[ CAS No. 52833-94-0 ]

Name: 52833-94-0|2-Amino-5-bromonicotinic acid|97% HPLC
Brand: Ambeed
SKU: A179954
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Quality Control of [ 52833-94-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 52833-94-0 ]

Product Details of [ 52833-94-0 ]

CAS No. :	52833-94-0	MDL No. :	MFCD01860227
Formula :	C₆H₅BrN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IEPDTLRHISNBLB-UHFFFAOYSA-N
M.W :	217.02	Pubchem ID :	737445
Synonyms :

Calculated chemistry of [ 52833-94-0 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	43.3
TPSA :	76.21 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.72 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.6
Log Po/w (XLOGP3) :	1.27
Log Po/w (WLOGP) :	1.13
Log Po/w (MLOGP) :	-0.52
Log Po/w (SILICOS-IT) :	0.72
Consensus Log Po/w :	0.64

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.32
Solubility :	1.03 mg/ml ; 0.00475 mol/l
Class :	Soluble
Log S (Ali) :	-2.47
Solubility :	0.736 mg/ml ; 0.00339 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.9
Solubility :	2.74 mg/ml ; 0.0126 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.57

Safety of [ 52833-94-0 ]

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 [ 52833-94-0 ]

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

Upstream synthesis route of [ 52833-94-0 ]
Downstream synthetic route of [ 52833-94-0 ]

[ 52833-94-0 ] Synthesis Path-Upstream 1~9

1
[ 67-56-1 ]
[ 52833-94-0 ]
[ 50735-34-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	at 80℃; for 18 h; Inert atmosphere	To a solution of 2-amino-5-bromonicotinic acid 22 (1.0 g, 4.6 mmol)in MeOH (10 mL) was added sulphuric acid (2.0 mL, 36.8 mmol)dropwise and the mixture was stirred at 80 °C for 18 h. After completionmonitored by TLC, the solvent was removed under reduced pressure.The residue was neutralised with sat. NaHCO3 (aq.) and extracted withethyl acetate (3×20 mL). The combined organic layers were driedover MgSO4 and concentrated in vacuo to afford the product 23 as awhite powder (1.0 g, 94percent) without further purification. m.p.148–149 °C; Rf (CH2Cl2/MeOH 20:1): 0.55; 1H NMR (400 MHz, d6-DMSO): δ 8.24 (1H, d, J=2.4 Hz), 8.21 (1H, d, J=2.4 Hz), 6.68–6.19(2H, br.s), 3.89 (3H, s); 13C NMR (100 MHz, d6-DMSO): δ 166.6, 158.0,154.4, 142.0, 107.5, 106.1, 52.4. HRMS (ESI+) Calc. for C7H7N2O2Br [M+H]+ 230.9764/232.9743, found 230.9765/232.9745. IR (neat,cm−1): v 3425, 3131, 2918, 1704, 1620, 1223, 796, 526.
63%	Stage #1: for 0.25 h; Cooling with ice Stage #2: at 80℃; for 8 h; Inert atmosphere	Compound 1 (27.40 g, 126.88 mmol) obtained in Step 1 of Example 1 was placed in a well-dried 1000 mL three-neck round bottom flask and placed in a water bath containing ice water. 250 mL of methanol was added and stirred for 15 minutes. Sulfuric acid (125.80 mL, 2360.00 mmol) was slowly added dropwise thereto. The mixture was stirred for 8 hours at a temperature of 80 ° C under a stream of nitrogen. The product was poured into 1500 mL of ice water and neutralized with NaHCO 3 until the pH reached 7. Extraction with dichloromethane followed by column separation with 100percent dichloromethane. The resulting solid was dried to give compound 2 (18.5 g, 63percent yield).

Reference： [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 22, p. 5852 - 5869
[2] Patent: KR2018/82356, 2018, A, . Location in patent: Paragraph 0154; 0159-0161

2
[ 52833-94-0 ]
[ 18107-18-1 ]
[ 50735-34-7 ]

Reference： [1] Patent: WO2007/67416, 2007, A2, . Location in patent: Page/Page column 111

3
[ 5345-47-1 ]
[ 52833-94-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With bromine In acetic acid	EXAMPLE 1 2-Amino-5-bromo-3-pyridine carboxylic acid To a solution of 2-amino-nicotinic acid (10 g, 72.5 mmol) in acetic acid (70 mL) was dropwise added bromine (9.8 mL, 79.8 mmol) at room temperature under nitrogen. Upon completion of the reaction, the solvent was removed in vacuo, the residue triturated with ether and collected on a filter to give 2-amino-5-bromo-3-pyridine carboxylic acid as a yellow solid (15.7 g, 99percent): mp 272° C., (decomposed); ¹H-NMR (DMSO-d₆) δ8.8-7.8 (bs, 2H), 8.44 (d, 1H, J=2.48 Hz), 8.34 (d, 1H, J=2.48 Hz); MS (EI) m/z 216/218 ([M+]⁺, 100percent)
99%	With bromine In acetic acid	EXAMPLE 1 2-Amino-5-bromo-3-pyridine Carboxylic Acid To a solution of 2-amino-nicotinic acid (10 g, 72.5 mmol) in acetic acid (70 mL) was dropwise added bromine (9.8 mL, 79.8 mmol) at room temperature under nitrogen. Upon completion of the reaction, the solvent was removed in vacuo, the residue triturated with ether and collected on a filter to give 2-amino-5-bromo-3-pyridine carboxylic acid as a yellow solid (15.7 g, 99percent): mp 272° C., (decomposed); ¹H-NMR (DMSO-d₆) δ 8.8-7.8 (bs, 2H), 8.44 (d, 1H, J=2.48 Hz), 8.34 (d, 1H, J=2.48 Hz); MS (EI) m/z 216/218 ([M+H]⁺, 100percent).
98%	With bromine In acetic acid at 20℃; for 20 h;	Step 1: Synthesis of 2-amino-5-bromonicotinic acid 25.00 g (0.181 mol) of 2-aminonicotinic acid were dispersed in 100 ml of glacial acetic acid. To this suspension was added a solution of 12.0 ml (0.23 mol) of bromine in 50 ml of glacial acetic acid. The mixture was stirred at room temperature for 20 hours. The precipitate formed was filtered off and washed with 100 ml of glacial acetic acid in several portions until the filtrate remained colorless. The crude was dried by suction and crystallized from boiling methanol to afford 38.63 g (0.178 mol, 98percent yield) of 2-amino-5-bromonicotinic acid as slightly greenish to off-white crystalline needles. ¹H-NMR (d₆-DMSO) d: 8.45 [1H] d, 8.34 [1H] d.; MS: m/z 217 [MH⁺].

96%	at 20℃;	Equipped with a blender,Reflux condenser 500mL three-necked flask,20.7 g (0.15 mol) of 2-aminonicotinic acid,80 mL acetic acid,Stirred at room temperature,A constant pressure dropping funnel was added dropwise with a mixed solution of 40 mL of acetic acid and 4.1 mL of bromine (0.08 mol)Drop end to continue mixing 4-5h.filter,Washed with acetic acid,dry,The solid was refluxed with methanol 100mL 10min 10min at room temperature,Filter and dry.31.2g of white solid was obtained,Yield 96percent.
95%	With bromine In acetic acid at 20℃; for 20 h;	2-Amino-nicotinic acid (2 g, 14.48 mmol) was dispersed in glacial acetic acid. To this suspension was added a solution of bromine (1.2 mL) in glacial acetic acid (5 mL). The mixture was stirred at room temperature for 20 h. The mixture was filtered and washed with glacial acetic acid (10 mL) and water in several portions. The precipitate was collected and dried to give 2-amino-5-bromonicotinic acid (3.0 g, 95 percent yield) as yellow solid. ^XH-NMR (DMSO- d₆, 400 MHz) δ 8.31 (d, J= 2.4 Hz, 1H), 8.18 (d, J= 2.8 Hz, 1H), 5.06-5.27 (m, 2H). MS (M+H)⁺: 218 / 220.
95%	at 25℃; for 20 h;	2-Amino-nicotinic acid (2 g, 14.48 mmol) was dispersed in glacial acetic acid. To this suspension was added a solution of bromine (1.2 mL) in glacial acetic acid (5 mL). The mixturewas stirred at room temperature for 20 h. The mixture was filtered and washed with glacial aceticacid (10 mE) and water in several portions. The precipitate was collected and dried to give 2-amino-5-bromonicotinic acid (3.0 g, 95 percent yield) as yellow solid. ‘H-NMR (DMSO-d6, 400 MHz) ö 8.31(d, J= 2.4 Hz, 1H), 8.18 (d, J= 2.8 Hz, 1H), 5.065.27 (m, 2H). MS (M+Hj: 218 / 220.
92%	at 20℃; for 0.5 h;	2-Aminonicotinic acid (10.00 g, 72.40 mmol) was suspended in 40 ml of glacial acetic acid. To this suspension was added dropwise a solution of 4.82 ml (94.12 mmol) of bromine in 20 ml of glacial acetic acid. The mixture was stirred vigorouly at room temperature for 30 min. The formed precipitate was filtered off and washed with glacial acetic acid. The filter cake was collected and crystallized from the boiling methol to afford compound 8 as a white solid (14.5 g, 92percent yield). 1H NMR (300 MHz, DMSO-d6) δ 8.30 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H); MS (ESI, m/z): 216.8 [M+H]+.
92.6%	at 20℃; for 18 h;	2-Amino-5-bromo-nicotinic acid: To a solution of pyridine-2-amino-3-carboxylic acid (2.05 g, 81.1 mmol) in AcOH (250 mL) was added bromine (11.0 mL, 199.2 mmol) at RT. The reaction mixture was stirred for 18 h at RT. On completion of the reaction, the solvent was evaporated completely under reduced pressure, filtered, washed with diethyl ether (3 x 75 mL) to afford the title compound as a yellow solid. Yield: 50.0 g (92.6percent) 'HNMR (DMSO-de, 400 MHz, TMS) δ: 11.7 (3H, br, s), 8.33 (1H, s), 8.20 (1H, s).
90%	at 20℃; for 2 h;	2-aminonicotinic acid (10.0 g, 72 mmol) was dissolved in acetic acid (40 ml),Slowly add bromine (9.64 mL,388 mmol) in acetic acid (20 mL),Stir at room temperature for 2 hours, filter by suction, and wash the filter cake with acetic acid.The cake was recrystallized from methanol,After suction filtration and drying, 14.1 g of a white solid is obtained.The yield is 90percent.
90%	at 25℃; for 20 h; Inert atmosphere	This compound was prepared following a literature procedure.25 Toa suspension of 2-aminonicotinic acid 21 (3.75 g, 27 mmol) in glacialacetic acid (15 mL) was added a solution of bromine (1.8 mL, 35 mmol)in glacial acetic acid (3 mL) and the mixture was stirred at RT for 20 h.After completion monitored by TLC, the resulting precipitate was filteredand washed with glacial acetic acid 3 times. The remaining solidwas air dried and then recrystallised from boiling methanol to affordthe product 22 as white crystalline needles (5.2 g, 90percent). 1H NMR(400 MHz, d6-DMSO): δ 8.36 (1H, d, J=2.6 Hz), 8.25 (1H, d,J=2.6 Hz), 7.95–7.79 (2H, br.s); 13C NMR (100 MHz, d6-DMSO): δ166.6, 156.5, 149.9, 143.8, 109.3, 103.7. The spectroscopic data matchedthat reported in the literature.
70%	at 20℃; for 20 h; Inert atmosphere	2-aminonicotinic acid (25.0 g, 181.00 mmol) was added to a well-dried 1000 mL three-neck round bottom flask, and acetic acid (150 mL) was added thereto. Bromine (11.85 mL, 230.02 mmol) was slowly added dropwise to acetic acid (50 mL). And the mixture was stirred at room temperature for 20 hours in a stream of nitrogen. The resulting product was poured into 500 mL of distilled water and stirred for 30 minutes. The product was filtered through a glass filter, washed with ether and acetone, and dried to obtain Compound 1 (27.4 g, yield 70percent).

Reference： [1] Patent: US6369056, 2002, B1,
[2] Patent: US6399593, 2002, B1,
[3] Patent: US2006/30583, 2006, A1, . Location in patent: Page/Page column 113
[4] Patent: CN106565684, 2017, A, . Location in patent: Paragraph 0177; 0178; 0179; 0180
[5] Patent: WO2014/209727, 2014, A1, . Location in patent: Page/Page column 60-61
[6] Patent: WO2014/205593, 2014, A1, . Location in patent: Page/Page column 64
[7] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5169 - 5180
[8] Patent: WO2014/106612, 2014, A1, . Location in patent: Page/Page column 22
[9] Patent: CN104592217, 2018, B, . Location in patent: Paragraph 0029; 0030; 0031
[10] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 22, p. 5852 - 5869
[11] Patent: KR2018/82356, 2018, A, . Location in patent: Paragraph 0154-0157
[12] Organic Process Research and Development, 2009, vol. 13, # 4, p. 698 - 705
[13] Patent: US3974161, 1976, A,
[14] Patent: WO2007/67416, 2007, A2, . Location in patent: Page/Page column 111
[15] European Journal of Medicinal Chemistry, 2016, vol. 118, p. 276 - 289
[16] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 18, p. 4500 - 4505
[17] Patent: US3950160, 1976, A,

4
[ 52833-94-0 ]
[ 335031-01-1 ]

Reference： [1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 38, p. 8966 - 8970

5
[ 52833-94-0 ]
[ 58483-98-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 25℃;	A mixture of 2-amino-5-bromonicotinic acid (2.0 g, 9.20 mmol), HOBT (1.40 g, 11.2 mmol), EDCI (3.52 g, 18.4 mmol), Et3N (4.68 g, 46.0 mmol) and NH4C1 (2.48 g, 46.0 mmol) in DMF (100 mL) was stirred overnight at room temperature. The reaction mixture was concentratedin vacuo, suspended in water and extracted with CH2C12. The organic layer was washed with brine,dried over Na2504 and concentrated to give the product of 2-amino-5-bromonicotinamide (1.80 g,yield: 80percent), which was used for the next step without further purification. ‘H NMR (DMSO-d6,400 MHz) 8.14 (dd, J= 4.4 Hz, 2.4 Hz, 2H), 8.04 (s, 1H), 7.46 (s, 1H), 7.37 (s, 2H). MS (M+H):216/218.

