paragraph 000201

81
[ 808744-34-5 ]
[ 761446-44-0 ]
7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; N,N-dimethyl-formamide; for 10h;Inert atmosphere;	Compound 8 (3.10 g, 15.7 mmol), Compound 39 (4.00 g, 1.2 eq.) was dissolved in a mixture of DMF (55 mL) and H2O (5 mL).Stir well, add K2CO3 (7.70 g, 55.80 mmol), Pd(dppf)Cl2·DCM (1.00 g, 1.22 mmol),The air was replaced with nitrogen three times and stirred under the protection for 10 hours.The reaction solution was concentrated and purified by silica gel column chromatography. The mobile phase was taken from dichloromethane and methanol (DCM:MeOH = 80:1 to 60:1).A brownish yellow solid 40 (2.50 g, 78%).
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 6h;Inert atmosphere;	7-bromoimidazo[l,2-a]pyridine (100 g, 507.54 mmol, 1 eq.), l-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazole (CAS 761446-44-0; 116.18 g, 558.29 mmol, 1.1 eq.), Na2C03 (161.37 g, 1522.61 mmol, 3 eq.) are added to a dioxane/water solvent mixture: 3/1 (1 L). The mixture is degassed with N2, then Pd(dppf)Cl2-DCM adduct (2.07 g, 2.54 mmol, 0.005 eq.) is added and the mixture is stirred to 100 C for 6 h. The mixture is cooled to RT, filtered over Celite, rinsed with DCM and the filtrate is concentrated in vacuo. The residue is dissolved in DCM/n-BuOH mixture (9/1, 1 L) and water (1 L) is added. The organic layer is separated and the aqueous layer is extracted with DCM (1 L) then DCM n- BuOH mixture (9/1, 0.5 L). The combined organic layer is washed with brine (0.5 L), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue is triturated in MTBE (0.3 L) at RT, the suspension is filtered and the solid is washed with MTBE then dried in vacuo to afford the expected intermediate.

Reference： [1]Patent: CN110003202,2019,A .Location in patent: Paragraph 0226-0230
[2]Patent: WO2019/105886,2019,A1 .Location in patent: Paragraph 0396; 0483

82
[ 50735-34-7 ]
[ 761446-44-0 ]
C₁₁H₁₂N₄O₂ [ No CAS ]

Reference： [1]Patent: WO2017/39331,2017,A1 .Location in patent: Paragraph 170-175

83
[ 58235-80-6 ]
[ 761446-44-0 ]
methyl 4-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 7264 - 7288

84
[ 1123169-45-8 ]
[ 761446-44-0 ]
tert-butyl 6-(1-methyl-1H-pyrazol-4-yl)-3.4-dihydroquinoline-1(2H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%		A mixture of ieri-butyl 6-bromo-3, 4-dihydroquino line- l(2//)-carboxy late (0.55 g, 1.76 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.439 g, 2.11 mmol) and cesium carbonate (1.43 g, 4.40 mmol) in mixture of 4:1 Dioxane: water (10 ml) was purged for 20 minutes with argon gas. S-Phos Pd-G3-precatalyst (0.066 g, 0.08 mmol) was added and purging was continued for another 10 minutes. The reaction mixture was heated at 100 C for 2 hours. The reaction mixture was poured into water (25 ml) and extracted with ethyl acetate (2 x 30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na2S04 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford the title compound (0.55 g, 99%) as a solid. 1H NMR (400 MHz, DMSO-d6): 1.08 (s, 9H), 1.81-1.87 (m, 2H), 2.74 (t,J = 6.4 Hz, 2H), 3.63 (t, J = 6.0 Hz, 2H), 3.85 (s, 3H), 7.29-7.31 (m, 2H), 7.54 (d, J = 9.2 Hz, 1H), 7.80 (s, 1H), 8.07 (s, 1H) ; LCMS: m/z = 314.2 [M+l]

Reference： [1]Patent: WO2019/161162,2019,A1 .Location in patent: Paragraph 00313-00314

85
[ 58530-53-3 ]
[ 761446-44-0 ]
4-bromo-2-(1-methyl-1H-pyrazol-4-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52.74%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 100℃; for 1h;Microwave irradiation; Inert atmosphere;	Compound 3a (1 g, 4.22 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 12a (0.79 g, 0.90 mmol, prepared according to the method disclosed in the patent application "WO2009155527"), tetrakis(triphenylphosphine)palladium (0.49 g, 0.42 mmol) and sodium carbonate (0.89 mg, 8.44 mmol) were dissolved in 7 mL of a mixed solvent of toluene, ethanol and water (V/V/V=4:2:1), then the reaction solution was warmed up to 100C and reacted under microwave for 1 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and washed with water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with elution system B to obtain the title compound 12b (530 mg, yield: 52.74%).

Reference： [1]Patent: EP3527570,2019,A1 .Location in patent: Paragraph 0086; 0093; 0115; 0205; 0206

86
[ 460081-18-9 ]
[ 761446-44-0 ]
ethyl 2-(1-methylpyrazol-4-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 4h;Inert atmosphere;	To a solution of <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (1.87 g, 10.7 mmol, CAS4600081-18-9) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2.22 g, 10.7 mmol, CAS761446-44-0) in a mixed solvent of H2O (6 mL) and dioxane (30 mL) was added K2CO3 (2.94 g, 21.3 mmol) and Pd(dppf)Cl2.CH2Cl2 (870 mg, 1.07 mmol). The reaction mixture was stirred at 80 C. for 4 hours under nitrogen. On completion, the reaction mixture was diluted with EA (100 mL) and filtered. The organic layers were dried with anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica column chromatography (SiO2) to give the title compound (1.50 g, 64% yield) as a white solid. LC-MS (ESI+) m/z 222.1 (M+H)+.

Reference： [1]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2991; 2992

87
[ 16019-34-4 ]
[ 761446-44-0 ]
7-benzyl-4-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 16770 - 16774
Angew. Chem.,2019,vol. 131,p. 16926 - 16930,5

88
[ 26156-48-9 ]
[ 761446-44-0 ]
methyl 2-(1-methyl-1H-pyrazol-4-yl)pyridine-4-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 10272 - 10293

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[ CAS No. 761446-44-0 ] {[proInfo.proName]}

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Organoboron

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Pyrazoles

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