[ CAS No. 13535-01-8 ] {[proInfo.proName]}

Name: 13535-01-8|5-Bromopyridin-3-amine|98%
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Quality Control of [ 13535-01-8 ]

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Product Details of [ 13535-01-8 ]

CAS No. :	13535-01-8	MDL No. :	MFCD01646060
Formula :	C₅H₅BrN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MDQXGHBCDCOOSM-UHFFFAOYSA-N
M.W :	173.01	Pubchem ID :	817681
Synonyms :		Chemical Name :	5-Bromopyridin-3-amine

Calculated chemistry of [ 13535-01-8 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	36.34
TPSA :	38.91 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.74 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.23
Log Po/w (XLOGP3) :	0.86
Log Po/w (WLOGP) :	1.43
Log Po/w (MLOGP) :	0.58
Log Po/w (SILICOS-IT) :	1.41
Consensus Log Po/w :	1.1

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.01
Solubility :	1.69 mg/ml ; 0.00978 mol/l
Class :	Soluble
Log S (Ali) :	-1.26
Solubility :	9.49 mg/ml ; 0.0549 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.51
Solubility :	0.531 mg/ml ; 0.00307 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.54

Safety of [ 13535-01-8 ]

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

Application In Synthesis of [ 13535-01-8 ]

* 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 [ 13535-01-8 ]
Downstream synthetic route of [ 13535-01-8 ]

[ 13535-01-8 ] Synthesis Path-Upstream 1~30

1
[ 13535-01-8 ]
[ 407-20-5 ]

Yield	Reaction Conditions	Operation in experiment
55%	With tetrafluoroboric acid; sodium nitrite In water at -8℃; for 1 h;	Step 2: 3-Bromo-5-fluoropyridine A at -10° C. cooled solution of 10.0 g (0.058 mol) of 3-Amino-5-bromopyridine in 59 ml of 50percent Tetrafluoroboric acid was treated by dropwise addition of a solution of 4.19 g (0.06 mol) of sodium nitrite in 13 ml of water. After stirring for 1 h at -8° C., 150 ml of ether was added to the brown suspension. The crude diazonium salt was filtered off, and washed with ether. This crude salt was then added in portions to 200 ml of toluene heated at 80° C. After stirring for 1 h at 90° C., the organic phase was concentrated. The light yellow residue was suspended in 150 ml of water and the pH was adjusted to 11 with 32percent sodium hydroxide solution. The resulting solution was extracted three times with 200 ml of methylene chloride. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated. The crude material 15.4 g (brown oil) was purified by vaccum distillation (10 mBar, 35° C.) and yielded 5.6 g (0.032 mol, 55percent) of the title compound as a colorless oil (ISP): m/e=176.1, 178.1 (M+H⁺).

Reference： [1] Patent: US2006/199960, 2006, A1, . Location in patent: Page/Page column 21
[2] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1062,1068

2
[ 13535-01-8 ]
[ 233770-01-9 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1062,1068

3
[ 13535-01-8 ]
[ 74115-13-2 ]

Reference： [1] Patent: US2009/170886, 2009, A1, . Location in patent: Page/Page column 28
[2] Roczniki Chemii, 1936, vol. 16, p. 136,137[3] Chem. Zentralbl., 1936, vol. 107, # II, p. 1167

4
[ 13535-01-8 ]
[ 7732-18-5 ]
[ 3543-01-9 ]

Reference： [1] Chemische Berichte, 1936, vol. 69, p. 32,37

5
[ 28733-43-9 ]
[ 13535-01-8 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium hydroxide; bromine In water at 0 - 70℃;	EXAMPLE P; 3-Bromo-5-fluoropyridine; Step 1; 3-Amino-5-bromopyridine; To a ice-cold solution of 31.8 g (0.79 mol) of Sodium hydroxide and 40.7 g (0.255 mol) of Bromine in 340 ml of water were added 42.0 g (0.209 mol) of commercially available 5-Bromonicotinamide. The mixture was allowed to warm up to room temperature and then heated for 1 h at 70° C. The resulting brown suspension was allowed to cool to room temperature. The aqueous phase was saturated with brine and extracted three times with a 1:1 mixture of THF and t-Butyl-methyl ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vaccuo. Concentration in vaccuo yielded 39.1 g of a dark brown residue which was purified by flash chromatography (heptane/ethyl acetate 1:1) to yield the title compound as a brown solid (total 70.2 g, 70percent)
70%	With sodium hydroxide; bromine In water at 0 - 70℃; for 1 h;	Step 1: 3-Amino-5-bromopyridine To a ice-cold solution of 31.8 g (0.79 mol) of Sodium hydroxide and 40.7 g (0.255 mol) of Bromine in 340 ml of water were added 42.0 g (0.209 mol) of commercially available 5-Bromonicotinamide. The mixture was allowed to warm up to room temperature and then heated for 1 h at 70° C. The resulting brown suspension was allowed to cool to room temperature. The aqueous phase was saturated with brine and extracted three times with a 1:1 mixture of THF and t-Butyl-methyl ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vaccuo. Concentration in vaccuo yielded 39.1 g of a dark brown residue which was purified by flash chromatography (heptane/ethyl acetate 1:1) to yield the title compound as a brown solid (total 70.2 g, 70percent), MS (ISP): m/e=173.1, 175.1 (M+H+).
62%	Stage #1: With sodium hydroxide; bromine In water at 0 - 5℃; Stage #2: at 0 - 75℃; for 1 h;	To a solution of NaOH (22.9 g, 572 mmol) in water (245 mL) at 0-5° C. (ice salt bath) was added bromine (9.44 mL, 184 mmol) maintaining the temperature at 0-5° C., to produce a sodium hypobromite solution. To this NaOBr-sol. was added commercially available 3-bromonicotinamide (30.15 g, 150 mmol) all at once with vigorous stirring. After being stirred for 15 min, the solution is clear and mixture was heated to 70-75° C. for 45 min. Cooled to 23° C., saturated with solid NaCl, extracted with TBME/THF (3.x.300 mL), dried over Na₂SO₄. Removal of the solvent in vacuum gave a dark brown oil which was purified by silica gel column chromatography with heptane/EtOAc 1:1-->2:3 to give the title compound as a brown solid (16.036 g, 62percent). MS (ISP) 173.1 [(M+H)⁺], 175.2 [(M+2+H)⁺].

62%	With sodium hydroxide; bromine In water at 85 - 100℃; for 3 h;	Example 23B 3-amino-5-bromopyridine A solution of 3M NaOH (250 mL) at room temperature was treated with bromine (25.9 g, 162 mmol), stirred for 15 minutes, treated with 5-bromonicotinamide (25 g, 124 mmol), stirred for 45 minutes, heated to 85-100° C. for 3 hours, cooled to room temperature, adjusted to pH 1 with 10percent HCl (aq.) washed twice with diethyl ether. The aqueous layer was adjusted to pH~10-11 with solid NaOH, and extracted four times with diethyl ether and twice with dichloromethane. The combined extracts were dried (MgSO₄), filtered, and concentrated to provide the desired product (13.3 g, 62percent).
58.5%	With sodium hydroxide; bromine In water at 75℃; for 0.75 h;	Bromine (18.76 g, 117.4 mmol) was added to a solution of sodium hydroxide (23.88 g, 597 mmol) in water (200 mL). To this solution was added 5-bromonicotinamide (20.00 g, 99.49 mmol). The reaction mixture was heated to 75° C. for 45 minutes. The reaction was cooled and acidified with concentrated hydrochloric acid. Some insoluble material was present. The insolubles were removed by filtration. The solution was washed with ethyl acetate (150 mL, 2 times). The aqueous solution was basified with sodium hydroxide solution (pH 10). The mixture was extracted into ethyl acetate (200 mL, 2 times). The ethyl acetate was dried and condensed to yield compound A (10.07 g, 58.5percent yield).

Reference： [1] ChemMedChem, 2014, vol. 9, # 1, p. 217 - 232
[2] Patent: US2006/160857, 2006, A1, . Location in patent: Page/Page column 56
[3] Patent: US2006/199960, 2006, A1, . Location in patent: Page/Page column 21
[4] Patent: US2006/217387, 2006, A1, . Location in patent: Page/Page column 31
[5] Patent: US2003/199511, 2003, A1, . Location in patent: Page/Page column 23
[6] Patent: US2009/170886, 2009, A1, . Location in patent: Page/Page column 28
[7] Yakugaku Zasshi, 1931, vol. 51, p. 542,571; dtsch. Ref. S. 73, 76[8] Chem.Abstr., 1931, p. 5427
[9] Journal of Medicinal Chemistry, 2007, vol. 50, # 24, p. 6265 - 6273

6
[ 625-92-3 ]
[ 13535-01-8 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1062,1068
[2] Roczniki Chemii, 1936, vol. 16, p. 136,137[3] Chem. Zentralbl., 1936, vol. 107, # II, p. 1167

7
[ 20826-04-4 ]
[ 13535-01-8 ]

Reference： [1] ChemMedChem, 2014, vol. 9, # 1, p. 217 - 232

8
[ 39620-02-5 ]
[ 13535-01-8 ]

Reference： [1] ChemMedChem, 2014, vol. 9, # 1, p. 217 - 232

9
[ 15862-30-3 ]
[ 13535-01-8 ]

Reference： [1] Roczniki Chemii, 1938, vol. 18, p. 210[2] Chem. Zentralbl., 1939, vol. 110, # II, p. 2779

10
[ 626-55-1 ]
[ 13535-01-8 ]

Reference： [1] Roczniki Chemii, 1938, vol. 18, p. 210[2] Chem. Zentralbl., 1939, vol. 110, # II, p. 2779

11
[ 625-92-3 ]
[ 13535-01-8 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1936, vol. 55, p. 122,126

12
[ 13535-01-8 ]
[ 64-17-5 ]
[ 17117-17-8 ]

Reference： [1] Yakugaku Zasshi, 1931, vol. 51, p. 542,571; dtsch. Ref. S. 73, 76[2] Chem.Abstr., 1931, p. 5427

13
[ 13535-01-8 ]
[ 108-24-7 ]
[ 15862-46-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With pyridine In dichloromethane at 20℃; for 17 h;	To a solution of 3-amino-5-bromopyridine (1.0 g, 5.78 mmol) and pyridine (1.3 mL, 12.9 mmol) in DCM (5 mL) is added acetic anhydride (0.6 mL, 6.358 mmol) dropwise. The mixture is stirred at room temperature for 17 h. The mixture is concentrated and the resulting crude product is purified by normal phase using 0-75percent EtOAc in heptane as the gradient to afford N-(5-bromo-pyridin-3-yl)-acetamide (1.18 g, 95percent yield).
89.04%	at 20℃; Industrial scale	To a 1 L four-necked flask equipped with a magnetic stirrer and thermometer, 45.04 g (0.259 mol)3-amino-5-bromopyridine, adding 500mL of dichloromethane to dissolve at room temperature, slowly adding dropwise 26.44g (0.259mol) of acetic anhydride, dropping the reaction for 2 to 5 hours,TLC control to the end of the reaction, the vacuum distillation, the residue was dissolved in ethyl acetate, 200mL saturated sodium bicarbonate was washed twice and evaporated to dryness, to give 3-acetylamino-5-bromopyridine 49.57g, yield 89.04percent.