Reference： [1] Patent: WO2014/205593, 2014, A1, . Location in patent: Page/Page column 55
[2] Patent: WO2014/209727, 2014, A1, . Location in patent: Page/Page column 52-53

6
[ 52833-94-0 ]
[ 77287-34-4 ]
[ 155690-79-2 ]

Yield	Reaction Conditions	Operation in experiment
36%	at 150℃; for 0.5 h; Microwave irradiation	To a vial was charged with 2-amino-5-bromonicotinic acid 8 (1 g, 4.61 mmol) and 1.1 ml of formamide. The vial was capped and heated at 150 °C for 30 min under microwave irradiation. To the reaction mixture was added water. The precipitate was filtered off and recrystallized from water to afford brown solid in 36percent yield. ¹H NMR (300 MHz, DMSO-d₆) δ 12.72 (s, 1H), 9.03 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.35 (s, 1H); MS (ESI, m/z): 225.8 [M+H]⁺.

Reference： [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1713 - 1726
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5169 - 5180

7
[ 3473-63-0 ]
[ 52833-94-0 ]
[ 155690-79-2 ]

Yield	Reaction Conditions	Operation in experiment
1.7 g	at 120℃; for 36 h; Inert atmosphere	2-Amino-S -bromonictoinic acid (2 g) and formamidine acetate (3.0 g) were heated at 120 °C in2-methoxyethanol (15 ml) for 36 h under argon. The heterogeneous reaction mixture was diluted with water and filtered. The solid was suction dried to obtain 1.7 g of 6-bromopyrido[2,3- d]pyrimidin-4(3H)-one. ‘H NMR (300 MHz, DMSO-d6) ö 12.70 (s, 1H), 9.01 (d, J= 2.6 Hz, 1H), 8.59 (d, J= 2.6 Hz, 1H), 8.33 (s, 1H).

Reference： [1] Patent: WO2015/157093, 2015, A1, . Location in patent: Paragraph 1314; 1315

8
[ 97-97-2 ]
[ 52833-94-0 ]
[ 903129-78-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: With hydrogenchloride; sodium acetate In ethanol; water for 2.5 h; Reflux Stage #2: With sodium hydrogencarbonate In water	To a stirred solution of 2-amino-5-bromonicotinic acid (5.0 g, 23.04 mmol) and sodium acetate (3.78 g, 46.1 mmol) in 100 ml_ of 60 percent ethanol in water, were added a refluxed solution of sodium acetate (3.78 g, 46.1 mmol) followed by 2-chloro-1 ,1 - dimethoxyethane (5.74 g, 46.1 mmol) in concentrated hydrochloric acid (1 .0 ml_) in water (6 ml_) and the reaction mass was refluxed for 2.5 h. The solvent was removed, residue obtained was diluted with cold water and pH adjusted to neutral (~7) with saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate (2x100 ml_), washed with water (2x100 ml_) and brine (2x100 ml_) and dried over anhydrous sodium sulphate. The crude material obtained was purified by trituration using 2 percent ethyl acetate in petroleum ether. Yield: 4.8 g (86 percent); ¹ H NMR (DMSO-d₆, 300 MHz): δ 7.66 (d, 1 H, J=1 .2 Hz, Ar), 7.79 (d, 1 H, J=1 .5 Hz, Ar), 8.04 (s, 1 H, Ar), 8.96 (d, 1 H, J=1 .5 Hz, Ar); MS (ES+): m/e 242 (M+1 ).

Reference： [1] Patent: WO2014/80241, 2014, A1, . Location in patent: Page/Page column 41

9
[ 52833-94-0 ]
[ 1215787-31-7 ]

Reference： [1] Patent: WO2015/157093, 2015, A1,
[2] European Journal of Medicinal Chemistry, 2016, vol. 118, p. 276 - 289
[3] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1713 - 1726

[ 52833-94-0 ] Synthesis Path-Downstream 1~68

1
[ 6638-79-5 ]
[ 52833-94-0 ]
[ 875639-72-8 ]

Yield	Reaction Conditions	Operation in experiment
74%		b) Isolated as the Hydrochloride Salt In a nitrogen flushed flask 3.00 g (30.76 mmol) of N,O-dimetylhydroxylamine hydrochloride and 3.53 g (16.27 mmol) of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> are dissolved in a mixture of 350 ml of dichloromethane, and 30 ml of N-methylmorpholine. 12.70 g (24.40 mmol) of PyBOP (1-benzotriazolyloxy-tris(pyrrolidino)phosphonium hexafluorophosphate) is added and the reaction mixture stirred at room temperature for 5 hours. The mixture is then washed with 150 ml of a 2 M solution of sodium hydroxide in water and then twice with 100 ml of a 10percent aqueous citric acid solution and dried over sodium sulfate. The solvent is evaporated and the resulting oil is dissolved in 300 ml of ether. The precipitate formed is filtered off and discarded. The clear filtrate is concentrated to about half its volume and diluted with 30-60 ml of dichloromethane. The resulting solution is stirred vigorously and a 1 M solution of hydrogen chloride in anhydrous ether is added until formation of the resulting precipitate is complete. The precipitate is filtered off, washed with ether and dried by suction to afford 3.15 g (12.04 mmol, 74percent yield) of N-methoxy-N-methyl-2-amino-5-bromonicotinamide hydrochloride as an off-white to beige-brown powder. 1H-NMR (d6-DMSO) delta: 8.24 [1H] d, 7.97 [1H] d, 3.56 [3H] s, 3.26 [3H] s. MS: m/z 260 [MH+]

Reference： [1]Patent: US2006/30583,2006,A1 .Location in patent: Page/Page column 113-114

2
[ 6638-79-5 ]
[ 52833-94-0 ]
[ 875639-69-3 ]

Yield	Reaction Conditions	Operation in experiment
63%	With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In dichloromethane; at 20℃; for 18h;	Intermediate 16:2-amino-5-bromo-N-methoxy-N-methylnicotinamide[00400] To a solution of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (7 g, 32.3 mmol), N,0- dimethylhydroxylamine (5.99 g, 61.37 mmol) in N-methylmorpholine (60 ml) and dichloromethane (500 ml) at O°C was added PyBop (25.2 g, 48.45 mmol) portionwise. The solution was allowed to warm to room temperature and the mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with a 2M aqueous solution of NaOH and with a 10wtpercent solution of citric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was dissolved in ether and the <n="185"/>formed solid was filtered off. The mother liquors were concentrated in vacuo to approximatively half of the original volume. This solution was diluted with dichloromethane and stirred vigorously while adding a 2M HCl solution in diethylether until complete formation of the precipitate. The solid was filtered off and partitioned between a 2M aqueous solution of NaOH and EtOAc. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to dryness to afford the title compound as a cream solid (5.26 g, 63percent yield). 1H NMR (DMSO-d6, 400 MHz) delta 3.24 (3H, s), 3.55 (3H, s), 6.35 (2H, s), 7.70 (IH, d), 8.10 (IH, d); MS (ES+) 260, 262.
46%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 95℃; for 20h;Product distribution / selectivity;	a) Isolated as the Free Base <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (4.000 g, 18.43 mmol), N,O-dimethylhydroxylamine hydrochloride (4.550 g, 46.6 mmol) and PyBOP (1-benzotriazolyloxy-tris(pyrrolidino)phosphonium hexafluorophosphate) (15.00 g, 28.82 mmol) were placed in a nitrogen flushed flask. 150 ml of acetonitrile and 25 ml of di-iso-propylethylamine were added and the mixture was heated to 95° C. for 20 hours. The solvent was then evaporated and the residue distributed between 200 ml of chloroform and 100 ml of a 10percent solution of citric acid in water. The organic phase was separated and washed with 100 ml of 1 M aqueous sodium hydroxide and dried over sodium sulfate. The solvent was evaporated and the crude material purified by chromatography on silica gel using a non-linear gradient of ethyl acetate and hexane affording 2.193 g (8.436 mmol, 46percent yield) of N-methoxy-N-methyl-2-amino-5-bromonicotinamide as an off-white solid. 1H-NMR (d6-DMSO) delta: 8.10 [1H] d, 7.71 [1H] d, 6.35 [2H] s, 3.55 [3H] s, 3.24 [3H] s.; MS: m/z 260 [MH+].
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	To a solution of 2-Amino-5-bromonicotinic acid (1 g, 4.6 mmol) in DMF (15 ml) is added EDC hydrochloride (1.06 g, 5.53 mmol), HOBt (0.747 g, 5.53 mmol), diisopropylethylamine (2 ml, 11.5 mmol) and N-methoxy-N-methylamine hydrochloride (0.54 g, 5.53 mmol), and the resulting solution is stirred at room temperature overnight. The reaction is concentrated in vacuo, and the residue is dissolved in EtOAc, washed with sat. aq. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (SiO2, 0-10percent ethanol in DCM) yields 2-Amino-5-bromo-N-methoxy-N-methyl-nicotinamide.

Reference： [1]Patent: WO2008/94992,2008,A2 .Location in patent: Page/Page column 183-184
[2]Patent: US2006/30583,2006,A1 .Location in patent: Page/Page column 113
[3]Patent: US2009/239847,2009,A1 .Location in patent: Page/Page column 45

3
[ 5345-47-1 ]
[ 52833-94-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With bromine; In acetic acid;	EXAMPLE 1 2-Amino-5-bromo-3-pyridine carboxylic acid To a solution of <strong>[5345-47-1]2-amino-nicotinic acid</strong> (10 g, 72.5 mmol) in acetic acid (70 mL) was dropwise added bromine (9.8 mL, 79.8 mmol) at room temperature under nitrogen. Upon completion of the reaction, the solvent was removed in vacuo, the residue triturated with ether and collected on a filter to give 2-amino-5-bromo-3-pyridine carboxylic acid as a yellow solid (15.7 g, 99%): mp 272 C., (decomposed); 1H-NMR (DMSO-d6) delta8.8-7.8 (bs, 2H), 8.44 (d, 1H, J=2.48 Hz), 8.34 (d, 1H, J=2.48 Hz); MS (EI) m/z 216/218 ([M+]+, 100%)
99%	With bromine; In acetic acid;	EXAMPLE 1 2-Amino-5-bromo-3-pyridine Carboxylic Acid To a solution of <strong>[5345-47-1]2-amino-nicotinic acid</strong> (10 g, 72.5 mmol) in acetic acid (70 mL) was dropwise added bromine (9.8 mL, 79.8 mmol) at room temperature under nitrogen. Upon completion of the reaction, the solvent was removed in vacuo, the residue triturated with ether and collected on a filter to give 2-amino-5-bromo-3-pyridine carboxylic acid as a yellow solid (15.7 g, 99%): mp 272 C., (decomposed); 1H-NMR (DMSO-d6) delta 8.8-7.8 (bs, 2H), 8.44 (d, 1H, J=2.48 Hz), 8.34 (d, 1H, J=2.48 Hz); MS (EI) m/z 216/218 ([M+H]+, 100%).
98%	With bromine; In acetic acid; at 20℃; for 20h;	Step 1: Synthesis of 2-amino-5-bromonicotinic acid 25.00 g (0.181 mol) of 2-aminonicotinic acid were dispersed in 100 ml of glacial acetic acid. To this suspension was added a solution of 12.0 ml (0.23 mol) of bromine in 50 ml of glacial acetic acid. The mixture was stirred at room temperature for 20 hours. The precipitate formed was filtered off and washed with 100 ml of glacial acetic acid in several portions until the filtrate remained colorless. The crude was dried by suction and crystallized from boiling methanol to afford 38.63 g (0.178 mol, 98% yield) of 2-amino-5-bromonicotinic acid as slightly greenish to off-white crystalline needles. 1H-NMR (d6-DMSO) d: 8.45 [1H] d, 8.34 [1H] d.; MS: m/z 217 [MH+].

