[ CAS No. 1186050-58-7 ] {[proInfo.proName]}

Name: 1186050-58-7|2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid|95%
Brand: Ambeed
SKU: A279169
Price: 62.0 USD
Availability: InStock
Rating: 98 (28 reviews)

,{[proInfo.pro_purity]}

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

DV 2D 3D

3d Animation Molecule Structure of 1186050-58-7

Structure of 1186050-58-7 * Storage: {[proInfo.prStorage]}

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

Search after Editing

* Storage: {[proInfo.prStorage]}

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

Quality Control of [ 1186050-58-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1186050-58-7 ]

SDS Specification

Alternatived Products of [ 1186050-58-7 ]

Product Details of [ 1186050-58-7 ]

CAS No. :	1186050-58-7	MDL No. :	MFCD23135320
Formula :	C₉H₆FN₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NTPOZDBAGMLNQA-UHFFFAOYSA-N
M.W :	207.16	Pubchem ID :	67086627
Synonyms :

Calculated chemistry of [ 1186050-58-7 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	11
Fraction Csp3 :	0.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	48.28
TPSA :	68.01 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.48 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.21
Log Po/w (XLOGP3) :	1.53
Log Po/w (WLOGP) :	1.52
Log Po/w (MLOGP) :	0.59
Log Po/w (SILICOS-IT) :	0.77
Consensus Log Po/w :	1.12

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.5
Solubility :	0.657 mg/ml ; 0.00317 mol/l
Class :	Soluble
Log S (Ali) :	-2.57
Solubility :	0.561 mg/ml ; 0.00271 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.21
Solubility :	1.27 mg/ml ; 0.00611 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.71

Safety of [ 1186050-58-7 ]

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

Application In Synthesis of [ 1186050-58-7 ]

* 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 [ 1186050-58-7 ]
Downstream synthetic route of [ 1186050-58-7 ]

[ 1186050-58-7 ] Synthesis Path-Upstream 1~3

1
[ 111771-08-5 ]
[ 288-36-8 ]
[ 1186050-58-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate In 1,4-dioxane; water at 60 - 100℃; for 4 h; Inert atmosphere	Method B: 2-Fluoro-6-[1 ,2,3]triazol-2-yl-benzoic acid. To a 2 L, 3- necked, round-bottomed flask equipped with an overhead mechanical stirrer, thermocouple probe, heating mantle, reflux condenser, and nitrogen inlet were added 2-fluoro-6-iodobenzoic acid (127.6 g, 480 mmol), copper iodide (4.57 g, 24 mmol), and Cs₂C0₃ (312.6 g, 959 mmol). To these solids were added dioxane (640 mL), then water (2.6 mL, 144 mmol), then 1 H-1 ,2,3-triazole (55.6 mL, 959 mmol), and finally frans-1 ,2-dimethylcyclohexane-1 ,2-diamine (15.1 mL, 96 mmol). The mixture was then warmed to 60 °C for 30 min, then to 83 °C for 30 min, and then to 100 °C for 3 h. After the 3 h at 100 °C, the mixture was cooled and then 1 L of MTBE and 1 L of water were added. After vigorous mixing, the layers were separated and the bottom aqueous layer was acidified to pH 1 .72 with -148 mL of concentrated hydrochloric acid. The aqueous was then extracted twice with EtOAc. The combined organic layers were dried over Na₂S0₄, filtered, and concentrated to provide a dark oil. The oil was stirred overnight in EtOAc (450 mL) and the resulting precipitate was removed by filtration. The mother-liquors were concentrated to a brown solid (106.21 g, 75 wtpercent by quantitative HPLC, 79.7 g, 80percent). ¹H NMR (400 MHz, DMSO-d₆): 8.22 - 8.13 (bs, 2H), 7.84-7.80 (m, 1 H), 7.74 - 7.65 (m, 1 H), 7.50 - 7.41 (m, 1 H).

Reference： [1] Patent: WO2012/145581, 2012, A1, . Location in patent: Page/Page column 50

2
[ 288-36-8 ]
[ 111771-08-5 ]
[ 1186050-58-7 ]

Yield	Reaction Conditions	Operation in experiment
140 mg	With copper(l) iodide; (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine; caesium carbonate In 1,4-dioxane; water at 18 - 100℃; for 18 h; Inert atmosphere; Sealed tube	A suspension of 2-fluoro-6-iodobenzoic acid (300 mg, 1 .1 mmol), (1 R,2R)-N,N- dimethylcyclohexane-1 ,2-diamine (32 mg, 0.23 mmol), Cs₂C0₃ (735 mg, 2.3 mmol), 1 H- 1 ,2,3-triazole (0.13 mL, 2.3 mmol), water (0.01 mL) in 1 ,4-dioxane (5 mL) was degassed under nitrogen for 10 mins. Cul (10.7 mg, 0.06 mmol) was added and the mixture was further degassed under nitrogen for 10 mins. The pressure tube was sealed and the mixture was heated to 100 for 18 hrs. After cooling, the reaction mixture was quenched with 13percentwt NaCI in 2.5M hydrochloric acid (50 mL) and extracted with EtOAc. The combined organics were dried over MgSO₄, filtered and concentrated in vacuo. The crude product was purified by chromatography on the Biotage Isolera Four™ (25 g column, 0 to 75percent (10percent AcOH in EtOAc) in heptane) to afford the title compound as an oil (140 mg). ¹H NMR (250 MHz, MeOD) 7.94 (s, 2 H), 7.80 (m, 1 H), 7.62 (m, 1 H), 7.29 (m, 1 H).
445.6 mg	With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate In N,N-dimethyl-formamide at 100℃; for 0.5 h;	To a solution of 2-fluoro-6-iodobenzoic acid (502.5 mg), copper(I) iodide (36.5 mg), cesium carbonate (1.25 g) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.047 mL) in N,N-dimethylformamide (2.0 mL) was added 1H-1,2,3-triazole (330.3 mg), and the mixture was stirred at 100° C. for 0.5 hr. To the reaction mixture were added ethyl acetate and water. The obtained aqueous layer was neutralized with 1N aqueous hydrogen chloride solution, and extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (445.6 mg). MS: [M+H]⁺ 208.1.