Reference： [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53, # 1, p. 83 - 89
[2] Patent: US2014/323468, 2014, A1, . Location in patent: Paragraph 0601
[3] Patent: CN103601745, 2017, B, . Location in patent: Paragraph 0035; 0036
[4] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1062,1068
[5] Journal fuer Praktische Chemie (Leipzig), 1933, vol. <2> 138, p. 244,257

14
[ 13535-01-8 ]
[ 75-36-5 ]
[ 15862-46-1 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: With pyridine In dichloromethane for 0.333333 h;	To a stirred suspension of 5-bromopyridin-3-amine (500 mg, 2.89 mmol) in DCM (10 mL), was added pyridine (0.467 mL, 5.78 mmol). The mixture was stirred for 20 min and acetyl chloride (0.236 mL, 3.32 mmol) was added. The mixture was stirred for 3 h. The mixture was diluted with water (20 mL) and DCM (20 mL). The layers were separated and the aqueous layer was re-extracted with DCM (3 x 20 mL). The combined organics were washed with brine (20 mL), dried using a hydrophobic frit and concentrated in vacuo to give A/-(5-bromopyridin-3- yl)acetamide as an orange solid (563 mg, 91 percent). LCMS (2 min, Formic): Rt = 0.59 min, MH⁺ 215/217

Reference： [1] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 8, p. 730 - 734
[2] Patent: WO2014/140077, 2014, A1, . Location in patent: Page/Page column 55

15
[ 13535-01-8 ]
[ 65001-21-0 ]

Reference： [1] Patent: WO2018/85348, 2018, A1, . Location in patent: Paragraph 0322-0323

16
[ 13535-01-8 ]
[ 56-81-5 ]
[ 17965-71-8 ]

Reference： [1] ChemMedChem, 2014, vol. 9, # 1, p. 217 - 232
[2] Patent: WO2017/144639, 2017, A1, . Location in patent: Page/Page column 105

17
[ 13535-01-8 ]
[ 17965-71-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 16, p. 3748 - 3752

18
[ 13535-01-8 ]
[ 591-50-4 ]
[ 73183-34-3 ]
[ 142137-17-5 ]

Reference： [1] Journal of Organic Chemistry, 2013, vol. 78, # 5, p. 1923 - 1933

19
[ 13535-01-8 ]
[ 24424-99-5 ]
[ 361550-43-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 20℃; for 0.333333 h; Stage #2: at 20℃; for 24 h;	To 5-bromopyridin-3-amine (2.00 g, 11.5 mmol) in THF (25 mL) was added sodium hexamethyldisilazide (25.4 mL, 25.4 mmol, 1 M in THF) and the reaction mixture was stirred at room temperature for 20 min. Boc-anhydride (2.52 mL, 15.6 mmol) in THF (10 mL) was added slowly and the reaction mixture was stirred for an additional 24 h at room temperature. 0.1 M HC1 (30 mL) was added and the reaction mixture was extracted with ethyl acetate. The combined organic extracts were washed successively with water and brine. The organic layer was dried, filtered and concentrated under reduced pressure to afford tert-butyl 5-bromopyridin-3- ylcarbamate (2.5 g, 81 percent), which was used without further purification. LCMSMethod 0018: retention time 1.84 min, [M+l] = 275.0 ^XH NMR (400 MHz, DMSO- d₆) δ (ppm): 9.82 (s, 1H), 8.57 (d, 1H, J= 2.4Hz), 8.30 (d, 1H, J= 2Hz), 8.18 (s, lH), 1.49 (s, 9H).
70%	With dmap; triethylamine In N,N-dimethyl-formamide at 90℃;	3-Amino-5-bromopyridine (2.0 g,11.6 mmol), di-tert-butyl-dicarbonate (3.03 g, 13.9 mmol), triethylamine (2.42 mL,17.3 mmol) and 4-dimethylaminopyridine (142 mg, 1.16 mmol) were dissolved in dryDMF (20 mL) and heated at 90°C overnight. Upon cooling, the reaction mixture wasdiluted with water (100 mL) and the resulting solid extracted into EtOAc (3x80 mL). Thecombined EtOAc fractions were washed with water (3x100 mL), brine (2x100 mL), dried(Na2SO4) and filtered. The solvent was removed under reduced pressure to afford a crudesolid which was purified by filtration through a plug of flash silica gel(20percent EtOAc/hexanes as eluent). The title compound was isolated as a white solid (2.22 g,70percent). ‘H NMR [400 MHz, (CD3)2S0] 6 8.33 (br d, J = 1.5 Hz, 1 H), 8.24 (br s, 2 H),6.62 (br s, 1 H), 1.53 (s, 9 H). LRMS (APCI’) calcd for C10H,3BrN2O2 273, 275 (MH4),found 273, 275.
54.9%	With sodium hexamethyldisilazane In tetrahydrofuran; dichloromethane at 0℃;	To a solution of 5-bromopyridin-3-amine (3 g, 17.34 mmol) in dry DCM (25 ml), di-tert-butyl dicarbonate (3.78 g, 17.34 mmol) was added under stirring. The resulting solution was cooled to 0 °C and a solution of sodium bis(trimethylsilyl)amide 1 M in THF (17.34 ml, 17.34 mmol) was added dropwise over 20 mm. The solution was stirred overnight. Then, solution was diluted with DCM (40 mL) and washed once with sat.NaHCO3. Organic phase was dried over Na2SO4, filtered and concentrated. Crude was finally purified on Biotage Si 50 g with a gradient of hexane and EtOAc. The title compound was recovered (2.60g, 54.9 percent yield) as a white solid.UPLC-MS: 1.07 mm, 273 [M+H]+, method 9.

54.9%

With sodium hexamethyldisilazane In tetrahydrofuran; dichloromethane at 0℃;

To a solution of 5-bromopyridin-3-amine (3 g, 17.34 mmol) in dry DCM (25 ml), di-tert-butyl dicarbonate (3.78 g, 17.34 mmol) was added under stirring. The resulting solution was cooled to 0° C. and a solution of sodium bis(trimethylsilyl)amide 1 M in THF (17.34 ml, 17.34 mmol) was added dropwise over 20 min. The solution was stirred overnight. Then, solution was diluted with DCM (40 mL) and washed once with sat. NaHCO₃. Organic phase was dried over Na₂SO₄, filtered and concentrated. Crude was finally purified on Biotage Si 50 g with a gradient of hexane and EtOAc. The title compound was recovered (2.60 g, 54.9percent yield) as a white solid.UPLC-MS: 1.07 min, 273 [M+H]+, method 9.

Reference： [1] Patent: WO2011/28741, 2011, A1, . Location in patent: Page/Page column 247-248
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 24, p. 8709 - 8715
[3] Patent: WO2014/28968, 2014, A1, . Location in patent: Page/Page column 101
[4] Patent: WO2015/91685, 2015, A1, . Location in patent: Page/Page column 141
[5] Patent: US2015/166549, 2015, A1, . Location in patent: Paragraph 0870; 0871; 0872
[6] Patent: US2009/181941, 2009, A1, . Location in patent: Page/Page column 55
[7] Journal of Medicinal Chemistry, 2017, vol. 60, # 9, p. 3795 - 3803

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[ 433226-05-2 ]

Reference： [1] Patent: WO2012/6680, 2012, A1, . Location in patent: Page/Page column 76
[2] Patent: US9242996, 2016, B2,
[3] Patent: WO2017/7756, 2017, A1,
[4] European Journal of Medicinal Chemistry, 2017, vol. 140, p. 383 - 391
[5] Patent: CN104876860, 2018, B,

21
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[ 667932-40-3 ]

Reference： [1] Patent: WO2012/101184, 2012, A1,
[2] Patent: WO2012/101186, 2012, A1,
[3] Patent: EP2546249, 2013, A1,
[4] Patent: US2013/23533, 2013, A1,
[5] Dalton Transactions, 2016, vol. 45, # 19, p. 8050 - 8060
[6] Patent: EP3127900, 2017, A1,

22
[ 13535-01-8 ]
[ 98-80-6 ]
[ 31676-54-7 ]

Yield	Reaction Conditions	Operation in experiment
13%	With sodium carbonate In ethanol; toluene at 20 - 90℃; for 20 h;	Step A: 5-Phenylpyridin-3-amine A mixture of 5-bromopyridin-3-amine (248 mg, 1.43 mmol), Pd(PPh₃)₄(50.4 mg, 0.04 mmol), toluene (3 mL), sodium carbonate (2 M, 3 mL, 6 mmol), and phenylboronic acid (195 mg, 1.60 mmol) dissolved in ethanol (3 mL) was heated for 4 hours in an oil bath at 90° C. and allowed to cool to room temperature for 16 hours. The reaction mixture was transferred to a separatory funnel and partitioned between ethyl acetate and water. The aqueous phase was washed once more with ethyl acetate, and the combined organic phases were washed with brine and dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (80percent ethyl acetate/hexanes) to afford 5-phenylpyridin-3-amine (31.9 mg, 0.19 mmol, 13percent yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.17-8.42 (m, 1H), 8.02-8.20 (m, 1H), 7.32-7.62 (m, 4H), 7.25 (s, 1H), 7.06-7.20 (m, 1H). MS (LC/MS) R.T.=0.91; [M+H]⁺=171.09.
13%	With sodium carbonate In ethanol; toluene at 90℃; for 4 h; oil bath heating	Step A: 5-Phenylpyridin-3 -amineA mixture of 5-bromopyridin-3-amine (248 mg, 1.43 mmol), Pd(PPli₃)4 (50.4 mg, 0.04 mmol), toluene (3 mL), sodium carbonate (2 M, 3 mL, 6 mmol), and phenylboronic acid (195 mg, 1.60 mmol) dissolved in ethanol (3 mL) was heated for 4 hours in an oil bath at 90 °C and allowed to cool to room temperature for 16 hours. The reaction mixture was transferred to a separatory funnel and partitioned between ethyl acetate and water. The aqueous phase was washed once more with ethyl acetate, and the combined organic phases were washed with brine and dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (80percent ethyl acetate/hexanes) to afford 5-phenylpyridin-3- amine (31.9 mg, 0.19 mmol, 13 percent yield) as a white solid. 3/4 NMR (500 MHz, CDCli) δ ppm 8.17 - 8.42 (m, 1 H), 8.02 - 8.20 (m, 1 H), 7.32 - 7.62 (m, 4 H), 7.25 (s, 1 H), 7.06 - 7.20 (m, 1 H). MS (LC/MS) R.T. = 0.91 ; [M+H]⁺ = 171.09.
13%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In ethanol; toluene at 90℃; for 4 h;	A mixture of 5-bromopyridin-3-amine (248 mg,1.43 mmol), Pd(PPh3)4 (50.4 mg, 0.04 mmol), toluene (3ml.), sodium carbonate (2 M, 3 ml., 6 mmol), and phenylboronicacid (195 mg, 1.60 mmol) dissolved in ethanol (3 mL) was heated for 4 hours in an oil bath at 90° C. and allowed to cool to room temperature for 16 hours. The reaction mixturewas transferred to a separatory funnel and partitioned between ethyl acetate and water. The aqueous phase waswashed once more with ethyl acetate, and the combinedorganic phases were washed with brine and dried over magnesiumsulfate, filtered and concentrated in vacuo. The residuewas purified by colunm chromatography (80percent ethylacetatelhexanes) to afford 5-phenylpyridin-3-amine (31.9mg, 0.19 mmol, 13percent yield) as a white solid.

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 695 - 709
[2] Patent: US2009/270405, 2009, A1, . Location in patent: Page/Page column 84
[3] Patent: WO2011/53292, 2011, A1, . Location in patent: Page/Page column 136
[4] Patent: JP5714745, 2015, B2, . Location in patent: Paragraph 0271; 0272
[5] New Journal of Chemistry, 2017, vol. 41, # 24, p. 15420 - 15432

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[ 1201645-46-6 ]

Reference： [1] Patent: WO2014/140077, 2014, A1,

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[ 73183-34-3 ]
[ 1073354-99-0 ]

Reference： [1] Patent: WO2013/126608, 2013, A1, . Location in patent: Paragraph 00394
[2] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 1031 - 1050
[3] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 270 - 285

25
[ 13535-01-8 ]
[ 1276110-06-5 ]

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2455 - 2466

26
[ 13535-01-8 ]
[ 1309774-03-5 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 16, p. 3748 - 3752

27
[ 13535-01-8 ]
[ 1309774-03-5 ]
[ 97267-61-3 ]

Reference： [1] ChemMedChem, 2014, vol. 9, # 1, p. 217 - 232

28
[ 13535-01-8 ]
[ 768-35-4 ]
[ 1214384-10-7 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium phosphate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ In water; N,N-dimethyl-formamide at 180℃; for 1 h; Microwave irradiation; Inert atmosphere	To a microwave vial was added 3-amino-5-bromopyridine (LII) (0.400 g, 2.31 mmol), 3 -fluorophenyl boronic acid (XLIX) (0.356 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.133 g, 0.116 mmol), potassium phosphate (0.736 g, 3.47 mmol), water (1 mL), and DMF (5 niL). The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180°C. The solution was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by column chromatography (4:6 EtOAc:hexanes → 7:3 EtOAc:hexanes) to afford the 5-(3-fluorophenyl)pyridin-3-amine (LIII) (0.360 g, 1.92 mmol, 83percent> yield) as a yellow-white solid. ESIMS found for C_nH₉FN₂ mlz 189.1 (M+H).
83%	With potassium phosphate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ In water; N,N-dimethyl-formamide at 180℃; for 1 h; Microwave irradiation; Inert atmosphere; Sealed tube	To a microwave vial was added 3-amino-5-bromopyridine (LII) (0.400 g, 2.31 mmol), 3 -fluorophenyl boronic acid (XLIX) (0.356 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.133 g, 0.116 mmol), potassium phosphate (0.736 g, 3.47 mmol), water (1 mL), and DMF (5 mL). The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180°C. The solution was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by column chromatography (4:6 EtOAc:hexanes → 7:3 EtOAc:hexanes) to afford the 5-(3- fluorophenyl)pyridin-3 -amine (LIII) (0.360 g, 1.92 mmol, 83percent yield) as a yellow -white solid. ESIMS found for CnH₉FN₂ mlz 189.1 (M+H).

