[ CAS No. 107504-08-5 ] {[proInfo.proName]}

Name: 107504-08-5|5-Fluoro-2-picolinic acid|98%
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Quality Control of [ 107504-08-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 107504-08-5 ]

Product Details of [ 107504-08-5 ]

CAS No. :	107504-08-5	MDL No. :	MFCD04114196
Formula :	C₆H₄FNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JTKFIIQGMVKDNZ-UHFFFAOYSA-N
M.W :	141.10	Pubchem ID :	2762876
Synonyms :

Calculated chemistry of [ 107504-08-5 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	31.15
TPSA :	50.19 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) :	-6.59 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.86
Log Po/w (XLOGP3) :	0.81
Log Po/w (WLOGP) :	1.34
Log Po/w (MLOGP) :	-0.69
Log Po/w (SILICOS-IT) :	1.17
Consensus Log Po/w :	0.7

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-1.6
Solubility :	3.52 mg/ml ; 0.0249 mol/l
Class :	Very soluble
Log S (Ali) :	-1.45
Solubility :	5.06 mg/ml ; 0.0358 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.65
Solubility :	3.15 mg/ml ; 0.0223 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.46

Safety of [ 107504-08-5 ]

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

Application In Synthesis of [ 107504-08-5 ]

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

Upstream synthesis route of [ 107504-08-5 ]
Downstream synthetic route of [ 107504-08-5 ]

[ 107504-08-5 ] Synthesis Path-Upstream 1~13

1
[ 107504-08-5 ]
[ 31181-88-1 ]

Reference： [1] Patent: WO2004/14902, 2004, A2,

2
[ 107504-08-5 ]
[ 802325-29-7 ]

Yield	Reaction Conditions	Operation in experiment
52%	With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 12 h; Inert atmosphere	A mixture of 14 (500 mg, 4 mmol) and LiAIH₄(202 mg, 5 mmol) in THF (10 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 0 °C for 12 h under N₂atmosphere. The reaction mixture was quenched by saturated sodium potassium tartrate (0.8 mL) at 15 °C, and then filtered. The mixture was diluted with H₂0 (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine (5 mL x 2), dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 15 (236 mg, 52percent) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) 8.43 (d, J - 2.8 Hz, 1 H), 7.45-7.41 (m, 1 H), 7.31-7.27 (m, 1 H), 4.76 (s, 2H). A mixture of 15 (1 g, 8 mmol), DCC (3 g, 16 mmol), DMAP (96 mg, 786 umol) and A/-BOC-(S)-valine (2 g, 9 mmol) in DCM (5 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 25 "C for 12 h under N₂atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si0₂, PE/EtOAc = 5:1) to give 16 (1 .3 g, 51 percent) as a yellow liquid.¹H N R (400 MHz, DMSO-de) 8.55 (s, 1 H), 7.71-7.83 (m, 1 H), 7.54-7.51 (m, 1 H), 7.25 (d, J = 8.0 Hz, 1 H), 5.22-5.13 (m, 2H), 3.91 (t, J = 7.2 Hz, 1 H), 2.06-2.02 (m, 1 H), 1.38 (s, 9H), 0.87 (d, J - 6.4 Hz, 6H).

Reference： [1] Patent: WO2017/195069, 2017, A1, . Location in patent: Page/Page column 61

3
[ 107504-08-5 ]
[ 67-56-1 ]
[ 107504-07-4 ]

Yield	Reaction Conditions	Operation in experiment
5.9 g	at 65℃; for 2 h; Sealed tube	5-fluoro-pyridine-2-carboxylic acid methyl ester2.7 mL Thionylchloride was dropped to 5 g 5-fluor-pyridine-2-carboxylic acid in 50 mL methanol. The reaction was stirred for 2 h at 65°C in a sealded micro wave vial. The solvents were removed and the residue was desolved in a mixture of DCM and methanol and filtered over silica gel. The filtrate was evaporated to give 5.9 g of the desired product.R_t: 0.77 (method K). (M+H)⁺: 156
5.9 g	With thionyl chloride In methanol at 65℃; for 2 h; Microwave irradiation; Sealed tube	6.01.06 5-fluoro-pyridine-2-carboxylic acid methyl ester 2.7 mL Thionylchloride was dropped to 5 g 5-fluor-pyridine-2-carboxylic acid in 50 mL methanol. The reaction was stirred for 2 h at 65° C. in a sealed micro wave vial. The solvents were removed and the residue was desolved in a mixture of DCM and methanol and filtered over silica gel. The filtrate was evaporated to give 5.9 g of the desired product. R_t: 0.77 (method K). (M+H)⁺: 156 By using the same synthesis strategy as for 5-fluoro-pyridine-2-carboxylic acid methyl ester the following compound was obtained:
9.895 g	at 80℃; for 8 h; Cooling with ice	In the ice bath,To a solution of 5-fluoro-2-pyridinecarboxylic acid (10 g) in methanol was slowly added dropwise thionyl chloride (10.3 mL).Dripping is completed.After moving to 80°C for 8 hours,Cool to room temperatureMethanol was distilled off under reduced pressure.Diluted with ethyl acetate,In the ice bath,Saturated sodium bicarbonate solution was added to the reaction mixture,Adjust pH = 8 or so.Extract with ethyl acetate,The combined organic phases are washed with saturated brine,Dried over anhydrous sodium sulfate,Filter and concentrate the filtrate in vacuoThe residue was separated by silica gel column chromatography to give the title compound (9.895 g).

Reference： [1] Patent: WO2013/79460, 2013, A1, . Location in patent: Page/Page column 46
[2] Patent: US2013/137688, 2013, A1, . Location in patent: Paragraph 0239; 0240; 0241
[3] Patent: CN108003161, 2018, A, . Location in patent: Paragraph 0628; 0630-0632

4
[ 31181-88-1 ]
[ 107504-08-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium chlorite; potassium dihydrogenphosphate In water; dimethyl sulfoxide for 1 h;	Potassium phosphate monobasic (1.4 g, 10 mmol) in water (10 mL) was added to a solution of 5-fluoropyridine-2-carbaldehyde (0.50 g, 4.0 mmol, Frontier) in DMSO (10 mL). Sodium chlorite (0.9 g, 0.008 mol) in water (10 mL) was added, and the reaction continued for 1 hour. The mixture was saturated with NaCl, then diluted with EtOAc. The organic layer was further washed with brine, dried over sodium sulfate and concentrated to afford product (370 mg, 65percent). 3/4 NMR (400 MHz, CDC1₃): δ 8.50 (d, 1H), 8.29 (ddd, 1H), 7.66 (ddd, 1H); LCMS (M+H)⁺: 142.0.

Reference： [1] Patent: WO2011/28685, 2011, A1, . Location in patent: Page/Page column 85; 86

5
[ 860296-24-8 ]
[ 107504-08-5 ]

Reference： [1] European Journal of Organic Chemistry, 2005, # 10, p. 2116 - 2123

6
[ 31181-53-0 ]
[ 107504-08-5 ]

Yield	Reaction Conditions	Operation in experiment
28%	With potassium permanganate In water	1 5-Fluoro-2-pyridinecarboxylic acid To water (100 ml) were added 5-fluoro-2-methylpyridine (J. Med. Chem., 32, 1970(1989): 2.2 g, 20 mmol) and potassium permanganate (19.1 g, 120 mmol), and heated under reflux for 4 hours. The reaction mixture was filtrated and the filtrate was concentrated, acidified with KHSO₄, extracted with ethyl acetate and the extract was dried over Na₂SO₄. The sol vent was evaporated to give the title compound (0.80 g; 28percent). ¹H-NMR(270 MHz, DMSO-d₆) 8.70 (d, J=2.8 Hz, 1H), 8.14 (dd, J=8.7, 4.6 Hz, 1H), 7.89 (td, J=8.7, 2.8 Hz, 1H)

Reference： [1] Patent: US6384033, 2002, B1,

7
[ 327056-62-2 ]
[ 107504-08-5 ]

Reference： [1] Patent: EP1621537, 2006, A1, . Location in patent: Page/Page column 58
[2] Patent: EP1803719, 2007, A1, . Location in patent: Page/Page column 27-28

8
[ 860296-22-6 ]
[ 107504-08-5 ]

Reference： [1] European Journal of Organic Chemistry, 2005, # 10, p. 2116 - 2123

9
[ 860296-23-7 ]
[ 107504-08-5 ]

Reference： [1] European Journal of Organic Chemistry, 2005, # 10, p. 2116 - 2123

10
[ 372-47-4 ]
[ 107504-08-5 ]

Reference： [1] European Journal of Organic Chemistry, 2005, # 10, p. 2116 - 2123

11
[ 77332-77-5 ]
[ 107504-08-5 ]

Reference： [1] European Journal of Organic Chemistry, 2005, # 10, p. 2116 - 2123

12
[ 107504-08-5 ]
[ 860296-24-8 ]

Reference： [1] Patent: WO2016/161960, 2016, A1,

13
[ 107504-08-5 ]
[ 499796-71-3 ]

Reference： [1] Patent: WO2015/51479, 2015, A1, . Location in patent: Page/Page column 76; 77
[2] Patent: WO2015/51479, 2015, A1,
[3] Patent: WO2015/54038, 2015, A1,

[ 107504-08-5 ] Synthesis Path-Downstream 1~88

1
[ 860296-22-6 ]
[ 107504-08-5 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 2116 - 2123

2
[ 860296-23-7 ]
[ 107504-08-5 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 2116 - 2123

3
[ 372-47-4 ]
[ 107504-08-5 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 2116 - 2123

4
[ 77332-77-5 ]
[ 107504-08-5 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 2116 - 2123

5
[ 107504-08-5 ]
[ 64-17-5 ]
[ 148541-70-2 ]

Yield	Reaction Conditions	Operation in experiment
49.3%	With hydrogenchloride; In 1,4-dioxane; at 90℃; for 20h;	5-Fluoro-pyridine-2-carboxylic acid (200 mg, 1.13 mmol) was mixed with ethanol (6 mL) and 4 M [HC1] in dioxane (0.5 mL) at 90 [C] for 20 h. The mixture was concentrated and mixed with saturated sodium carbonate and dichloromethane. The dichloromethane layer was washed with brine, dried to give 94 mg (49.3%) of <strong>[107504-08-5]5-fluoro-pyridine-2-carboxylic acid</strong> ethyl ester. To <strong>[107504-08-5]5-fluoro-pyridine-2-carboxylic acid</strong> ethyl ester (94 mg, 0.556 mmol) in dichloromethane (4.0 [ML),] [1] M DIBAL in toluene (1.23 mL, 1. 23 mmol) was added at room temperature and the mixture was stirred for 30 min. The reaction mixture was quenched with 2 M sodium carbonate and extracted with dichloromethane. The dichloromethane was dried and concentrated to give 39 mg (54.7%) of crude 5-fluoro- pyridine-2-carbaldehyde which could be used for the next step reaction without further purification. GC-MS [(M+)] : 125

Reference： [1]Patent: WO2004/14902,2004,A2 .Location in patent: Page 42

6
[ 107504-08-5 ]
[ 478366-23-3 ]
N-[6-(1-methylpiperidin-4-yloxy)pyridin-2-yl]-5-fluoro-2-pyridinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-trimethyl-pyridine; HATU; In DMF (N,N-dimethyl-formamide); for 48h;	Combine R-acid (300 UL of 0. 5M solution in DMF), HATU (57 mg, 0. 15 MMOL), collidine (19 muL, 0.15 mmol), 6- (1-METHYL-PIPERIDIN-4-YLOXY)-PYRIDIN-2-YLAMINE AND DMF (1.5 ML) and stir. After 48 hr. , dilute the reaction mixture with 10% acetic ACID/METHANOL (0.5 mL) and directly apply the resulting solution to a 2 g SCX column. Thoroughly wash the column with methanol, elute with 1 M ammonia-methanol, concentrate the eluant, and further purify by HIGH-THROUGHPUT mass guided chromatography. The procedure is repeated in parallel for products R30-R38.