Reference： [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5620 - 5636
[2] Patent: WO2016/34882, 2016, A1, . Location in patent: Page/Page column 119; 120
[3] Patent: US2018/155333, 2018, A1, . Location in patent: Paragraph 1763; 1764; 1765

3
[ 111771-08-5 ]
[ 288-36-8 ]
[ 1186050-58-7 ]

Reference： [1] Patent: WO2015/55994, 2015, A1, . Location in patent: Page/Page column 79

[ 1186050-58-7 ] Synthesis Path-Downstream 1~46

Yield	Reaction Conditions	Operation in experiment
67.9%	With copper(l) iodide; caesium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 100℃; for 4.0h;Inert atmosphere;	General procedure: 1,2,3-Triazole (3.45 g, 50 mmol),2-iodo-5-methylbenzoic acid (5.24 g, 20 mmol),Cesium carbonate (11.72 g, 36 mmol),Trans-N, N'-dimethyl-1,2-cyclohexanediamine (0.51 g, 3.6 mmol),Cuprous iodide (0.38 g, 2 mmol),N, N-dimethylformamide (30 mL) were sequentially added into a 100 mL single-necked round bottom flask, and the mixture was gradually heated to 100 C. under a nitrogen atmosphere for reaction for 4 hours. The reaction was stopped, cooled, diluted with tap water and extracted with ethyl acetate (200 mL x 2). The aqueous layer was acidified with concentrated hydrochloric acid (pH = 1-2) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were combined and dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure and subjected to column chromatography Purification (dichloromethane / methanol (v / v) = 50/1) afforded the title compound (yellow solid, 2.76 g, 68%).
67.9%	With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4.0h;Inert atmosphere;	General procedure: The 2 H - 1, 2, 3 - triazole (3.45 g, 50 mmol), 2 - iodo -5 - methyl benzoic acid (5.24 g, 20 mmol), cesium carbonate (11.72 g, 36 mmol), trans - N, N' - dimethyl - 1, 2 - diaminocyclohexane (0.51 g, 3.6 mmol), cuprous iodide (0.38 g, 2 mmol) and N, N - dimethyl formamide (30 ml) are added to the 100 ml round bottom flask in a single port, under the protection of nitrogen reaction solution gradually raising the temperature to 100 C reaction 4 hours. Stopping the reaction, cooling, liquid water (60 ml) diluted with water and ethyl acetate (200 ml × 2) extraction. The water layer is acidified to pH concentrated hydrochloric acid for 1 - 2, then adding ethyl acetate (200 ml × 2) extraction, the resulting organic layer dried with anhydrous sodium sulfate, filtered, filtrate turns on lathe does after separation and purification by column chromatography (dichloromethane/methanol (v/v)=50/1) to obtain the title compound (yellow solid, 2.76 g, 68%).
67.9%	With copper(l) iodide; caesium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 100℃; for 4.0h;Inert atmosphere;	General procedure: Combine 1,2,3-triazole (3.45g, 50mmol), 2-iodo-5-methylbenzoic acid (5.24g, 20mmol), cesium carbonate (11.72g, 36mmol), trans-N, N ' -Dimethyl-1,2-cyclohexanediamine (0.51g, 3.6mmol), cuprous iodide (0.38g, 2mmol), N, N-dimethylformamide (30mL) were added to 100mL single-port round In a bottom flask, the temperature was gradually raised to 100 C under nitrogen protection for 4 hours. The reaction was stopped, cooled, diluted with tap water and extracted with ethyl acetate (200 mL × 2).The aqueous layer was acidified with concentrated hydrochloric acid (pH = 1-2) and extracted with ethyl acetate (200 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure and purified by column chromatography ( Dichloromethane / methanol (v / v) = 50/1) gave the title compound (yellow solid, 2.76 g, 68%).