Reference： [1] Patent: WO2013/40215, 2013, A1, . Location in patent: Paragraph 00274
[2] Patent: WO2018/75858, 2018, A1, . Location in patent: Paragraph 0306; 0307

29
[ 13535-01-8 ]
[ 1180678-40-3 ]

Yield	Reaction Conditions	Operation in experiment
42%	Reflux	General procedure: NIS (24.75 g, 110.0 mmol) was added to a solution of 2-chloropyridin-4-ylamine (12.85 g, 100.0 mmol) in MeCN (400 mL),and the mixture was stirred and held at reflux overnight. Uponcooling to r.t. the solvent was removed in vacuo and the residuepartitioned between EtOAc (250 mL), sat. Na2S2O3 (100 mL), andH2O (250 mL). The organic layer was separated, washed withH2O (2 × 250 mL), separated, and the solvent removed in vacuoto afford an orange oil that was subjected to column chromatographyon silica gel. Elution with 30–50percent EtOAc in PE afforded apale orange solid that was rinsed with 25percent EtOAc in PE (80 mL).The solids were collected by filtration and sucked dry to afford2-chloro-5-iodopyridin-4-ylamine (7.32 g) as an off-white solid.The mother liquors were concentrated to dryness in vacuo andthe residues subjected to column chromatography on silica.Elution with 30–50percent EtOAc in PE afforded further pure material(1.90 g)
11.5 g	at 20℃; Inert atmosphere	3-Amino-5-bromopyridine (13.8 g, 79.8 mmol) was dissolved in acetic acid (440 mL) and placed under a nitrogen atmosphere. N-lodosuccinimide (16.15 g, 71.8 mmol) was charged to the reaction which was stirred at room temperature overnight. The reaction wasconcentrated and the residue partitioned between EtOAc (200 mL) and saturated aqueous sodium hydrogen carbonate (200 mL). The layers were separated and the organic phase was washed with saturated aqueous sodium hydrogen carbonate (200 mL). The aqueous phase was extracted with EtOAc (3 x 200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated. Chromatography (silica; 1.4 Kg packed in70percent DCM:30percent heptane, eluting with 70-100percent DCM in heptane) gave the title compound (11.5 g). 1H NMR (270 MHz, CDCI3): 7.83 (1H, m), 7.04 (1H, m), 4.33 (2H, brs).
11.5 g	at 20℃; Inert atmosphere	Preparation 14: 5-Bromo-2-iodo-pyridin-3-ylamine 3-Amino-5-bromopyridine (13.8 g, 79.8 mmol) was dissolved in acetic acid (440 mL) and placed under a nitrogen atmosphere. N-lodosuccinimide (16.15 g, 71.8 mmol) was charged to the reaction which was stirred at room temperature overnight. The reaction was concentrated andthe residue partitioned between EtOAc (200 mL) and saturated aqueous sodium hydrogen carbonate (200 mL). The layers were separated and the organic phase was washed with saturated aqueous sodium hydrogen carbonate (200 mL). The aqueous phase was extracted with EtOAc (3 x 200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated. Chromatography (silica; 1.4 Kg packed in 70percent DCM:30percent heptane, eluting with70-100percent DCM in heptane) gave the title compound (11.5 g). 1H NMR (270 MHz, CDCI3): 7.83 (1H, m), 7.04 (1H, m), 4.33 (2H, brs).

11.5 g

at 20℃; Inert atmosphere

Preparation II: 5-Bromo-2-iodo-pyridin-3-ylamine H2N3-Amino-5-bromopyridine (13.8 g, 79.8 mmol) was dissolved in acetic acid (440 mL) and placed under a nitrogen atmosphere. N-lodosuccinimide (16.15 g, 71.8 mmol) was charged to the reaction which was stirred at room temperature overnight. The reaction wasconcentrated and the residue partitioned between EtOAc (200 mL) and saturated aqueous sodium hydrogen carbonate (200 mL). The layers were separated and the organic phase was washed with saturated aqueous sodium hydrogen carbonate (200 mL). The aqueous phase was extracted with EtOAc (3 x 200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated. Chromatography (silica; 1.4 Kg packed in70percent DCM:30percent heptane, eluting with 70-100percent DCM in heptane) gave the title compound (11.5g). 1H NMR(27OMHz, CDCI3): 7.83(1H, m), 7.04(1H, m),4.33(2H, brs).

Reference： [1] Synlett, 2015, vol. 26, # 18, p. 2570 - 2574
[2] Patent: WO2014/60768, 2014, A1, . Location in patent: Page/Page column 94; 95
[3] Patent: WO2014/60767, 2014, A1, . Location in patent: Page/Page column 107
[4] Patent: WO2014/60770, 2014, A1, . Location in patent: Page/Page column 126
[5] Journal of Organic Chemistry, 2015, vol. 80, # 21, p. 10806 - 10816

30
[ 13535-01-8 ]
[ 411235-57-9 ]
[ 1314353-68-8 ]

Yield	Reaction Conditions	Operation in experiment
56%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 1,4-dioxane; water at 100℃; for 15 h;	To a solution of 5-bromopyridin-3-amine (4.75 g, 27.45 minol) in dioxane (45 mL) was added cyclopropylboronic acid (4.75 g, 55.30 minol), C52CO3(28 g, 85.67 minol), tetrakis(triphenylphosphane) palladium(1.66 g, 1.44 minol) and water (5 mL) at room temperature. The resultingminxture was then stirred for 15 h at 100 °C. After cooling to room temperature, the reaction mxiture was diluted with water (200 mL). The resultingminxture was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0percent to 100percent gradient) to yield 5-cyclopropylpyridin-3-amine as light brown oil (2.08 g, 56percent). MS: m/z = 135.0 [M+Hj .
314 mg	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 1,4-dioxane; water at 100℃; for 5 h; Inert atmosphere; Sealed tube	Reference Example 45 Cyclopropylboronic acid (360 mg), cesium carbonate (1.4 g), and Pd(PPh₃)₄ (166 mg) were added to a 1,4-dioxane/water (4.5 ml/0.5 ml) solution containing 5-bromopyridin-3-amine (500 mg) in a nitrogen atmosphere, followed by stirring in a sealed tube at 100° C. for 5 hours. The reaction solution was adjusted to room temperature and water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform:MeOH=1:0 to 30:1). A brown solid of 5-cyclopropyl pyridin-3-amine (314 mg) was thus obtained. MS (ESI m/z): 135 (M+H)

Reference： [1] Patent: WO2017/106607, 2017, A1, . Location in patent: Paragraph 00477
[2] Patent: EP2762476, 2014, A1, . Location in patent: Paragraph 0174
[3] Patent: US2014/309225, 2014, A1, . Location in patent: Paragraph 0700; 0701; 0702; 0703

[ 13535-01-8 ] Synthesis Path-Downstream 1~84

1
[ 13535-01-8 ]
[ 64-17-5 ]
[ 17117-17-8 ]

Reference： [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1931,vol. 51,p. 542,571; dtsch. Ref. S. 73, 76
Chem.Abstr.,1931,p. 5427

2
[ 13535-01-8 ]
[ 108-24-7 ]
[ 15862-46-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	With pyridine; at 25℃; for 12h;Inert atmosphere;	To a solution of 5 -bromopyri din-3 -amine (1.00 g, 5.78 mmol) in pyridine (10 mL) was added acetic anhydride (708 mg, 6.94 mmol) at N2 atmosphere. The resulting mixture was stirred at 25 C for 12 h. A yellow solution was formed. LCMS (Rt = 0.422 min; MS Calcd: 214.0; MS Found: 214.7 [M+H]+). The reaction mixture was concentrated under reduced pressure. Water (20 mL) was added to the resulting mixture and then extracted with EtOAc (20 mL x3). The combined organic layer was washed with saturated aqueous NaHCCb (50 mL x3), brine (20 mL), dried over anhydrous Na2S04 and concentrated to give N-(5-bromopyridin-3- yl)acetamide (1.21 g, yield: 97%) as a yellow solid. (1309) NMR (400MHz, CDCb) d 2.21 (3H, s), 7.78 (1H, brs), 8.37-8.41 (1H, m), 8.42-8.47 (2H, m)
95%	With pyridine; In dichloromethane; at 20℃; for 17h;	To a solution of <strong>[13535-01-8]3-amino-5-bromopyridine</strong> (1.0 g, 5.78 mmol) and pyridine (1.3 mL, 12.9 mmol) in DCM (5 mL) is added acetic anhydride (0.6 mL, 6.358 mmol) dropwise. The mixture is stirred at room temperature for 17 h. The mixture is concentrated and the resulting crude product is purified by normal phase using 0-75% EtOAc in heptane as the gradient to afford N-(5-bromo-pyridin-3-yl)-acetamide (1.18 g, 95% yield).
89.04%	In dichloromethane; at 20℃;Industrial scale;	To a 1 L four-necked flask equipped with a magnetic stirrer and thermometer, 45.04 g (0.259 mol)<strong>[13535-01-8]3-amino-5-bromopyridine</strong>, adding 500mL of dichloromethane to dissolve at room temperature, slowly adding dropwise 26.44g (0.259mol) of acetic anhydride, dropping the reaction for 2 to 5 hours,TLC control to the end of the reaction, the vacuum distillation, the residue was dissolved in ethyl acetate, 200mL saturated sodium bicarbonate was washed twice and evaporated to dryness, to give 3-acetylamino-5-bromopyridine 49.57g, yield 89.04%.

Reference： [1]Patent: WO2019/126730,2019,A1 .Location in patent: Paragraph 0466
[2]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2014,vol. 53,p. 83 - 89
[3]Patent: US2014/323468,2014,A1 .Location in patent: Paragraph 0601
[4]Patent: CN103601745,2017,B .Location in patent: Paragraph 0035; 0036
[5]Recueil des Travaux Chimiques des Pays-Bas,1955,vol. 74,p. 1062,1068

3
[ 13535-01-8 ]
[ 407-20-5 ]

Yield	Reaction Conditions	Operation in experiment
55%	With tetrafluoroboric acid; sodium nitrite; In water; at -8℃; for 1h;	Step 2: 3-Bromo-5-fluoropyridine A at -10 C. cooled solution of 10.0 g (0.058 mol) of 3-Amino-5-bromopyridine in 59 ml of 50% Tetrafluoroboric acid was treated by dropwise addition of a solution of 4.19 g (0.06 mol) of sodium nitrite in 13 ml of water. After stirring for 1 h at -8 C., 150 ml of ether was added to the brown suspension. The crude diazonium salt was filtered off, and washed with ether. This crude salt was then added in portions to 200 ml of toluene heated at 80 C. After stirring for 1 h at 90 C., the organic phase was concentrated. The light yellow residue was suspended in 150 ml of water and the pH was adjusted to 11 with 32% sodium hydroxide solution. The resulting solution was extracted three times with 200 ml of methylene chloride. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated. The crude material 15.4 g (brown oil) was purified by vaccum distillation (10 mBar, 35 C.) and yielded 5.6 g (0.032 mol, 55%) of the title compound as a colorless oil (ISP): m/e=176.1, 178.1 (M+H+).