Reference： [1]Patent: WO2004/94380,2004,A1 .Location in patent: Page 157-158

7
[ 107504-08-5 ]
[ 13433-00-6 ]
[ 787564-31-2 ]

Yield	Reaction Conditions	Operation in experiment
53%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 19.5h;	The above 5-fluoropyridine-2-carbonitrile (11.8 g) in 6N HCl (100 mL) was refluxed for 4 hours and then cooled in air. NaCl was added to the reaction mixture to saturate the mixture, and ethyl acetate was added thereto for partitioning the mixture. The organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure, and the residue was dissolved in N,N-dimethylformamide (140 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.0 g), 1-hydroxybenzotriazole (770 mg), and aminomalonic acid diethyl ester hydrochloride (7.2 g) were added to the solution, and the mixture was stirred for 19.5 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (hexane - ethyl acetate), to thereby give 2-[(5-fluoropyridine-2-carbonyl)amino]malonic acid diethyl ester as a solid product (9.4 g, 53%). 1H-NMR (400MHz, CDCl3) delta:1.33 (6H, t, J=7.1Hz), 4.27-4.38(4H,m), 5.36 (1H, d, J=7.4Hz), 7.51-7.56 (1H, m), 8.20-8.21 (1H, m), 8.46 (1H, d, J=2.7Hz), 8.74 (1H, d, J=10.0Hz).
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 19.5h;	2) 2-[(5-Fluoropyridine-2-carbonyl)amino]malonic acid diethyl ester A 6 N aqueous solution of hydrochloric acid (100 mL) containing the 5-fluoropyridine-2-carbonitrile (11.8 g) was heated to reflux for 4 hours. After air cooling, Nacl was added to the reaction solution for saturation, and ethyl acetate was further added thereto. The resultant mixture was partitioned, and the organic layer was dried over anhydrous sodium sulfate. After separating the organic layer by filtration, the solvent was evaporated under reduced pressure, and a residue thus obtained was dissolved in N,N-dimethylformamide (140mL). Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.0 g), 1-hydroxybenzotriazole (770mg), and aminomalonic acid diethyl ester hydrochloride (7.2 g) were added to the solution, and the resultant mixture was stirred at room temperature for 19.5 hours. Water and ethyl acetate were added to the reaction solution, and the mixture was partitioned. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After separating the organic layer by filtration, the solvent was evaporated under reduced pressure, and a residue thus obtained was purified by silica gel column chromatography (hexane-ethyl acetate), to obtain 2-[(5-fluoropyridine-2-carbonyl)amino]malonic acid diethyl ester (9.4 g, 53%) as a solid. 1H-NMR (400MHz, CDCl3) delta: 1.33 (6H, t, J=7.1Hz), 4.27-4.38 (4H, m), 5.36 (1H, d, J=7.4Hz), 7.51-7.56 (1H, m), 8.20-8.21 (1H, m), 8.46 (1H, d, J=2.7Hz), 8.74 (1H, d, J=10.0Hz).

Reference： [1]Patent: EP1621537,2006,A1 .Location in patent: Page/Page column 58
[2]Patent: EP1803719,2007,A1 .Location in patent: Page/Page column 27-28

8
[ 327056-62-2 ]
[ 107504-08-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; water; for 4h;Heating / reflux;	2) 2-[(5-Fluoropyridine-2-carbonyl)amino]malonic acid diethyl ester The above 5-fluoropyridine-2-carbonitrile (11.8 g) in 6N HCl (100 mL) was refluxed for 4 hours and then cooled in air. NaCl was added to the reaction mixture to saturate the mixture, and ethyl acetate was added thereto for partitioning the mixture. The organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure, and the residue was dissolved in N,N-dimethylformamide (140 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.0 g), 1-hydroxybenzotriazole (770 mg), and aminomalonic acid diethyl ester hydrochloride (7.2 g) were added to the solution, and the mixture was stirred for 19.5 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (hexane - ethyl acetate), to thereby give 2-[(5-fluoropyridine-2-carbonyl)amino]malonic acid diethyl ester as a solid product (9.4 g, 53%). 1H-NMR (400MHz, CDCl3) delta:1.33 (6H, t, J=7.1Hz), 4.27-4.38(4H,m), 5.36 (1H, d, J=7.4Hz), 7.51-7.56 (1H, m), 8.20-8.21 (1H, m), 8.46 (1H, d, J=2.7Hz), 8.74 (1H, d, J=10.0Hz).
	With hydrogenchloride; water; for 4h;Heating / reflux;	2) 2-[(5-Fluoropyridine-2-carbonyl)amino]malonic acid diethyl ester A 6 N aqueous solution of hydrochloric acid (100 mL) containing the 5-fluoropyridine-2-carbonitrile (11.8 g) was heated to reflux for 4 hours. After air cooling, Nacl was added to the reaction solution for saturation, and ethyl acetate was further added thereto. The resultant mixture was partitioned, and the organic layer was dried over anhydrous sodium sulfate. After separating the organic layer by filtration, the solvent was evaporated under reduced pressure, and a residue thus obtained was dissolved in N,N-dimethylformamide (140mL). Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.0 g), 1-hydroxybenzotriazole (770mg), and aminomalonic acid diethyl ester hydrochloride (7.2 g) were added to the solution, and the resultant mixture was stirred at room temperature for 19.5 hours. Water and ethyl acetate were added to the reaction solution, and the mixture was partitioned. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After separating the organic layer by filtration, the solvent was evaporated under reduced pressure, and a residue thus obtained was purified by silica gel column chromatography (hexane-ethyl acetate), to obtain 2-[(5-fluoropyridine-2-carbonyl)amino]malonic acid diethyl ester (9.4 g, 53%) as a solid. 1H-NMR (400MHz, CDCl3) delta: 1.33 (6H, t, J=7.1Hz), 4.27-4.38 (4H, m), 5.36 (1H, d, J=7.4Hz), 7.51-7.56 (1H, m), 8.20-8.21 (1H, m), 8.46 (1H, d, J=2.7Hz), 8.74 (1H, d, J=10.0Hz).

Reference： [1]Patent: EP1621537,2006,A1 .Location in patent: Page/Page column 58
[2]Patent: EP1803719,2007,A1 .Location in patent: Page/Page column 27-28

9
[ 107504-08-5 ]
[ 79-37-8 ]
[ 453565-60-1 ]
[ 453567-20-9 ]

Yield	Reaction Conditions	Operation in experiment
24 mg (15.5%)	With triethylamine; In N-methyl-acetamide; dichloromethane;	3-(3-Cyano-5-dimethylaminophenyl)-5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole A mixture of 5-fluoro-picolinic acid acid (177.5 mg, 1 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (2 ml, 4 mmol, dichloromethane). The mixture was stirred 2 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 3-cyano-5-dimethylaminophenyl-amidoxime (102 mg, 0.5 mmol) and triethylamine (404 mg, 4 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (1 mL) for 1 hours at 130 C. Standard work up, afforded 24 mg (15.5%) of 3-(3-cyano-5-dimethyaminophenyl)-5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole. 1H-NMR (CDCl3), delta (ppm): 8.72 (d, 1H), 8.37 (dd, 1H), 7.81 (s, 1H), 7.68 (dt, 2H), 7.02 (d, 1H), 3.10 (s, 6H).

Reference： [1]Patent: US2003/55085,2003,A1

10
[ 107504-08-5 ]
[ 75-64-9 ]
[ 223444-93-7 ]

Yield	Reaction Conditions	Operation in experiment
		2 N-t-Butyl-5-fluoro-2-pyridinecarboxamide The title compound was prepared by the same method as that described in Example 39-3), using <strong>[107504-08-5]5-fluoro-2-pyridinecarboxylic acid</strong> and t-butyl amine. 1H-NMR(270 MHz, CDCl3) 8.35 (d, J=2.8 Hz, 1H), 8.21 (dd, J=8.6, 4.5 Hz, 1H), 7.82 (br, 1H), 7.52 (td, J=8.6, 2.8 Hz, 1H), 1.49 (s, 9H)

Reference： [1]Patent: US6384033,2002,B1

11
[ 31181-53-0 ]
[ 107504-08-5 ]

Yield	Reaction Conditions	Operation in experiment
28%	With potassium permanganate; In water;	1 5-Fluoro-2-pyridinecarboxylic acid To water (100 ml) were added 5-fluoro-2-methylpyridine (J. Med. Chem., 32, 1970(1989): 2.2 g, 20 mmol) and potassium permanganate (19.1 g, 120 mmol), and heated under reflux for 4 hours. The reaction mixture was filtrated and the filtrate was concentrated, acidified with KHSO4, extracted with ethyl acetate and the extract was dried over Na2SO4. The sol vent was evaporated to give the title compound (0.80 g; 28%). 1H-NMR(270 MHz, DMSO-d6) 8.70 (d, J=2.8 Hz, 1H), 8.14 (dd, J=8.7, 4.6 Hz, 1H), 7.89 (td, J=8.7, 2.8 Hz, 1H)

Reference： [1]Patent: US6384033,2002,B1

12
[ 107504-08-5 ]
[ 1017598-58-1 ]

Reference： [1]Chem,2020,vol. 6,p. 497 - 511

13
[ 107504-08-5 ]
[ 915226-40-3 ]
[ 915226-66-3 ]

Yield	Reaction Conditions	Operation in experiment
14%		45(A) (S)-3-[5-(5-Fluoro-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester A mixture of 3-fluoro-pyridine-6-carboxylic acid (0.2 g, 1.43 mmol), HOAT (0.195 g, 1.43 mmol), EDCI.HCl (0.415 g, 2.14 mmol) in dry dioxane (30 mL) was heated at 50 C. for 2 h, under nitrogen atmosphere, then (S)-3-(N-hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (350 mg, 1.43 mmol), prepared as described in Example 1(C), was added and the reaction mixture was heated at 80 C. overnight. The solvent was evaporated under reduced pressure. The residue was diluted with water (40 mL) and ethyl acetate (40 mL), the phases were separated and the organic layer was washed sequentially with water (40 mL, twice), 1N Na2CO3 (40 mL, twice) and with brine. The organic layer was dried over sodium sulphate and the solvent was removed under vacuum to give a residue that was purified by flash chromatography (silica gel, eluent gradient: from hexane/ethyl acetate 8:2 to hexane/ethyl acetate 6:4) to give the pure title compound (70 mg). Yield: 14%; LCMS (RT): 4.3 min (Method A); MS (ES+) gave m/z: 349.0.

Reference： [1]Patent: US2009/215822,2009,A1 .Location in patent: Page/Page column 24

14
[ 107504-08-5 ]
[ 915226-65-2 ]
[ 915226-27-6 ]

Yield	Reaction Conditions	Operation in experiment
24%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1,4-dioxane; at 20 - 80℃;	44(E) (S)-(4-fluorophenyl)-{3-[5-(5-fluoropyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidin-1-yl}-methanone A mixture of (S)-1-(4-fluoro-benzoyl)-N-hydroxy-piperidine-3-carboxamidine (150 mg, 0.56 mmol), <strong>[107504-08-5]5-fluoro-pyridine-2-carboxylic acid</strong> (79 mg, 0.56 mmol), HOAT (76 mg, 0.56 mmol), EDCI.HCl (163 mg, 0.85 mmol) in dry dioxane (15 mL) was kept under stirring at ambient temperature overnight, under nitrogen atmosphere. The reaction mixture was then heated at 80 C. for 5 h and the solvent was evaporated under reduced pressure. The residue was diluted with water (40 mL) and ethyl acetate (40 mL), the phases were separated and the organic layer was washed sequentially with water (40 mL, twice), 1N NaOH (40 mL, twice) and with brine. The organic layer was dried over sodium sulphate and the solvent was removed under vacuum to give a residue that was purified by flash chromatography (silica gel, eluent: hexane/ethyl acetate 1:1) and successive preparative HPLC to give the pure title compound (50 mg). Yield: 24% (White powder); [alpha]D20=+67.5 (c=1.0, MeOH); mp=108-110 C.; LCMS (RT): 2.70 min (Method I); MS (ES+) gave m/z: 371.1. 1H-NMR (DMSO-d6, 353K), delta (ppm): 8.80 (d, 1H); 8.27 (dd, 1H); 7.97 (ddd, 1H); 7.48 (dd, 2H); 7.23 (dd, 2H); 4.25 (m, 1H); 3.83 (m, 1H); 3.43 (dd, 1H); 3.31-3.14 (m, 2H); 2.22 (m, 1H); 1.94 (m, 1H); 1.83 (m, 1H); 1.66 (m, 1H).