96%	With bromine; acetic acid; at 20℃;	Equipped with a blender,Reflux condenser 500mL three-necked flask,20.7 g (0.15 mol) of 2-aminonicotinic acid,80 mL acetic acid,Stirred at room temperature,A constant pressure dropping funnel was added dropwise with a mixed solution of 40 mL of acetic acid and 4.1 mL of bromine (0.08 mol)Drop end to continue mixing 4-5h.filter,Washed with acetic acid,dry,The solid was refluxed with methanol 100mL 10min 10min at room temperature,Filter and dry.31.2g of white solid was obtained,Yield 96%.
95%	With bromine; In acetic acid; at 20℃; for 20h;	2-Amino-nicotinic acid (2 g, 14.48 mmol) was dispersed in glacial acetic acid. To this suspension was added a solution of bromine (1.2 mL) in glacial acetic acid (5 mL). The mixture was stirred at room temperature for 20 h. The mixture was filtered and washed with glacial acetic acid (10 mL) and water in several portions. The precipitate was collected and dried to give 2-amino-5-bromonicotinic acid (3.0 g, 95 % yield) as yellow solid. XH-NMR (DMSO- d6, 400 MHz) delta 8.31 (d, J= 2.4 Hz, 1H), 8.18 (d, J= 2.8 Hz, 1H), 5.06-5.27 (m, 2H). MS (M+H)+: 218 / 220.
95%	With bromine; acetic acid; at 25℃; for 20h;	2-Amino-nicotinic acid (2 g, 14.48 mmol) was dispersed in glacial acetic acid. To this suspension was added a solution of bromine (1.2 mL) in glacial acetic acid (5 mL). The mixturewas stirred at room temperature for 20 h. The mixture was filtered and washed with glacial aceticacid (10 mE) and water in several portions. The precipitate was collected and dried to give 2-amino-5-bromonicotinic acid (3.0 g, 95 % yield) as yellow solid. ?H-NMR (DMSO-d6, 400 MHz) oe 8.31(d, J= 2.4 Hz, 1H), 8.18 (d, J= 2.8 Hz, 1H), 5.065.27 (m, 2H). MS (M+Hj: 218 / 220.
92%	With bromine; acetic acid; at 20℃; for 0.5h;	<strong>[5345-47-1]2-Aminonicotinic acid</strong> (10.00 g, 72.40 mmol) was suspended in 40 ml of glacial acetic acid. To this suspension was added dropwise a solution of 4.82 ml (94.12 mmol) of bromine in 20 ml of glacial acetic acid. The mixture was stirred vigorouly at room temperature for 30 min. The formed precipitate was filtered off and washed with glacial acetic acid. The filter cake was collected and crystallized from the boiling methol to afford compound 8 as a white solid (14.5 g, 92% yield). 1H NMR (300 MHz, DMSO-d6) delta 8.30 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H); MS (ESI, m/z): 216.8 [M+H]+.
92.6%	With bromine; acetic acid; at 20℃; for 18h;	2-Amino-5-bromo-nicotinic acid: To a solution of <strong>[5345-47-1]pyridine-2-amino-3-carboxylic acid</strong> (2.05 g, 81.1 mmol) in AcOH (250 mL) was added bromine (11.0 mL, 199.2 mmol) at RT. The reaction mixture was stirred for 18 h at RT. On completion of the reaction, the solvent was evaporated completely under reduced pressure, filtered, washed with diethyl ether (3 x 75 mL) to afford the title compound as a yellow solid. Yield: 50.0 g (92.6%) 'HNMR (DMSO-de, 400 MHz, TMS) delta: 11.7 (3H, br, s), 8.33 (1H, s), 8.20 (1H, s).
90%	With bromine; acetic acid; at 20℃; for 2h;	2-aminonicotinic acid (10.0 g, 72 mmol) was dissolved in acetic acid (40 ml),Slowly add bromine (9.64 mL,388 mmol) in acetic acid (20 mL),Stir at room temperature for 2 hours, filter by suction, and wash the filter cake with acetic acid.The cake was recrystallized from methanol,After suction filtration and drying, 14.1 g of a white solid is obtained.The yield is 90%.
90%	With bromine; acetic acid; at 25℃; for 20h;Inert atmosphere;	This compound was prepared following a literature procedure.25 Toa suspension of 2-aminonicotinic acid 21 (3.75 g, 27 mmol) in glacialacetic acid (15 mL) was added a solution of bromine (1.8 mL, 35 mmol)in glacial acetic acid (3 mL) and the mixture was stirred at RT for 20 h.After completion monitored by TLC, the resulting precipitate was filteredand washed with glacial acetic acid 3 times. The remaining solidwas air dried and then recrystallised from boiling methanol to affordthe product 22 as white crystalline needles (5.2 g, 90%). 1H NMR(400 MHz, d6-DMSO): delta 8.36 (1H, d, J=2.6 Hz), 8.25 (1H, d,J=2.6 Hz), 7.95-7.79 (2H, br.s); 13C NMR (100 MHz, d6-DMSO): delta166.6, 156.5, 149.9, 143.8, 109.3, 103.7. The spectroscopic data matchedthat reported in the literature.
89%	With bromine; acetic acid; In water; at 0 - 20℃; for 8h;	2-Amino-5-bromonicotinicacid (3) (C6H5BrN2O2): Acetic acid (250 mL) and water (10 mL)were poured into the solution of 2-aminonicotinic acid 1 (10 g, 72.4mmol). The suspension was placed at 0C and Br2 (4 mL, 79 mmol,1.1 equiv) was added dropwise. After 8 h of stirring at room temperature,the mixture was filtered and then concentrated underreduced pressure. The crude material obtained was washed withEt2O to afford compound 3 as a white solid in 89% yield.
70%	With bromine; acetic acid; at 20℃; for 20h;Inert atmosphere;	2-aminonicotinic acid (25.0 g, 181.00 mmol) was added to a well-dried 1000 mL three-neck round bottom flask, and acetic acid (150 mL) was added thereto. Bromine (11.85 mL, 230.02 mmol) was slowly added dropwise to acetic acid (50 mL). And the mixture was stirred at room temperature for 20 hours in a stream of nitrogen. The resulting product was poured into 500 mL of distilled water and stirred for 30 minutes. The product was filtered through a glass filter, washed with ether and acetone, and dried to obtain Compound 1 (27.4 g, yield 70%).
	With bromine; In diethyl ether; acetic acid;	B. 2-Amino-5-bromonicotinic acid and hydrobromide <strong>[5345-47-1]2-Aminonicotinic acid</strong> (3.6 g.) in 450 ml. of acetic acid is treated dropwise over a period of 10-15 minutes with 4 ml. of bromine in 50 ml. of acetic acid. The reaction mixture is allowed to stir at room temperature for 1.5-2 hours, and is then diluted with 2 liters of diethyl ether. The precipitate which forms, 2-amino-5-bromonicotinic acid hydrobromide, is filtered and dried, 5.6 g., m.p. 280 C. (dec.). The free acid is liberated by adding sufficient ammonium hydroxide to an aqueous solution of the hydrobromide salt to provide a solution of pH 5. The resulting free acid is filtered from the cooled mixture and dried in vacuo.
		A solution of bromine (7 mL, 136 mmol) in acetic acid (20 mL) was added dropwise to an acetic acid (230 mL) suspension of 2-aminonicotinic acid (9.37 g, 68 mmol) at 100C. After stirring the mixture for 6 hours, ether (600 mL) was added and the stirring was continued for 14 hours. The mixture was cooled to 00C, the precipitate was filtered, washed with ether and dried to give 18.2 g (90%) of a hydrobromide salt. The salt was dissolved in water (200 mL) and sodium hydroxide solution (60 mL, 2N) then neutralized with IN HCl. The resulting precipitate was filtered and dried to afford of the title compound (12.01 g, 82%). 1H NMR (300 MHz, OMSO-d6, delta): 8.25 (d, J= 2.6Hz, IH), 8.09 (d, J= 2.6Hz, IH).
	With bromine; In diethyl ether; acetic acid;	h. 2-Amino-5-bromonicotinic acid and hydrobromide In a manner similar to Preparation D-g, 3.6 g. of 2-aminonicotinic acid in 450 ml. of acetic acid is treated dropwise over a period of 10-15 min. with 4 ml. of bromine in 50 ml. of the same solvent. The reaction mixture is allowed to stir at room temperature for 1.5-2 hrs., and is then diluted with 2 l. of diethyl ether. The precipitate which is formed, 2-amino-5-bromonicotinic acid hydrobromide, is filtered and dried, 5.6 g., m.p. 280 C. (dec.). The free acid is liberated by adding sufficient ammonium hydroxide to an aqueous solution of the hydrobromide salt to provide a solution of pH 5. The resulting free acid is filtered from the cooled mixture and dried in vacuo.

Reference： [1]Patent: US6369056,2002,B1
[2]Patent: US6399593,2002,B1
[3]Patent: US2006/30583,2006,A1 .Location in patent: Page/Page column 113
[4]Patent: CN106565684,2017,A .Location in patent: Paragraph 0177; 0178; 0179; 0180
[5]Patent: WO2014/209727,2014,A1 .Location in patent: Page/Page column 60-61
[6]Patent: WO2014/205593,2014,A1 .Location in patent: Page/Page column 64
[7]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180
[8]Patent: WO2014/106612,2014,A1 .Location in patent: Page/Page column 22
[9]Patent: CN104592217,2018,B .Location in patent: Paragraph 0029; 0030; 0031
[10]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 5852 - 5869
[11]Comptes Rendus Chimie,2019,vol. 22,p. 294 - 298
[12]Patent: KR2018/82356,2018,A .Location in patent: Paragraph 0154-0157
[13]Organic Process Research and Development,2009,vol. 13,p. 698 - 705
[14]Patent: US3974161,1976,A
[15]Patent: WO2007/67416,2007,A2 .Location in patent: Page/Page column 111
[16]European Journal of Medicinal Chemistry,2016,vol. 118,p. 276 - 289
[17]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4500 - 4505
[18]Patent: US3950160,1976,A

4
[ 52833-94-0 ]
[ 304467-35-4 ]

Yield	Reaction Conditions	Operation in experiment
23%	With methylmagnesium bromide; In tetrahydrofuran; ethyl acetate;	EXAMPLE 2 2-(2-Amino-5-bromo-pyridin-3-yl)-propan-2-ol To a solution of <strong>[52833-94-0]2-amino-5-bromo-3-pyridine carboxylic acid</strong> (5 g, 23 mmol) in THF (70 mL) at 0° C. was added methyl magnesium bromide (13.7 g, 115 mmol) under nitrogen. After addition, the reaction mixture was heated at 65° C. for 12 hours, cooled to room temperature and quenched with saturated aqueous ammonium chloride. The ethyl acetate was added and organic layer was separated, dried over sodium sulfate and concentrated. The residue was purified via flash chromatography to give 2-(2-amino-5-bromo-pyridin-3-yl)-propan-2-ol as a yellow solid (1.2 g, 23percent): mp 107-108° C.; 1H-NMR (DMSO-d6) delta7.89 (d, 1H, J=2.3 Hz), 7.40 (d, 1H, J=2.3 Hz), 6.28 (bs, 2H), 5.51 (s, 1H), 1.4 (s, 6H); MS (APCI) m/z 231 ([M+H]+, 100percent).
23%	With methylmagnesium bromide; In tetrahydrofuran; ethyl acetate;	EXAMPLE 2 2-(2-Amino-5-bromo-pyridin-3-yl)-propan-2-ol To a solution of <strong>[52833-94-0]2-amino-5-bromo-3-pyridine carboxylic acid</strong> (5 g, 23 mmol) in THF (70 mL) at 0° C. was added methyl magnesium bromide (13.7 g, 115 mmol) under nitrogen. After addition, the reaction mixture was heated at 65° C. for 12 hours, cooled to room temperature and quenched with saturated aqueous ammonium chloride. The ethyl acetate was added and organic layer was separated, dried over sodium sulfate and concentrated. The residue was purified via flash chromatography to give 2-(2-amino-5-bromo-pyridin-3-yl)propan-2-ol as a yellow solid (1.2 g, 23percent): mp 107-108° C.; 1H-NMR (DMSO-d6) delta 7.89 (d, 1H, J=2.3 Hz), 7.40 (d, 1H, J=2.3 Hz), 6.28 (bs, 2H), 5.51 (s, 1H), 1.4 (s, 6H); MS (APCI) m/z 231 ([M+H]+, 100percent).

Reference： [1]Patent: US6369056,2002,B1
[2]Patent: US6399593,2002,B1

5
[ 52833-94-0 ]
[ 18107-18-1 ]
[ 50735-34-7 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; diethyl ether; dichloromethane; at 10℃; for 1h;	Trimethylsilyldiazomethane (15 mL, 30 mmol, 2M in ether) was added dropwise to a stirred suspension of 2-amino-5-bromonicotinic acid (2.51 g, 11.6 mmol) in methylene chloride (50 mL) and methanol (50 mL) at 10 0C. After stirring one hour, the excess reagent was destroyed with acetic acid and the mixture was evaporated to a paste. The crude product was recrystallized from methanol to give the title compound (2.41 g, 90%). 1H NMR (300 MHz, OMSO-d6, delta): 8.29 (d, J= 2.5Hz, IH), 8.12 (d, J= 2.5Hz, IH), 7.33 (s, br, 2H), 3.82 (s, 3H).

Reference： [1]Patent: WO2007/67416,2007,A2 .Location in patent: Page/Page column 111

6
[ 4381-25-3 ]
[ 52833-94-0 ]
[ 1027729-84-5 ]

Yield	Reaction Conditions	Operation in experiment
84%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 60℃; for 20h;	Example 469 <n="79"/>(S)-2-amino-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-lambda6-sulfanylidene]nicotinamideStep 1(S)-2-amino-5-bromo-N-[methyl(oxo)phenyl-lambda6-sulfanylidene]nicotinamide To a solution of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (189 mg, 0.87 mmol), N, N- diisopropylethylamine (0.30 mL, 1.7 mmol), and (S)-(+)-S-methyl-S-phenylsulfoximine (162 mg, 1.0 mmol) in 4.0 mL DMF at room temperature was added BOP (423 mg, 0.96 mmol). The solution was stirred 30 minutes, then heated at 60 0C for 30 minutes, and then cooled back to room temperature. After 19 hours, the mixture was dissolved in EtOAc, washed with Na2CO3 solution, H2O, brine, dried with anhydrous Na2Spsi4 and rotary evaporated. The yellow foam was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a light yellow solid (260 mg, 84percent).