Reference： [1]Patent: US2006/199960,2006,A1 .Location in patent: Page/Page column 21
[2]Recueil des Travaux Chimiques des Pays-Bas,1955,vol. 74,p. 1062,1068

4
[ 13535-01-8 ]
[ 233770-01-9 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1955,vol. 74,p. 1062,1068

5
[ 28733-43-9 ]
[ 13535-01-8 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium hydroxide; bromine; In water; at 0 - 70℃;	EXAMPLE P; 3-Bromo-5-fluoropyridine; Step 1; 3-Amino-5-bromopyridine; To a ice-cold solution of 31.8 g (0.79 mol) of Sodium hydroxide and 40.7 g (0.255 mol) of Bromine in 340 ml of water were added 42.0 g (0.209 mol) of commercially available 5-Bromonicotinamide. The mixture was allowed to warm up to room temperature and then heated for 1 h at 70° C. The resulting brown suspension was allowed to cool to room temperature. The aqueous phase was saturated with brine and extracted three times with a 1:1 mixture of THF and t-Butyl-methyl ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vaccuo. Concentration in vaccuo yielded 39.1 g of a dark brown residue which was purified by flash chromatography (heptane/ethyl acetate 1:1) to yield the title compound as a brown solid (total 70.2 g, 70percent)
70%	With sodium hydroxide; bromine; In water; at 0 - 70℃; for 1h;	Step 1: 3-Amino-5-bromopyridine To a ice-cold solution of 31.8 g (0.79 mol) of Sodium hydroxide and 40.7 g (0.255 mol) of Bromine in 340 ml of water were added 42.0 g (0.209 mol) of commercially available 5-Bromonicotinamide. The mixture was allowed to warm up to room temperature and then heated for 1 h at 70° C. The resulting brown suspension was allowed to cool to room temperature. The aqueous phase was saturated with brine and extracted three times with a 1:1 mixture of THF and t-Butyl-methyl ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vaccuo. Concentration in vaccuo yielded 39.1 g of a dark brown residue which was purified by flash chromatography (heptane/ethyl acetate 1:1) to yield the title compound as a brown solid (total 70.2 g, 70percent), MS (ISP): m/e=173.1, 175.1 (M+H+).
62%		To a solution of NaOH (22.9 g, 572 mmol) in water (245 mL) at 0-5° C. (ice salt bath) was added bromine (9.44 mL, 184 mmol) maintaining the temperature at 0-5° C., to produce a sodium hypobromite solution. To this NaOBr-sol. was added commercially available <strong>[28733-43-9]3-bromonicotinamide</strong> (30.15 g, 150 mmol) all at once with vigorous stirring. After being stirred for 15 min, the solution is clear and mixture was heated to 70-75° C. for 45 min. Cooled to 23° C., saturated with solid NaCl, extracted with TBME/THF (3.x.300 mL), dried over Na2SO4. Removal of the solvent in vacuum gave a dark brown oil which was purified by silica gel column chromatography with heptane/EtOAc 1:1-->2:3 to give the title compound as a brown solid (16.036 g, 62percent). MS (ISP) 173.1 [(M+H)+], 175.2 [(M+2+H)+].

62%	With sodium hydroxide; bromine; In water; at 85 - 100℃; for 3h;	Example 23B 3-amino-5-bromopyridine A solution of 3M NaOH (250 mL) at room temperature was treated with bromine (25.9 g, 162 mmol), stirred for 15 minutes, treated with <strong>[28733-43-9]5-bromonicotinamide</strong> (25 g, 124 mmol), stirred for 45 minutes, heated to 85-100° C. for 3 hours, cooled to room temperature, adjusted to pH 1 with 10percent HCl (aq.) washed twice with diethyl ether. The aqueous layer was adjusted to pH~10-11 with solid NaOH, and extracted four times with diethyl ether and twice with dichloromethane. The combined extracts were dried (MgSO4), filtered, and concentrated to provide the desired product (13.3 g, 62percent).
58.5%	With sodium hydroxide; bromine; In water; at 75℃; for 0.75h;	Bromine (18.76 g, 117.4 mmol) was added to a solution of sodium hydroxide (23.88 g, 597 mmol) in water (200 mL). To this solution was added <strong>[28733-43-9]5-bromonicotinamide</strong> (20.00 g, 99.49 mmol). The reaction mixture was heated to 75° C. for 45 minutes. The reaction was cooled and acidified with concentrated hydrochloric acid. Some insoluble material was present. The insolubles were removed by filtration. The solution was washed with ethyl acetate (150 mL, 2 times). The aqueous solution was basified with sodium hydroxide solution (pH 10). The mixture was extracted into ethyl acetate (200 mL, 2 times). The ethyl acetate was dried and condensed to yield compound A (10.07 g, 58.5percent yield).

Reference： [1]ChemMedChem,2014,vol. 9,p. 217 - 232
[2]Patent: US2006/160857,2006,A1 .Location in patent: Page/Page column 56
[3]Patent: US2006/199960,2006,A1 .Location in patent: Page/Page column 21
[4]Patent: US2006/217387,2006,A1 .Location in patent: Page/Page column 31
[5]Patent: US2003/199511,2003,A1 .Location in patent: Page/Page column 23
[6]Patent: US2009/170886,2009,A1 .Location in patent: Page/Page column 28
[7]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1931,vol. 51,p. 542,571; dtsch. Ref. S. 73, 76
Chem.Abstr.,1931,p. 5427
[8]Journal of Medicinal Chemistry,2007,vol. 50,p. 6265 - 6273

6
[ 15862-30-3 ]
[ 13535-01-8 ]

Reference： [1]Roczniki Chemii,1938,vol. 18,p. 210
Chemisches Zentralblatt,1939,vol. 110,p. 2779

7
[ 13535-01-8 ]
[ 7732-18-5 ]
[ 3543-01-9 ]

Reference： [1]Chemische Berichte,1936,vol. 69,p. 32,37

8
[ 13535-01-8 ]
[ 2719-23-5 ]
N-[5-(5-aminopyridin-3-yl)thiazol-2-yl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of <strong>[2719-23-5]2-acetamidothiazole</strong> (0.285 g), 3-amino-5-bromopyridine (0.381 g), caesium fluoride (0.906 g,), palladium(II) acetate (0.036 g) and dry DMSO (15 ml) was stirred <n="78"/>and purged with nitrogen for 10 minutes. Tri-tert-butylphosphine (0.34M solution in hexane; 1 ml) was added and the mixture was heated to 160C for 4 hours. The reaction mixture was cooled, diluted with n-butanol (200 ml) and partitioned between n-butanol and water (200 ml). The organic phase was washed with water and with an aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The residual solid was triturated under water. The solid so obtained was dried under vacuum. There was thus obtained N-[5-(5-aminopyridin-3-yl)thiazol-2-yl]acetamide as a solid (0.3 g); 1H nuMR Spectrum: (DMSOd6) 2.17 (s, 3H), 5.42 (d, 2H), 7.07 (t, IH), 7.81 (s, IH), 7.85 (d, IH), 8.04 (d, IH); Mass Spectrum: M+H+ 235.

Reference： [1]Patent: WO2007/129044,2007,A1 .Location in patent: Page/Page column 76-77

9
[ 13535-01-8 ]
[ 213318-44-6 ]
[ 1000068-56-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 80℃; for 1h;	To 3-amino-5-bromo-pyridine (2.2 mmol), l-Boc-indole-2-boronic acid (2.2 mmol), Pd(PPh3)4 (70 mg, 0.061 mmol) and K2CO3 (7.2 mmol) was added 7 mL MeCN and 3 mL H2O and the mixture was heated in a sealed tube at 80 0C for 1 h. The water layer was separated and the organic phase was dried over MgSO4. Filtration and removal of the solvent gave 0.80 g of the title compound.

Reference： [1]Patent: WO2007/147874,2007,A1 .Location in patent: Page/Page column 132

10
[ 13535-01-8 ]
[ 167678-46-8 ]
3-(5-bromo-pyridin-3-yl-carbamoyl)-2-methyl-phenyl-acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With triethylamine In tetrahydrofuran at 20℃; for 18h;	Preparation of 3-(5-bromo-pyridin-3-yl-carbamoyl)-2-methyl-phenyI-acetate; To a solution of 3-amino-5-bromo pyridine (500mg, 2.89mmol) and NEt3 in THF(5ml), a solution of acetic acid 3-chlorocarbonyl-2-methyl-phenyl ester (614mg,2.89mmol) in THF (5ml) was added dropwise. Reaction was stirred for 18 hoursat room temperature. Solvent was removed under vacuum. Residue wasdissolved in EtOAc (30ml) and extracted with 10% citric acid (30ml), de-ionisedwater (30ml), 1M NaOH (30ml) and brine (30ml), dried over MgSO4 filtered andevaporated. Residue was purified by flash chromatography. Mixture was preabsorbed onto flash silica and eluted with 50% EtOAc/petroleum ether 40/60 (v:v).3-(5-Bromo-pyridin-3-yl-carbamoyl)-2-methyl-phenyl-acetate was isolated in a 51%yield.LC-MS, m/z [MHf 349. Retention time, 1.89 minutes. Method B.1H NMR (CDCI3, 400MHz): 8 = 2.26 (s, 3H, CH3), 2.29 (s, 3H, CH3), 7.11 (d, 1H,Ar-H), 7.25 (m, 2H, Ar-H), 8.18 (s, 1H, Ar-H), 8.41 (s, 1H, Ar-H), 8.72 (d, 2H, Ar-H,N-H).

Reference： [1]Current Patent Assignee: VICHEM CHEMIE KFT - WO2006/10637, 2006, A2 Location in patent: Page/Page column 109

11
[ 13535-01-8 ]
[ 7151-68-0 ]
N-(5-bromo-pyridin-3-yl)-3-methoxy-4-methyl-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In tetrahydrofuran; at 20 - 50℃; for 18.5h;	Preparation of 5-[5-(3-hydroxy-phenyl)-pyridin-3-ylamino]-methyl>-2-methylphenol (247); NB(OH)2HBTUEt,NTHFPd(OAc)2PPh3NaHCO3DMF/H2OBH3-SMe2THFOHOH268BBr,DCMOHPreparation of N-(5-bromo-pyridin-3-yl)-3-methoxy-4-methyl-benzamide; To a suspension of 4-methyl-3-methoxy benzoic acid (480mg, 2.9mmol), 3-bromo-5-amino pyridine (500mg, 2,9mmol) and NEt3 (604pJ, 3.44mmol) in THF (10ml) at room temperature under a Na atmosphere, HBTU (1.1 Og-, 2.90mmol) was added. Reaction was stirred for 30 minutes before being warmed to 50C and stirred for 18 hours. Solvent was removed under vacuum, residue was dissolved in EtOAc(30ml) and washed with 10% citric acid (30ml), Na2CO3 (30ml), de-ionised water(30ml) and brine (30ml), dried over MgSO4, filtered and evaporated. Residue waspurified by column chromatography. Mixture was pre absorbed onto flash silicaand eluted with 40% EtOAc/petroleum ether 40/60 (v:v). N-(5-Bromo-pyridin-3-yl)-3-methoxy-4-methyl-benzamide was isolated in 52% yield.LC-MS, m/z [MH]+ 321. Retention time, 2.14 minutes, Method B.1H NMR (DMSO-c/6, 400MHz): 8 = 2.02 (s, 3H, CH3), 3.67 (s, 3H, CH3), 7.11 (d,1H, Ar-H), 7.27 (s, 1H, Ar-H), 7.30 (d, 1H, Ar-H), 8.21 (s, 1H, Ar-H), 8.30 (s, 1H,Ar-H), 8.70 (s, 1H, Ar-H), 10.29 (s, 1H, NH).

Reference： [1]Patent: WO2006/10637,2006,A2 .Location in patent: Page/Page column 106-107

12
[ 13535-01-8 ]
[ 110-46-3 ]
[ 212332-40-6 ]

Yield	Reaction Conditions	Operation in experiment
	In hydrogenchloride; isopropyl alcohol	10 5-Isopropoxy-3-bromopyridine 5-Isopropoxy-3-bromopyridine A slurry of 5-amino-3-bromopyridine (1.29 g, 7.46 mmol) in 6M HCl solution (5 mL) was stirred 30 min at ambient temperature. The mixture was concentrated under high vacuum, and the residue was vacuum dried for 15 h at 50° C., affording a tan solid. The solid was slurried in 2-propanol (25 mL), and treated with isoamyl nitrite (1.70 g, 15.00 mmol). The mixture was stirred and heated under reflux for 1.5 h. The solution was concentrated by rotary evaporation, and the residue was partitioned between diethyl ether and 1M NaOH solution. The aqueous layer was separated and extracted with ether. The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation producing an orange oil (2.03 g). The oil was purified by vacuum distillation, collecting the fraction with bp 105-115° C. at 9 mm Hg. The distilled product was further purified by column chromatography on silica gel, eluding with 10-20% (v/v) diethyl ether in hexane. Selected fractions, based upon TLC analysis (Rf 0.40 in hexane-ether, (4:1, v/v)) were combined and concentrated by rotary evaporation to give 566.0 mg (35.2%) of a clear, colorless oil.