64.33%	With copper(l) iodide; caesium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 100℃;Inert atmosphere;	General procedure: Step 1) Synthesis of 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) benzoic acid To a solution of N, N-dimethylformamide (30 mL) were added sequentially 2H-1, 2, 3-triazole (3.45 g, 50 mmol) , 2-iodo-5-methyl benzoic acid (5.24 g, 20 mmol) , cesium carbonate (11.72 g, 36 mmol) , trans-N, N'-dimethyl-1, 2-cyclohexanediamine (0.51 g, 3.6 mmol) and cuprous iodide (0.38 g, 2 mmol) . The reaction was heated to 100 ? under N2. After reaction for 4 hours, the reaction mixture was cooled to rt, diluted with water (60 mL) and extracted with ethyl acetate (200 mL × 2) . The aqueous layer was acidified to pH 1 to 2 with concentrated hydrochloric acid, and then extracted with ethyl acetate (200 mL × 2) . The combined organic layers were dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/methanol (v/v) =50/1) to give the title compound as a yellow solid (2.76 g, 68 %) .MS (ESI, neg. ion) m/z: 202.1 [M-H] -;1H NMR (CD3OD, 600 MHz) d (ppm) : 7.88 (s, 2H) , 7.66 (d, 1H) , 7.59 (d, J= 8.2 Hz, 1H) , 7.50-7.48 (dd, J = 8.1 Hz, 1.1 Hz, 1H) , 2.45 (s, 3H) ; and13C NMR (CD3OD, 151 MHz) d (ppm) : 169.8, 140.7, 137.5, 136.7, 133.5, 131.5, 129.3, 126.0, 21.0.
		Intermediate 43: 2-Fluoro-6-[1 ,2,3]triazol-2-yl-benzoic acid.The title compound was prepared in a manner analogous to Intermediate 41 , substituting 6-fluoro-2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoic acid. 1H NMR (400 MHz, CD3OD): 7.96 (s, 2H), 7.87-7.82 (m, 1 H), 7.70 (td, J = 8.1 , 5.1 Hz, 1 H), 7.59 (ddd, J = 9.7, 8.4, 1 .4 Hz, 1 H).
	With copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 80℃;	General procedure: In a dry Schlenk Tube at RT under nitrogen are successively charged 2-fluoro-6-iodo-3-methyl-benzoic acid (1.786 mmol, 1 eq), Cul (0.089 mmol, 0.05 eq), 1 H-1 ,2,3-triazole (3.571 mmol, 2 eq), Cs2C03 (3.571 mmol, 2 eq) and DMF (2.5 ml_). The resulting blue suspension is stirred at 80C overnight. The obtained reaction mixture is taken up in 1 M aq. HCI and extracted twice with EtOAc. The combined organic layers are dried over Na2S04, filtered and concentrated under reduced pressure. Purification is achieved by prep. HPLC (conditions D) to give the titled compound as a pale yellow solid. LC-MS (conditions B): tR = 0.55 min, [M + 1]+ = 222.19.
	With copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃;Inert atmosphere;	General procedure: 2-Fluoro-3-methyl-6-(2H-1,2,3-triazol-2-yl)benzoic acid (E-1)The title compound was prepared in analogy to the procedure described in WO2008/069997.Cs2C03 (6.98 g, 21.4 mmol) was added portionwise to a RT solution of 2-fluoro-6-iodo-3- methyl-benzoic acid (3.0 g, 10.7 mmol) in DMF (15 mL) under argon followed by 1H-1 ,2,3- triazole (1.24 mL, 21.4 mmol) and Cu(l)l (103 mg, 0.536 mmol) and the resulting blue suspension was stirred at 80C overnight. The reaction mixture was quenched with 2M aq. HCI and filtered through a celite plug before being extracted with DCM (3x). The combined organic layers were dried over Na2S04, filtered and evaporated in vacuo to give the crude product that was purified by prep. HPLC (method E) to give the title compound as a pale yellow solid. LC-MS B: tR = 0.55 min; [M+H]+ = 222.01.
	With copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere;	General procedure: 2-Fluoro-3-methyl-6-(2H-1,2,3-triazol-2-yl)benzoic acid (E-1) The title compound was prepared in analogy to the procedure described in WO2008/069997. Cs2CO3 (6.98 g, 21.4 mmol) was added portionwise to a RT solution of 2-fluoro-6-iodo-3-methyl-benzoic acid (3.0 g, 10.7 mmol) in DMF (15 mL) under argon followed by 1H-1,2,3-triazole (1.24 mL, 21.4 mmol) and Cu(I)I (103 mg, 0.536 mmol) and the resulting blue suspension was stirred at 80 C. overnight. The reaction mixture was quenched with 2M aq. HCl and filtered through a celite plug before being extracted with DCM (3*). The combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by prep. HPLC (method E) to give the title compound as a pale yellow solid
	With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 110℃;	General procedure: To a mixture of 2-bromo-4-fluorobenzoic acid (30 g, 137 mmol), cesium carbonate (89.26 g, 274 mmol) and Cul (5.27 g, 27.4 mmol) in DMF (200mL) were added N,N?-dimethylcyclohexane-1,2-diamine (3.7 mL, 23.3 mmol) and 1H-1,2,3-triazole (18.92 g, 274 mmol). The resulting mixture was stirred at 110C overnight, cooled,concentrated in vacuo and diluted with water (150 mL). The aqueous layer was extracted with EtOAc (300 mLx 3). The aqueous layer was acidified with 2N HC1 and extracted with EtOAc (300mL x 4). The combined organic layers were washed with brine (150 mL x 3), dried over Na2S04, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether : EtOAc =100: 1 ~ 5 : l) to provide the title compound as a solid. LRMS m/z (M+H) 208.0 found, 208.0 required.
	With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In N,N-dimethyl-formamide; at 110℃;	General procedure: To a mixture of 2hromo4-fiuorohenzoic acid (30 g, 137 mmoi), cesium carbonate (89.26 g, 274 mmol) and Cul (5.27 g, 27.4 mmol) in I)MF (200 mL) were added N,N?dimethyicyciohexane-i,2-diamine (3.7 mL,23.3 mnioi) and 1H-L2,34riazoie (18.92 g, 274 mmoi). The resulting mixture was stirred at 110 C overnight, cooling, concentrated in vacuo and diluted with water (150 mL). The aqueous layer was extracted with ELOAc (300 mL x 3).The aqueous layer was acidified with 2N HCI and extracted with EtOAc (300 mL x 4). The combined organic layers were washed with brine (150 mL x 3), dried over Na2SO4, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether: EtOAc = 100: 1 5 : 1) to provide the title compound (18.13 g)compound (18.13 g) as a yellow solid

2
[ 1186050-58-7 ]
[ 1293284-71-5 ]
[ 1293281-49-8 ]