Reference： [1]Patent: WO2008/61236,2008,A2 .Location in patent: Page/Page column 77-78

7
[ 53981-25-2 ]
[ 52833-94-0 ]
[ 1146951-10-1 ]

Yield	Reaction Conditions	Operation in experiment
	With PPA; In tetrahydrofuran;	The 5-bromo-3-(7-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine used as starting material was prepared as follows: A mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g), 2-amino-6-fluoro-phenol (0.586 g) and polyphosphoric acid (10 g) was stirred at 200 C. for 5 hours. The resulting mixture was cooled to room temperature, diluted with water (4 ml) and basified to pH 12 with aqueous NaOH 10N, then 2N. The precipitate was filtered, washed with water, diethyl ether, and dried. The compound was stirred in THF during 2 days, the insoluble was filtered, the filtrate was concentrated to dryness and dried under vacuum to give 5-bromo-3-(7-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (0.475 g). NMR Spectrum: (DMSOd6) 7.37-7.48 (m, 2H), 7.69 (dd, 1H), 7.83 (bs, 2H), 8.34 (d, 1H), 8.38 (d, 1H); Mass spectrum: M+H+ 307-309

Reference： [1]Patent: US2009/118305,2009,A1

8
[ 115551-33-2 ]
[ 52833-94-0 ]
[ 1146951-08-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In PPA; water;	The 5-bromo-3-(6,7-difluoro-1,3-benzoxazol-2-yl)pyridin-2-amine used as starting material was prepared as follows: To a mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g) and <strong>[115551-33-2]6-amino-2,3-difluoro-phenol</strong> (0.669 g) placed in a round bottom flask was added polyphosphoric acid (10 g). The mixture was heated at 200 C. for 5 hours. A homogenous black mixture was obtained. The mixture was diluted in water and neutralizing to pH 8 with NaOH 2N. The heterogeneous mixture was diluted with dichloromethane. The insoluble was filtered. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with brine, dried on sodium sulfate, evaporated and dried to afford 5-bromo-3-(6,7-difluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (0.338 g). NMR Spectrum: (DMSOd6) 7.54 (ddd, 1H), 7.70 (ddd, 1H), 7.79 (bs, 2H), 8.34 (d, 1H), 8.38 (d, 1H); Mass spectrum: M+H+ 326-328

Reference： [1]Patent: US2009/118305,2009,A1

9
[ 52833-94-0 ]
[ 53981-23-0 ]
[ 1146950-94-8 ]
[ 1146950-93-7 ]

Yield	Reaction Conditions	Operation in experiment
	In PPA; water;	The 3-(4-fluoro-1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine used as starting material was prepared as follows: 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g) and <strong>[53981-23-0]2-amino-3-fluoro-phenol</strong> (0.586 g) in polyphosphoric acid were stirred at 200° C. for 22 hours. After cooling, water (75 ml) was added and the mixture was stirred for 30 min. The mixture was basified to pH 12 with concentrated sodium hydroxide solution (6N and 2N). The solid was filtered, washed with water (320 ml), and ether (310 ml). After drying under vacuum over phosphorus pentoxide; the desired compound 5-bromo-3-(4-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (0.995 g) was obtained as a solid which was used without further purification in the next step. NMR Spectrum: (DMSOd6): 7.34 (dd, 1H), 7.50 (ddd, 1H), 7.68 (dd, 1H), 7.81 (bs, 2H), 8.35 (d, 1H), 8.38 (d, 1H); Mass spectrum: M+H+ 307-309

Reference： [1]Patent: US2009/118305,2009,A1

10
[ 52334-53-9 ]
[ 52833-94-0 ]
[ 1146633-96-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In PPA;	4-Aminopyridin-3-ol (0.074 g) and 2-amino-5-bromo-pyridine-3-carboxylic acid (0.146 g) were stirred in polyphosphoric acid (5 ml) at 200 C. for 4 hours. The reaction mixture was quenched with water (5 ml) and the mixture was basified to pH 13.4 by addition of 10N sodium hydroxide solution. The precipitate was collected by filtration, washed with water (5 ml) and dried under vacuum. There was thus obtained 5-bromo-3-oxazolo[5,4-c]pyridin-2-yl-pyridin-2-amine (0.121 g); Mass Spectrum: M+H+ 291.17; RT 1.88 min; NMR Spectrum: (DMSOd6) 9.14 (1H, s), 8.62 (1H, d), 8.38 (1H, s), 8.35 (1H, s), 7.88 (1H, d), 7.83 (2H, s).

Reference： [1]Patent: US2009/118305,2009,A1

11
[ 52833-94-0 ]
[ 124-40-3 ]
[ 1092580-97-6 ]

Yield	Reaction Conditions	Operation in experiment
79.8%		[00282] 2-Amino-5-bromonicotinicacid (390 mg, 1.8 mmol) and DIEA (2.38 mL, 13.7 mmol) were allowed to stir in DCM (46.5 mL). TBTU (1.44 g, 4.49 mmol) was added and the reaction was allowedstir at ii for 15 mm. Dimethylamine (2 M in THF; 7.19 mL, 14.4 mmol) was added and the reaction was allowed to stir at ii overnight. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude material residue was purified by column chromatography to yield 2-amino-5-bromo-N,N- dimethylnicotinamide (350 mg, 79.8percent). LCMS (FA): m/z = 244/246 (M+H).
79.8%		Step 1: 2-amino-5-bromo-N,N-dimethylnicotinamide 2-Amino-5-bromonicotinicacid (390 mg, 1.8 mmol) and DIEA (2.38 mL, 13.7 mmol) were allowed to stir in DCM (46.5 mL). TBTU (1.44 g, 4.49 mmol) was added and the reaction was allowed to stir at rt for 15 min. Dimethylamine (2 M in THF; 7.19 mL, 14.4 mmol) was added and the reaction was allowed to stir at rt overnight. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude material residue was purified by column chromatography to yield 2-amino-5-bromo-N,N-dimethylnicotinamide (350 mg, 79.8percent). LCMS (FA): m/z=244/246 (M+H).
44%	With diethyl cyanophosphonate; triethylamine; In tetrahydrofuran; at 20℃;	To a stirred solution of <strong>[52833-94-0]2-amino-5-bromo-3-carboxypyridine</strong> (1 .0 g, 4.60 mmol, 1 .0 eq.), dimethylamine (0.227 g, 5.06 mmol, 1.1 eq.) and TEA (1 .2 ml, 9.20 mmol, 2.0 eq.) dissolved in THE (20 mL) was added diethyl cyanophosphate (0.8 ml, 5.06 mmol, 1 .1 eq.) drop wise. Stirring at rt was continued for 4 h. The reaction mixture was partitioned between water and ethyl acetate (2 x 30 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2504 solution and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel(100-200 mesh) using a solvent gradient of 4percent MeOH in DCM as eluant to afford 500 mg(44percent) of 1-36 as a off-white solid. 1H NMR (400 MHz, DMSO) 6 8.05 (5, 1 H), 7.54 (5, 1 H),6.20 (brs, 2H), 2.90 (brs, 6H); ESI-LC/MS (m/z): [M÷H] 244.01, [(M÷2)÷H] 246.01, RT0.84 mm.

With diethyl cyanophosphonate; triethylamine; In tetrahydrofuran; at 0 - 20℃; for 4.5h;

To a suspension of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (0.35 g, 1.61 mmol) in tetrahydrofuran (5 mL) was added dimethylamine (0.8 mL of a 2M solution in tetrahydrofuran, 1.60 mmol), diethylphosphoryl cyanide (0.29 g, 1.77 mmol), and triethylamine (0.34 g, 3.38 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min and then at room temperature for 4 h. Concentration and purification by column chromatography on silica (5-10percent methanol in dichloromethane) gave the title Compound as a white solid. MS (EI) for C8H10BrN3O: 244 (MH+).

Reference： [1]Patent: WO2015/108861,2015,A1 .Location in patent: Paragraph 00282
[2]Patent: US2015/225422,2015,A1 .Location in patent: Paragraph 0387-0388
[3]Patent: WO2014/78802,2014,A1 .Location in patent: Page/Page column 93; 94
[4]Patent: WO2010/135524,2010,A1 .Location in patent: Page/Page column 240

12
[ 52833-94-0 ]
[ 74-89-5 ]
[ 625470-59-9 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (Combi-Blocks, San Diego, USA, 1.355 mmol) and triethylamine (0.378 ml) in dichloromethane (10 ml) cooled with an ice-bath was added a solution of trichloromethyl chloroformate (Acros, , Basel, Switzerland, 0.677 mmol) in dichloromethane (10 ml). After 40 min stirring at 00C, was added a solution 8 M of methylamine in EtOH (1.7 ml). The RM was stirred for 30 min at rt then was diluted with dichlromethane, washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was taken in DMF and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with dichloromethane (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a white solid. (HPLC: tR 1.69 min (Method C); M+H = 230, 231 MS-ES)

Reference： [1]Patent: WO2010/139747,2010,A1 .Location in patent: Page/Page column 159

13
[ 52833-94-0 ]
[ 62-53-3 ]
[ 1349770-45-1 ]

Yield	Reaction Conditions	Operation in experiment
64%	With N-ethyl-N,N-diisopropylamine; 1-(methanesulfonyl)-1H-1,2,3-benzotriazole; In tetrahydrofuran; at 160℃; for 0.166667h;Microwave irradiation;	Example 1; 2-Amino-iV-phenyl-5-(3-pyridyl)pyridine-3-carboxamide (Compound III-7) SCHEME ICompound 111-7METHOD A:Step 1: 2-Amino-5-bromo-iV-phe amide[00141] A mixture of <strong>[52833-94-0]2-amino-5-bromo-pyridine-3-carboxylic acid</strong> (203 mg, 0.9354 mmol), aniline (87.11 mg, 85.23 mu, 0.9354 mmol), 1 -methylsulfonylbenzotriazole (276.7 mg, 1.403 mmol) and DIPEA (241.8 mg, 325.9 mu, 1.871 mmol) in THF (2.0 mL) was heated in the microwave at 160 C for 10 mins. The reaction mixture was concentrated and the residue partitioned between EtOAc and 2M NaOH. The organic phase was washed with brine, dried (MgS04) and concentrated in vacuo to give the product as a yellow solid (174 mg, 64% Yield). XH NMR (400.0MHz, DMSO) delta 7.77 (br s, 2H), 8.18 (d, 1H) and 8.32 (d, 1H); ppm; MS (ES+) 293.94.
51.5%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	Accurately weighed <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong>(4 mmol) and EDCI 576 mg (3 mmol) in a 25 mL round bottom flask were added 10 mL of DMF and 186 mg (2 mmol) of aniline dispersed in 5 mL of DMF was added dropwise with stirring to control the10 minutes or so drops finished. Stirring at room temperature overnight, TLC detection reaction is complete after the reaction solution into the water to BEthyl acetate extraction three times, combined organic phase washed with a small amount of water three times, saturated salt water washed by adding anhydrous sodium sulfate after drying. organicWas distilled under reduced pressure and purified by column chromatography on ethyl acetate / petroleum ether to give 300 mg of a white solid in 51.5% yield.

Reference： [1]Patent: WO2011/143422,2011,A1 .Location in patent: Page/Page column 39
[2]Patent: CN104788449,2017,B .Location in patent: Paragraph 0257; 0258; 0259
[3]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 1928 - 1933

14
[ 613-94-5 ]
[ 52833-94-0 ]
[ 1349770-47-3 ]

Yield	Reaction Conditions	Operation in experiment
62%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20℃;	Example 2; 5-(4-(Methylsulfonyl)phenyl)-3-(5-phenyl-l,3,4-oxadiazol-2-yl)pyridin-2- amine (Compound III-3)METHOD B:Step 1: 2-Amino-5-bromo-iV-(phenylcarbonyl)pyridine-3-carbohydrazide [00143] TBTU (2.219 g, 6.912 mmol) and triethylamine (466.3 mg, 642.3 mu,, 4.608 mmol) were added to a solution of <strong>[52833-94-0]2-amino-5-bromo-pyridine-3-carboxylic acid</strong> (1 g, 4.608 mmol) and benzohydrazide (752.9 mg, 5.530 mmol) in DMF (40.00 mL) and the resulting solution stirred at ambient temperature over the weekend. The reaction was treated with water / EtOAc and the organics separated. The organic layer was washed with water (3x), dried (MgS04), filtered and concentrated in vacuo to give a yellow oil which was triturated with ether and dried under high vacuum to give the product as an off-white solid that was used directly in the next step without further purification (1.177g, 62percent Yield). MS (ES+) 336.86.

Reference： [1]Patent: WO2011/143422,2011,A1 .Location in patent: Page/Page column 40-41

15
[ 1232424-40-6 ]
[ 52833-94-0 ]
[ 1349770-55-3 ]

Yield	Reaction Conditions	Operation in experiment
58%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 60h;	Example 5; 5-(4-Isopropylsulfonylphenyl)-3-[5-[4-(methylaminomethyl)phenyl]-l,3,4- oxadiazol-2-yl]pyridin-2-amine (Compound III-ll) Scheme VMETHOD EStep 1: tert-Butyl N-[[4-[[(2-amino-5-bromo-pyridine-3- carbonyl)amino]carbamoyl]phenyl]methyl]-N-methyl-carbamate[00151] <strong>[52833-94-0]2-amino-5-bromo-pyridine-3-carboxylic acid</strong> (776.9 mg, 3.580 mmol) and triethylamine (724.5 mg, 997.9 mu,, 7.160 mmol) were added to a stirred solution of tert-butyl N-[[4-(hydrazinecarbonyl)phenyl]methyl]-N-methyl-carbamate (1 g, 3.580 mmol in DMF (8 mL). To the stirred slurry was added TBTU (1.724 g, 5.370 mmol) and the mixture stirred at ambient for 60 hours. The mixture was diluted with EtO Ac/water and the layers separated. The mixture was extracted with ethyl acetate (x 3) and the combined extracts washed with saturated aqueous aHC03 (x 1) and brine (x 1), dried (MgS04), filtered and concentrated in vacuo. . The resultant residue was purified by column chromatography (ISCO Companion.(TM)., 12g column, 0-100percent EtO Ac/Petroleum ether) and the product containing fractions concentrated in vacuo. The residue was triturated from acetonitrile to give the desired subtitle product as a cream soild (992 mg, 58percent Yield). XH NMR (400.0 MHz, DMSO) delta 1.39 - 1.45 (m, 9H), 2.80 (s, 3H), 4.45 (s, 2H), 7.28 (s, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 7. Hz, 2H), 8.20 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.2 Hz, 1H), 10.50 (s, 1H) and 10.54 (s, 1H) ppm; MS (ES+) 480.2.

Reference： [1]Patent: WO2011/143422,2011,A1 .Location in patent: Page/Page column 46-48

16
[ 452-58-4 ]
[ 52833-94-0 ]
[ 1261222-14-3 ]

Yield	Reaction Conditions	Operation in experiment
		50 mg (0.230 mmol) I) of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> and 27.6 mg (0.253 mmol) of pyridine-2,3-diamine are added to 451.5 mg (5 mmol) of polyphosphoric acid, and the mixture is stirred at 160° C. for 4 days. The reaction mixture is cooled to room temperature, water is added, and the mixture is adjusted to pH 12 by means of 1N NaOH. The precipitate formed is filtered off with suction and dried, giving 5-bromo-3-(1H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-ylamine.