Reference： [1]Patent: US2009/215822,2009,A1 .Location in patent: Page/Page column 24

15
[ 107504-08-5 ]
[ 1075230-69-1 ]
[ 1076189-11-1 ]

Yield	Reaction Conditions	Operation in experiment
		5-fluroro-2-pyridine carboxylic acid (70.7 mg) was dissolved into methanol (2 ml), and 4-(4, 6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (180.1 mg) was added to the mixture with stirring at room temperature. The mixture was stirred for 5 minutes and a solution of the compound (19-10) (119.9 mg) in methanol (2 ml) was added to the reaction solution with stirring under cooling with ice-water bath. After stirred for 3 hours, a 0.5M aqueous solution of sodium hydroxide was added to the mixture with stirring under cooling with ice-water bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel chromatography to afford the compound (949) (149.4 mg). 1 H-NMR (CDCl3) delta: 1.63 (3H, s), 1.82-2.00 (1H, m), 2.43-2.58 (1H, m), 2.72-2.82 (1H, m), 2.95-3.02 (1H, m), 7.06 (1H, dd, J = 11.7, 9.0 Hz), 7.43-7.48 (1H, m), 7.97-8.03 (1H, m), 8.15-8.18 (1H, m), 8.42 (1H, d, J = 8.1Hz), 8.72 (1H, s), 9.91 (1H, br s)

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 5080 - 5095
[2]Patent: EP2151435,2010,A1 .Location in patent: Page/Page column 76

16
[ 107504-08-5 ]
[ 1231881-82-5 ]
[ 1231883-83-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18h;	Example 5-3Preparation of 4-(3-(5-fluoropicolinamido)-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide A mixture of 4-(3-amino-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 3-2, 100 mg, 0.204 mmol), <strong>[107504-08-5]5-fluoropicolinic acid</strong> (43.1 mg, 0.306 mmol), and HOAT (41.6 mg, 0.306 mmol) in acetonitrile (2 mL) was treated with DIEA (0.053 mL, 0.306 mmol) and EDC (78 mg, 0.408 mmol) and the mixture was stirred at rt. After 18 h, the mixture was diluted with methanol and purified by preparative HPLC. The aqueous residue from concentration of the appropriate effluent fractions was made basic with NaHCO3 (aq) and extracted three times with EtOAc. The combined organic phases were dried and concentrated to provide 4-(3-(5-fluoropicolinamido)-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as a light gray powder (111.5 mg, 92%). 1H NMR (400 MHz, methanol-d4) delta 8.58 (d, J=3.1 Hz, 1H) 8.31 (dd, J=8.8, 4.8 Hz, 1H) 7.96-8.03 (m, 2H) 7.82 (td, J=8.6, 2.6 Hz, 1H) 7.68 (d, J=0.9 Hz, 1H) 7.45 (t, J=7.9 Hz, 1H) 7.23 (dd, J=7.5, 0.9 Hz, 1H) 7.09 (d, J=7.9 Hz, 1H) 7.03-7.08 (m, 1H) 6.95-7.00 (m, 1H) 3.78 (br. s., 2H) 3.49 (br. s., 2H) 2.52 (br. s., 2H) 2.40 (br. s., 2H) 2.31 (s, 3H) 2.04 (s, 3H). Mass spectrum m/z 565.2 (M+H)+.

Reference： [1]Patent: US2010/160303,2010,A1 .Location in patent: Page/Page column 69
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 7915 - 7935

17
[ 107504-08-5 ]
[ 1158975-01-9 ]
[ 1254364-40-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5839 - 5842

18
[ 107504-08-5 ]
[ 74-89-5 ]
[ 1177421-97-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In methanol; dichloromethane; for 15h;	(123a) 5-Fluoro-N-methylpyridine-2-carboxamide 5-Fluoropyridine-2-carboxylic acid (495 mg, 3.51 mmol) was dissolved in methylene chloride (10 mL), and HOBt·H2O (591 mg, 3.86 mmol), WSCI·HCl (1.35 g, 7.02 mmol), triethylamine (2.44 mL, 17.5 mmol) and 40% methylamine/methanol solution (0.82 mL, 10.5 mmol) were added, followed by stirring for 15 hours. To the reaction solution, water (30 mL) was added, and extraction was carried out twice with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-50%) to afford the desired compound (490 mg, yield 91%) as a white solid. 1H-NMR (CDCl3, 400 MHz): delta 3.03 (3H, d, J=5.5 Hz), 7.53 (1H, dt, J=2.7, 8.6 Hz), 7.85 (1H, br s), 8.24 (1H, dd, J=8.2, 4.7 Hz), 8.38 (1H, d, J=2.7 Hz).

Reference： [1]Patent: EP2239253,2010,A1 .Location in patent: Page/Page column 161
[2]Organic Process Research and Development,2019,vol. 23,p. 900 - 911
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 5472 - 5492

19
[ 107504-08-5 ]
[ 1253200-95-1 ]
[ 1253200-98-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; HATU; In N,N-dimethyl-formamide; for 0.0833333h;	Intermediate 3-6 (274 mg, 1.063 mmol) and <strong>[107504-08-5]5-fluoropyridine-2-carboxylic acid</strong> (150 mg, 1.063 mmol) were combined in DMF (10 mLl), and to this was added Et3N (0.319 mL, 2.339 mmol) and HATU (485 mg, 1.276 mmol). The resulting mixture was stirred for 5 min. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 X 20 mL). The organic phase was combined and washed with brine, dried over Na2SO4 and concentrated. The crude product was dissolved in CH3CN and left standing at RT. The crystals that formed were collected by filtration and washed with water and dried to give 4-1 which was used directly in the next step.

Reference： [1]Patent: WO2010/124055,2010,A1 .Location in patent: Page/Page column 46

20
[ 107504-08-5 ]
[ 1262037-64-8 ]
[ 1262037-71-7 ]

Yield	Reaction Conditions	Operation in experiment
79%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N,N-dimethyl-formamide; In dichloromethane; at 22℃; for 1.33333h;	A mixture of N-((4aS,7aS)-7a-(5-amino-2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (20.4 g, 51.8 mmol), <strong>[107504-08-5]5-fluoropicolinic acid</strong> (8.77 g, 62.2 mmol), 1-hydroxybenzotriazole hydrate (10.3 g, 67.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.2 g, 67.4 mmol) in a mixture of dichloromethane (345 mL) and DMF (6.5 mL) is stirred at 22 C. for 80 min. A solution of 2 M sodium hydroxide (129.5 mL, 259 mmol) is added and the stirring is continued for 10 min. The mixture is separated and the aqueous phase is extracted with twice with dichloromethane (2×100 mL). The organic layer is concentrated under reduced pressure and the residue is diluted with ethyl acetate (200 mL). The organic layer is washed with cooled water (2×50 mL), brine (50 mL) and filtered through a short pad of silica using 100% ethyl acetate to give title compound (23.8 g, 79%). ES/MS m/e: 495 (M+1).

Reference： [1]Patent: US2011/9395,2011,A1 .Location in patent: Page/Page column 11

21
[ 31181-88-1 ]
[ 107504-08-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium chlorite; potassium dihydrogenphosphate; In water; dimethyl sulfoxide; for 1h;	Potassium phosphate monobasic (1.4 g, 10 mmol) in water (10 mL) was added to a solution of 5-fluoropyridine-2-carbaldehyde (0.50 g, 4.0 mmol, Frontier) in DMSO (10 mL). Sodium chlorite (0.9 g, 0.008 mol) in water (10 mL) was added, and the reaction continued for 1 hour. The mixture was saturated with NaCl, then diluted with EtOAc. The organic layer was further washed with brine, dried over sodium sulfate and concentrated to afford product (370 mg, 65%). ¾ NMR (400 MHz, CDC13): delta 8.50 (d, 1H), 8.29 (ddd, 1H), 7.66 (ddd, 1H); LCMS (M+H)+: 142.0.

Reference： [1]Patent: WO2011/28685,2011,A1 .Location in patent: Page/Page column 85; 86

22
[ 107504-08-5 ]
4-piperazin-1-yl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride [ No CAS ]
C₂₉H₃₆FN₉O₂Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Triethylamine (155 uL, 1.12 mmol) and N,N,N',N'-Tetramethyl-0-(7-azabenzotriazol- l-yl)uronium Hexafluorophosphate (85 mg, 0.22 mmol) were added to a solution of 5- fluoropyridine-2-carboxylic acid (39 mg, 0.28 mol) in THF (2.0 mL). After stirring for 15 minutes, 4-piperazin-l-yl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl]butanenitrile hydrochloride (1 10 mg, 0.18 mmol, from Example 12, Step 2) was added. The reaction was stirred for 16 hours. The reaction was partitioned between water and ethyl acetate. The organic layer was washed successively with water, 0. IN NaOH and brine, dried over sodium sulfate and concentrated. The residue was stirred in a 1 : 1 mixture of DCM:TFA for 2 hours, concentrated, and stirred in methanol (2 mL) containing ethylenediamine (0.2 mL) for one hour. Purification via preparative HPLC- MS, eluting with a gradient of MeCN/H20 containing 0.1% TFA, afforded the product as the trifluoroacetate salt (72 mg, 50%). ¾ NMR (400 MHz, d6-dmso): delta 12.50 (br s, 1H), 8.99 (s, 1H), 8.82 (s, 1H), 8.58 (d, 1H), 8.53 (s, 1H), 7.87 (dt, 1H), 7.78 (br s, 1H), 7.71 (dd, 1H), 7.12 (br s, 1H), 5.29-5.14 (br m, 1H), 3.99-2.54 (br, 12H); LCMS (M+H)+: 460.2.

Reference： [1]Patent: WO2011/28685,2011,A1 .Location in patent: Page/Page column 86

Yield	Reaction Conditions	Operation in experiment
7%	With Hexafluorobenzene; tetra-n-butylammonium cyanide; In dimethylsulfoxide-d6; at 20℃; for 24h;	General procedure: In Situ TBAF* with DS-2 [0087] It was found that pre-formation of TBAF* is not necessary to facilitate fluorination at room temperature. Weighing the substrate and TBACN into the reaction vessel followed by DMSO and the appropriate amount of C6F6 furnishes the desired product in excellent yield (Table 1). [TABLE-US-00001] TABLE 1 Fluorination of DS-2 with in situ generated anhydrous TBAF* Entry TBAF* Equiv Yield 1 2.0 >99% 2 2.0 >99% 3 4.0 >99% 4 4.0 >99% In addition to the model substrate DS-2, other chloropicolinates, as well as simple chloropyridines, underwent fluorination with the disclosed methods. 5-Chloropicolinates went to full conversion as demonstrated in Scheme 2 (top row). 5-Fluoropicolinic acid, however, was only formed in small quantities presumably due to deprotonation by fluoride thereby inactivating the substrate to nucleophilic aromatic substitution. Simpler chloropyridines were less effective as substrates for this method in accordance to the reactivity observed by DiMagno et al. 4,5-Dichloro-6-arylpicolinates (Scheme 2, bottom row) demonstrated fluorination first at the more activated 4-position followed by fluorination of the less activated 5-position, although the total yield was diminished due to the production of the undesired bis-cyanopicolinate product. [0091]

24
[ 107504-08-5 ]
[ 1383985-65-6 ]
[ 1383982-88-4 ]