Reference： [1]Current Patent Assignee: CATALYST BIOSCIENCES, INC. - US2003/125345, 2003, A1

13
[ 13535-01-8 ]
C₁₁H₁₈O₆ [ No CAS ]
[ 847436-88-8 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol at 60 - 70℃; for 0.5h; Heating / reflux;	1.A A mixture of triethyl orthoformate (10 mL, 60.1 mmol) and 2,2-dimethyl-[l,3]- dioxane-4,6-dione (40.9 g, 0.23 mol) (Meldrum's acid) was heated at 92 0C for 90 minutes and then cooled to 70 °C over one hour. 3-Amino-5-bromopyridine (40.9 g, 0.Z0 mol) was slowly added over 10 minutes with an ethanol rinse while maintaining the reaction temperature between 60 and 70 °C. The reaction was then heated for an additional 20 minutes and allowed to cool to room temperature. The reaction mixture was filtered and washed with ethanol (150 mL) yielding a tan solid. The solid was dried under v^acuum for 2 hours to yield 59.14 g of 5-[(5-bromopyridin-3-yl)imino]methyl}-2,2-dimethLyl-l,3- dioxane-4,6-dione as a light yellow crystalline solid, mp 200-202 0C. 1H NMR (300 MHz, CDCl3) δ 11.26 (d, J= 14.3 Hz, IH), 8.80 (d, J= 2.3 Hz, I H), 8.62 (d, J- 14.3 Hz, IH), 8.56(d, J= 1.9 Hz, IH), 8.44-8.40 (m, IH), 1.68 (s, 6H).

Reference： [1]Current Patent Assignee: 3M CO - WO2006/38923, 2006, A2 Location in patent: Page/Page column 66

14
[ 13535-01-8 ]
[ 5527-95-7 ]
[ 887374-79-0 ]

Yield	Reaction Conditions	Operation in experiment
		Synthesis of the intermediate: (5-Bromo-pyridin-3-yl)-(4-chloro-3- fluoro-benzyl)-amine; To 5-Bromo-pyridin-3-ylamine (2.2g, 17.34mmol) and 4-chloro-3-fluoro- benzaldehyde (2.75g, 17.34mmol) in dry DCM (25ml) was added sodium triacetoxyborohydride (5.51g, 26.01mmol) and stirred at room temperature overnight. The reaction was then quenched with NaHCO3 (aq), diluted with DCM, washed with water, dried (MgSO4), evaporated and purified on silica gel by flash chromatography eluting with petroleum ether: ethyl acetate (1:1) to give (5-Bromo-pyridin-3-yl)-(4-chloro-3- fluoro-benzyO-amine (2.16g). IH (400MHz, CDCI3) 4.11-4.15 (IH, bs, NH), 4.31-4.33 (2H, m), 6.97-6.98 (IH, m, Ar), 7.06-7.15 (2H, m, Ar), 7.37-7.41 (IH, m, Ar), 7.95-7.96 (IH, m, Ar), 8.04 (IH, s, Ar); m/z 316 (M+l).

Reference： [1]Patent: WO2006/51311,2006,A1 .Location in patent: Page/Page column 39

15
[ 13535-01-8 ]
[ 214470-55-0 ]
[ 214484-43-2 ]

Yield	Reaction Conditions	Operation in experiment
74.5%	toluene-4-sulfonic acid; In 2-methoxy-ethanol; at 153℃; for 7h;Heating / reflux;	A mixture of 249 mg (1 mmole) of 3-cyano-4-chloro-6,7-dimethoxy quinoline, 346 mg (2 mmoles) of 3-amino-5-bromo pyridine and 20 mg (about 0.1 mmole) of p-toluene-sulfonic acid monohydrate in 5 ml of 2-methoxy ethanol was stirred and refluxed in an oil bath at 153C for 7 hours. On cooling overnight to room temperature, the solid was filtered and washed with ethanol, then with ether to give 287 mg (74.5%) of N-[4-[(5-bromo-3-_pyridinyl)amino] -6,7-dimethoxy-3-quinolinecarbonitrile, which melted at 272-275 C. mass spectrum (electrospray, m/e) M+H = 384.9, 386.8.

Reference： [1]Patent: EP973746,2003,B1 .Location in patent: Page/Page column 44-45

16
[ 13535-01-8 ]
[ 2033-24-1 ]
[ 122-51-0 ]
[ 847436-88-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: cycl-isopropylidene malonate; orthoformic acid triethyl ester at 92℃; for 1.5h; Stage #2: 3-amino-5-bromopyridine In ethanol at 60 - 70℃; for 0.5h;	10.A Part A A mixture of triethyl orthoformate (10 mL, 60.1 mmol) and 2,2-dimethyl-[1,3]- dioxane-4,6-dione (40.9 g, 0.23 mol) (Meldrum's acid) was heated at 92 °C for 90 minutes and then cooled to 70 °C over one hour. 3-Amino-5-bromopyridine (40.9 g, 0.20 mol) was slowly added over 10 minutes with an ethanol rinse while maintaining the reaction temperature between 60 and 70 °C. The reaction was then heated for an additional 20 minutes and allowed to cool to room temperature. The reaction mixture was filtered and washed with ethanol (150 mL) yielding a tan solid. The solid was dried under vacuum for 2 hours to yield 59.14 g of 5-[(5-bromopyridin-3-yl)imino]methyl}-2,2-dimethyl-1,3- dioxane-4,6-dione as a light yellow crystalline solid, mp 200-202 °C.
	Stage #1: cycl-isopropylidene malonate; orthoformic acid triethyl ester at 70 - 92℃; for 2.5h; Stage #2: 3-amino-5-bromopyridine In ethanol at 60 - 70℃; for 0.5h;	155.A mixture of triethyl orthoformate (10 mL, 60.1 mmol) and 2,2~dimethyl-[l,3]- dioxane-4,6-dione (40.9 g, 0.23 mol) (Meldrum's acid) was heated at 92 °C for 90 minutes and then cooled to 70 °C over one hour. 3-Amino-5-bromopyridine (40.9 g, 0.20 mol) was slowly added over 10 minutes with an ethanol rinse while maintaining the reaction temperature between 60 and 70 0C. The reaction was then heated for an additional 20 minutes and allowed to cool to room temperature. The reaction mixture was filtered and washed with ethanol (150 mL) yielding a tan solid. The solid was dried under vacuum for 2 hours to yield 59.14 g of 5-[(5-bromopyridin-3-yl)imino]methyl}-2,2-dimethyl-l,3- dioxane-4,6-dione as a light yellow crystalline solid, mp 200-202 °C. 1H NMR (300 MHz, CDCl3) δ 11.26 (d, J= 14.3 Hz, IH), 8.80 (d, J= 2.3 Hz, IH), 8.62 (d, J= 14.3 Hz, IH), 8.56(d, J= 1.9 Hz, IH), 8.44-8.40 (m, IH), 1.68 (s, 6H).
	Stage #1: cycl-isopropylidene malonate; orthoformic acid triethyl ester at 70 - 92℃; for 2.5h; Stage #2: 3-amino-5-bromopyridine In ethanol at 60 - 70℃; for 0.5h;	205.A Part A A mixture of triethyl orthoformate (10 ML, 60.1 mmol) and 2,2-dimethyl- 1, 3-dioxane-4,6-dione (40.9 g, 0.23 mol) (Meldrum's acid) was heated at 92 °C for 90 minutes and then cooled to 70 °C over one hour. 3-Amino-5-bromopyridine (40.9 g, 0.20 mol) was slowly added over 10 minutes with an ethanol rinse while maintaining the reaction temperature between 60 and 70 °C. The reaction was then heated for an additional 20 minutes and allowed to cool to room temperature. The reaction mixture was filtered and washed with ethanol (150 mL) yielding a tan solid. The solid was dried under vacuum for 2 hours to yield 59.14 g of 5- { [ (5- bromopyridin-3-yl) imino] METHYL}-2, 2-DIMETHYL-1, 3-dioxane-4,6-dione as a light yellow crystalline solid, mp 200-202 °C.

Reference： [1]Current Patent Assignee: 3M CO - WO2005/123080, 2005, A2 Location in patent: Page/Page column 69
[2]Current Patent Assignee: 3M CO - WO2006/28545, 2006, A2 Location in patent: Page/Page column 222
[3]Current Patent Assignee: 3M CO - WO2005/18551, 2005, A2 Location in patent: Page/Page column 197

17
[ 13535-01-8 ]
[ 13918-92-8 ]
[ 1083326-23-1 ]

Yield	Reaction Conditions	Operation in experiment
70%		To a solution of 5-bromo-2-chloropyridin-3-amine (0.500 g, 2.89 mmol) in pyridine (1.45 ml) was dropwise added 2,4-difluorobenzene-1-sulfonyl chloride (0.614 ml, 2.89 mmol) at 0 C. The mixture was stirred for 40 min at room temperature and acidified with 1 N HCl. The residue was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give N-(5-bromopyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.70 g, 70% yield) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) delta 6.92-7.04 (2H, m), 7.76-7.84 (1H, m), 7.86-7.95 (1H, m), 8.27 (1H, d, J=2.4 Hz), 8.44 (1H, d, J=2.4 Hz); NH peak was not observed.
	With pyridine; In dichloromethane; at 20 - 45℃;Inert atmosphere;	General procedure: To a solution of 76 (120 mg, 0.37 mmol) in dry pyridine (12 mL) under N2 at RT, was added 2,4-difluorobenzenesulphonyl chloride (159 mg, 0.74 mmol) in CH2Cl2 (1.5 mL) dropwise over 5 min. The mixture was stirred at 45 C under N2 for 16 , and the solvent then removed under reduced pressure. The reaction was quenched with a little water and the resulting solid collected by filtration and washed with water and Et2O. Purification was carried out by trituration with hot CH2Cl2/MeOH solution to give 4 as a pale brown solid (65%)
		General procedure: To 5-(5-(5-Aminopyridin-3-yl)thiophen-2-yl)-2-methyl- isoindolin-1-one (49) (225 mg, 0.79 mmol) in dry pyridine (23 mL) under N2 at RT,was added dropwise, 2,4-difluorobenzenesulphonyl chloride (336 mg, 1.58 mmol) in CH2Cl2(3 mL) over 5 min. The suspension was heated to 45 C under N2 for 4 h., at which pointanother portion of 2,4-difluorobenzenesulphonyl chloride (169 mg, 0.79 mmol) in CH2Cl2 (2mL) was added. The whole mixture was left to stir for at 45 C under N2 for 16 h., then thesolvent removed under reduced pressure. The resulting residue was suspended in acetone (10mL), 1 M HCl (20 mL) added, and the entire mixture stirred for 10 minutes. The solid wasthen collected by filtration, washed well with 1 M HCl and water, dried, and purified bychromatography as described below. In cases where the bis-sulphonamide was also formed, a second step was introduced wherethe crude product above was treated with a 1:1 mixture of 1,4-dioxane and 2 M NaOH. Thecrude sulphonamide resulting from subsequent acidification of the reaction mixture wasisolated by filtration, washed well with water, and dried. Purification was carried out by flashcolumn chromatography (2% MeOH/CH2Cl2 as eluant), giving the title compound as a paleyellow solid (211 mg, 545).