Yield	Reaction Conditions	Operation in experiment
74%	With thionyl chloride; sodium carbonate; sodium hydroxide; In water; toluene; at 0 - 50℃; for 4.5h;Inert atmosphere;	To a 3-necked, 3 L, round- bottomed flask equipped with a nitrogen line, temperature probe, heating mantle, reflux condenser, mechanical stirrer, and 1 N aq. NaOH scrubber were added 2-fluoro-6-[1 ,2,3]triazol-2-yl-benzoic acid (Intermediate 12, 120.98 g, 75 wt%, 90.74 g actual, 438 mmol) and toluene (1 L). The mixture was warmed to 50 oC for 1 h with stirring. The mixture was then cooled to 25 oC and thionyl chloride (47.9 mL, 657 mmol) was added. The mixture was warmed back to 50 oC and held for 1 h. During this time, in a separate 5 L jacketed reactor equipped with a mechanical stirrer and temperature probe were added toluene (600 mL), aqueous sodium carbonate (185.7 g, 1 .75 mol in 1 .6 L water), and 2- (4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrroleHOAc(Intermediate 23, 122 g, 438 mmol). This biphasic mixture was cooled to 0 oC. After cooling to 0 oC, the original slurry was poured through a filter and over the stirring biphasic mixture of amine and aqueous sodium carbonate. The mixture was allowed to warm to room temperature. After 2 h, additional 2-(4,6- dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrroleHOAc (4 g, 14 mmol) was added and the mixture was stirred for 30 additional minutes. At the end of this period, the layers were separated and 100 mL of methanol were added to the organic layer. The organic layer was dried over MgSO , filtered, and concentrated to a white solid. This solid was taken up in ethanol (1 .4 L) and warmed to 77 oC. The mixture was then cooled to 55 oC and seeded with previously crystallized material. (Note: The seeds were generated from slurrying the initial product in 2-propanol at room temperature [100 mg/mL]). The mixture was cooled to room temperature at a rate of 5 oC per hour. After stirring at room temperature for 14 h, the mixture was filtered and dried to provide the final product as a white crystalline solid (136.84 g, 74%). 1H NMR (400 MHz, CDCIs): 7.88 - 7.78 (m, 1 .78H), 7.75 - 7.69 (s, 1 .22H), 7.51 - 7.43 (m, 1 H), 7.17 - 7.1 1 (m, 1 H), 6.30 - 6.28 (m, 1 H), 4.03 - 3.48 (m, 7H), 3.29 - 3.21 (m, 1 H), 3.15 - 2.92 (m, 2H), 2.30 (s, 6H). MS (ESI) mass calcd forC21 H22FN7O, 407.19; m/z found, 408 [M+H]+. Anal, calcd. for C21 H22FN7O C, 61 .90, H, 5.44, N, 24.06; found C, 61 .83, H, 5.42, N, 24.08

Reference： [1]Patent: WO2011/50198,2011,A1 .Location in patent: Page/Page column 144-145

3
[ 1186050-58-7 ]
[ 1293284-78-2 ]
[ 1293280-46-2 ]

Yield	Reaction Conditions	Operation in experiment
23.4%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 0.5h;	A mixture of [6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin- 4-yl]-dimethyl-amine (50 mg, 0.17 mmol), 2-fluoro-6-[1 ,2,3]triazol-2-yl-benzoic acid (37.8 mg, 0.18 mmol), HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF (4.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2 X 100 mL). The organic phase was dried (Na2SO ), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (19.0 mg, 23.4 %). MS (ESI) mass calcd. for C22H22F4N8O, 490.46; m/z found [M+H]+. 1 H NMR (CDCI3): 7.89-7.79 (m, 2H), 7.74 (s, 1 H), 7.55-7.37 (m, 1 H), 7.21 -7.05 (m, 1 H), 5.25-5.09 (m, 1 H), 4.25-3.51 (m, 6H), 3.50-2.95 (m, 10H).

Reference： [1]Patent: WO2011/50198,2011,A1 .Location in patent: Page/Page column 101-102

4
[ 1186050-58-7 ]
[ 1293284-75-9 ]
[ 1293280-44-0 ]

Yield	Reaction Conditions	Operation in experiment
81.5%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 0.5h;	A mixture of [4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]- dimethyl-amine (60.0 mg, 0.23 mmol), 2-fluoro-6-[1 ,2,3]triazol-2-yl-benzoic acid (52.0 mg, 0.25 mmol), HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68 mmol) was stirred into DMF (4.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2 X 100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness to yield crude title compound (354.0 mg, 343 %). The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (84.0 mg, 81 .5 %). MS (ESI) mass calcd. for C22H25FN8O2,452.49; m/z found 453.3 [M+H]+. 1 H NMR (CDCI3): 7.88-7.79 (m, 2H), 7.72 (d, J = 6.7, 1 H), 7.54-7.41 (m, 1 H), 7.19-7.08 (m, 1 H), 5.02-4.92 (m, 1 H), 3.96-3.86 (m, 1 H), 3.87-3.83 (m, 3H), 3.81 -3.50 (m, 5H), 3.43-3.19 (m, 2H), 3.15-3.09 (m, 6H)), 3.09-2.91 (m, 2H).

Reference： [1]Patent: WO2011/50198,2011,A1 .Location in patent: Page/Page column 100