Yield	Reaction Conditions	Operation in experiment
37%		Example 20xN-[(1r,4r)-4''-Amino-4-methoxy-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-6'-yl]-5-fluoropyridine-2-carboxamide; N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (39.1 mg, 0.20 mmol) was added to a suspension of <strong>[107504-08-5]5-fluoropicolinic acid</strong> (26.6 mg, 0.19 mmol) in DCM (0.5 mL). The solution was stirred for 10 min at r.t. and then dropwise added to an ice-cooled solution of 4-methoxy-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4'',6'-diamine (Example 20j, step 1, 49 mg, 0.16 mmol) and 2M HCl (0.078 mL, 0.16 mmol) in DMF (0.500 mL). The mixture was stirred at 0 C. for 1 h. The solvent was evaporated. The crude product was purified using preparative chromatography. The fractions containing the product were pooled and the MeOH was evaporated. DCM was added and the organic phase was extracted, dried through a phase separator and evaporated to give the title compound (25 mg, 37% yield): 1H NMR (500 MHz, CD3CN) delta ppm 0.99-1.10 (m, 1H), 1.18-1.27 (m, 2H), 1.45 (td, 1H), 1.50-1.57 (m, 2H), 1.83-1.90 (m, 2H), 2.20 (s, 3H), 2.94-3.06 (m, 2H), 3.06-3.15 (m, 1H), 3.25 (s, 3H), 5.29 (br. s., 2H), 7.15 (d, 1H), 7.28 (d, 1H), 7.48 (dd, 1H), 7.72 (td, 1H), 8.24 (dd, 1 H), 8.52 (d, 1H), 9.78 (br. s., 1H); MS (ES+) m/z 436 [M+H]

Reference： [1]Patent: US2012/165347,2012,A1 .Location in patent: Page/Page column 66

25
[ 107504-08-5 ]
bis[2-(2,4-difluorophenyl)pyridinato-N,C₆']iridium(III) chloride dimer [ No CAS ]
[ 1392214-96-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium carbonate; In 1,2-dimethoxyethane;Inert atmosphere; Reflux;	General procedure: A 100mL round-bottom flask was charged with 1.75g (16.5mmol) sodium carbonate and 0.81g (6.6mmol) pyridine-2-carboxylic acid in 53mL 1,2-dimethoxyethane. The mixture was purged with nitrogen and 2.00g (1.64mmol)[(dfppy)2IrCl]2 was added. The reaction was brought to reflux and heated for 9 hr under a nitrogen atmosphere. The reaction was then chilled in an ice-water bath prior to filtration through a glass frit. The solids were washed with three portions of water and three portions of methanol and dried under vacuum. This yielded 2.08g yellow product (91%).

Reference： [1]Inorganica Chimica Acta,2019,vol. 496
[2]Dalton Transactions,2012,vol. 41,p. 9373 - 9381

26
[ 107504-08-5 ]
[ 1383742-57-1 ]
[ 1383741-33-0 ]

Yield	Reaction Conditions	Operation in experiment
37%		5-Fluoro-2-pyridinecarboxylic acid (0.10 mg, 0.68 mmol) was added to a solution of 4- (4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmo holinium chloride (205 mg, 0.74 mmol) in MeOH (3 mL). The mixture was stirred at room temperature for 5 minutes. The mixture was cooled to 0 C and a solution of (R)-6-(5-amino-2-fluoro-phenyl)-6- methyl-5,6-dihydro-imidazo[l,2-a]pyrazin-8-ylamine (160 mg, 0.62 mmol) in MeOH (3 mL) was added. The mixture was warmed to room temperature and stirred for 18 hours. The mixture was treated with sat. Na2C03 and water and extracted with DCM. The organic layer was separated, dried (Na2S04), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica; 7N H3 in MeOH in DCM 0/100 to 3/97). The desired fractions were collected and the solvents evaporated in vacuo. The residue was triturated with diethyl ether, filtered and dried in vacuo to yield (R)-<strong>[107504-08-5]5-fluoro-pyridine-2-carboxylic acid</strong> [3-(8-amino-6-methyl-5,6- dihydro-imidazo[l,2-a]pyrazin-6-yl)-4-fluoro-phenyl]-amide (0.088 g, 37% yield) as a white solid.

Reference： [1]Patent: WO2012/85038,2012,A1 .Location in patent: Page/Page column 88

27
[ 107504-08-5 ]
[ 1383742-79-7 ]
[ 1383742-83-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In methanol; at 0 - 20℃; for 24h;	5-Fluoro-2-pyridinecarboxylic acid (15 mg, 0.11 mmol) was added to a solution of 4- (4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmo holinium chloride (31.7 mg, 0.11 mmol) in MeOH (0.95 mL). The mixture was stirred at room temperature for 5 minutes. The mixture was cooled to 0 C and a solution of (R)-tert-buty [6-(5-amino-2- fluorophenyl)-2-chloro-3-cyano-6-methyl-5,6-dihydroimidazo[l,2-a]pyrazin-8- yl]carbamate (40 mg, 0.095 mmol) in MeOH (0.95 mL) was added. The mixture was warmed to room temperature and stirred for 24 hours. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7N H3 in MeOH in DCM 0/100 to 3/97). The desired fractions were collected and the solvents evaporated in vacuo to yield (R)-tert-buty [2-chloro-3-cyano-6-(2-fluoro-5- [(5-fluoropyridin-2-yl)carbonyl]amino}phenyl)-6-methyl-5,6-dihydroimidazo[l,2- a]pyrazin-8-yl]carbamate (40 mg, 77% yield).

Reference： [1]Patent: WO2012/85038,2012,A1 .Location in patent: Page/Page column 75

28
[ 107504-08-5 ]
[ 1397683-78-1 ]
[ 1397683-23-6 ]

Yield	Reaction Conditions	Operation in experiment
60%		Example B 11Preparation of compound 20: rac-<strong>[107504-08-5]5-fluoro-pyridine-2-carboxylic acid</strong> [3-(4-amino-6- difluoromethyl-6,7-dihydro-pyrazolo[l,5-a]pyrazin-6-yl)-4-fluoro-phenyl]-amide and compound 21: (S)-<strong>[107504-08-5]5-fluoro-pyridine-2-carboxylic acid</strong> [3-(4-amino-6-difluoromethyl- 6,7-dihydro-pyrazolo[l,5-a]pyrazin-6-yl)-4-fluoro-phenyl]-amide and compound 22: (R)-<strong>[107504-08-5]5-fluoro-pyridine-2-carboxylic acid</strong> [3-(4-amino-6-difluoromethyl-6,7-dihydro- pyrazolo[l,5-a]pyrazin-6-yl)-4-fluoro-phenyl]-amide5-Fluoro-2-pyridinecarboxylic acid (74.5 mg, 0.528 mmol) was added to a mixture of4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (146 mg,0.528 mmol) in MeOH (3 mL). The mixture was stirred at room temperature for 5 min. Then the mixture was cooled to 0 C and a solution of intermediate A58 (130 mg, 0.44 mmol) in MeOH (2 mL) was added. The mixture was warmed to roomtemperature and stirred for 1 hour, then treated with a saturated solution of Na2C03 and H20 and extracted with DCM. The organic layer was separated, dried (MgS04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 7 M NH3 in MeOH/DCM). The desired fractions were collected and the solvents evaporated in vacuo. The resulting product was triturated with heptane, sonicated and filtered, to afford compound 17 (112 mg, 60% yield) as a white solid. This racemic compound was then further purified by preparative SFC on a Chiralpak AD-H column (5 muiotaeta, 250 x 20 mm), mobile phase [70% C02, 30% EtOH (+ 0.3% iPr H2)]. The desired fractions for each enantiomer were collected and concentrated in vacuo to yield compound 21 (41 mg, 22% yield), for which the 1H NMR was in agreement with the one of compound 22, and compound 22 (43 mg, 23% yield). 1H NMR (400 MHz, DMSO-i ) delta ppm 4.53 - 4.61 (m, 1 H), 4.74(br. d, J=13.4 Hz, 1 H), 6.26 (t, J=55.9 Hz, 1 H), 6.67 (d, J=1.8 Hz, 1 H), 6.93(br. s, 2 H), 7.20 (dd, J=12.0, 9.0 Hz, 1 H), 7.47 (d, J=1.8 Hz, 1 H), 7.79 (ddd, J=8.8, 3.9, 2.8 Hz, 1 H), 7.98 (td, J=8.7, 2.9 Hz, 1 H), 8.16 (dd, J=7.1, 2.7 Hz, 1 H), 8.21 (dd, J=8.8, 4.6 Hz, 1 H), 8.73 (d, J=2.8 Hz, 1 H), 10.62 (br. s, 1 H).

Reference： [1]Patent: WO2012/117027,2012,A1 .Location in patent: Page/Page column 61-62

29
[ 107504-08-5 ]
[ 1397683-78-1 ]
(R*)-5-fluoro-pyridine-2-carboxylic acid[3-(4-amino-6-difluoromethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazin-6-yl)-4-fluoro-phenyl]-amide [ No CAS ]
(S*)-5-fluoro-pyridine-2-carboxylic acid[3-(4-amino-6-difluoromethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazin-6-yl)-4-fluoro-phenyl]-amide [ No CAS ]

Reference： [1]Patent: WO2012/117027,2012,A1

30
[ 107504-08-5 ]
[ 1397683-82-7 ]
[ 1397683-27-0 ]

Yield	Reaction Conditions	Operation in experiment
41%		Example B13Preparation of compound 24: (7?)-<strong>[107504-08-5]5-fluoro-pyridine-2-carboxylic acid</strong> [3-(4-amino-2- cyano-6-methyl-6,7-dihydro-pyrazolo[l,5-a]pyrazin-6-yl)-4-fluoro-phenyl]-amideN. F 5-Fluoro-2-pyridinecarboxylic acid (87.4 mg, 0.619 mmol) was added to a mixture of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (171.3 mg, 0.619 mmol) in MeOH (3 mL). The mixture was stirred at room temperature for 30 min, then it was cooled to 0 C and a solution of intermediate A63 (160 mg,0.563 mmol) in MeOH (3 mL) was added. The mixture was warmed to roomtemperature and stirred for 20 hour, then treated with a saturated solution of Na2C03 and stirred for few min. The mixture was then extracted with DCM. The organic layer was separated, dried (MgS04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; MeOH/DCM). The desired fractions were collected and the solvents evaporated in vacuo, to afford an oil that was triturated with DIPE. The resulting solid was filtered and dried to givecompound 24 (95 mg, 41% yield) as a solid. 1H NMR (400 MHz, CDC13) delta ppm 1.58 (br. s, 3 H) 4.46 (br. d, J=13.4 Hz, 1 H) 4.66 (d, J=13.4 Hz, 1 H) 4.90 (br. s., 2 H) 6.81 (s, 1 H) 7.10 (dd, J=11.8, 8.8 Hz, 1 H) 7.60 (td, J=8.3, 2.8 Hz, 1 H) 7.78 - 7.86 (m, 1 H) 7.96 (dd, J=7.1, 2.7 Hz, 1 H) 8.32 (dd, J=8.7, 4.5 Hz, 1 H) 8.45 (d, J=2.8 Hz, 1 H) 9.80 (br. s, 1 H).

Reference： [1]Patent: WO2012/117027,2012,A1 .Location in patent: Page/Page column 62-63

31
[ 107504-08-5 ]
[ 1397683-88-3 ]
[ 1397683-30-5 ]

Yield	Reaction Conditions	Operation in experiment
33%		Example B16Preparation of compound 27: (7?)-<strong>[107504-08-5]5-fluoro-pyridine-2-carboxylic acid</strong> [3-(4-amino-2- difluoromethyl-6-methyl-6,7-dihydro-pyrazolo[l,5-a]pyrazin-6-yl)-4-fluoro-phenyl]- amide5-Fluoro-2-pyridinecarboxylic acid (68 mg, 0.485 mmol) was added to a mixture of4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (148 mg,0.533 mmol) in MeOH (3 mL). The mixture was stirred at room temperature for 5 min, then it was cooled to 0 C and a solution of intermediate A70 (150 mg, 0.485 mmol) in MeOH (2 mL) was added. The mixture was warmed to room temperature and stirred for 4 hours, then concentrated in vacuo in a cold bath. The crude product was purified by flash column chromatography (dry load, silica gel; MeOH/DCM). The desired fractions were collected and the solvents evaporated in vacuo, to afford an off-white solid, that was further purified by RP HPLC on CI 8 Sunfire (30 x 100 5um). Mobile phase: gradient from 80% 0.1% TFA solution in H20, 20% CH3CN to 0% 0.1% TFA solution in H20, 100%) CH3CN, yielding compound 27 (57 mg, 33%>) as a white solid. 1H NMR (500 MHz, DMSO- ,) delta ppm 1.84 (br. s, 3 H), 4.79 (br. d, J=13.9 Hz, 1 H), 5.02 (br. d, J=13.3 Hz, 1 H), 7.10 (t, J=54.3 Hz, 1 H), 7.30 (dd, J=12.0, 8.8 Hz, 1 H), 7.46 (br. s., 1 H), 7.86 - 7.91 (m, 1 H), 7.93 (dd, J=7.5, 2.3 Hz, 1 H), 7.98 (td, J=8.7, 2.9 Hz, 1 H), 8.20 (dd, J=8.7, 4.6 Hz, 1 H), 8.73 (d, J=2.9 Hz, 1 H), 9.33 (br. s., 1 H), 10.07 (br. s., 1 H), 10.80 (br. s, 1 H), 11.09 (br. s., 1 H).