Reference： [1]Patent: US2012/115861,2012,A1 .Location in patent: Page/Page column 47

17
[ 954257-36-4 ]
[ 52833-94-0 ]
[ 1394930-32-5 ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 6h;Cooling with ice;	To an ice-cold solution of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (0.6 mmol) in anhydrous DMF (5 mL), HATU (0.66 mmol), DIPEA (0.72 mmol) and 1-(2,6-dichloro-3-fluorophenyl)ethan-1-amine (0.72 mmol) was added portion-wise. The reaction mixture was warmed to room temperature and stirred at rt for 6 h. After the completion of the reaction, 20 mL of H2O was added and the reaction mixture was extracted with EtOAc for 3 times. The combined organic layer was collected and rinsed with brine. The mixture was evaporated to obtain the crude product and purified by silica gel for 12. Yield: 84%. 1H NMR (500 MHz, CDCl3) d 8.17 (d, J = 2.5 Hz, 1H),7.71 (d, J = 2.5 Hz, 1H), 7.29 (s, 1H), 7.07- 6.97 (m, 2H), 6.33 (s, 2H),6.10-6.00 (m, 1H), 1.67 (d, J = 7.5 Hz, 3H). HRMS (ESI) m/z calcd forC14H12BrCl2FN3O, [M+H]+: 405.9519, Found: 405.9519.
69.5%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	2-Amino-5-bromonicotinic acid (130 mg, 0.60 mmol) was dissolved in 5 mL of DMF. The solution was cooled in an ice bath. Then to the solution were successively added HATU (228 mg, 0.66 mmol), DIPEA (126 muL, 0.72 mmol), 1-(2,6-dichloro-3-fluorophenyl)ethan-1-amine (150 mg, 0.72 mmol). The resulting solution was stirred at room temperature for 2 h and then the saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (EA). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by flash column chromatography (0-20% EA/PE gradient) to afford 170 mg of 8a as a white solid (69.5% yield). 1H NMR (300 MHz, DMSO-d6) delta 9.12 (d, J = 5.4 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.46 (dd, J = 5.1, 8.7 Hz, 1H), 7.36 (t, J = 8.7 Hz, 1H), 7.12 (s, 2H), 5.61-5.54 (m, 1H), 1.56 (d, J = 7.2 Hz, 3H).
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	General procedure: 2-Amino-5-bromonicotinic acid (250 mg, 1.15 mmol) was dissolved in 4 ml of DMF. The solution was cooled in an ice bath. Then to the solution were successively added HATU (460 mg, 1.21 mmol), DIPEA (210.68 mul, 1.21 mmol), (2,3-difluorophenyl)methanamine (173 mg, 1.21 mmol). The resulting solution was stirred at room temperature for 2 h and then the saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (EA). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was used in the next step without purification.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 183
[2]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 6804 - 6820
[3]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

18
[ 72235-51-9 ]
[ 52833-94-0 ]
[ 1394930-52-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	2-Amino-5-bromonicotinic acid (250 mg, 1.15 mmol) was dissolved in 4 ml of DMF. The solution was cooled in an ice bath. Then to the solution were successively added HATU (460 mg, 1.21 mmol), DIPEA (210.68 mul, 1.21 mmol), (2,3-difluorophenyl)methanamine (173 mg, 1.21 mmol). The resulting solution was stirred at room temperature for 2 h and then the saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (EA). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was used in the next step without purification. 1H NMR (400 MHz, DMSO-d6) delta 9.12 (t, J = 5.6 Hz, 1H), 8.16 (s, 2H), 7.38-7.09 (m, 5H), 4.49 (d, J = 5.6 Hz, 2H); MS (ESI, m/z): 341.8 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

19
[ 72235-52-0 ]
[ 52833-94-0 ]
[ 1394930-54-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	General procedure: 2-Amino-5-bromonicotinic acid (250 mg, 1.15 mmol) was dissolved in 4 ml of DMF. The solution was cooled in an ice bath. Then to the solution were successively added HATU (460 mg, 1.21 mmol), DIPEA (210.68 mul, 1.21 mmol), (2,3-difluorophenyl)methanamine (173 mg, 1.21 mmol). The resulting solution was stirred at room temperature for 2 h and then the saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (EA). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was used in the next step without purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

20
[ 85118-06-5 ]
[ 52833-94-0 ]
[ 1394930-55-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	General procedure: 2-Amino-5-bromonicotinic acid (250 mg, 1.15 mmol) was dissolved in 4 ml of DMF. The solution was cooled in an ice bath. Then to the solution were successively added HATU (460 mg, 1.21 mmol), DIPEA (210.68 mul, 1.21 mmol), (2,3-difluorophenyl)methanamine (173 mg, 1.21 mmol). The resulting solution was stirred at room temperature for 2 h and then the saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (EA). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was used in the next step without purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

21
[ 90390-27-5 ]
[ 52833-94-0 ]
[ 1394930-57-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	General procedure: 2-Amino-5-bromonicotinic acid (250 mg, 1.15 mmol) was dissolved in 4 ml of DMF. The solution was cooled in an ice bath. Then to the solution were successively added HATU (460 mg, 1.21 mmol), DIPEA (210.68 mul, 1.21 mmol), (2,3-difluorophenyl)methanamine (173 mg, 1.21 mmol). The resulting solution was stirred at room temperature for 2 h and then the saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (EA). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was used in the next step without purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

22
[ 52833-94-0 ]
[ 72235-53-1 ]
[ 1394930-59-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	General procedure: 2-Amino-5-bromonicotinic acid (250 mg, 1.15 mmol) was dissolved in 4 ml of DMF. The solution was cooled in an ice bath. Then to the solution were successively added HATU (460 mg, 1.21 mmol), DIPEA (210.68 mul, 1.21 mmol), (2,3-difluorophenyl)methanamine (173 mg, 1.21 mmol). The resulting solution was stirred at room temperature for 2 h and then the saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (EA). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was used in the next step without purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

23
[ 15205-15-9 ]
[ 52833-94-0 ]
[ 1394930-61-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	General procedure: 2-Amino-5-bromonicotinic acid (250 mg, 1.15 mmol) was dissolved in 4 ml of DMF. The solution was cooled in an ice bath. Then to the solution were successively added HATU (460 mg, 1.21 mmol), DIPEA (210.68 mul, 1.21 mmol), (2,3-difluorophenyl)methanamine (173 mg, 1.21 mmol). The resulting solution was stirred at room temperature for 2 h and then the saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (EA). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was used in the next step without purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

24
[ 261762-46-3 ]
[ 52833-94-0 ]
[ 1394930-63-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	General procedure: 2-Amino-5-bromonicotinic acid (250 mg, 1.15 mmol) was dissolved in 4 ml of DMF. The solution was cooled in an ice bath. Then to the solution were successively added HATU (460 mg, 1.21 mmol), DIPEA (210.68 mul, 1.21 mmol), (2,3-difluorophenyl)methanamine (173 mg, 1.21 mmol). The resulting solution was stirred at room temperature for 2 h and then the saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (EA). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was used in the next step without purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

25
[ 261762-45-2 ]
[ 52833-94-0 ]
[ 1394930-65-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	General procedure: 2-Amino-5-bromonicotinic acid (250 mg, 1.15 mmol) was dissolved in 4 ml of DMF. The solution was cooled in an ice bath. Then to the solution were successively added HATU (460 mg, 1.21 mmol), DIPEA (210.68 mul, 1.21 mmol), (2,3-difluorophenyl)methanamine (173 mg, 1.21 mmol). The resulting solution was stirred at room temperature for 2 h and then the saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (EA). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was used in the next step without purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

26
[ 886501-27-5 ]
[ 52833-94-0 ]
[ 1394930-67-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	General procedure: 2-Amino-5-bromonicotinic acid (250 mg, 1.15 mmol) was dissolved in 4 ml of DMF. The solution was cooled in an ice bath. Then to the solution were successively added HATU (460 mg, 1.21 mmol), DIPEA (210.68 mul, 1.21 mmol), (2,3-difluorophenyl)methanamine (173 mg, 1.21 mmol). The resulting solution was stirred at room temperature for 2 h and then the saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (EA). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was used in the next step without purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

27
[ 52833-94-0 ]
[ 77287-34-4 ]
[ 155690-79-2 ]

Yield	Reaction Conditions	Operation in experiment
36%	at 150℃; for 0.5h;Microwave irradiation;	To a vial was charged with 2-amino-5-bromonicotinic acid 8 (1 g, 4.61 mmol) and 1.1 ml of formamide. The vial was capped and heated at 150 C for 30 min under microwave irradiation. To the reaction mixture was added water. The precipitate was filtered off and recrystallized from water to afford brown solid in 36% yield. 1H NMR (300 MHz, DMSO-d6) delta 12.72 (s, 1H), 9.03 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.35 (s, 1H); MS (ESI, m/z): 225.8 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 1713 - 1726
[2]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

28
[ 52833-94-0 ]
C₆H₄BrClN₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20 - 55℃; for 2h;	2-Amino-5-bromonicotinic acid 8 (100 mg, 0.46 mmol) was susppended in 4 ml of CH2Cl2. To this susppension was added one drop DMF and then oxalyl dichloride (47 mul, 0.55 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h and heated at 55 0C for 1 h. Removal of the solvent under under vacuum afforded a white solid. The white solid was then added to an ice-cooled solution of Et3N (78 mul, 0.55 mmol) and (1R)-1-(2,6-dichloro-3-fluorophenyl)ethan-1-amine (105 mg, 0.50 mmol) in 4 ml of CH2Cl2. The resulting medium was stirred overnight and diluted with water. The mixture was extracted with CH2Cl2. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude was dissolved in 3 ml of 3M HCl and heated at 80 0C for 3 h. Then the reaction solution was cooled to room temperature and neutralized with saturated Na2CO3. The mixture was extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (EA/PE, 1/4) to afford compound 33 in 40% yield . ee > 98%; 1H NMR (400 MHz, CDCl3) delta 8.16 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.29-7.26 (m, 1H), 7.13 (d, J = 6.0 Hz, 1H), 7.07-7.00 (m, 1H), 6.34 (s, 2H), 6.07-5.99 (m, 1H), 1.65 (d, J = 7.2 Hz, 3H).
	With thionyl chloride; In toluene; at 130℃; for 2h;	A mixture of 2-Amino-5-bromo-nicotinic acid (1 g, 4.61 mmol) and SOd2 (5 mL) in toluene (15 mE) was stirred at 130C for 2 h. After concentrated, the residue was dissolved in tetrahydrofuran (20 mE), and then 2-fluoro-phenylamine (1.09 g, 9.81 mmol) was added dropwise at 0C. The reaction mixture was heated to 90C for 4 h. After being cooled to room temperature andquenched with saturated aqueous K2C03 (10 mE), the mixture was extracted with ethyl acetate (50 mE * 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with silica gel column chromatograph (PE : EtOAc = 2: 1) to give 2-amino-5-bromo-N-(2-fluorophenyl) nicotinamide (1.0 g, 70 % yield). as yellow solid. ?H-NMR (CDC13, 400 MHz) 8.258.28 (m, 2H), 7.86 (d, J 2.4 Hz, 2H), 7.137.22 (m, 3H), 6.36 (s, 2H). MS (M+H): 311 /313.
	With thionyl chloride; In toluene; at 110℃; for 2h;	Compound 9b (2.16 g, 10 mmol) and thionyl chloride (10 mL) were placed in 30 mL of toluene, and reacted at 110 °C for 2 h, then The reaction mixture was concentrated under reduced pressure, and then the remaining solid compound was dissolved in THF (40 mL), 2-chloro-6-methylaniline (3.186 g, 22.6 mmol) was slowly added in an ice bath, and the reaction was held at 90 °C for 6 h. After cooling to room temperature, 20 mL of a saturated aqueous solution of potassium carbonate was added, and then the mixture was extracted with EtOAc. Then, it was extracted with EA three times, and the EA layer was combined, washed with brine, dried over anhydrous sodium sulfate and filtered. The crude material was separated and purified by silica gel column chromatography (PE/EA = 8:1) and then recrystallized to afford the compound 10b. White solid (1.36 g), yield: 40.0percent, m.p.: 248.3?249.7 oC. 1H NMR (400 MHz, DMSO-d6): delta (ppm) 10.09 (s, 1H), 8.36 (s, 1H), 8.25 (d, J = 2.1 Hz, 1H), 7.40 (dd, J = 7.3, 1.9 Hz, 1H), 7.32 ? 7.23 (m, 4H), 2.23 (s, 3H). 13C NMR (101 MHz, DMSO-d6): delta (ppm) 165.8, 158.3, 152.6, 139.2, 139.1, 133.9, 132.7, 129.5, 128.7, 127.5, 110.4, 104.4, 18.7. MS (ESI+) m/z: 341.9755.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180
[2]Patent: WO2014/205593,2014,A1 .Location in patent: Page/Page column 64; 65
[3]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 1928 - 1933

29
[ 1394930-90-5 ]
[ 52833-94-0 ]
[ 1394930-93-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	General procedure: 2-Amino-5-bromonicotinic acid (250 mg, 1.15 mmol) was dissolved in 4 ml of DMF. The solution was cooled in an ice bath. Then to the solution were successively added HATU (460 mg, 1.21 mmol), DIPEA (210.68 mul, 1.21 mmol), (2,3-difluorophenyl)methanamine (173 mg, 1.21 mmol). The resulting solution was stirred at room temperature for 2 h and then the saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (EA). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was used in the next step without purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

30
[ 1394930-91-6 ]
[ 52833-94-0 ]
[ 1394930-94-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	General procedure: 2-Amino-5-bromonicotinic acid (250 mg, 1.15 mmol) was dissolved in 4 ml of DMF. The solution was cooled in an ice bath. Then to the solution were successively added HATU (460 mg, 1.21 mmol), DIPEA (210.68 mul, 1.21 mmol), (2,3-difluorophenyl)methanamine (173 mg, 1.21 mmol). The resulting solution was stirred at room temperature for 2 h and then the saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (EA). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was used in the next step without purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

31
[ 1394930-92-7 ]
[ 52833-94-0 ]
[ 1394930-95-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	General procedure: 2-Amino-5-bromonicotinic acid (250 mg, 1.15 mmol) was dissolved in 4 ml of DMF. The solution was cooled in an ice bath. Then to the solution were successively added HATU (460 mg, 1.21 mmol), DIPEA (210.68 mul, 1.21 mmol), (2,3-difluorophenyl)methanamine (173 mg, 1.21 mmol). The resulting solution was stirred at room temperature for 2 h and then the saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (EA). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was used in the next step without purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

32
[ 956907-34-9 ]
[ 52833-94-0 ]
[ 1414951-84-0 ]

Yield	Reaction Conditions	Operation in experiment
		.1 2-Amino-5-{1 -[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1 H-pyrazol-4-yl}-nicotinic acid:1 .5 g 1 -[2-(tetrahydropyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxa- borolan-2-yl)-1 H-pyrazol and 808 mg <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> are disolved in 10 ml of DMF. 3.3 g of potassium carbonate are added to the solution. The mixure is heated to 80 °C. 395 mg of 1 ,1 '-bis(diphenylphosphino)ferrocenedichloropalla- dium(l l), dichlormethane adduct are added and the mixture is heated for 2h. The solution is evaporated and the crude product is purified by silica gel chromatography using ethyl acetate/MeOH 9:1 ; 496 mg of 2-Amino-5-{1 -[2- (tetrahydro-pyran-2-yloxy)-ethyl]-1 H-pyrazol-4-yl}-nicotinic acid as a brown oil; HPLC/MS: 1 .27 min, [M+H] = 333.