	With pyridine; at 0℃; for 1.05h;	Intermediate 4Preparation of lambda/-(5-bromo-3-pyridinyl)-2,4-difluorobenzenesulfonamide <n="78"/>To a cold (0 0C) stirred solution of <strong>[13535-01-8]3-amino-5-bromopyridine</strong> (18.6 g, 107.4 mMol) in dry pyridine (100 mL) was added 2,4-difluorobenzenesulfonyl chloride (25 g, 112.8 mMol) over 3 minutes. The reaction mixture was stirred at 0 0C for 1 h and evaporated to dryness under vacuum. The residue was diluted with H2O (400 mL) and EtOAc (400 mL). The organic layer was washed with H2O and brine, and the combined aqueous layers were extracted with EtOAc (100 mL). The combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in boiling EtOAc (200 mL), and placed in a freezer for 2 days. Two crops were obtained through filtration, which were combined and triturated with boiling 35% EtOAc in hexanes. After cooling to room temperature, the precipitate was collected by filtration and dried to constant weight to provide 27.2 g of iV-(5-bromo-3-pyridinyl)-2,4- difluorobenzenesulfonamide as a light orange solid. MS (ES) m/e 351.0 (M + H)+.
	With pyridine; at 0℃; for 1.05h;	To a cold (0 0C) stirred solution of <strong>[13535-01-8]3-amino-5-bromopyridine</strong> (107.4 mmol) in dry pyridine (100 mL) was added 2,4-difluorobenzenesulfonyl chloride (112.8 mmol) over 3 min. The reaction mixture was stirred at 0 0C for 1 h and evaporated to dryness under vacuum. The residue was diluted with water (400 mL) and ethyl acetate (400 mL). The organic layer was washed with water and brine, and the combined aqueous layers were extracted with ethyl acetate (100 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in boiling ethyl acetate (200 mL) and then placed in a freezer for 2 days. Two crops of solid were obtained through filtration, which were combined and triturated with boiling 35% ethyl acetate/hexanes. After cooling to room temperature, the precipitate was collected by filtration and dried to constant weight to provide 27.2 g of N-(5-bromo-3-pyridinyl)- 2,4-difluorobenzenesulfonamide as a light orange solid. MS (ES) m/e 351.0 (M + H)+

Reference： [1]Patent: US2012/238587,2012,A1 .Location in patent: Page/Page column 18
[2]European Journal of Medicinal Chemistry,2017,vol. 137,p. 139 - 155
[3]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1050 - 1054
[4]Patent: WO2008/157191,2008,A2 .Location in patent: Page/Page column 76-77
[5]Patent: WO2008/150827,2008,A1 .Location in patent: Page/Page column 75

18
[ 13535-01-8 ]
[ 24424-99-5 ]
[ 361550-43-8 ]

Yield	Reaction Conditions	Operation in experiment
81%		To 5-bromopyridin-3-amine (2.00 g, 11.5 mmol) in THF (25 mL) was added sodium hexamethyldisilazide (25.4 mL, 25.4 mmol, 1 M in THF) and the reaction mixture was stirred at room temperature for 20 min. Boc-anhydride (2.52 mL, 15.6 mmol) in THF (10 mL) was added slowly and the reaction mixture was stirred for an additional 24 h at room temperature. 0.1 M HC1 (30 mL) was added and the reaction mixture was extracted with ethyl acetate. The combined organic extracts were washed successively with water and brine. The organic layer was dried, filtered and concentrated under reduced pressure to afford tert-butyl 5-bromopyridin-3- ylcarbamate (2.5 g, 81 %), which was used without further purification. LCMSMethod 0018: retention time 1.84 min, [M+l] = 275.0 XH NMR (400 MHz, DMSO- d6) delta (ppm): 9.82 (s, 1H), 8.57 (d, 1H, J= 2.4Hz), 8.30 (d, 1H, J= 2Hz), 8.18 (s, lH), 1.49 (s, 9H).
70%	With dmap; triethylamine; In N,N-dimethyl-formamide; at 90℃;	3-Amino-5-bromopyridine (2.0 g,11.6 mmol), di-tert-butyl-dicarbonate (3.03 g, 13.9 mmol), triethylamine (2.42 mL,17.3 mmol) and 4-dimethylaminopyridine (142 mg, 1.16 mmol) were dissolved in dryDMF (20 mL) and heated at 90C overnight. Upon cooling, the reaction mixture wasdiluted with water (100 mL) and the resulting solid extracted into EtOAc (3x80 mL). Thecombined EtOAc fractions were washed with water (3x100 mL), brine (2x100 mL), dried(Na2SO4) and filtered. The solvent was removed under reduced pressure to afford a crudesolid which was purified by filtration through a plug of flash silica gel(20% EtOAc/hexanes as eluent). The title compound was isolated as a white solid (2.22 g,70%). ?H NMR [400 MHz, (CD3)2S0] 6 8.33 (br d, J = 1.5 Hz, 1 H), 8.24 (br s, 2 H),6.62 (br s, 1 H), 1.53 (s, 9 H). LRMS (APCI?) calcd for C10H,3BrN2O2 273, 275 (MH4),found 273, 275.
54.9%	With sodium hexamethyldisilazane; In tetrahydrofuran; dichloromethane; at 0℃;	To a solution of 5-bromopyridin-3-amine (3 g, 17.34 mmol) in dry DCM (25 ml), di-tert-butyl dicarbonate (3.78 g, 17.34 mmol) was added under stirring. The resulting solution was cooled to 0 C and a solution of sodium bis(trimethylsilyl)amide 1 M in THF (17.34 ml, 17.34 mmol) was added dropwise over 20 mm. The solution was stirred overnight. Then, solution was diluted with DCM (40 mL) and washed once with sat.NaHCO3. Organic phase was dried over Na2SO4, filtered and concentrated. Crude was finally purified on Biotage Si 50 g with a gradient of hexane and EtOAc. The title compound was recovered (2.60g, 54.9 % yield) as a white solid.UPLC-MS: 1.07 mm, 273 [M+H]+, method 9.

54.9%	With sodium hexamethyldisilazane; In tetrahydrofuran; dichloromethane; at 0℃;	To a solution of 5-bromopyridin-3-amine (3 g, 17.34 mmol) in dry DCM (25 ml), di-tert-butyl dicarbonate (3.78 g, 17.34 mmol) was added under stirring. The resulting solution was cooled to 0 C. and a solution of sodium bis(trimethylsilyl)amide 1 M in THF (17.34 ml, 17.34 mmol) was added dropwise over 20 min. The solution was stirred overnight. Then, solution was diluted with DCM (40 mL) and washed once with sat. NaHCO3. Organic phase was dried over Na2SO4, filtered and concentrated. Crude was finally purified on Biotage Si 50 g with a gradient of hexane and EtOAc. The title compound was recovered (2.60 g, 54.9% yield) as a white solid.UPLC-MS: 1.07 min, 273 [M+H]+, method 9.
	With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 2h;	Intermediate 212 (5-Bromo-pyridin-3-yl)-carbamic acid tert-butyl ester; To a solution of <strong>[13535-01-8]3-amino-5-bromopyridine</strong> (Sigma-Aldrich, St. Louis, USA) (1 eq, 5.7 mmol, 1.00 g) in DMF (10 ml) are added Boc2O (1.1 eq, 6.3 mmol, 1.37 g) and TEA (0.25 eq, 1.44 mmol, 0.2 ml). The resulting mixture is stirred for 2 h at 90 C., then poured into water and extracted with EtOAc. The organic layer is washed with water and sat. aqueous NaCl solution, dried over MgSO4, and concentrated under reduced pressure. The crude product is purified by column chromatography (hexane/EtOAc) to give the title compound; [M+H]+=273/275.

Reference： [1]Patent: WO2011/28741,2011,A1 .Location in patent: Page/Page column 247-248
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 8709 - 8715
[3]Patent: WO2014/28968,2014,A1 .Location in patent: Page/Page column 101
[4]Patent: WO2015/91685,2015,A1 .Location in patent: Page/Page column 141
[5]Patent: US2015/166549,2015,A1 .Location in patent: Paragraph 0870; 0871; 0872
[6]Patent: US2009/181941,2009,A1 .Location in patent: Page/Page column 55
[7]Journal of Medicinal Chemistry,2017,vol. 60,p. 3795 - 3803

19
[ 13535-01-8 ]
[ 14788-12-6 ]
[ 1171897-16-7 ]

Yield	Reaction Conditions	Operation in experiment
	With tributyl-amine; 2-chloro-1-methyl-pyridinium iodide; In dichloromethane; at 50℃; for 4h;	Intermediate 26 N-(5-Bromo-pyridin-3-yl)-3-dimethylamino-propionamide; To a solution of 3-amino-5-bromopyridine (Sigma-Aldrich, St. Louis, USA) (1 eq, 11.2 mmol, 2.00 g) and 3-dimethylaminopropionic acid hydrochloride (ABCR GmbH & Co. KG, Karlsruhe, Germany) (1 eq, 11.2 mmol, 1.74 g) in DCM (50 ml), tributylamine (3.6 eq, 40.4 mmol, 9.8 ml) and 2-chloro-1-methylpyridinium iodide (1.2 eq, 13.5 mmol, 3.54 g) are added. The resulting mixture is heated at 50 C. for 4 h, then the solvents are removed in vacuo, aqueous NaOH solution (1 M) is added, and the mixture is extracted with DCM. The organic layer is dried with MgSO4, filtered, and the solvent is removed in vacuo. Purification by column chromatography (DCM/MeOH) yields the title compound; [M+H]+=273.

Reference： [1]Patent: US2009/181941,2009,A1 .Location in patent: Page/Page column 49

20
[ 13535-01-8 ]
[ 98-80-6 ]
[ 31676-54-7 ]

Yield	Reaction Conditions	Operation in experiment
13%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 20 - 90℃; for 20h;	Step A: 5-Phenylpyridin-3-amine A mixture of 5-bromopyridin-3-amine (248 mg, 1.43 mmol), Pd(PPh3)4 (50.4 mg, 0.04 mmol), toluene (3 mL), sodium carbonate (2 M, 3 mL, 6 mmol), and phenylboronic acid (195 mg, 1.60 mmol) dissolved in ethanol (3 mL) was heated for 4 hours in an oil bath at 90 C. and allowed to cool to room temperature for 16 hours. The reaction mixture was transferred to a separatory funnel and partitioned between ethyl acetate and water. The aqueous phase was washed once more with ethyl acetate, and the combined organic phases were washed with brine and dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (80% ethyl acetate/hexanes) to afford 5-phenylpyridin-3-amine (31.9 mg, 0.19 mmol, 13% yield) as a white solid. 1H NMR (500 MHz, CDCl3) delta ppm 8.17-8.42 (m, 1H), 8.02-8.20 (m, 1H), 7.32-7.62 (m, 4H), 7.25 (s, 1H), 7.06-7.20 (m, 1H). MS (LC/MS) R.T.=0.91; [M+H]+=171.09.
13%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 90℃; for 4h;oil bath heating;	Step A: 5-Phenylpyridin-3 -amineA mixture of 5-bromopyridin-3-amine (248 mg, 1.43 mmol), Pd(PPli3)4 (50.4 mg, 0.04 mmol), toluene (3 mL), sodium carbonate (2 M, 3 mL, 6 mmol), and phenylboronic acid (195 mg, 1.60 mmol) dissolved in ethanol (3 mL) was heated for 4 hours in an oil bath at 90 C and allowed to cool to room temperature for 16 hours. The reaction mixture was transferred to a separatory funnel and partitioned between ethyl acetate and water. The aqueous phase was washed once more with ethyl acetate, and the combined organic phases were washed with brine and dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (80% ethyl acetate/hexanes) to afford 5-phenylpyridin-3- amine (31.9 mg, 0.19 mmol, 13 % yield) as a white solid. ¾ NMR (500 MHz, CDCli) delta ppm 8.17 - 8.42 (m, 1 H), 8.02 - 8.20 (m, 1 H), 7.32 - 7.62 (m, 4 H), 7.25 (s, 1 H), 7.06 - 7.20 (m, 1 H). MS (LC/MS) R.T. = 0.91 ; [M+H]+ = 171.09.
13%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; toluene; at 90℃; for 4h;	A mixture of 5-bromopyridin-3-amine (248 mg,1.43 mmol), Pd(PPh3)4 (50.4 mg, 0.04 mmol), toluene (3ml.), sodium carbonate (2 M, 3 ml., 6 mmol), and phenylboronicacid (195 mg, 1.60 mmol) dissolved in ethanol (3 mL) was heated for 4 hours in an oil bath at 90 C. and allowed to cool to room temperature for 16 hours. The reaction mixturewas transferred to a separatory funnel and partitioned between ethyl acetate and water. The aqueous phase waswashed once more with ethyl acetate, and the combinedorganic phases were washed with brine and dried over magnesiumsulfate, filtered and concentrated in vacuo. The residuewas purified by colunm chromatography (80% ethylacetatelhexanes) to afford 5-phenylpyridin-3-amine (31.9mg, 0.19 mmol, 13% yield) as a white solid.