Reference： [1]Patent: WO2012/117027,2012,A1 .Location in patent: Page/Page column 64-65

32
[ 107504-08-5 ]
[ 1254073-41-0 ]

Reference： [1]Patent: EP2511265,2012,A1

33
[ 107504-08-5 ]
[ 1310805-86-7 ]

Reference： [1]Patent: EP2511265,2012,A1

34
[ 107504-08-5 ]
[ 1310807-73-8 ]

Reference： [1]Patent: EP2511265,2012,A1

35
[ 107504-08-5 ]
[ 1310807-74-9 ]

Reference： [1]Patent: EP2511265,2012,A1

36
[ 107504-08-5 ]
[ 1398113-30-8 ]
[ 1398112-70-3 ]

Yield	Reaction Conditions	Operation in experiment
37%		5-Fluoro-pyridine-2-carboxylic acid (123 mg, 0.869 mmol) was added to a solution of 4- (4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmophiholinium chloride (240 mg,0.869 mmol) in MeOH (4 rriL). The mixture was stirred at room temperature for5 min. Then, the mixture was cooled to 0 C and a solution of intermediate A38 (200 mg, 0.724 mmol) in MeOH (2 rriL) was added. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was treated with a sat. solution of Na2CC>3 and H20 and extracted with DCM. The organic layer was separated, dried (Na2SC>4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash columnchromatography (silica gel; 7 N NH3 in MeOH in DCM 0/100 to 4/96). The desired fractions were collected and the solvents evaporated in vacuo to yield a residue that was triturated with heptane to yield compound 8 (196 mg, 68% yield) as a white solid. ¾ NMR (400 MHz, DMSO-

Reference： [1]Patent: WO2012/120023,2012,A1 .Location in patent: Page/Page column 51

37
[ 107504-08-5 ]
[ 1402738-60-6 ]
[ 1402738-61-7 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; at 20℃; for 16h;	Step 4 To 45 (28 mg, 0.06 mmol) in pyridine (0.5 mL) was added 5-fluoropyridine-2- carboxylic acid (13 mg, 0.09 mmol) and BOP-C1 (35 mg, 0.14 mmol). The reaction was stirred at room temperature for 16 h and then concentrated in vacuo. The residue was take up into EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine. The organic layer was dried (MgSO,)), filtered, and concentrated in vacuo. The residue was purified by preparative silica TLC (80% EtOAc hex) to provide 46 (20 mg, 57 %).

Reference： [1]Patent: WO2012/138590,2012,A1 .Location in patent: Page/Page column 79

38
[ 107504-08-5 ]
[ 1402738-66-2 ]
[ 1402738-67-3 ]

Yield	Reaction Conditions	Operation in experiment
44%	With pyridine; bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; at 20℃; for 1h;	Step 6To 51 (48 mg, 0.087 mmol) in pyridine (0.5 mL) was added <strong>[107504-08-5]5-fluoropyridine-2-carboxylic acid</strong> (18 mg, 0.13 mmol) and BOP-C1 (51 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was taken up into water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine. The organic layer was dried (MgS04), filtered, and concentrated in vacuo. The residue was purified by preparative silica gel TLC (30%EtOAc/hex) to provide 52 (26 mg, 44%).

Reference： [1]Patent: WO2012/138590,2012,A1 .Location in patent: Page/Page column 81

39
[ 107504-08-5 ]
[ 1402742-24-8 ]
[ 1402742-32-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 0 - 25℃;	To A2-15 in THF at 0 C is added <strong>[107504-08-5]5-fluoropyridine-2-carboxylic acid</strong>, diisopropylethylamine, and T3P (50% wt/wt in EtOAc). The cold bath is removed and the reaction is stirred at room temperature until starting material is consumed as determined by TLC. Water is added and the mixture is stirred for 10 minutes at room temperature. The mixture is then extracted with ethyl acetate. The combined organic layers are washed with water and brine, dried (MgS04), filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography to provide El.

Reference： [1]Patent: WO2012/138734,2012,A1 .Location in patent: Page/Page column 68-69

40
[ 107504-08-5 ]
[ 1312308-81-8 ]
[ 1312306-89-0 ]

Reference： [1]Patent: US2012/258951,2012,A1

41
[ 107504-08-5 ]
[ 1312308-81-8 ]
[ 1312308-90-9 ]

Yield	Reaction Conditions	Operation in experiment
		5-Fluoro-2-pyridine carboxylic acid (169 mg) was suspended in methylene dichloride (3 ml), and thereto were added oxalyl chloride (131 mul) and DMF (5 mul) at 0 C. After stirring the solution at room temperature for 2 h, the solvent was evaporated in vacuo. To the evaporated residue was added ethyl acetate (3 ml), and thereto at 0 C. were added an ethyl acetate solution (3 ml) of the compound 1 (the same as the compound of Reference Example 4) (284 mg) and an aqueous 10%-potassium carbonate solution (3 ml). After the solution was stirred at room temperature for 2 h, the organic layer was separated, washed with an aqueous solution saturated with sodium chloride (or saline solution) and dried with anhydrous sodium sulfate. After the solution was filtrated and concentrated, the concentrated residue was purified by the silica gel column chromatography, and the compound 2 (356 mg) was obtained.MS m/z 408 [M+H]+, APCI(+)

Reference： [1]Patent: US2012/258951,2012,A1 .Location in patent: Page/Page column 19-20

42
[ 107504-08-5 ]
[ 870-46-2 ]
[ 1310807-72-7 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;	5-Fluoropyridine-2-carboxylic acid (2.846 g) and DMF (30 mL) were mixed, and EDCI (4.98 g), 1-hydroxy-7-azabenzotriazole (3.53 g), tert-butyl hydrazinecarboxylate (3.73 g), and triethylamine (7.9 mL) were added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to obtain tert-butyl 2-[(5-fluoropyridin-2-yl)carbonyl]hydrazinecarboxylate (3.372 g) as a white solid..

Reference： [1]Patent: EP2511265,2012,A1 .Location in patent: Page/Page column 19

43
[ 107504-08-5 ]
[ 1403467-65-1 ]
[ 1403467-66-2 ]

Yield	Reaction Conditions	Operation in experiment
74%		To a suspension of the aniline compound 1-3 (0.17 g, 0.57 mmol) and 0.104 g (0.74 mmol) of <strong>[107504-08-5]5-fluoropyridine-2-carboxylic acid</strong> in 5 mL of dichloromethane were added 0.289 g (1.14 mmol) of BOPC1 and 0.22 g (1.7 mmol) of diiosopropylethylamine. The solution was stirred at room temperature for 40 min, and quenched with water (10 mL). The mixture was extracted with two 30 mL portions of dichloromethane. The combined organic extracts were concentrated; the residue was purified by flash chromatography (12 g of Si02: 0 to 4% MeOH in CH2C12 plus 1% NH4OH) to give a free base, which was treated with HCl in ether to form the salt l-4a (0.192 g, 74%). LCMS for l-4a (conditions A): tR = 1.94 min, m/e = 423 (M+H).

Reference： [1]Patent: WO2012/139425,2012,A1 .Location in patent: Page/Page column 74-75

44
[ 107504-08-5 ]
[ 1403468-07-4 ]
[ 1403463-92-2 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In dichloromethane; ethyl acetate; at 25℃; for 1h;	To a suspension of compounds 2E-2 (0.023 g, 0.077 mmol) and 0.014 g (0.1 mmol) of <strong>[107504-08-5]5-fluoropyridine-2-carboxylic acid</strong> in 1.5 mL of dichloromethane was added T3P (50% solution in EtOAc, 0.069 mL, 0.115 mmol) at room temperature. The solution was stirred at room temperature for 1 h, and then quenched with saturated aq. sodium bicarbonate solution. It was extracted with dichloromethane (3X). The combined organic extracts were dried over Na2S04, filtered, and concentrated. The residue was purified by flashchromatography (23 g of Si02: 0 to 7.5% MeOH in CH2C12 with 0.1% NH4OH) to giveExample 9ca (0.0016 g). LCMS (conditions A): tR = 1.94 min, m/e = 423 (M+H).

Reference： [1]Patent: WO2012/139425,2012,A1 .Location in patent: Page/Page column 92-93

45
[ 107504-08-5 ]
[ 1403467-94-6 ]
[ 1403463-36-4 ]

Yield	Reaction Conditions	Operation in experiment
65%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In dichloromethane; ethyl acetate; at 0 - 25℃; for 3h;	To a suspension of compound 2A-5 (0.286 g, 0.90 mmol) and 0.165 g (1.17 mmol) of <strong>[107504-08-5]5-fluoropyridine-2-carboxylic acid</strong> in 10 mL of dichloromethane was added T3P (0.859 g, 50% in ethyl acetate, 1.35 mmol) at 0 C. The solution was stirred at 0 C for 1 h and at room temperature for 2 h, and then quenched with saturated aq. sodium bicarbonate solution (30 mL). The mixture was extracted with two 50 mL portions of dichloromethane. The combined organic extracts were concentrated, and the residue was purified by flash chromatography (24 g of Si02, gradient 0 to 4% MeOH in CH2C12 plus 1% NH4OH) to give Example 9k (0.255 g, 65%). LCMS for Example 9k (conditions A): tR = 1.99 min, m/e = 441 (M+H).

Reference： [1]Patent: WO2012/139425,2012,A1 .Location in patent: Page/Page column 80; 82

46
[ 107504-08-5 ]
[ 100-36-7 ]
[ 1420844-62-7 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 895 - 901

47
[ 107504-08-5 ]
[ 67-56-1 ]
[ 107504-07-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With thionyl chloride; at 70℃; for 16h;	General procedure: <strong>[107504-08-5]5-fluoropicolinic acid</strong> (8.0 g, 56.7 mmol) was dissolved in methanol (50 mL),Dichlorosulfoxide (13.5 g, 113.4 mmol) was added, heated to 70 C. for 16 hours, and concentrated, and the residue was used directly in the next step. (8.0g, yield: 90.9%)
5.9 g	With thionyl chloride; at 65℃; for 2h;Sealed tube;	<strong>[107504-08-5]5-fluoro-pyridine-2-carboxylic acid</strong> methyl ester2.7 mL Thionylchloride was dropped to 5 g 5-fluor-pyridine-2-carboxylic acid in 50 mL methanol. The reaction was stirred for 2 h at 65C in a sealded micro wave vial. The solvents were removed and the residue was desolved in a mixture of DCM and methanol and filtered over silica gel. The filtrate was evaporated to give 5.9 g of the desired product.Rt: 0.77 (method K). (M+H)+: 156
5.9 g	With thionyl chloride; In methanol; at 65℃; for 2h;Microwave irradiation; Sealed tube;	6.01.06 <strong>[107504-08-5]5-fluoro-pyridine-2-carboxylic acid</strong> methyl ester 2.7 mL Thionylchloride was dropped to 5 g 5-fluor-pyridine-2-carboxylic acid in 50 mL methanol. The reaction was stirred for 2 h at 65 C. in a sealed micro wave vial. The solvents were removed and the residue was desolved in a mixture of DCM and methanol and filtered over silica gel. The filtrate was evaporated to give 5.9 g of the desired product. Rt: 0.77 (method K). (M+H)+: 156 By using the same synthesis strategy as for <strong>[107504-08-5]5-fluoro-pyridine-2-carboxylic acid</strong> methyl ester the following compound was obtained:

9.895 g

With thionyl chloride; at 80℃; for 8h;Cooling with ice;

In the ice bath,To a solution of <strong>[107504-08-5]5-fluoro-2-pyridinecarboxylic acid</strong> (10 g) in methanol was slowly added dropwise thionyl chloride (10.3 mL).Dripping is completed.After moving to 80C for 8 hours,Cool to room temperatureMethanol was distilled off under reduced pressure.Diluted with ethyl acetate,In the ice bath,Saturated sodium bicarbonate solution was added to the reaction mixture,Adjust pH = 8 or so.Extract with ethyl acetate,The combined organic phases are washed with saturated brine,Dried over anhydrous sodium sulfate,Filter and concentrate the filtrate in vacuoThe residue was separated by silica gel column chromatography to give the title compound (9.895 g).