5
[ 1186050-58-7 ]
[ 1293286-15-3 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In toluene; at 50℃; for 1.0h;	Step A: (1 S,6R)-tert-Butyl 8-(2-fluoro-6-(2H-1 ,2,3-triazol-2-yl)benzoyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate. To 2-fluoro-6-(2H-1 ,2,3-triazol-2- yl)benzoic acid (406 mg, 1 .5 mmol) in PhCH3 (5ml_) was added SOCI2 (1 17 u?_, 1 .6 mmol). The flask was heated with an oil bath to 50 C for 1 h. To (1 S,6R)- tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate (260 mg, 1 .3 mmol) and Na2CO3 (519 mg, 4.9 mmol) in PhCH3 (5ml_) and H2O (5mL) at 0 C was added the above solution dropwise. The reaction was allowed to warm slowly to rt and stir for 15h and extracted with DCM (2 X). The combined organics were dried (Na2SO4). Purification via silica gel chromatography (1 -7% 2MNHs/MeOH in CH2CI2) gave 335 mg (68%) of the title compound. MS (ESI) mass calcd. C2oH24FN5O3, 401 .44; m/z found 346.1 [M-C(CH3)3]+
	With thionyl chloride; N,N-dimethyl-formamide; sodium hydroxide; In toluene;	Method B:Step A: A one-piece EasyMax reactor was equipped with a mechanical stirred, a temperature probe, a reflux condenser and an NaOH scrubber. To the reactor was added 2-fluoro-6-triazol-2-yl benzoic acid (15.01 g, 72.5 mmol) and toluene (150.0 g), N, N dimethylformamide (0.06 g, 0.26 mmol) was then added, the reaction was held at 20 C prior to the addition of thionyl chloride (1 1 .31 g, 94.1 mmol) via syringe pump. The reaction mixture was then heated to 50 C over 15 minutes and then was stirred at that temperature for 1 .5 hours. The mixture was then heated to 55 C and 20.4 g of solvent were distilled in vacuo to give 139.4 g of acid chloride solution which was used as is in Step C below.
	With pyridine; thionyl chloride; In dichloromethane;	Step 2) Synthesis of 2-fluoro-6- (2H-1, 2, 3-triazol-2-yl) benzoyl chlorideTo a solution of 2-fluoro-6- (2H-1, 2, 3-triazol-2-yl) benzoic acid (1.026 g, 4.953 mmol) in anhydrous DCM (20 mL) were added slowly sulfoxide chloride (11 mL, 150 mmol) and pyridine (0.08 mL, 1 mmol) . The reaction was heated to reflux and stirred for 3 hours, and then cooled and the solvent was removed in vacuo to give a product, which was used directly in the next step.

With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; for 3.0h;Reflux;

Dissolve 2-fluoro-6- (2H- 1,2,3 -triazol-2-yl) benzoic acid (0.69 g, 3.33 mmol) with anhydrous dichloromethaneThionyl chloride (8 mL, 109.0 mmol) and DMF (0.04 mL, 0.5 mmol) were slowly added and the reaction was gradually warmed to reflux for 3 hours. The reaction was stopped, cooled and the solvent was slowly evaporated under reduced pressure. The resulting product was used directly in the next step.

Reference： [1]Patent: WO2011/50202,2011,A1 .Location in patent: Page/Page column 67
[2]Patent: WO2012/145581,2012,A1 .Location in patent: Page/Page column 146
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 5620 - 5636
[4]Patent: WO2017/88759,2017,A1 .Location in patent: Paragraph 00195
[5]Patent: CN105949203,2016,A .Location in patent: Paragraph 0233; 0239; 0240

6
[ 1186050-58-7 ]
[ 1293940-76-7 ]

Reference： [1]Patent: WO2011/50202,2011,A1

7
[ 1186050-58-7 ]
[ 1293941-03-3 ]

Reference： [1]Patent: WO2011/50202,2011,A1

8
[ 111771-08-5 ]
[ 288-36-8 ]
[ 1186050-58-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In 1,4-dioxane; water; at 60 - 100℃; for 4h;Inert atmosphere;	Method B: 2-Fluoro-6-[1 ,2,3]triazol-2-yl-benzoic acid. To a 2 L, 3- necked, round-bottomed flask equipped with an overhead mechanical stirrer, thermocouple probe, heating mantle, reflux condenser, and nitrogen inlet were added <strong>[111771-08-5]2-fluoro-6-iodobenzoic acid</strong> (127.6 g, 480 mmol), copper iodide (4.57 g, 24 mmol), and Cs2C03 (312.6 g, 959 mmol). To these solids were added dioxane (640 mL), then water (2.6 mL, 144 mmol), then 1 H-1 ,2,3-triazole (55.6 mL, 959 mmol), and finally frans-1 ,2-dimethylcyclohexane-1 ,2-diamine (15.1 mL, 96 mmol). The mixture was then warmed to 60 C for 30 min, then to 83 C for 30 min, and then to 100 C for 3 h. After the 3 h at 100 C, the mixture was cooled and then 1 L of MTBE and 1 L of water were added. After vigorous mixing, the layers were separated and the bottom aqueous layer was acidified to pH 1 .72 with -148 mL of concentrated hydrochloric acid. The aqueous was then extracted twice with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated to provide a dark oil. The oil was stirred overnight in EtOAc (450 mL) and the resulting precipitate was removed by filtration. The mother-liquors were concentrated to a brown solid (106.21 g, 75 wt% by quantitative HPLC, 79.7 g, 80%). 1H NMR (400 MHz, DMSO-d6): 8.22 - 8.13 (bs, 2H), 7.84-7.80 (m, 1 H), 7.74 - 7.65 (m, 1 H), 7.50 - 7.41 (m, 1 H).

Reference： [1]Patent: WO2012/145581,2012,A1 .Location in patent: Page/Page column 50

9
[ 1186050-58-7 ]
[ 1293281-49-8 ]

Reference： [1]Patent: WO2012/145581,2012,A1

10
[ 1186050-58-7 ]
[ 1293282-91-3 ]

Reference： [1]Patent: WO2012/145581,2012,A1

11
[ 1186050-58-7 ]
[ 1293286-18-6 ]

Reference： [1]Patent: WO2012/145581,2012,A1

12
[ 1186050-58-7 ]
[ 1293283-00-7 ]

Reference： [1]Patent: WO2012/145581,2012,A1

13
[ 1186050-58-7 ]
[ 1293284-63-5 ]

Reference： [1]Patent: WO2012/145581,2012,A1

14
[ 1186050-58-7 ]
[ 1293284-64-6 ]