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 695 - 709
[2]Journal of Medicinal Chemistry,2019
[3]Patent: US2009/270405,2009,A1 .Location in patent: Page/Page column 84
[4]Patent: WO2011/53292,2011,A1 .Location in patent: Page/Page column 136
[5]Patent: JP5714745,2015,B2 .Location in patent: Paragraph 0271; 0272
[6]New Journal of Chemistry,2017,vol. 41,p. 15420 - 15432

21
[ 13535-01-8 ]
[ 124-63-0 ]
[ 1083326-18-4 ]

Yield	Reaction Conditions	Operation in experiment
97.3%	In pyridine; dichloromethane; at 10 - 35℃;Cooling with ice;	5-l3romo-3-aminopyridine (2.12 g, 11.84 mmol) was dissolved in dichioromethane (100.0 mE) and pyridine (20.0 mE). The solution was cooled with an ice bath, and methylsulfonyl chloride (0.9 mE, 11.84 mmol) was slowly added dropwise. The reaction solution was stirred at room temperature overnight, and then partitioned between water and dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 31-f (2.9 g, 97.3%). EC-MS (ESI): mlz=250.9 (M+H).
97.3%	In pyridine; dichloromethane; at 20℃;Cooling with ice;	5-l3romo-3-aminopyridine (2.12 g, 11.84 mmol) was dissolved in dichioromethane (100.0 mE) and pyridine (20.0 mE). The solution was cooled with an ice bath, to which was slowly added dropwise methylsulfonyl chloride (0.9 mE, 11.84 mmol). The reaction solution was stirred overnight at room temperature, and then partitioned between water and dichloromethane. The organic layer was separated, dried over anhydrous sodium sulphate, and concentrated under reduce pressure to give compound 13-f (2.9 g, 97.3%). EC-MS (ESI): mlz=250.9 (M+H).
96%	With pyridine; In dichloromethane; at 0 - 20℃; for 16h;	A solution of 5-bromopyridin-3-amine (500 mg, 2.89 mmol) and pyridine (4.3 mL, 54 mmol) was stirred in DCM (20 mL), then MsCl (331 mg, 2.89 mmol) was added into the above solution at 0 C, which was stirred at 20 C for 16 h. A yellow solution was formed. TLC showed the starting material was consumed completely. The solution was diluted with H2O (30 mL) and was extracted with DCM (15 mL x3). The organic layer was washed with brine (15 mL), dried over Na2SCri to give N-(5-bromopyridin-3-yl)methanesulfonamide (700 mg, yield: 96%) as a yellow solid.

90%	With pyridine; In dichloromethane; at 0 - 20℃;	A solution of 5-bromopyridin-3-amine (1.73 g, 10 mmol) and pyridine (15 mL) was stirred in DCM (80 mL), then MsCl (1.15 g, 10 mmol) was added into the above solution at O0C, which was stirred at room temperature for 12 h. The solution was diluted with H2O and was extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 to give N-(5- bromopyridin-3-yl)methanesulfonamide (2.8 g, 90%). MS for Ci2H9BrN2O (m/z) (M++H): 277, 279.
	With pyridine; at 0℃; for 1.16667h;	5-Bromo-3-pyridinamine (200 mg) was dissolved in pyridine (5 ml), cooled to 0 C and stirred for 10 min. Methanesulfonyl chloride (0.05 ml) was added dropwise and the reaction continued stirring for 1 hr. 2M HCI (aq) (5 ml) was added and the reaction was extracted with DCM, passed through a hydrophobic frit and evaporated to dryness. The residue was dissolved in DCM and adsorbed onto fluorosil and purified by column chromatography on silica, eluting with 50% ether:cyclohexane then 0 - 10 % MeOH:DCM to give the title compound, 96 mg.LCMS (method B); Rt = 0.68 min, MH+ = 251
		Intermediate 58 lambda/-(5-Bromo-3-pyridinyl)methanesulfonamide 5-Bromo-3-pyridinamine (200 mg) was dissolved in pyridine (5 ml), cooled to 0 0C and stirred for 10 min. Methanesulfonyl chloride (0.05 ml) was added dropwise and the reaction continued stirring for 1 hr. 2M HCI (aq) (5 ml) was added and the reaction was extracted with DCM, passed through a hydrophobic frit and evaporated to dryness. The residue was dissolved in DCM and adsorbed onto fluorosil and purified by column chromatography on silica, eluting with 50% ether/cyclohexane then 0-10% MeOH/DCM to give the title compound (96 mg). LCMS (Method B) R1 = 0.68 min, MH+ = 251/253.

Reference： [1]Patent: US2016/214994,2016,A1 .Location in patent: Paragraph 0205; 0206
[2]Patent: US2016/244432,2016,A1 .Location in patent: Paragraph 0260; 0261
[3]Patent: WO2019/126730,2019,A1 .Location in patent: Paragraph 0312
[4]Patent: WO2009/155527,2009,A2 .Location in patent: Page/Page column 130
[5]Journal of Medicinal Chemistry,2015,vol. 58,p. 7381 - 7399
[6]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 4749 - 4752
[7]Patent: WO2011/67365,2011,A1 .Location in patent: Page/Page column 84
[8]Patent: WO2009/147187,2009,A1 .Location in patent: Page/Page column 130

22
[ 13535-01-8 ]
[ 191162-40-0 ]
[ 1202550-08-0 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 85℃; for 3h;	A flask is charged with 3-amino-5-bromopyridine (0.173 g, 0.950 mmol), Lambda/-methyl-indole boronic acid (0.262 g, 1.425 mmol), s-Phos (0.030 g, 0.071 mmol), finely crushed potassium phosphate (0.407 g, 1.900 mmol) and toluene (4 ml_). After degassing for 30 min, Pd2dba3 (0.018 g, 0.019 mmol) is added, the flask is flushed with nitrogen and the mixture is heated to 85 0C. After 3 h, the mixture is allowed to cool to r.t., diluted with ethyl acetate and filtered through a plug of silica gel (elution with ethyl acetate). The <n="133"/>residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 3:7 to 0:1 ) to give 2-(5-amino-pyridin-3-yl)-1-methyl-1 H-indole as an off-white powder. 1H NMR (400 MHz, DMSO-cfe) delta ppm 3.74 (s, 3 H), 5.49 (s, 2 H), 6.56 (s, 1 H), 7.05 - 7.09 (m, 1 H), 7.09 - 7.10 (m, 1 H), 7.17 - 7.21 (m, 1 H), 7.49 (d, J=7.6 Hz, 1 H), 7.57 (d, J=7.6 Hz, 1 H), 7.94 (d, J=2.0 Hz, 1 H), 7.99 (d, J=2.5 Hz, 1 H). MS (ESI) m/z 224 (M+H)+.

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 9382 - 9394
[2]Patent: WO2009/156462,2009,A2 .Location in patent: Page/Page column 131-132

23
[ 13535-01-8 ]
3-(methylsulfonamido)phenylboronic acid [ No CAS ]
[ 1220690-56-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	With cesium fluoride;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In acetonitrile; at 180℃; for 0.25h;microwave irradiation;	To a microwave vial 5-bromopyridin-3-amine (1.0 g, 5.78 mmol), 3-(methylsulfonamido) phenylboronic acid (1.49 g, 6.94 mmol), CH3CN (10 mL), CsF (1.69 g, 11.56 mmol), Pd(dppf)Cl2 (0.85 g, 1.16 mmol) were added and the mixture was heated at 180 0C for 15 minutes. Mixture was cooled to room temperature, concentrated and separated by flash silica gel column chromatography using 1-5 % dichloromethane in methanol as solvent to afford N-(3 -(5 -aminopyridin-3-yl)phenyl)methanesulfonamide (1.14 g, 76 % yield).

Reference： [1]Patent: WO2010/39957,2010,A1 .Location in patent: Page/Page column 24

24
[ 13535-01-8 ]
[ 89635-82-5 ]
[ 1239131-83-9 ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 9973 - 9975

25
[ 13535-01-8 ]
[ 541-41-3 ]
[ 152684-24-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	With pyridine; In dichloromethane; at 20℃; for 1.5h;	Step 1. Ethyl (5-bromopyridin-3-yl)carbamate 5-bromopyridin-3-amine (20 g, 116 mmol) was dissolved in DCM (500 mL) and pyridine (28.0 mL, 347 mmol) was added, followed by ethyl chloroformate (11.44 mL, 119 mmol) dropwise. The reaction mixture was stirred for 1.5 h at room temperature. The reaction mixture was diluted with DCM. The two phases were separated and the organic phase was washed with 10% CuSO4 solution (2) sat. NaHCO3 solution (1) Brine (1*) dried (Na2SO4) and evaporated. The residue was triturated with diethyl ether filtered and dried obtaining ethyl (5-bromopyridin-3-yl)carbamate (21.58 g, 76%) as a white solid. LCMS (m/z): 247.0 (MH+), 0.58 min; 1H NMR (400 MHz, CDCl3) delta ppm 8.62-8.15 (m, 3H) 7.00 (br. s., 1H) 4.27 (q, J=7.0 Hz, 2H) 1.34 (t, J=7.0 Hz, 3H).
70%	With pyridine; at 20℃; for 2h;Cooling with ice;	Synthesis of 224-1. To a solution of 155-0 (20.0 g, 116.3 mmol) in pyridine (400 mL) was added ethyl carbonochloridate (15.1 g, 139.5 mmol) dropwise under ice bath. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo. The residue was dissolved in EtOAc (200 mL) and the resulting solution was washed with water (30 mL × 5). The organic layer was dried over Na2SO4 and concentrated to give 224-1 (20.0 g, 70 %) as a yellow solid.
29 g	With pyridine; In tetrahydrofuran; at 0 - 35℃;Inert atmosphere;	A) ethyl (5-bromopyridin-3-yl)carbamate To a mixture of 5-bromopyridin-3-amine (35.4 g) and pyridine (19.8 mL) in tetrahydrofuran (600 mL) was slowly added ethyl chloroformate (23.4 mL) at 0C. The reaction mixture was stirred overnight at room temperature under nitrogen atmosphere, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added diisopropyl ether (400 mL), the mixture was stirred at room temperature for 20 min, and the obtained solid was collected by filtration to give the title compound (29.0 g). MS (API+): [M+H]+ 245.1.

29.0 g

With pyridine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;

To a mixture of 5-bromopyridin-3-amine (35.4 g) and pyridine (19.8 mL) in tetrahydrofuran (600 mL) was slowly added ethyl chloroformate (23.4 mL) at 0C. The reaction mixture was stirred overnight at room temperature under nitrogen atmosphere, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added diisopropyl ether (400 mL), the mixture was stirred at room temperature for 20 min, and the obtained solid was collected by filtration to give the title compound (29.0 g). MS (API+): [M+H]+ 245.1.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5913 - 5917
[2]Patent: US9242996,2016,B2 .Location in patent: Page/Page column 82; 83
[3]Patent: WO2017/7756,2017,A1 .Location in patent: Paragraph 222
[4]Patent: EP2848618,2015,A1 .Location in patent: Paragraph 1267
[5]Patent: EP2873669,2015,A1 .Location in patent: Paragraph 0583; 0584

26
[ 13535-01-8 ]
[ 548797-51-9 ]
[ 1255870-55-3 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 95℃; for 18h;	(General Suzuki reaction procedure 1) A mixture of 2-chloro-4-(4,4.5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile (1.32 g, 5 mmol), 5-Bromo-pyridin«3-ylamine (865 mg, 5 mmol), s-PHOS (103 mg, 0.25 mmoi), potassium phosphate (2.12 g, 10 mmol) and Pd2(dba)3 (41.2 mg, 0.1 mmol) in toluene (20 mL) was heated to 95 0C overnight (18 h). After filtration and concentration, the residue was dissolved into CH2CI2 and mixed with celite. After concentration, the residue was loaded to column (MeOH-CH2CI2, v/v, 1% - 3.5%) and resulted in a tight brown solid (500 mg). 1HNMR (400 MHz, CDCI3): δ 4.82 (brs, 2H), 7.11 (t, J « 2 Hz, 1H), 7.55 (dd, J = 2 Hz, 8 Hz1 1H), 7.69 (d, J = 2 Hz, 1H)1 7.75 (d, J * 8 Hz, 1H), 8.16 (d, J * 2 Hz. 1H), 8.22 <;d, J = 2 Hz1 1H).