Reference： [1]Patent: CN110698471,2020,A .Location in patent: Paragraph 0138-0142
[2]Patent: WO2013/79460,2013,A1 .Location in patent: Page/Page column 46
[3]Patent: US2013/137688,2013,A1 .Location in patent: Paragraph 0239; 0240; 0241
[4]Patent: CN108003161,2018,A .Location in patent: Paragraph 0628; 0630-0632

48
[ 107504-08-5 ]
[ 1310350-45-8 ]
[ 1310347-27-3 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 3980 - 3995

49
[ 107504-08-5 ]
[ 1431571-83-3 ]
[ 1431571-85-5 ]

Reference： [1]Journal of Fluorescence,2013,vol. 23,p. 865 - 875

50
[ 107504-08-5 ]
tert-butyl 4-(5-amino-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate [ No CAS ]
tert-butyl 4-(2-fluoro-5-(5-fluoropicolinamido)phenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18 mg	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 21915h;Cooling with ether-dry ice;	tert-Butyl 4-(5-amino-2-fluorophenyl)-4-methyl-l,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate (117, 15 mg, 0.04 mmol), <strong>[107504-08-5]5-fluoropicolinic acid</strong> (118, 6 mg, 0.045 mmol), and[benzotriazol- 1 -yloxy(dimethylamino)methylene] -dimethyl-ammoniumhexafluorophosphate (19 mg, 0.05 mmol) were dissolved in 0.6 mL of DMF. The mixture was cooled over an ice-water bath and N-ethyl-N-isopropyl-propan-2-amine (7 mg, 0.057 mmol) was added. The mixture was stirred at room temperature for 30 minutes, then diluted with 10 mL of EtOAc, and washed with saturated aqueous NaHC03and brine. The organic portion was dried, filtered and the filtrateconcentrated under vacuum to provide the desired compound as a yellow solid (119, 18 mg, 0.035 mmol).

Reference： [1]Patent: WO2013/142613,2013,A1 .Location in patent: Page/Page column 160

51
[ 107504-08-5 ]
C₂₇H₃₄FN₃O₆S [ No CAS ]
C₃₃H₃₆F₂N₄O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
450 mg	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃;	To a solution of compound 21-13 (450 mg, 0.86 mmol), <strong>[107504-08-5]5-fluoropyridine-2-carboxylic acid</strong> (182 mg, 1.29 mmol) and DIEA (665 mg, 5.15 mmol) in THF (10 mL) at 0 C was added T3P (820 mg, 2.58 mmol, 50% in EtOAc) dropwise. The mixture was stirred at 0 C for 0.5 h and then RT overnight. It was diluted with water, and then extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous a2S04, and concentrated. The residue was purified by silica gel chromatography (PE: EA = 10: 1) to give 450 mg of compound 21- 14. LCMS (conditions F5): m/e = 671 (M+H), tR = 1.37 min.
450 mg	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 0 - 20℃;	Step 13 (0742) To a solution of compound 21-13 (450 mg, 0.86 mmol), <strong>[107504-08-5]5-fluoropyridine-2-carboxylic acid</strong> (182 mg, 1.29 mmol) and DIEA (665 mg, 5.15 mmol) in THF (10 mL) at 0 C. was added T3P (820 mg, 2.58 mmol, 50% in EtOAc) dropwise. The mixture was stirred at 0 C. for 0.5 h and then RT overnight. It was diluted with water, and then extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography (PE: EA=10:1) to give 450 mg of compound 21-14. LCMS (conditions F5): m/e=671 (M+H), tR=1.37 min.

Reference： [1]Patent: WO2013/28670,2013,A1 .Location in patent: Page/Page column 118
[2]Patent: US9181236,2015,B2 .Location in patent: Page/Page column 141

52
[ 107504-08-5 ]
C₂₈H₃₆FN₃O₆S [ No CAS ]
C₃₄H₃₈F₂N₄O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of compound 22-lla (0.1 g, 0.18 mmol), <strong>[107504-08-5]5-fluoropicolinic acid</strong> (28 mg, 0.2 mmol) and DIEA (45 mg, 0.36 mmol) in THF (5 mL) was added T3P (81 mg, 0.26 mmol, 50% in EtOAc) at 0 C under N2. The resulting solution was stirred at 0 C for 30 min followed by an additional 16 h at RT. Water was added to the reaction, and the mixture was stirred at RT for 10 min. The aqueous layer was separated and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (PE: EA = 3: 1) to give 70 mg of compound 22-12a. LCMS (conditions F5): m/e = 685 (M+H), tR = 1.23 min. Compound 22-12b (70 mg) was synthesized similarly from compound 22-llb. LCMS (conditions F5): m/e = 685 (M+H), tR = 1.32 min.
70 mg	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 0 - 20℃; for 16.5h;Inert atmosphere;	Step 11 (0758) To a solution of compound 22-11a (0.1 g, 0.18 mmol), <strong>[107504-08-5]5-fluoropicolinic acid</strong> (28 mg, 0.2 mmol) and DIEA (45 mg, 0.36 mmol) in THF (5 mL) was added T3P (81 mg, 0.26 mmol, 50% in EtOAc) at 0 C. under N2. The resulting solution was stirred at 0 C. for 30 min followed by an additional 16 h at RT. Water was added to the reaction, and the mixture was stirred at RT for 10 min. The aqueous layer was separated and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE: EA=3:1) to give 70 mg of compound 22-12a. LCMS (conditions F5): m/e=685 (M+H), tR=1.23 min. Compound 22-12b (70 mg) was synthesized similarly from compound 22-11b. LCMS (conditions F5): m/e=685 (M+H), tR=1.32 min.

Reference： [1]Patent: WO2013/28670,2013,A1 .Location in patent: Page/Page column 122
[2]Patent: US9181236,2015,B2 .Location in patent: Page/Page column 145; 146

53
[ 107504-08-5 ]
[ 1504390-99-1 ]
[ 1504391-05-2 ]

Yield	Reaction Conditions	Operation in experiment
136 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 60h;	A mixture of tert-butyl(6'-aminodispiro[cyclopropane-1,3'-chromene-4',4"-[1,3]oxazol]-2"-yl)carbamate (115 mg,0.333 mmol), <strong>[107504-08-5]5-fluoropyridine-2-carboxylic acid</strong> (62.3 mg, 0.433 mmol),N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (83.0 mg, 0.433 mmol),1-hydroxybenzotriazole (58.5 mg, 0.433 mmol), N,N-diisopropylethylamine (0.074 mL,0.433 mmol) and CH2Ch (1.2 mL) was stirred for 2.5 days at ambient temperature. Thereaction mixture was purified with column chromatography on silica gel (hexane-EtOAc, alinear gradient of EtOAc from 10 to 90%) to afford tert-butyl( 6'- { [ (5-fluoropyridin-2-yl)carbonyl]amino }dispiro[ cyclopropane- ,3 '-chromene-4' ,4"-[ 1 ,3]oxazol]-2"-yl)carbamate (136 mg).

Reference： [1]Patent: WO2013/181202,2013,A2 .Location in patent: Paragraph 0234

54
[ 107504-08-5 ]
C₁₃H₁₆N₆O₂ [ No CAS ]
[ 1410041-06-3 ]

Yield	Reaction Conditions	Operation in experiment
0.04 g	With 1,1'-carbonyldiimidazole; In N,N-dimethyl-formamide; at 40 - 90℃; for 16h;	An aqueous 50% hydroxylamine solution (0.057 mL, 0.86 mmol) was added to a solution of N-(2-cyanoethyl)-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (0.20 g, 0.78 mmol) prepared in Reference Example 26 in EtOH (0.8 mL), followed by stirring at 90 C. for 1 hour. After cooling to room temperature, an aqueous 50% hydroxylamine solution (0.057 mL, 0.86 mmol) was further added thereto, and the mixture was stirred again at 90 C. for 1 hour. After cooling at room temperature, the reaction solution was concentrated under reduced pressure. A solution of the resulting residue in DMF (0.3 mL) was added to a solution of <strong>[107504-08-5]5-fluoropyridin-2-carboxylic acid</strong> (0.12 g, 0.82 mmol) and carbonyldiimidazole (0.15 g, 0.94 mmol) in DMF (0.5 mL) that was stirred in advance at 40 C. for 1 hour. The reaction solution was warmed to 90 C., followed by stirring for 15 hours. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with water and brine and was dried with Na2SO4. The desiccant was then removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (KP-NH: 28 g, hexane/EtOAc=75/25 to 0/100) to give the titled compound (0.040 g, colorless and amorphous). MS (ESI pos.) m/z: 394 [M+H]+

Reference： [1]Patent: US2014/81025,2014,A1 .Location in patent: Paragraph 0299; 0300; 0301

55
[ 107504-08-5 ]
ethyl (E)-3-[2-(diethylcarbamoyl)-5-fluoropyridin-3-yl]acrylate [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2014,vol. 356,p. 1038 - 1046

56
[ 107504-08-5 ]
[ 1565638-64-3 ]

Reference： [1]Advanced Synthesis and Catalysis,2014,vol. 356,p. 1038 - 1046
[2]Synlett,2014,vol. 25,p. 1036 - 1040

57
[ 107504-08-5 ]
[ 717871-83-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; toluene; at 0 - 20℃; for 2h;	5-Fluoropicolinic acid (45.2 mg, 320 muiotaetaomicron) was suspended in dichloromethane (5 mL), the suspension was cooled to 0-5C (ice bath) and oxalyl chloride (56.9 mg, 39.3 mu, 448 muiotaetaomicron) as well as dimethylformamide (0.308 M in toluene, 51.9 mu, 16 muiotaetaomicron) were added. The mixture was stirred for 2 h at room temperature. Then, it was concentrated in vacuo (40C, 5 mbar) and dried azeotropically by two cycles of addition of toluene (3 mL) followed by concentration in vacuo to afford 5-fluoropicolinoyl chloride as yellow oil (51 mg, quant.). After that, tert-butyl ((3aS,4R,8R)-4-(5-amino-2-fluorophenyl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-6-yl)carbamate (Int-16ABp, 80 mg, 188 muiotaetaomicron) was dissolved in dichloromethane (5 mL), the solution cooled to 10C and N,N-diisopropylethylamine (36.5 mg, 49.4 mu, 283 muiotaetaomicron) was added, followed by a solution of 5-fluoropicolinoyl chloride (vide supra, 40.8 mg, 256 muiotaetaomicron) in dichloromethane (4 mL). The reaction mixture was stirred for 15 min at 10C. Then, methanol (2 mL) was added, the mixture was stirred for 5 min at room temperature and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichloromethane, gradient 1:99 to 3:97) to yield, after drying in vacuo (40C, 5 mbar), the title compound as an off-white solid (90 mg, 87% yield). HPLC (method LCMS_fglm) tR = 1.28 min. MS (ES+) m/z 548.3 [M+H].
97%	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; toluene; at 0 - 20℃; for 3h;	5-Fluoropicolinic acid (47.6 mg, 337 muiotaetaomicron) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5C (ice bath) and oxalyl chloride (56.9 mg, 39.3 mu, 449 mupiiotaomicron) as well as a drop of a mixture of dimethylformamide and toluene (1 :3, v/v) were added. The mixture was stirred for 2 h at room temperature. A second portion of oxalyl chloride (28.7 mg, 19.8 mu^, 226 muiotaetaomicron) was added and the mixture was stirred for additional 1 h at room temperature to drive the reaction to completion. Then, it was concentrated in vacuo, the residue was treated with toluene (5 mL) and again concentrated and dried in vacuo (40C, 5 mbar) to afford 5-fluoropicolinoyl chloride as red oil (52.1 mg, 97%). After that, tert-butyl ((4aR,5R,9R)- 5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-51AA, 115 mg, 242 muiotaetaomicron) was dissolved in dichloromethane (6 mL), the solution cooled to 0-5C (ice bath) and N,N-diisopropylethylamine (61.9 mg, 83.6 muL·, 479 muiotaetaomicron) was added, followed by a solution of 5-fluoropicolinoyl chloride (vide supra, 52.1 mg, 326 muiotaetaomicron) in dichloromethane (5 mL). The reaction mixture was stirred for 15 min at 0-5C, followed by 14 h at room temperature. Then, methanol (2 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 20:80 to 35:65) to yield, after drying in vacuo (40C, 5 mbar), the title compound as a white solid (100 mg, 69%). HPLC (method LCMS_gradient) tR = 3.4 min. MS (ES+) m/z 599.2 [M+H].
	With oxalyl dichloride; N,N-dimethyl-formamide; In acetonitrile; for 0.666667h;	Oxalyl chloride (180 muL, 2.07 mmol) is added to a solution of dimethylformamide (180 muL, 2.33 mmol) in acetonitrile (10 mL), and the resulting reaction is stirred for 10 min 5-Huoropyridine-2-carboxylic acid (300 mg, 2.13 mmol) is added to the resulting solution. The resulting reaction is stirred for an additional 40 minutes