Reference： [1]Patent: WO2012/145581,2012,A1

15
[ 111771-08-5 ]
[ 288-36-8 ]
[ 1186050-58-7 ]
C₉H₆FN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; caesium carbonate; N,N-dimethylethylenediamine; In N,N-dimethyl-formamide; at 0 - 125℃; for 0.25h;Microwave irradiation;	Intermediate 21: 2-Fluoro-6-(2H-l,2,3-triazol-2-yl)benzoic acid To a solution of 2H-l,2,3-triazole (5.0 g, 72.46 mmol ) in DMF (20 ml) was added cesium carbonate (23.55 g, 72.46 mmol), N,N-dimethylethylenediamine (1.02 g, 7.24 mmol), copper(I) iodide (0.34 g, 1.811 mmol) and <strong>[111771-08-5]2-fluoro-6-iodobenzoic acid</strong> (9.63 g, 36.23 mmol ) at 0-10 C. The reaction was stirred at 125C for 15 min in the microwave and then poured into water (100 ml) and extracted with ethyl acetate (100 ml x 3). The aqueous layer was acidified with dilute HC1 to pH 2 and extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with brine, dried over sodium sulphate and concentrated in vacuo. This was then purified by column chromatography (0-3% methanol / dichloromethane) to afford the title compound.1H NMR (400 MHz DMSO- d6): delta ppm 7.43-7.47 (m, 1H), 7.66-7.72 (m, 1H), 7.78-7.80 (m, 1H), 8.13 (s, 2H), 13.71 (s, 1H)MS ES+: 208

Reference： [1]Patent: WO2015/55994,2015,A1 .Location in patent: Page/Page column 79

16
[ 1186050-58-7 ]
(1S,2S)-1-N-(6-fluoro-1,3-benzothiazol-2-yl)cyclopentane-1,2-diamine hydrochloride [ No CAS ]
2-fluoro-N-[(1S,2S)-2-[(6-fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-6-(2H-1,2,3-triazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; triethylamine; In dichloromethane; at 20 - 25℃; for 18.0h;	General procedure: Exarm}le 69: 2-Fluoro-N-[(/5,25)-2-[(6-fluoro-l,3-benzotliiazol-2- yl)amino]cyclopentyl]-6-(2H-l,2,3-triazol-2-yl)benzamide To a solution of (iS,2S)-l-N-(6-fluoro-l,3-benzothiazol-2-yl)cyclopentane-l,2-diamine hydrochloride (Intermediate 16a, 50 mg, 0.174 mmol) in dry DCM (2 ml) was added 2- fluoro-6-(2H-l,2,3-triazol-2-yl)benzoic acid (Intermediate 21, 54.0 mg, 0.261 mmol), triethylamine (0.073 ml, 0.521 mmol) and HATU (99 mg, 0.261 mmol). The reaction was stirred at room temperature for 18 hours then diluted with DCM, washed with water, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC (acetonitrile / water with 0.1% ammonia) to afford the title compound.1H NMR (400 MHz, MeOD -d4) : delta ppm 1.56 - 1.72 (m, 2 H), 1.75 - 1.89 (m, 2 H), 2.16 - 2.32 (m, 2 H), 4.09 - 4.18 (m, 1 H), 4.22 - 4.31 (m, 1 H), 6.93 - 7.02 (m, 1 H), 7.19 - 7.30 (m, 2 H), 7.33 - 7.40 (m, 1 H), 7.53- 7.62 (m, 1 H), 7.74 (s, 2 H), 7.76 - 7.80 (m, 1 H) MS ES+: 441

Reference： [1]Patent: WO2015/55994,2015,A1 .Location in patent: Page/Page column 134; 135

17
[ 1186050-58-7 ]
1,1-dimethyl-4-(((3R,6R)-6-methylpiperidin-3-yl)oxy)furo[3,4-c]pyridin-3(1H)-one hydrochloride [ No CAS ]
4-[(3R,6R)-1-[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}-1,1-dimethylfuro[3,4-c]pyridin-3(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃;	A solution of 1 , 1 -dimethyl-4-(((3i?,6i?)-6-methylpiperidin-3-yl)oxy)furo[3.4- c]pyridin-3(lH)-one hydrogen chloride (0.050 g, 0.16 mmol), 2-fluoro-6-(2H)-l,2,3-triazol-2-yl) benzoic acid (0.036 g, 0.18 mmol), benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexaflurophosphate (Bop, 0.092 g, 0.21 mmol), and triethylamine (0.067 mL, 0.48 mmol) in DMF (1 mL) was stirred at RT overnight. The reaction was concentrated in vacuo and azeotroped 3x with toluene. The residue was purified by silica gel gradient chromatography (0-80% ethyl acetate in hexanes), providing the titled compound. HRMS m z (M+H) 466.1890 found, 466.1887 required.

Reference： [1]Patent: WO2015/95442,2015,A1 .Location in patent: Page/Page column 37

18
[ 1186050-58-7 ]
(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)-methanone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5620 - 5636

19
[ 288-36-8 ]
[ 111771-08-5 ]
[ 1186050-58-7 ]