Reference： [1]Patent: WO2012/161877,2012,A1 .Location in patent: Page/Page column 72-73

33
[ 52833-94-0 ]
5-bromo-2-aminonicotinic acid 1-oxide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 9482 - 9495

34
[ 97-97-2 ]
[ 52833-94-0 ]
[ 903129-78-2 ]

Yield	Reaction Conditions	Operation in experiment
86%		To a stirred solution of 2-amino-5-bromonicotinic acid (5.0 g, 23.04 mmol) and sodium acetate (3.78 g, 46.1 mmol) in 100 ml_ of 60 % ethanol in water, were added a refluxed solution of sodium acetate (3.78 g, 46.1 mmol) followed by 2-chloro-1 ,1 - dimethoxyethane (5.74 g, 46.1 mmol) in concentrated hydrochloric acid (1 .0 ml_) in water (6 ml_) and the reaction mass was refluxed for 2.5 h. The solvent was removed, residue obtained was diluted with cold water and pH adjusted to neutral (~7) with saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate (2x100 ml_), washed with water (2x100 ml_) and brine (2x100 ml_) and dried over anhydrous sodium sulphate. The crude material obtained was purified by trituration using 2 % ethyl acetate in petroleum ether. Yield: 4.8 g (86 %); 1 H NMR (DMSO-d6, 300 MHz): delta 7.66 (d, 1 H, J=1 .2 Hz, Ar), 7.79 (d, 1 H, J=1 .5 Hz, Ar), 8.04 (s, 1 H, Ar), 8.96 (d, 1 H, J=1 .5 Hz, Ar); MS (ES+): m/e 242 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 41

35
[ 52833-94-0 ]
[ 3619-17-8 ]
[ 1617499-08-7 ]

Yield	Reaction Conditions	Operation in experiment
50%	With trichlorophosphate; at 100℃; for 18h;	5-Bromo-3-(5-isopropyl-[l,3,4]oxadiazol-2-yl)-pyridin-2-ylamine: To a solution of 2-amino-5-bromo-nicotinic acid (1.0 g, 4.60 mmol) in POCl3 (20 mL) was added isobutyric acid hydrazide (705 mg, 6.912 mmol) at RT. The reaction temperature was slowly heated to 100° C and stirred for 18 h. The solvent was evaporated under reduced pressure, the residue was basified with saturated cold sodium bicarbonate solution (50 mL), extracted with ethyl acetate (3 X 50 mL), organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel. The column was eluted with 40percent EtOAc in petroleum ether to afford the title compound as a yellow solid. Yield: 650 mg (50percent) 1HNMR (DMSO-dg, 400 MHz, TMS) delta: 8.28-8.27 (IH, d), 8.18-8.17 (IH, d), 7.45 (2H, br, s), 3.32-3.24 (IH, m), 1.38-1.37 (6H, d)

Reference： [1]Patent: WO2014/106612,2014,A1 .Location in patent: Page/Page column 23-24
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4500 - 4505

36
[ 52833-94-0 ]
[ 187834-88-4 ]
[ 1617499-10-1 ]

Yield	Reaction Conditions	Operation in experiment
53.19%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;	4-[N'-(2-Amino-5-bromo-pyridine-3-carbonyl)-hydrazinocarbonyl]-piperidine-^ acid tert-butyl ester: To a solution of 2-amino-5-bromo-nicotinic acid (1.2 g, 5.53 mmol) in DMF (30 mL) were added 4-hydrazinocarbonyl-piperidine-l-carboxylic acid tert-butyl ester (1.5 g, 6.173 mmol), HATU (2.35 g, 6.184 mmol) and DIPEA (4 mL, 23.56 mmol) at RT. The reaction mixture was stirred for 18 h at RT. The reaction mixture was poured into ice-water (30 mL), extracted with ethyl acetate (3 X 50 mL), organic layer was washed with brine dried over anhydrous sodium sulphate concentrated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel. The column was eluted with 60% EtOAc in petroleum ether to afford the title compound as an off- white solid. Yield: 1.3 g (53.19%) FontWeight="Bold" FontSize="10" HNMR (DMSO-de, 400 MHz, TMS) delta: 10.32 (1H, s), 9.92 (1H, s), 8.20 (1H, s), 8.12-8.11 (1H, d), 7.2 (2H, s), 3.96-3.94 (2H, m), 2.77-2.69 (2H, m), 2.50-2.41 (1H, m), 1.73-1.70 (2H, m), 1.49-1.44 (2H, m), 1.40 (9H, s).

Reference： [1]Patent: WO2014/106612,2014,A1 .Location in patent: Page/Page column 24-25

37
[ 6952-93-8 ]
[ 52833-94-0 ]
[ 1617499-07-6 ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate; at 65℃; for 18h;	5-Bromo-3-(5-cyclopropyl- [ 1 ,3 ,4] oxadiazol-2-yl)-pyridin-2-ylamine: A solution of 2-amino-5-bromo-nicotinic acid (300 mg, 1.38 mmol) and cyclopropanecarboxylic acid hydrazide (300 mg, 3.0 mmol) in POCI3 (30.0 mL,) was stirred for 18 h at 65 °C. The reaction mixture was distilled under reduced pressure to obtain a residue, which was cooled to 0 °C by adding iced water and neutralizing with saturated NaHC03 solution (100 mL). The aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was separated, dried over anhydrous Na2S04 and evaporated to afford 370 mg of crude 5- bromo-3-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)-pyridin-2-ylamine. Crude compound was purified by column chromatography using silica gel (100-200 mesh). The column was eluted with 15 percent EtOAc in petroleum ether to afford the title compound as a pale yellow solid used without further purification. Yield: 300 mg (Yield: 81 percent)

Reference： [1]Patent: WO2014/106612,2014,A1 .Location in patent: Page/Page column 23
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4500 - 4505

38
[ 52833-94-0 ]
[ 58483-98-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 25.0℃;	A mixture of 2-amino-5-bromonicotinic acid (2.0 g, 9.20 mmol), HOBT (1.40 g, 11.2 mmol), EDCI (3.52 g, 18.4 mmol), Et3N (4.68 g, 46.0 mmol) and NH4C1 (2.48 g, 46.0 mmol) in DMF (100 mL) was stirred overnight at room temperature. The reaction mixture was concentratedin vacuo, suspended in water and extracted with CH2C12. The organic layer was washed with brine,dried over Na2504 and concentrated to give the product of 2-amino-5-bromonicotinamide (1.80 g,yield: 80%), which was used for the next step without further purification. ?H NMR (DMSO-d6,400 MHz) 8.14 (dd, J= 4.4 Hz, 2.4 Hz, 2H), 8.04 (s, 1H), 7.46 (s, 1H), 7.37 (s, 2H). MS (M+H):216/218.
	With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20.0℃;	A mixture of 2-amino-5-bromonicotinic acid (2.0 g, 9.20 mmol), HOBT (1.40 g, 11.2 mmol), EDCI (3.52 g, 18.4 mmol), Et3N (4.68 g, 46.0 mmol) and NH4C1 (2.48 g, 46.0 mmol) in DMF (100 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, suspended in water and extracted with CH2C12. The organic layer was washed with brine, dried over Na2S04 and concentrated to give the product of 2-amino-5- bromonicotinamide (1.80 g, yield: 80%), which was used for the next step without further purification. NMR (DMSO-i, 400 MHz) delta 8.14 (dd, J= 4.4 Hz, 2.4 Hz, 2H), 8.04 (s, 1H), 7.46 (s, 1H), 7.37 (s, 2H). MS (M+H)+: 216 / 218.

Reference： [1]Patent: WO2014/205593,2014,A1 .Location in patent: Page/Page column 55
[2]Patent: WO2014/209727,2014,A1 .Location in patent: Page/Page column 52-53

39
[ 348-54-9 ]
[ 52833-94-0 ]
2-amino-5-bromo-N-(2-fluorophenyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		A mixture of 2-Amino-5-bromo-nicotinic acid (1 g, 4.61 mmol) and SOCI2 (5 mL) in toluene (15 mL) was stirred at 130°C for 2 h. After concentrated, the residue was dissolved in tetrahydrofuran (20 mL), and then 2-fluoro-phenylamine (1.09 g, 9.81 mmol) was added dropwise at 0°C. The reaction mixture was heated to 90°C for 4 h. After being cooled to room temperature and quenched with saturated aqueous K2CO3 (10 mL), the mixture was extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with silica gel column chromatograph (PE : EtOAc = 2 : 1) to give 2-amino-5-bromo-N-(2- fluorophenyl) nicotinamide (1.0 g, 70 percent yield) as yellow solid. XH-NMR (CDC13, 400 MHz) delta 8.25-8.28 (m, 2H), 7.86 (d, J= 2.4 Hz, 2H), 7.13-7.22 (m, 3H), 6.36 (s, 2H). MS (M+H)+: 31 1 / 313.

Reference： [1]Patent: WO2014/209727,2014,A1 .Location in patent: Page/Page column 61

40
[ 52833-94-0 ]
[ 140-75-0 ]
2-amino-5-bromo-N-(4-fluorobenzyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; at 0℃; for 0.333333h;Inert atmosphere;	To a degassed solution of (4-fluorophenyl)methanamine (500 mg, 4.0 mmol), 2- amino-5-bromonicotinic acid (867 mg, 4.0 mmol) and Ets (1.21 g, 12.0 mmol) in dry DCM (10 mL) was added T3P (2.54 g, 8.0 mmol) at 0°C under 2 protection. The mixture was stirred at 0°C for 20 minutes. The mixture was diluted with water, and then it was extracted with EtOAc, dried over Na2S04, filtrated and concentrated to give the crude product of 2-amino-5-bromo-N- (4-fluorobenzyl)nicotinamide (1.05 g, yield: 81percent). XH-NMR (CDC13, 400 MHz) delta 8.18 (s, 1H), 7.64 (d, J= 2.0 Hz, 1H), 7.31 (t, J= 8.0 Hz, 2H), 7.05 (d, J= 8.8 Hz, 2H), 6.38 (d, J= 4.0 Hz, 2H), 6.17 (d, J= 5.2 Hz, 1H), 5.12 (d, J= 6.4 Hz, 2H). MS (M+H)+: 324 / 326.
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; at 0℃; for 0.333333h;Inert atmosphere;	To a degassed solution of (4-fluorophenyl)methanamine (500 mg, 4.0 mmol), <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (867 mg, 4.0 mmol) and Et3N (1.21 g, 12.0 mmol) in dry DCM (10mL) was added T3P (2.54 g, 8.0 mmol) at 0°C under N2 protection. The mixture was stirred at 0°Cfor 20 minutes. The mixture was diluted with water, and then it was extracted with EtOAc, driedover Na2SO4, filtrated and concentrated to give the crude product of 2-amino-5-bromo-N-(4-fluorobenzyl)nicotinamide (1.05 g, yield: 8 1percent). ?H-NMR (CDC13, 400 MHz) oe 8.18 (s, 1H), 7.64 (d, J= 2.0 Hz, 1H), 7.31 (t, J= 8.0 Hz, 2H), 7.05 (d, J= 8.8 Hz, 2H), 6.38 (d, J= 4.0 Hz, 2H), 6.17 (d, J= 5.2 Hz, 1H), 5.12 (d, J= 6.4 Hz, 2H). MS (M+H): 324 / 326.

Reference： [1]Patent: WO2014/209727,2014,A1 .Location in patent: Page/Page column 57-58
[2]Patent: WO2014/205593,2014,A1 .Location in patent: Page/Page column 60; 61

41
[ 52833-94-0 ]
[ 93103-00-5 ]
2-amino-5-bromo-N-(2-oxo-2-(pyridin-3-yl)ethyl)pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃;	C. To a suspension of <strong>[52833-94-0]2-amino-5-bromopyridine-3-carboxylic acid</strong> (0.566 g, 2.60 mmol) and 2-amino-l-(pyridin-3-yl)ethanone hydrochloride (0.500 g, 2.90 mmol) in 40 mL of dichloromethane was added HATU (1.97 g, 5.20 mmol), followed by the addition of N,N-diisopropylethylamine (1.00 mL, 5.80 mmol). The mixture was stirred at room temperature overnight to yield white precipitates. After filtration, the white precipitates were washed with water to afford 2-amino-5-bromo-N- (2-oxo-2-(pyridin-3-yl)ethyl)pyridine-3-carboxamide as a white solid in 69percent> yield (0.60 g). 1H NMR (400 MHz, DMSO-d6): 5 9.17-9.14 (m, 1H), 9.00 (t, J = 5.6 Hz, 1H), 8.82-8.78 (m, 1H), 8.35-8.28 (m, 1H), 8.18-8.13 (m, 2H), 7.60-7.53 (m, 1H), 7.21 (br s, 2H), 4.74 (d, J = 5.6 Hz, 2H).