	With thionyl chloride; at 80℃; for 1.5h;	Into a 100-mL round-bottom flask, was placed <strong>[107504-08-5]5-fluoropicolinic acid</strong> (2.00 g, 14.2 mmol, 1.00 equiv) in thionyl chloride (40 mL). The resulting mixture was stirred for 1.5 h at 80 C. The reaction mixture was concentrated under reduced pressure. This resulted in 2.30 g of the crude 5- fluoropicolinoyl chloride as yellow oil, which was used directly without further purification.
	With thionyl chloride; at 80℃; for 1.5h;	Into a 100-mL round-bottom flask, was placed <strong>[107504-08-5]5-fluoropicolinic acid</strong> (2.00 g, 14.2 mmol,1.00 equiv) in thionyl chloride (40 mL). The resulting mixture was stirred for 1.5 h at 80 C. The reaction mixture was concentrated under reduced pressure. This resulted in 2.30 g of the crude 5- fluoropicolinoyl chloride as yellow oil, which was used directly without further purification.
	With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 50℃; for 3h;	General procedure: To a solution of the picolinic acid S7 (25.0 mmol) in DCM (100 mL) at room temperature was added SOCl2 (20 mL) and some drops of dry DMF. The reaction was allowed to stir at 50 C for 3 hours. The solvent was then removed under reduced pressure to afford the corresponding crude acid chloride (S8). Then DCM (40 mL) was added and the solution was cooled to 0C followed by dropwise addition of NEt3 (75.0 mmol, 3.0 eq) and N,O-dimethylhydroxylamine (50.0mmol, 2.0 eq). The reaction mixture was stirred at rt overnight, extracted by DCM, the organic layerwas dried over Na2SO4 and the solvent was evaporated, then purified by flash chromatography to gain the corresponding amides (S9).

Reference： [1]Patent: WO2017/25491,2017,A1 .Location in patent: Page/Page column 68
[2]Patent: WO2016/55496,2016,A1 .Location in patent: Page/Page column 171
[3]Advanced Synthesis and Catalysis,2014,vol. 356,p. 1038 - 1046
[4]Organic Letters,2014,vol. 16,p. 3142 - 3145
[5]Patent: US2014/371212,2014,A1 .Location in patent: Paragraph 0199; 0200
[6]Patent: WO2015/51479,2015,A1 .Location in patent: Page/Page column 65
[7]Patent: WO2015/54038,2015,A1 .Location in patent: Page/Page column 57
[8]Organic Process Research and Development,2015,vol. 19,p. 1214 - 1230
[9]Angewandte Chemie - International Edition,2016,vol. 55,p. 11897 - 11901
Angew. Chem.,2016,vol. 128,p. 12076 - 12080,5
[10]Chem,2020,vol. 6,p. 497 - 511

58
[ 107504-08-5 ]
C₆H₃ClFNO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 40℃; for 4h;	General procedure: To a solution of the picolinic acid (5.0 mmol) in DCM (20 mL) at room temperature was added SOCl2 (4 mL) and one drop of dry DMF. The reaction was allowed to stir at 40 C for 4 hours. The solvent was then removed under reduced pressure to afford the corresponding crude acid chloride. Then DCM (20 mL) was added and the solution was cooled to 0C followed by dropwise addition of Et3N (1.5 mL) and amine (10.0 mmol, 2.0 eq). The reaction mixture was stirred at rt overnight, extracted by DCM, the organic layer was dried over Na2SO4 and the solvent was evaporated, then purified by flash chromatography.

Reference： [1]Synlett,2014,vol. 25,p. 1036 - 1040

59
[ 107504-08-5 ]
[ 1610422-01-9 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 3142 - 3145
[2]Angewandte Chemie - International Edition,2016,vol. 55,p. 11897 - 11901
Angew. Chem.,2016,vol. 128,p. 12076 - 12080,5

60
[ 107504-08-5 ]
[ 1610422-11-1 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 3142 - 3145

61
[ 107504-08-5 ]
[ 1616110-18-9 ]
[ 1616110-19-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 25℃; for 3h;	To a solution of 8-2 (120 mg, 0.272 mmol) in THF (5 mL) at 0 C were added 5- fluoropyridine-2-carboxylic acid (57.5 mg, 0.408 mmol), DIEA (0.24 mL, 1.36 mmol), and a solution of T3P (50% in EtOAc, 345 mg, 0.544 mmol). The reaction mixture was then stirred for 3 h at RT. Water was added to the reaction mixture and the mixture was then extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by silca gel column chromatography using 40% ethyl acetate in petroleum ether as the eluent to afford 8-3. m/z: 565.2 (M+H+)

Reference： [1]Patent: WO2014/99794,2014,A1 .Location in patent: Page/Page column 74; 75

62
[ 107504-08-5 ]
[ 1616110-36-1 ]
[ 1616110-37-2 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; at 0 - 25℃; for 2h;	To a solution of 13-2 (500 mg, 1.10 mmol) in dichloromethane (8 mL) at 0 C were added <strong>[107504-08-5]5-fluoropyridine-2-carboxylic acid</strong> (155 mg, 1.10 mmol), DIEA (0.30 mL, 1.7 mmol), and a solution of T3P (50% in ethyl acetate, 0.52 mL, 1.7 mmol). The reaction mixture was then stirred for 2 h at RT .After that time, water was added to the reaction and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2S04, and concentrated. The crude product 13-3 was taken onto the next step without further purificaion. m/z: 577.4 (M+H- Boc)+

Reference： [1]Patent: WO2014/99794,2014,A1 .Location in patent: Page/Page column 83

63
[ 107504-08-5 ]
[ 1616109-94-4 ]
[ 1616109-45-5 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of l-12a (40 mg, 0.094 mmol), <strong>[107504-08-5]5-fluoropicolinic acid</strong> (27 mg, 0.19 mmol), HATU (110 mg, 0.28 mmol), and DIEA (40 mg, 0.28 mmol) in DMF (5 mL) was stirred at 25 C overnight. After that time, the reaction mixture was diluted with water, and then extracted with EtOAc. The combined extracts were washed with brine, dried (Na2S04), and concentrated. The residue was dissolved in DCM (2 mL), and then TFA (0.2 mL) was added. The resulting mixture was stirred at 25 C for 1 h, concentrated, and purified by RP-HPLC (YMC column, 150x30 mm; mobile phase A: water containing 0.075% TFA (v/v); mobile phase B: MeCN; gradient 20-50%> B, 8 min, 35mL/min) to afford Example la.

Reference： [1]Patent: WO2014/99794,2014,A1 .Location in patent: Page/Page column 59; 56

64
[ 107504-08-5 ]
C₁₅H₁₉F₂N₃O₃S [ No CAS ]
C₂₁H₂₁F₃N₄O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In tetrahydrofuran; at 25℃;	A mixture of compound 4-1 (20 mg, 0.056 mmol), <strong>[107504-08-5]5-fluoropicolinic acid</strong> (18 mg, 0.112 mmol), and T3P (150 mg, 0.236 mmol, 50% in EtOAc) in THF (5 mL) was stirred at 25 C overnight. The mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2S04, and concentrated. The residue was purified by preperative HPLC (column: Gemini 200x25 mm, 5 muiotaeta; mobile phases A: water containing 0.075% TFA, v/v; mobile phase B: CH3CN; gradient 18-48% B, 11 min, 25 mL/min) to afford Example 4a.

Reference： [1]Patent: WO2014/99794,2014,A1 .Location in patent: Page/Page column 67; 68

65
[ 107504-08-5 ]
[ 1624605-22-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 223 N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluoro-5-methylphenyl)-5-fluoropicolinamide The title compound was synthesized by procedure and steps analogous to those described in Method A3, Example 216 above, but using <strong>[107504-08-5]5-fluoro-2-pyridinecarboxylic acid</strong> (Frontier Scientific, Inc.) in step 10. MS m/z=446.9 [M+H]+. Calculated for C19H16F6N4O2: 446.12. 1H NMR (300 MHz, DMSO-d6) delta ppm 1.97 (t, J=12.93 Hz, 1H) 2.25 (d, J=1.90 Hz, 3H) 2.46 (br. s., 1H) 4.29-4.70 (m, 3H) 6.09 (s, 2H) 7.70 (dd, J=6.58, 2.78 Hz, 1H) 7.79 (dd, J=6.43, 2.48 Hz, 1H) 7.98 (td, J=8.70, 2.78 Hz, 1H) 8.22 (dd, J=8.92, 4.53 Hz, 1H) 8.73 (d, J=2.92 Hz, 1H) 10.60 (s, 1H).

Reference： [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column

66
[ 107504-08-5 ]
[ 1624603-61-7 ]

Yield	Reaction Conditions	Operation in experiment
		Example 57 Synthesis of N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-fluoropicolinamide The title compound was synthesized by procedures and steps analogous to those described in Method F (Example 32) above, but using <strong>[107504-08-5]5-fluoropicolinic acid</strong> (Matrix). MS m/z=433 [M+H]+. Calculated for C15H14F6N4O2: 432. 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 9.82 (br, 1H), 8.45 (d, 1H, J=2.7), 8.32 (dd, 1H, J=8.7, 4.6), 8.03 (m, 1H), 7.59 (m, 2H), 7.12 (dd, 1H, J=11.5, 8.8), 4.69 (dd, 1H), J=47.5, 8.6), 4.47 (dd, 1H, J=47.5, 8.6), 4.15 (m, 1H), 2.69 (dd, 1H, J=13.5, 2.7), 2.20 (t, 1H, J=13.3).

Reference： [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column

67
[ 107504-08-5 ]
tert-butyl (4aR,7aS)-7a-(3-aminophenyl)-2-benzamido-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate [ No CAS ]
tert-butyl (4aR,7aS)-2-benzamido-7a-[3-[(5-fluoropyridine-2-carbonyl)amino]phenyl]-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃;	A slurry of ieri-butyl (4aR,7aS)-7a-(3-aminophenyl)-2-benzamido-4,4a,5,7- tetrahydropyrrolo[3,4-d][l,3]thiazine-6-carboxylate (93 mg, 0.21 mmol), 5- fluoropyridine-2-carboxylic acid (31.9 mg, 0.23 mmol), 1-hydroxybenzotriazole hydrate (56.7 mg, 0.41 mmol) and l-(2-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol) in dichloromethane (4 mL) containing dimethylformamide (1 ml) is treated with diisopropylethylamine (179.2 mu, 1.03 mmol) and the resulting mixture is stirred at room temperature overnight. The reaction mixture is diluted with dichloromethane (5 mL) and saturated aqueous sodium bicarbonate (15 mL). The organic layer is separated and washed with saturated aqueous sodium chloride (10 mL), dried over sodium sulfate, filtered, and the solvent removed in vacuo to give the crude title compound (105 mg, 89%). ES/MS (m/e): 576 (M+H).