Yield	Reaction Conditions	Operation in experiment
56%	With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In 1,4-dioxane; water; at 100℃;	To a round-bottomed flask equipped with an overhead magnetic stirrer, reflux condenser, and nitrogen inlet were added 2-Fluoro-6-iodobenzoic acid (2.5 g, 9.4 mmol), Cul (0.09 g, 0.47 mmol), and CS2CO3 (6.1 g, 18.8 mmol). To these solids were added dioxane (12.5 ml_), water (0.05 ml_), 1 H-1 ,2,3-triazole (1.09 ml_, 18.8 mmol), and finally (1 R,2R)-N1 ,N2-dimethylcyclohexane-1 ,2-diamine (0.3 ml_, 1.88 mmol). The mixture was then warmed to 100 C ON. The day after the mixture was cooled and MTBE and water were added. After vigorous mixing, the layers were separated and the bottom aqueous layer was acidified to pH 2 with 6N HCI. The aqueous phase was then extracted with DCM (3x). The combined organic layers were dried, and concentrated The residue was purified by FC on S1O2 column (eluent : from DCM to DCM:MeOH 90:10) to afford 2-fluoro-6-(2H-1 ,2,3-triazol-2-yl)benzoic acid (p186, 1.1 g, y= 56%). MS (m/z): 208.0 [M+H]+
140 mg	With copper(l) iodide; (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine; caesium carbonate; In 1,4-dioxane; water; at 18 - 100℃; for 18h;Inert atmosphere; Sealed tube;	A suspension of <strong>[111771-08-5]2-fluoro-6-iodobenzoic acid</strong> (300 mg, 1 .1 mmol), (1 R,2R)-N,N- dimethylcyclohexane-1 ,2-diamine (32 mg, 0.23 mmol), Cs2C03 (735 mg, 2.3 mmol), 1 H- 1 ,2,3-triazole (0.13 mL, 2.3 mmol), water (0.01 mL) in 1 ,4-dioxane (5 mL) was degassed under nitrogen for 10 mins. Cul (10.7 mg, 0.06 mmol) was added and the mixture was further degassed under nitrogen for 10 mins. The pressure tube was sealed and the mixture was heated to 100 for 18 hrs. After cooling, the reaction mixture was quenched with 13%wt NaCI in 2.5M hydrochloric acid (50 mL) and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on the Biotage Isolera Four (25 g column, 0 to 75% (10% AcOH in EtOAc) in heptane) to afford the title compound as an oil (140 mg). 1H NMR (250 MHz, MeOD) 7.94 (s, 2 H), 7.80 (m, 1 H), 7.62 (m, 1 H), 7.29 (m, 1 H).
445.6 mg	With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.5h;	To a solution of <strong>[111771-08-5]2-fluoro-6-iodobenzoic acid</strong> (502.5 mg), copper(I) iodide (36.5 mg), cesium carbonate (1.25 g) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.047 mL) in N,N-dimethylformamide (2.0 mL) was added 1H-1,2,3-triazole (330.3 mg), and the mixture was stirred at 100 C. for 0.5 hr. To the reaction mixture were added ethyl acetate and water. The obtained aqueous layer was neutralized with 1N aqueous hydrogen chloride solution, and extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (445.6 mg). MS: [M+H]+ 208.1.

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5620 - 5636
[2]Patent: WO2019/43407,2019,A1 .Location in patent: Page/Page column 148-149
[3]Patent: WO2016/34882,2016,A1 .Location in patent: Page/Page column 119; 120
[4]Patent: US2018/155333,2018,A1 .Location in patent: Paragraph 1763; 1764; 1765

20
[ 1186050-58-7 ]
(1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride [ No CAS ]
2-fluoro-6-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 17.0h;	Example 102 2-Fluoro-6-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide To a solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 1.09 g, 3.87 mmol) in DCM (13 ml) was added <strong>[1186050-58-7]2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid</strong> (CAS number 1186050-58-7; 0.802 g, 3.87 mmol), DIPEA (2.027 ml, 11.61 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.579 g, 4.26 mmol) and EDC (0.816 g, 4.26 mmol). The reaction was stirred at room temperature for 17 hours and was then partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic fit and concentrated in vacuo. The residue was purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) and re-crystallised from IPA to afford the title compound. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.41-1.59 (m, 2H), 1.59-1.76 (m, 2H), 1.95-2.10 (m, 2H), 4.06-4.20 (m, 2H), 6.68 (d, J=8.8 Hz, 1H), 7.29-7.41 (m, 2H), 7.57-7.66 (m, 2H), 7.71-7.75 (m, 1H), 8.00 (s, 2H), 8.25-8.28 (m, 1H), 8.63 (d, J=6.8 Hz, 1H) MS ES+: 435

Reference： [1]Patent: US2015/232460,2015,A1 .Location in patent: Paragraph 1220-1223

21
[ 1186050-58-7 ]
C₁₄H₁₉FN₂O*(x)ClH [ No CAS ]
C₂₃H₂₃F₂N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3.0h;	Compound 9-2 (120 mg, 0.32 mmol), compound 9-3 (77 mg, 0.38 mmol), HATU (182 mg, 0.48 mmol) and DIEA (124mg, 0.96 mmol) were dissolved in 5 mL of DMF, and the mixture was stirred under room temperature for 3 hours. The reaction mixture was poured into aqueous saline and extracted with ethyl acetate (10 mL x 3). The organic phase was combined and washed with water (10 mL x 2) and saturated NaCl solution (10 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified with preparative HPLC to give product 9-4 (22 mg, white solid, yield: 21 %). 1H NMR (400 MHz, MeOD) delta= 8.20-7.98 (m, 3H), 7.85-7.72 (m, 1H), 7.71-7.50 (m, 2H), 7.48-7.17 (m, 1H), 7.03-6.75 (m, 1H), 4.87-4.66 (m, 1H), 4.54-4.36 (m, 1H), 4.31-4.05 (m, 1H), 3.86-3.55 (m, 1H), 2.14 (br. s., 1H), 2.08-1.95 (m, 1H), 1.88 (td, J=7.2, 19.8 Hz, 2H), 1.77 (dd, J=11.3, 18.1 Hz, 2H), 1.68-1.54 (m, 1H), 1.53-1.32 (m, 2H)

Reference： [1]Patent: EP3115362,2017,A1 .Location in patent: Paragraph 0105; 0108; 0109