Reference： [1]Patent: WO2015/81257,2015,A2 .Location in patent: Page/Page column 64-65

42
[ 5468-37-1 ]
[ 52833-94-0 ]
2-amino-5-bromo-N-(2-oxo-2-phenylethyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h;	PREPARATION 2 PREPARATION OF 2-AMiNO-5-BROMO-N-(2-oxo-2-PHENYLETHYL)NicoTiNAMiDE To a suspension of <strong>[52833-94-0]2-amino-5-bromopyridine-3-carboxylic acid</strong> (0.43 g, 2.00 mmol) and 2-amino-l-phenylethanone hydrochloride (0.51 g, 3.00 mmol) in 40 mL of dichloromethane was added l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (1.19 g, 6.00 mmol). The mixture was stirred at ambient temperature for 3 hours. After removal of the solvent in vacuo, the residue was purified by column chromatography eluted with 1 : 1 ethyl acetate :hexane to afford 2-amino-5-bromo-N-(2-oxo-2- phenylethyl)nicotinamide as a yellow solid in 72percent yield (0.48 g). 1H NMR (400 MHz, CDCI3): delta 8.21 (d, J= 2.0 Hz, 1H), 8.13-8.02 (m, 2H), 8.03 (d, J= 2.0 Hz, 1H), 7.70- 7.65 (m, 1H), 7.58-7.52 (m, 2H), 7.24 (t, J= 4.4 Hz, 1H), 6.57 (br s, 2H), 4.91 (d, J = 4.4 Hz, 2H).

Reference： [1]Patent: WO2015/81257,2015,A2 .Location in patent: Page/Page column 59

43
[ 51084-83-4 ]
[ 52833-94-0 ]
5-bromo-3-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	PREPARATION 4 PREPARATION OF 5 -BROMO-3 ZOL-2-YL)PYRIDIN-2-AMINE To a suspension of <strong>[52833-94-0]2-amino-5-bromopyridine-3-carboxylic acid</strong> (1.75 g, 8.09 mmol) and 2-amino-l-(3-chlorophenyl)ethanone hydrochloride (2.50 g, 12.1 mmol) in 100 mL of dichloromethane was added l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (3.19 g, 16.2 mmol). The mixture was stirred at ambient temperature overnight to yield yellow precipitates. After filtration, the yellow precipitates were washed with dichloromethane to afford a yellow solid which was mixed with 10 mL of concentrated sulfuric acid and was stirred at ambient temperature for 20 hours. The reaction mixture was mixed with 40 mL of ice cold water and neutralized with ammonia solution to yield yellow precipitates. After suction filtration, the yellow precipitates were washed with water to afford 5 -bromo-3 -(5 -(3- chlorophenyl)oxazol-2-yl)pyridin-2-amine as an orange solid in 77percent (2.00 g). 1H NMR (400 MHz, CDCI3): delta 8.27 (d, J = 2.4 Hz, 1H), 8.19 (d, J= 2.4 Hz, 1H), 7.71 (s, 1H), 7.65-7.57 (m, 1H), 7.55-7.45 (m, 1H), 7.45-7.33 (m, 2H), 6.78 (br s, 2H).

Reference： [1]Patent: WO2015/81257,2015,A2 .Location in patent: Page/Page column 61

44
[ 52833-94-0 ]
[ 613-92-3 ]
N'-((2-amino-5-bromonicotinoyl)oxy)benzimidamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	PREPARATION 14 PREPARATION OF N'-((2- YL)oxY)BENziMiD AMIDE To a mixture of N'-hydroxybenzamidine (0.50 g, 3.68 mmol) and 2- amino-5-bromopyridine-3-carboxylic acid (0.83 g, 4.05 mmol) in 30 mL of dichloromethane was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.45 g, 7.36 mmol). The resulting mixture was stirred at ambient temperature overnight. After removal of solvent in vacuo, the residue was purified by column chromatography eluted with 5percent methanol in dichloromethane to afford a yellow oil which was treated with dichloromethane and ethyl ether to afford N'-((2-amino-5-bromonicotinoyl)oxy)- benzimidamide as a yellow solid in 32percent yield (0.25 g). 1H NMR (400 MHz, DMSO- d6): £8.61 (d, J= 2.4 Hz, 1H), 8.25 (d, J= 2.4 Hz, 1H), 7.74-7.70 (m, 2H), 7.52-7.42 (m, 3H), 7.34 (br s, 2H), 7.04 (br s, 2H).

Reference： [1]Patent: WO2015/81257,2015,A2 .Location in patent: Page/Page column 77

45
bicyclo[1.1.1]pentan-1-amine hydrochloride [ No CAS ]
[ 52833-94-0 ]
2-amino-N-(bicyclo[1.1.1]pentan-1-yl)-5-bromonicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%		[00361] To <strong>[52833-94-0]2-amino-5-bromonicotinicacid</strong> (2.OOg, 9.22 mmol) in DCM (87 mL) were added DIEA (4.5 mL, 2Smmol) and TBTU (4.4 g, 13.8 mmol). The reaction mixture was allowed to stir at ii for 20 mm. To the reaction mixture was added bicyclo[1. 1. 1]pent-1-amine hydrochloride salt (0.73 g, 6.14 mmol). The reaction mixture was allowed to stir overnight at ii and was then diluted with water and DCM. The organic solution was separated, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography to give 2-amino-N- (bicyclo[1.1.1]pent-1-yl)-5-bromonicotinamide (0.67 g, 39percent) as a white solid. LCMS (FA): m/z 282.0 (M+H).

Reference： [1]Patent: WO2015/108861,2015,A1 .Location in patent: Paragraph 00361

46
[ 22287-35-0 ]
[ 52833-94-0 ]
2-amino-N-(bicyclo[1.1.1]pentan-1-yl)-5-bromonicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%		Step 1: 2-Amino-N-(bicyclo[1.1.1]pentan-1-yl)-5-bromonicotinamide To 2-amino-5-bromonicotinicacid (2.00 g, 9.22 mmol) in DCM (87 mL) were added DIEA (4.5 mL, 25 mmol) and TBTU (4.4 g, 13.8 mmol). The reaction mixture was allowed to stir at rt for 20 min. To the reaction mixture was added bicyclo[1.1.1]pent-1-amine hydrochloride salt (0.73 g, 6.14 mmol). The reaction mixture was allowed to stir overnight at rt and was then diluted with water and DCM. The organic solution was separated, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography to give 2-amino-N-(bicyclo[1.1.1]pent-1-yl)-5-bromonicotinamide (0.67 g, 39%) as a white solid. LCMS (FA): m/z=282.0 (M+H).

Reference： [1]Patent: US2015/225422,2015,A1 .Location in patent: Paragraph 0501-0502

47
[ 52833-94-0 ]
[ 1215787-31-7 ]

Reference： [1]Patent: WO2015/157093,2015,A1
[2]European Journal of Medicinal Chemistry,2016,vol. 118,p. 276 - 289
[3]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 1713 - 1726

48
[ 3473-63-0 ]
[ 52833-94-0 ]
[ 155690-79-2 ]

Yield	Reaction Conditions	Operation in experiment
1.7 g	In 2-methoxy-ethanol; at 120℃; for 36.0h;Inert atmosphere;	2-Amino-S -bromonictoinic acid (2 g) and formamidine acetate (3.0 g) were heated at 120 C in2-methoxyethanol (15 ml) for 36 h under argon. The heterogeneous reaction mixture was diluted with water and filtered. The solid was suction dried to obtain 1.7 g of 6-bromopyrido[2,3- d]pyrimidin-4(3H)-one. ?H NMR (300 MHz, DMSO-d6) oe 12.70 (s, 1H), 9.01 (d, J= 2.6 Hz, 1H), 8.59 (d, J= 2.6 Hz, 1H), 8.33 (s, 1H).

Reference： [1]Patent: WO2015/157093,2015,A1 .Location in patent: Paragraph 1314; 1315

49
(Z)-2,2-difluoro-N'-hydroxyacetimidamide [ No CAS ]
[ 52833-94-0 ]
5-bromo-3-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: 5-Bromo-3-(3-(difluoromethyl)-1 ,2,4-oxadiazol-5-yl)pyridin-2-amine To a stirring suspension of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (500 mg, 2.304 mmol) in DCM (11.5 ml) was added 1-chloro-N,N,2-trimethyl-1-propenylamine (Ghosez's reagent) (0.366 ml, 2.76 mmol). The reaction mixture was left stirring for 1.5 hrs. 2,2-Difluoro-N'- hydroxyacetimidamide (step 1) (507 mg, 4.61 mmol) was added followed by DIPEA (0.805 ml, 4.61 mmol) and the mixture was stirred overnight. T3P® (4.04 ml, 6.91 mmol) was added and the mixture was heated using microwave radiation for 135 mins at 100°C. The mixture was added to water (100ml) and the product extracted into EtOAc (2 x 90ml). The organic phase was washed with brine, dried over MgS04 and concentrated to dryness. The crude product was purified by flash column chromatography, eluting with 0-10percent gradient of (2M NH3 in MeOH) in DCM on a 24g Si-column to afford the title compound; LCMS: Rt = 1.11 mins; MS m/z 291.4 [M+H]+; Method 2minl_owpHv01 1H NMR (400 MHz, DMSO-d6) delta 8.43 (1 H, d), 8.39 (1 H, d), 7.55 (2H, br s), 7.47 (1 H, t).

Reference： [1]Patent: WO2015/162456,2015,A1 .Location in patent: Page/Page column 250-251

50
[ 1016726-53-6 ]
[ 52833-94-0 ]
5-bromo-3-(3-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-5-yl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: 5-Bromo-3-(3-(2,2,2-trifluoroethyl)-1 ,2,4-oxadiazol-5-vl)pyridin-2-amine To a stirring suspension of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (2.3 g, 10.60 mmol) in DCM (53.0 ml), 1-chloro-N,N,2-trimethyl-1-propenylamine (Ghosez's reagent) (1.683 ml, 12.72 mmol) was added. The reaction mixture was left stirring for 1.5 hours. 3,3,3-trifluoro-N'- hydroxypropanimidamide (step 1) (1.656 g, 11.66 mmol) was then added followed by DIPEA (3.70 ml, 21.20 mmol). The reaction mixture was stirred overnight. T3P® (18.56 ml, 31.8 mmol) was added to the mixture and this was microwaved for 3 hours at 100°C. The mixture was added to water (100ml) and product extracted into EtOAc (2 x 90ml). The organic extracts were washed with brine, dried over MgS04 and the filtrate was concentrated under reduced pressure. The crude product was purified by adding MeOH (~10ml). The mixture was sonicated and the resulting solid collected by filtration, washed with MeOH and dried to afford the title compound; LCMS: Rt = 1.17 mins; MS m/z 325.0 [M+H]+; Method 2minLowpHv01 1H NMR (400 MHz, DMSO-d6) delta 8.40 (1 H, d), 8.35 (1 H, d), 7.59 (2H, br s), 4.21 (2H, q).

Reference： [1]Patent: WO2015/162456,2015,A1 .Location in patent: Page/Page column 260-261

51
[ 52833-94-0 ]
[ 118493-85-9 ]
5-bromo-3-[1,2,4]oxadiazol-5-yl-pyridin-2-ylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
500 mg	With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; at 20℃;Inert atmosphere;	General procedure: Intermediate C3 (2891) 5-Bromo-3-[1,2,4]oxadiazol-5-yl-pyridin-2-ylamine (2892) (2893) To a stirring solution of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (1 g, 4.61 mmol) in THF (24 ml_), under N2, was added acetamide oxime (0.410 g, 5.53 mmol) & DIPEA (1.610 ml_, 9.22 mmol) followed by HATU. Reaction was stirred for 24 hours at RT. A further 0.5 Eq of HATU was added and reaction continued overnight. The reaction mixture was added to water (100ml) and product extracted into EtOAc (2 x 100ml). The organic phases were combined, washed with, brine, dried over MgS04, and concentrated to dryness. The residue was added to toluene (50ml) and heated to 90°C overnight. The reaction mixture was concentrated and added to water (100ml). The product was extracted into EtOAc (2 x 100ml). The organic phases were combined, washed with brine, dried over MgS04, and concentrated to dryness. The crude product was purified by flash column chromatography, eluting with a modified 0- 10percent gradient (2M NH3 in MeOH) in DCM on a 40g si-column, loading via dry loading to give 500mg of pale yellow solid; (2894) LCMS : Rt 0.97 mins; MS m/z 256.6 [M+H]+; Method 2minl_owpH (2895)

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4500 - 4505
[2]Patent: WO2015/162456,2015,A1 .Location in patent: Page/Page column 317

52
[ 52833-94-0 ]
[ 2450-71-7 ]
2-amino-5-bromo-N-(prop-2-yn-1-yl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; at 50℃; for 24h;Inert atmosphere;	Intermediate C9 5-Bromo-3-(5-methyloxazol-2-yl)pyridin-2-amineStep 1 : 2-Amino-5-bromo-N-(prop-2-yn-1-yl)nicotinamide To a stirring solution of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (1 g, 4.61 mmol) in THF (23.0 ml), under N2 was added HATU (3.15 g, 8.29 mmol) and DIPEA (1.610 ml, 9.22 mmol) followed by prop-2-yn-1 -amine (0.354 ml, 5.53 mmol). The reaction mixture was stirred at 50°C for 24 hours. The resulting mixture was added to water (100 ml) and the product was extracted into EtOAc (100 ml). The organic portion was washed with brine, dried over MgS04 and concentrated to dryness. To the crude residue was added DCM (~15 ml) and the mixture was sonicated. The resulting solid was filtered, washed with DCM and dried to afford the title compound;LCMS: Rt 0.75 mins; MS m/z 256.3[M+H]+; Method 2minl_owpH