Reference： [1]Patent: WO2014/143579,2014,A1 .Location in patent: Page/Page column 25-26

68
[ 107504-08-5 ]
N-[(4aR,7aS)-7a-(3-aminophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide [ No CAS ]
N-[3-[(4aR,7aS)-2-benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-fluoropyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 5h;Inert atmosphere;	N-[(4aR,7aS)-7a-(3-Aminophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7- tetrahydropyrrolo[3,4-d][l,3]thiazin-2-yl]benzamide (282 mg, 628.73 muiotaetaomicron) and 5- fluoropyridine-2-carboxylic acid (106.46 mg, 754.47 muiotaetaomicron) are combined in dichloromethane (3 mL) and dimethylformamide (0.5 mL). 1-Hydroxybenzotriazole (112.70 mg, 817.35 muiotaetaomicron) and then l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (159.07 mg, 817.35 muiotaetaomicron) is added and the resulting mixture is stirred for 5 hours at room temperature under nitrogen. The reaction mixture is diluted with water and the pH is adjusted with 1 N NaOH to -12. The mixture is extracted with ethyl acetate (3 x). The organic extracts are combined, dried over sodium sulfate, filtered and the solvent removed in vacuo to give the crude product. The crude product is purified over silica gel with a 20 minute 5% to 100% ethyl acetate in hexanes gradient to give the title compound (327 mg, 91%). ES/MS (m/e): 571 (M+H).

Reference： [1]Patent: WO2014/143579,2014,A1 .Location in patent: Page/Page column 29

69
[ 107504-08-5 ]
N-[7a-(5-amino-2-fluoro-phenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide [ No CAS ]
N-[3-[2-benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	N-[7a-(5-Amino-2-fluoro-phenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7- tetrahydropyrrolo[3,4-d][l,3]thiazin-2-yl]benzamide (302 mg, 647 mumol) and 5- fluoropyridine-2-carboxylic acid (110 mg, 777 mumol) are combined in dichloromethane (3 mL) and dimethylformamide (0.5 mL). 1-Hydroxybenzotriazole (116 mg, 842 muiotaetaomicron) and then l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (164 mg, 842 muiotaetaomicron) are added and the mixture is stirred overnight at room temperature under nitrogen. The reaction mixture is diluted with water and the pH adjusted with 1 N NaOH to -12 and then extracted with ethyl acetate (3 x). The organic layers are combined and filtered to collect the insoluble material. The solids are washed with water and ethyl acetate and dried under vacuum to give the title compound. The organic layer from the filtrate is dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue is purified over silica gel with a 20 minute 5% to 100% ethyl acetate in hexanes gradient to give additional title compound with a combined yield (275 mg, 72%). ES/MS (m/e): 590 (M+H).

Reference： [1]Patent: WO2014/143579,2014,A1 .Location in patent: Page/Page column 30-31

70
[ 107504-08-5 ]
N-[3-[(4aR,7aS)-2-amino-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: US2014/371212,2014,A1

71
[ 107504-08-5 ]
C₁₂H₁₂F₂N₆ [ No CAS ]
N-{3-[(6R)-4-amino-6-methyl-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6-yl]-4,5-difluorophenyl}-5-fluoropyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In methanol; isopropyl alcohol; at 20℃; for 3h;	5M HCl sol. in 2-propanol (0.11 mL, 0.54 mmol) was added to intermediate 1-21 (150 mg, 0.54 mmol) in MeOH (4 mL) at rt. Then 5 -fluoro-2 -pyridine carboxylic acid (76 mg, 0.54 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol) were added. The mixture was stirred at rt for 3 h. Sat. aq. Na2C03 sol. was added and the mixture was extracted with DCM. The organic layer was separated, washed with brine, dried (MgS04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7M ammonia in MeOH in DCM 0/100 to 5/95). The desired fractions were collected and the solvents evaporated in vacuo to afford a solid, which was suspended in DIPE, filtered and dried (vacuum oven, 50C) yielding compound 8 as a white solid (160 mg, 74%)

Reference： [1]Patent: WO2014/198854,2014,A1 .Location in patent: Page/Page column 47

72
[ 107504-08-5 ]
C₁₂H₁₂F₂N₆ [ No CAS ]
N-{3-[4-amino-6-(fluoromethyl)-6,7-dihydro[1,2,3 ]triazolo[1,5-a]pyrazin-6-yl]-4-fluorophenyl}-5-fluoropyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In methanol; isopropyl alcohol; at 20℃; for 2h;	HC1 (6 M in iPrOH, 0.23 mL, 1.35 mmol) was added to intermediate 1-25 (250 mg, 0.90 mmol) in MeOH (7 mL) at rt. Then <strong>[107504-08-5]5-fluoro-2-pyridine carboxylic acid</strong> (139 mg, 0.99 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (224 mg, 1.17 mmol) were added. The mixture was stirred at rt for 2 h. Sat. aq. Na2C03 sol. was added and the mixture was extracted with DCM. The organic layer was separated, washed with brine, dried (MgS04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7M ammonia in MeOH in DCM 0/100 to 3/97). The desired fractions were collected and the solvents evaporated in vacuo to yield compound 9 as a racemate (115 mg, 32%). This product was then purified by preparative SFC on Chiralpak Diacel AD (20 x 250 mm), mobile phase (C02, MeOH with 0.4% iPrNH2), yielding compound 10 (40 mg, 11%) and compound 11 (40 mg, 11%).

Reference： [1]Patent: WO2014/198854,2014,A1 .Location in patent: Page/Page column 48

73
[ 107504-08-5 ]
(R)-6-(5-amino-2-fluorophenyl)-6-methyl-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazin-4-amine [ No CAS ]
N-{3-[(6R)-4-amino-6-methyl-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6-yl]-4-fluorophenyl}-5-fluoropyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In methanol; water; at 20℃; for 3h;	1M aqueous HCl sol. (0.29 mL, 0.3 mmol) was added to intermediate compound 1-7 (75 mg, 0.3 mmol) in MeOH (1.5 mL) at rt. Then <strong>[107504-08-5]5-fluoro-2-pyridine carboxylic acid</strong> (41 mg, 0.3 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.4 mmol) were added. The mixture was stirred at rt for 3 h. A sat. sol. of Na2C03 was added and the mixture was extracted with DCM. The organic layer was separated, washed with brine, dried (MgS04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7M ammonia in MeOH in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield compound 1 as a white solid (79 mg, 71%).

Reference： [1]Patent: WO2014/198854,2014,A1 .Location in patent: Page/Page column 46

74
[ 107504-08-5 ]
C₁₅H₁₉N₅O₂ [ No CAS ]
[ 1410039-27-8 ]

Yield	Reaction Conditions	Operation in experiment
0.47 g		An aqueous 50% hydroxylamine solution (0.31 mL, 5.29 mmol)was added to a solution of N-(2-cyanoethyl)-N-ethyl-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide 8 (0.50 g, 1.76 mmol) in EtOH(10 mL), followed by stirring at 80 C for 4 h. After cooling at roomtemperature, the reaction solution was concentrated underreduced pressure. Water was added to the obtained residue, followedby extraction with EtOAc. The organic layer was washedwith brine and was dried over MgSO4. The desiccant was thenremoved by filtration, and the solvent was distilled off underreduced pressure. A solution of the resulting residue in CH3CN(5 mL) and DMF (0.5 mL) was added to a solution of <strong>[107504-08-5]5-fluoropyridin-2-carboxylic acid</strong> (0.27 g, 1.95 mmol) and carbonyldiimidazole(0.34 g, 2.12 mmol) in CH3CN (5 mL) and DMF (0.5 mL) that wasthen stirred in advance at room temperature for 3 h. The reactionsolution was stirred for 2 h at room temperature. Next, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.26 mL, 1.77 mmol) was addedto the reaction mixture, followed by stirring at 70 C for 1 h. Aftercooling at room temperature, water was added to the reaction mixture,followed by extraction with EtOAc. The organic layer waswashed with a 1.2 mol/L aqueous HCl solution and brine and wasdried over MgSO4. The desiccant was then removed by filtration,and the solvent was distilled off under reduced pressure. Theresulting residue was purified by column chromatography(20-80% EtOAc in hexanes) and washed with Et2O to give thetitle compound 9 as a colorless powder (0.47 g, 63% over 2 steps).

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 1260 - 1275

75
[ 107504-08-5 ]
[ 120737-78-2 ]
rac-4-(6-carboxy-pyridin-3-yl)-2-methyl-piperazine-1 carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	at 160℃; for 1h;Microwave irradiation;	Example C.4 Preparation of rac-4-(6-Carboxy-pyridin-3-yl)-2-methyl-piperazine-1 carboxylic acid tertbutylester A solution of <strong>[107504-08-5]5-fluoropicolinic acid</strong> (0.47g, 3.33 mmol) and 2-methylpiperazine N1 Boc (1.00 g,5.00 mmol) in DMA (2.00 ml) was heated to 160C in a microwave reactor for 1 hour. Thesolvent was evaporated under high vacuum. The residue was taken in water and acidified to pH 3.The aqueous phase was extracted 3 times with ethyl acetate, dried and concentrated. The crudeproduct was purified with flash column chromatography on silica gel (Eluent: Heptane/ethyl acetate 0 to 20) to provide 1.17 g (100 %) of the title compound.

Reference： [1]Patent: WO2014/209841,2014,A2 .Location in patent: Page/Page column 46

76
[ 107504-08-5 ]
[ 197075-61-9 ]
2-[3-(2,2-dimethoxyethyl)-1,2,4-oxadiazol-5-yl]-5-fluoropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.2 g	With 1,1'-carbonyldiimidazole; In N,N-dimethyl-formamide; at 40 - 90℃; for 16.5h;	Reference Example 20: 2-[3-(2,2-dimethoxyethyl)-1,2,4-oxadiazol-5-yl]-5-fluoropyridine A solution of N-hydroxy-3,3-dimethoxypropanimidamide obtained in Reference Example 19 (1.0 g, 6.8 mmol) in DMF (3 mL) was added to a solution of <strong>[107504-08-5]5-fluoropyridine-2-carboxylic acid</strong> (1.0 g, 7.1 mmol) and carbonyldiimidazole (1.3 g, 8.1 mmol) in DMF (4 mL), which was stirred for 1 hour at 40C, and the mixture was stirred for 30 minutes. The reaction solution was heated to 90C and stirred for 15 hours. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over Na2SO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane/EtOAc = 75/25 to 0/100) to obtain the title compound (1.2 g) (colorless solid). MS (ESI pos.) m/z: 254 [M+H]+

Reference： [1]Patent: EP2862860,2015,A1 .Location in patent: Paragraph 0073; 0074

77
[ 107504-08-5 ]
[ 499796-71-3 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 23℃; for 16h;	To a solution of <strong>[107504-08-5]5-fluoropicolinic acid</strong> (500 mg, 3.54 mmol) in DCM (14 mL)/DMF (3.5 mL) was added l-hydroxy-7 azabenzotriazole (HOAt) (487 mg, 3.58 mmol), and EDC (713 mg, 3.72 mmol). The resulting mixture was stirred at 23 0 for 10 min followed by the addition of ammonium hydroxide (641 mu, 4.61 mmol). The reaction mixture was stirred at 23 C for 16 hours. Saturated aqueous NaHC03 solution was added to the reaction and the resulting mixture was extracted with DCM (3 x 40 mL). Combined organic phases were washed with water, brine, dried (MgSC^), filtered, and concentrated to give 275 mg of the crude desired product as pale yellow oil, which was used without further purification: MS(ES,m/z): 141.1 (M + 1).

Reference： [1]Patent: WO2015/51479,2015,A1 .Location in patent: Page/Page column 76; 77
[2]Patent: WO2015/51479,2015,A1

78
[ 107504-08-5 ]
5-fluoropyridine-2-carbothioamide [ No CAS ]