22
[ 1186050-58-7 ]
N-[(2S)-2-(ethylamino)propyl]-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride [ No CAS ]
C₁₉H₁₉F₄N₇O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2-chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 4.0h;	Example 1 : CIP (76 mg, 0.27 mmol) is added to a stirred mixture of A-1 (48 mg, 0.25 mmol), B-1 (60 mg, 0.21 mmol) and DIPEA (109 muIota_, 0.63 mmol) in dry ACN (2.0 mL) at RT. After 16 h the reaction is treated with ACN/water and purified by preparative LCMS (using a solvent gradient H20/ACN with NH4OH) to afford 50 mg of compound Example 1. ESI-MS: 420 [M+Na]+; HPLC (Rt): 1.02 min (method G). For some examples the reaction times are adapted: 4h for Example 7; 1 h for Example 9; 2h at 60C for Example 16:

Reference： [1]Patent: WO2017/178341,2017,A1 .Location in patent: Page/Page column 50; 53

23
[ 2797-51-5 ]
[ 1186050-58-7 ]
(S)-2,7-dimethyl-3-(3,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine [ No CAS ]
[(7S)-2,7-Dimethyl-3-(3,4,5-trifluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate;	Example 288 [(7S)-2,7-Dimethyl-3-(3,4,5-trifluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone To a solution of (S)-2,7-dimethyl-3-(3,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (15 mg, 53.3 mumol) (Intermediate 40) in CH2Cl2 (0.48 mL) was added <strong>[1186050-58-7]2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid</strong> (prepared according to methods described in Pat. Pub. No. WO2012145581, Oct. 26, 2012) (12.2 mg, 58.7 mumol), HATU (26.4 mg, 69.3 mumol), and N,N-diisopropylethylamine (27.6 muL, 0.16 mmol). After stirring at room temperature for 30 min, the mixture was concentrated in vacuo and purified by preparative HPLC (XBridge C18 column (5 mum, 100*4.6 mm), mobile phase of 5-95% ACN in 20 mM aqueous NH4OH) to afford the title compound as a white powder (21 mg, 84% yield). MS (ESI): mass calcd. for C23H18F4N6O, 470.1; m/z found, 471.2 [M+H]+. 1H NMR (600 MHz, DMSO-d6) delta 8.19-8.05 (m, 1.62H), 7.93-7.90 (m, 0.40H), 7.87-7.83 (m, 0.91H), 7.74-7.66 (m, 1H), 7.59-7.38 (m, 3H), 5.59-5.49 (m, 0.74H), 4.73-4.62 (m, 0.28H), 4.57-4.51 (m, 0.17H), 3.81 (s, 2.26H), 3.76 (s, 0.22H), 3.70 (s, 0.52H), 3.64-3.52 (m, 0.72H), 3.38-3.17 (m, 0.73H), 3.07-3.00 (m, 0.22H), 2.84-2.76 (m, 0.15H), 2.71-2.60 (m, 0.63H), 2.45-2.22 (m, 1.47H), 1.47 (d, J=6.7 Hz, 2.28H), 1.35 (d, J=6.8 Hz, 0.6H).

Reference： [1]Patent: US2020/102303,2020,A1

24
[ 1186050-58-7 ]
(S)-2,7-dimethyl-3-(3,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine [ No CAS ]
[(7S)-2,7-dimethyl-3-(3,4,5-trifluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl][2-fluoro-6-(triazol-2-yl)phenyl]methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 0.5h;Inert atmosphere;	To a solution of (S)-2,7-dimethyl-3-(3,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (15 mg, 53.3 mumol) (Intermediate 40) in CH2Cl2 (0.48 mL) was added <strong>[1186050-58-7]2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid</strong> (prepared according to methods described in Pat. Pub. No. WO2012145581, Oct. 26, 2012) (12.2 mg, 58.7 mumol), HATU (26.4 mg, 69.3 mumol), and N,N-diisopropylethylamine (27.6 muL, 0.16 mmol). After stirring at room temperature for 30 min, the mixture was concentrated in vacuo and purified by preparative HPLC (XBridge C18 column (5 mum, 100*4.6 mm), mobile phase of 5-95% ACN in 20 mM aqueous NH4OH) to afford the title compound as a white powder (21 mg, 84% yield). MS (ESI): mass calcd. for C23H18F4N6O, 470.1; m/z found, 471.2 [M+H]+. 1H NMR (600 MHz, DMSO-d6) delta 8.19-8.05 (m, 1.62H), 7.93-7.90 (m, 0.40H), 7.87-7.83 (m, 0.91H), 7.74-7.66 (m, 1H), 7.59-7.38 (m, 3H), 5.59-5.49 (m, 0.74H), 4.73-4.62 (m, 0.28H), 4.57-4.51 (m, 0.17H), 3.81 (s, 2.26H), 3.76 (s, 0.22H), 3.70 (s, 0.52H), 3.64-3.52 (m, 0.72H), 3.38-3.17 (m, 0.73H), 3.07-3.00 (m, 0.22H), 2.84-2.76 (m, 0.15H), 2.71-2.60 (m, 0.63H), 2.45-2.22 (m, 1.47H), 1.47 (d, J=6.7 Hz, 2.28H), 1.35 (d, J=6.8 Hz, 0.6H).

Reference： [1]Patent: US2020/102303,2020,A1 .Location in patent: Paragraph 0371; 1296-1297

25
methyl (E)-2-fluoro-6-(2-(2-oxoethylidene)hydrazinyl)benzoate [ No CAS ]
[ 1186050-58-7 ]

Reference： [1]Patent: WO2021/23843,2021,A1
[2]Patent: WO2021/23843,2021,A1

26
(E)-2-fluoro-6-(2-(2-oxoethylidene)hydrazinyl)benzoic acid [ No CAS ]
[ 1186050-58-7 ]