Reference： [1]Patent: WO2015/162456,2015,A1 .Location in patent: Page/Page column 321

53
[ 52833-94-0 ]
[ 1068-57-1 ]
N'-acetyl-2-amino-5-bromonicotinohydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In d7-N,N-dimethylformamide; at 20℃; for 72h;Inert atmosphere;	Step 1 : N'-acetyl-2-amino-5-bromonicotinohydrazide To a mixture of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (2 g, 9.22 mmol), acetohydrazide (0.819 g, 11.06 mmol) and TEA (5.14 ml, 36.9 mmol) in DMF (60 ml) under N2 was added T3P (50percent in DMF) (8.23 ml, 27.6 mmol) over 5 mins and the reaction left stirring at room temperature for 3 days. The resulting mixture was added to 1 M HCI (10ml) and extracted into EtOAc, washed with 1M NaOH (10ml), brine and dried over magnesium sulfate before being concentrated under reduced pressure. The acidic washings were neutralised by addition of NaOH and extracted again into EtOAc, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Used without further purification. LCMS: Rt = 0.38mins MS m/z [M+H]+ = 273.3 (smaller Br isotope reported) Method: 2minl_owpHv01

Reference： [1]Patent: WO2015/162456,2015,A1 .Location in patent: Page/Page column 291

54
[ 52833-94-0 ]
[ 1068-57-1 ]
5-bromo-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate; at 100℃; for 1h;Inert atmosphere;	Intermediate C14 5-Bromo-3-(5-methyl-1 ,3,4-oxadiazol-2-yl)pyridin-2-amineA stirred mixture of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (200 mg, 0.922 mmol) in POCI3 (2 ml) was treated with acetohydrazide (68.3 mg, 0.922 mmol) and stirred under N2 at 100°C for 1 hour. The resulting mixture was added dropwise to crushed ice over 10 minutes and left for 5 minutes. The mixture was neutralized by addition of 2M NaOH and extracted with DCM (3x30 ml). The combined organic extracts were dried over MgS04, filtered and concentrated under reduced pressure. Purification of the crude residue by chromatography on silica eluting with 0-100percent EtOAc in iso-hexane afforded the title compound as a white solid;LCMS: Rt = 0.88 mins MS m/z 255.3 [M+H]+; Method 2minLowpHv01.

Reference： [1]Patent: WO2015/162456,2015,A1 .Location in patent: Page/Page column 325
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4500 - 4505

55
[ 7570-49-2 ]
[ 52833-94-0 ]
2-amino-5-bromo-N-(2-methyl-1H-indol-5-yl)nicotinamide [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 182 - 187

56
[ 3878-55-5 ]
[ 52833-94-0 ]
5-bromo-2-(3-(3-methoxy-3-oxopropyl)ureido)nicotinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39.3%		To a solution of 4-methoxy-4-oxobutanoic acid (14.6 g, 1 10.6 mmol) in toluene (530 mL) was added diphenylphosphoryl azide (30.4 g, 110.5 mmol) followed by triethylamine (18.3 g, 181.2 mmol). The reaction was stirred at RT for 30 min then <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (15.9 g, 73.61 mmol) was added. The reaction was refluxed for 6 h, cooled to RT then diluted with EA (530 mL) and washed with brine (2x300 mL). The combined aqueous layers were acidified to PH 5 by adding aq. 2N HCl and a solid formed which was filtered off. The solid was dried to give 5-bromo-2-(3-(3-methoxy-3-oxopropyl)ureido)nicotinic acid (15 g, 39.3percent yield) as pale yellow solid. LCMS: MH 347 and TR = 1.047 min. Used without further purification.

Reference： [1]Patent: WO2016/23830,2016,A1 .Location in patent: Page/Page column 60; 61

57
[ 52833-94-0 ]
[ 27489-62-9 ]
2-amino-5-bromo-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 23℃; for 2h;	To a solution of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (2.00 g, 9.22 mmol) in DMF (30 mL) was added trans-4-aminocyclohexanol (1.68 g, 11.1 mmol), HATU (7.01 g, 18.4 mmol) and N30 methylmorpholine (4.05 mL, 36.9 mmol) at RT. After stirring for 2 h the reaction mixture was dilutedwith EtOAc and a sat. aq. solution of NaHCO3. The aq. phase was extracted two times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under redcued pressure. The residue was purified by normal-phase chromatography (Method 2a) to give the title compound as a yellow solid. (UPLC-MS) tR 0.62 mm; ESI-MS 314/316 [M+H].

Reference： [1]Patent: WO2018/14829,2018,A1 .Location in patent: Page/Page column 39; 45; 46; 47

58
[ 54-85-3 ]
[ 52833-94-0 ]
N'-(2-amino-5-bromopyridine-3-carbonyl)-N-isonicotinoylhydrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.2%		2-Amino-5-bromonicotinic acid (3.24 g, 15 mmol), HOBT (2.43 g, 18 mmol) and EDCI (3.45 g,18mmol) dissolved in DMF (30mL)N-methylmorpholine (1.5 mL, 13 mmol) was added dropwise at room temperature.Stir thoroughly for 30 min and add 4-pyridinecarboxylic acid hydrazide (2.47 g, 18 mmol).After stirring for 48h at room temperature, the reaction solution was poured into ice water.Precipitation of white solids, suction filtration,The cake was washed three times with a small amount of ethanol and vacuum dried.4.21g of an off-white solid, yield 84.2percent,

Reference： [1]Patent: CN104592217,2018,B .Location in patent: Paragraph 0052; 0053; 0054

59
[ 553-53-7 ]
[ 52833-94-0 ]
N'-(2-amino-5-bromopyridine-3-carbonyl)-N-nicotinoylhydrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%		Weigh <strong>[52833-94-0]5-bromo-2-aminonicotinic acid</strong> (3.24 g, 15 mmol), HOBT (2.43 g, 18 mmol) and EDCI (3.45 g,18mmol) dissolved in DMF (30mL)N-methylmorpholine (1.5 mL, 13 mmol) was added dropwise at room temperature.After stirring for 30 minutes,3-pyridinecarboxylic acid hydrazide (2.47 g, 18 mmol) was added,After stirring for 48h at room temperature, the reaction solution was poured into ice water.There will be a white solid precipitated, suction filtration,The solid is washed three times with a small amount of ethanol and vacuum dried.Obtained 4.30g of an off-white solid with a yield of 86percent.

Reference： [1]Patent: CN104592217,2018,B .Location in patent: Paragraph 0035; 0036; 0037

60
[ 52833-94-0 ]
[ 761446-44-0 ]
2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinic acid [ No CAS ]

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

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

61
[ 877399-74-1 ]
[ 52833-94-0 ]
2-amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)nicotinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;	To a mixture of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (1 g, 4.61 mmol) and (1-(1-(tert- butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester (2.6 g, 6.91 mmol) in 25 mL of 1,4-dioxane/ water (3/1) was added K2CO3 (1.9 g, 13.8 mmol) followed by Pd(PPh3)4 (0.26 g, 0.23 mmol). The reaction mixture was heated at 100 °C for 3 h, cooled to room temperature, and partitioned between water and ethyl acetate. Water layer was separated and adjusted to pH value around 5. The precipitate was collected by filtration and triturated in mixture of methanol and water. The precipitate was filtered. The wet cake was dried to afford 1.5 g of the title compound. The crude product was used for the next step without further purification. MS (ESI, m/z): 388.1 [M+H]+

Reference： [1]Patent: WO2018/71343,2018,A1 .Location in patent: Paragraph 1282

62
(R)-[1,1'-biphenyl]-4-yl(3-aminopyrrolidin-1-yl)methanone [ No CAS ]
[ 52833-94-0 ]
(R)-N-(1-([1,1'-biphenyl]-4-carbonyl)pyrrolidin-3-yl)-2-amino-5-bromonicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.3 g	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h;	To a mixture of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (1.0 g, 4.58 mmol) and triethylamine (0.958 mL, 6.87 mmol) in 12 mL of N,N-dimethylformamide was added 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (1.7 g, 4.58 mmol) followed by (R)-[1,1'-biphenyl]-4-yl(3-aminopyrrolidin-1-yl)methanone (0.853 g, 4.58 mmol). The mixture was stirred at room temperature for 1 h and then saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified through silica gel column chromatography (0 to 60 percent ethyl acetate/hexanes for 30 min) to give an off-white solid. To a mixture of product in dichloromethane (12 mL) was added trifluoroacetic acid (3 mL) and stirred at room temperature for overnight. After removing volatiles, the crude product was diluted with diethyl ether and the precipitate was collected by filtration and dried to afford 1.3 g of the title compound. MS (ESI, m/z): 465.1/467.1 [M+H]+

Reference： [1]Patent: WO2018/71343,2018,A1 .Location in patent: Paragraph 1840

63
[ 52833-94-0 ]
[ 13374-30-6 ]
2-amino-5-bromo-N-((1S,2S)-2-hydroxycyclohexyl)nicotinamide [ No CAS ]

Reference： [1]ACS Chemical Neuroscience,2016,vol. 7,p. 647 - 661

64
[ 67-56-1 ]
[ 52833-94-0 ]
[ 50735-34-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sulfuric acid; at 80℃; for 18h;Inert atmosphere;	To a solution of 2-amino-5-bromonicotinic acid 22 (1.0 g, 4.6 mmol)in MeOH (10 mL) was added sulphuric acid (2.0 mL, 36.8 mmol)dropwise and the mixture was stirred at 80 C for 18 h. After completionmonitored by TLC, the solvent was removed under reduced pressure.The residue was neutralised with sat. NaHCO3 (aq.) and extracted withethyl acetate (3×20 mL). The combined organic layers were driedover MgSO4 and concentrated in vacuo to afford the product 23 as awhite powder (1.0 g, 94%) without further purification. m.p.148-149 C; Rf (CH2Cl2/MeOH 20:1): 0.55; 1H NMR (400 MHz, d6-DMSO): delta 8.24 (1H, d, J=2.4 Hz), 8.21 (1H, d, J=2.4 Hz), 6.68-6.19(2H, br.s), 3.89 (3H, s); 13C NMR (100 MHz, d6-DMSO): delta 166.6, 158.0,154.4, 142.0, 107.5, 106.1, 52.4. HRMS (ESI+) Calc. for C7H7N2O2Br [M+H]+ 230.9764/232.9743, found 230.9765/232.9745. IR (neat,cm-1): v 3425, 3131, 2918, 1704, 1620, 1223, 796, 526.
63%		Compound 1 (27.40 g, 126.88 mmol) obtained in Step 1 of Example 1 was placed in a well-dried 1000 mL three-neck round bottom flask and placed in a water bath containing ice water. 250 mL of methanol was added and stirred for 15 minutes. Sulfuric acid (125.80 mL, 2360.00 mmol) was slowly added dropwise thereto. The mixture was stirred for 8 hours at a temperature of 80 C under a stream of nitrogen. The product was poured into 1500 mL of ice water and neutralized with NaHCO 3 until the pH reached 7. Extraction with dichloromethane followed by column separation with 100% dichloromethane. The resulting solid was dried to give compound 2 (18.5 g, 63% yield).

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 5852 - 5869
[2]Patent: KR2018/82356,2018,A .Location in patent: Paragraph 0154; 0159-0161

65
[ 52833-94-0 ]
[ 205445-52-9 ]
tert-butyl (S)-(1-(6-bromo-4-oxo-4H-pyrido[2,3-d][1,3]oxazin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.4 g	With 4-methyl-morpholine; isobutyl chloroformate; In dichloromethane; at -20 - 45℃; for 22h;	To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5- difluorophenyl)propanoic acid (2.4 g, 7.97 mmol) in DCM (106 mL) was added N- methylmorpholine (2.2 mL, 19.91 mmol) followed by isobutyl chloroformate (2.1 mL, 15.93 mmol). The clear colorless reaction was then cooled to -20 °C (IP A, dry ice). 2- amino-5-bromonicotinic acid (1.73 g, 7.97 mmol) was then added and the slurry was allowed to slowly warm to ambient temperature over 2 h as cold bath thawed. The hazy orange solution was stirred for 18 h, then heated at 45 °C for 2 h and cooled to rt. The reaction was diluted with EtOAc. The organic mixture was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was then dried (Na2S04) and concentrated. The crude product was triturated from ether and filtered to provide the product as an off-white colored solid (1.4 g). NMR (500 MHz, CDCb) delta 9.04 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.4 Hz, 1H), 6.72 (br d, J = 7.6 Hz, 3H), 5.43 (br d, J = 7.6 Hz, 1H), 5.02 (br d, J = 5.7 Hz, 1H), 3.38 (br dd, J = 13.8, 4.8 Hz, 1H), 3.17 (br dd, J = 13.5, 7.5 Hz, 1H), 1.45 (s, 9H).

Reference： [1]Patent: WO2018/203235,2018,A1 .Location in patent: Page/Page column 177-178

66
[ 52833-94-0 ]
[ 1234616-70-6 ]

Reference： [1]Comptes Rendus Chimie,2019,vol. 22,p. 294 - 298

67
[ 107-20-0 ]
[ 52833-94-0 ]
[ 903129-78-2 ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 4703 - 4715

68
[ 50735-34-7 ]
[ 52833-94-0 ]

Reference： [1]Patent: WO2017/39331,2017,A1 .Location in patent: Paragraph 715-724

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P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 52833-94-0 ]

Quality Control of [ 52833-94-0 ]

Related Doc. of [ 52833-94-0 ]

Product Details of [ 52833-94-0 ]

Calculated chemistry of [ 52833-94-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 52833-94-0 ]

Application In Synthesis of [ 52833-94-0 ]

[ 52833-94-0 ] Synthesis Path-Upstream 1~9

[ 52833-94-0 ] Synthesis Path-Downstream 1~68

Related Functional Groups of [ 52833-94-0 ]

Bromides

Amines

Carboxylic Acids

Related Parent Nucleus of [ 52833-94-0 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 52833-94-0 ]

Related Parent Nucleus of
[ 52833-94-0 ]