Reference： [1]Patent: WO2010/130796,2010,A1 .Location in patent: Page/Page column 57-58

27
[ 13535-01-8 ]
[ 1171897-39-4 ]

Reference： [1]Patent: WO2011/28741,2011,A1
[2]Patent: WO2014/28968,2014,A1
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 3795 - 3803

28
[ 13535-01-8 ]
[ 628-36-4 ]
[ 1272357-00-2 ]

Yield	Reaction Conditions	Operation in experiment
33%	at 150℃; for 16h;	A mixture of 3-bromo-5-amino pyridine (0.30 g, 1.7 mmol) and N,N- diformaylhydrazine (0.15 g, 1.7 mmol) was heated at 150 °C in sealed tube for 16 h. A precipitate formed which was dissolved in hot ethanol and then filtered. Diethyl ether was added to the filtrate at room temperature and the slurry was stirred overnight. The resulting solid was separated and purified by silica gel column chromatography using ethyl acetate and hexanes mixture as the eluent to provide 3- bromo-5-(4H-l,2,4-triazol-4-yl)pyridine (130 mg, 33 percent yield) as a white solid. lH NMR (400 MHz, DMSO-i3/4) delta (ppm): 9.24 (s, 2H); 9.03 (d, 1H, J = 2Hz); 8.79 (d, lH, J = 2Hz); 8.60 (t, lH, J = 2Hz).

Reference： [1]Patent: WO2011/28741,2011,A1 .Location in patent: Page/Page column 298

29
[ 13535-01-8 ]
[ 1276110-06-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 20 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)CH₂Cl₂; potassium acetate / dichloromethane / 100 °C / Inert atmosphere 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)CH₂Cl₂; potassium carbonate / 1,4-dioxane; water / 12 h / 100 °C / Inert atmosphere

Reference： [1]Kim, Okseon; Jeong, Yujeong; Lee, Hyunseung; Hong, Sun-Sun; Hong, Sungwoo [Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2455 - 2466]

30
[ 13535-01-8 ]
[ 433226-05-2 ]

Yield	Reaction Conditions	Operation in experiment
		CICOOEt, Py 93% ii) HN03, H2S04, 30C, 20h, 68% iii) KOH/EtOH/H20, 75%

Reference： [1]Patent: WO2012/6680,2012,A1 .Location in patent: Page/Page column 76
[2]Patent: US9242996,2016,B2
[3]Patent: WO2017/7756,2017,A1
[4]European Journal of Medicinal Chemistry,2017,vol. 140,p. 383 - 391
[5]Patent: CN104876860,2018,B

31
[ 13535-01-8 ]
[ 98-88-4 ]
[ 15862-47-2 ]

Yield	Reaction Conditions	Operation in experiment
91%		To a solution of 5-bromopyridin-3-amine (0.3 g, 1.734 mmol) in THF (8.67 ml) was added TEA (0.363 ml, 2.60 mmol), and then benzoyl chloride (0.292 g, 2.081 mmol) was added to the mixture at 0 C. After stirred for 2 hours at room temperature, the reaction mixture was quenched with saturated aq. NaHCO3 (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=10:1) to give N-(5-bromopyridin-3-yl)benzamide (0.435 g, 91%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) delta 7.48 (2H, t, J=7.6 Hz), 7.58 (1H, t, J=7.4 Hz), 7.85-7.88 (2H, m), 8.38 (1H, brs), 8.40 (1H, d, J=1.6 Hz), 8.56-8.58 (2H, m).
72%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	[00287] 3-Amino-5-bromopyridine (0.589 g, 3.40 mmol), DCM (33.1 niL), DIEA (1.18 mL, 6.81 mmol), and benzoyl chloride (0.593 niL, 5.11 mmol) were combined and allowed to stir at ii overnight. The reaction mixture was concentrated by rotary evaporation and diluted with EtOAc and 1 N NaOH (aq). The organic layer was washed with water and brine, dried over sodium sulfate and concentrated by rotary evaporation. The crude material was purified by column chromatography to yield N-(5- bromopyridin-3-yl)benzamide (0.679 g, 72.0%). LCMS (AA): m/z 277/279 (M+H).
72.0%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	Step 1: N-(5-bromopyridin-3-yl)benzamide 3-Amino-5-bromopyridine (0.589 g, 3.40 mmol), DCM (33.1 mL), DIEA (1.18 mL, 6.81 mmol), and benzoyl chloride (0.593 mL, 5.11 mmol) were combined and allowed to stir at rt overnight. The reaction mixture was concentrated by rotary evaporation and diluted with EtOAc and 1 N NaOH (aq). The organic layer was washed with water and brine, dried over sodium sulfate and concentrated by rotary evaporation. The crude material was purified by column chromatography to yield N-(5-bromopyridin-3-yl)benzamide (0.679 g, 72.0%). LCMS (AA): m/z=277/279 (M+H).

Reference： [1]Patent: US2012/238587,2012,A1 .Location in patent: Page/Page column 22-23
[2]Patent: WO2015/108861,2015,A1 .Location in patent: Paragraph 00287
[3]Patent: US2015/225422,2015,A1 .Location in patent: Paragraph 0395-0396

32
[ 13535-01-8 ]
[ 1066-54-2 ]
[ 1207351-07-2 ]

Yield	Reaction Conditions	Operation in experiment
66%	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triphenylphosphine; In tetrahydrofuran; at 75℃;Inert atmosphere;	To a stirred solution of 7.23 g (41.8 mmol) 5 -bromo-3 -amino-pyridine in 70 mL dry THF under argon atmosphere is added 238.8 mg (1.3 mmol) Cul, 880 mg (1.3 mmol) bis(triphenylphosphine)palladium(II) chloride, 1.1 g (4.2 mmol) triphenylphosphine and 70 mL (501 mmol) triethylamin. Then 8.3 mL (58.5 mmol) trimethylsilylethyne are added and the reaction is heated at 75C over night. After cooling to RT, lOOmL DCM is added and the reaction mixture is extracted twice with 100 water. The organic layer is dried over MgS04 and the product is purified by chromatography on silica gel. Yield: 5.26 g (66%).
66%	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triphenylphosphine; In tetrahydrofuran; at 75℃;Inert atmosphere;	To a mixture of 7.23 g (41.8 mmol) 5 -bromo-3 -amino-pyridine in 70 mL dry THF under argon atmosphere is added 239 mg (1.3 mmol) Cul, 880 mg (1.3 mmol) bis(triphenyl- phosphine)palladium(II) chloride, 1 . 1 g (4.2 mmol) triphenylphosphine and 70 mL (0.50 mol) triethylamin. Then 8.3 mL (59 mmol) trimethylsilylacetylene are added and the reaction mixture is heated at 75C over night. After cooling to RT, 100 mL DCM is added and the reaction mixture is extracted twice with 100 mL water. The organic layer is dried over MgS04 and the product is purified by chromatography on silica gel. Yield: 5.26 g (66%).
66%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In tetrahydrofuran; at 75℃;Inert atmosphere;	To a mixture of 7.23 g (41.8 mmol) <strong>[13535-01-8]5-bromo-3-amino-pyridine</strong> in 70 mL dry THF under argon atmosphere is added 239 mg (1.3 mmol) Cul, 880 mg (1.3 mmol) bis(triphenylphosphine)palladium(II) chloride, 1.1 g (4.2 mmol) triphenylphosphine and 70 mL (0.50 mol) triethylamin. Then 8.3 mL (59 mmol) trimethylsilylacetylene are added and the reaction mixture is heated at 75C over night. After cooling to RT, 100 mL DCM is added and the reaction mixture is extracted twice with 100 mL water. The organic layer is dried over MgSO4 and the product is purified by chromatography on silica gel. Yield: 5.26 g (66%).

66%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In tetrahydrofuran; at 75℃;Inert atmosphere;	D-9) 5-Trimethylsilanylethynyl-pyridin-3-ylamine To a stirred solution of 7.23 g (41.8 mmol) <strong>[13535-01-8]5-bromo-3-amino-pyridine</strong> in 70 mL dry THF under argon atmosphere is added 238.8 mg (1.3 mmol) CuI, 880 mg (1.3 mmol) bis(triphenylphosphine)palladium(II) chloride, 1.1 g (4.2 mmol) triphenylphosphine and 70 mL (501 mmol) triethylamin. Then 8.3 mL (58.5 mmol) trimethylsilylethyne are added and the reaction is heated at 75 C. over night. After cooling to RT, 100 mL DCM is added and the reaction mixture is extracted twice with 100 water. The organic layer is dried over MgSO4 and the product is purified by chromatography on silica gel. Yield: 5.26 g (66%).
62%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; at 20℃; for 21.0833h;Reflux;	Triethylamine (20 mL) and trimethylsilylacetylene (3.32 mL, 24 mmol) were added to a solution of <strong>[13535-01-8]3-amino-5-bromopyridine</strong> (3.46 g, 20 mmol), PdCl2(PPh3)2 (561.5 mg, 0.80 mmol) and CuI (76.2 mg, 0.40 mmol) in tetrahydrofuran(5 mL) at room temperature, stirred for 5 minutes, and then stirred under heat reflux for 21 hours. After filtration of theresulting solution, the solvent was distilled away under a reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate (v/v) = 50/50 ? 0/100) to obtain the title compound (2.36 g, 62%) as a brownpowder.1H NMR (400 MHz, CDCl3) delta 8.10 (1H, d, J = 1.6 Hz), 8.01 (1H, d, J = 2.8 Hz), 7.03 (1H, dd, J = 2.8, 1.6 Hz), 3.68 (2H,br s), 0.25 (9H, s)

Reference： [1]Patent: WO2012/101184,2012,A1 .Location in patent: Page/Page column 61
[2]Patent: WO2012/101186,2012,A1 .Location in patent: Page/Page column 59
[3]Patent: EP2546249,2013,A1 .Location in patent: Paragraph 0240; 0241
[4]Patent: US2013/23533,2013,A1 .Location in patent: Paragraph 0262; 0263
[5]Patent: EP3127900,2017,A1 .Location in patent: Paragraph 0130; 0131

33
[ 13535-01-8 ]
[ 79-30-1 ]
[ 1266227-12-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With pyridine; In dichloromethane; at 0 - 20℃; for 15h;	Step 1[00188] 3-Amino-5-bromo pyridine (XXX)(leq) was dissolved in DCM and cooled to 0C before adding pyridine (2.2 eq) and isobutyryl chloride (XXXI) (1.1 eq). The reaction mixture was stirred at r.t. for 15 h until TLC showed the reaction was complete. The reaction mixture was diluted with DCM and washed with water. The organic extract was dried, concentrated and purified by column chromatography using silica gel (100-200 mesh) to afford N-(5-bromopyridin-3-yl)isobutyramide (XXXII) as a off white solid, (71% yield). 1H NMR (CDC13) delta ppm 8.55-8.35 (m, 3H), 7.32 (s, 1H), 2.59-2.48 (m, 1H), 1.28-1.27 (d, 6H); ESIMS found C9HnBrN20 mlz 243.05(M+H).
71%	With pyridine; In dichloromethane; at 0 - 20℃;	3-Amino-5-bromo pyridine (XXII) (1 eq) was dissolved in DCM and cooled to 0 C. before adding pyridine (2.2 eq) and isobutyryl chloride (XXIII) (1.1 eq). The reaction mixture was stirred at room temperature for 15 h until TLC showed the reaction was complete. The reaction mixture was diluted with DCM and washed with water. The organic extract was dried, concentrated and purified by column chromatography using silica gel (100-200 mesh) to afford N-(5-bromopyridin-3-yl)isobutyramide (XXIV) as an off-white solid, (71% yield). 1H NMR (CDCl3) delta ppm 8.55-8.35 (m, 3H), 7.32 (s, 1H), 2.59-2.48 (m, 1H), 1.28-1.27 (d, 6H); ESIMS found C9H11BrN2O m/z 243.05 (M+H).
71%	With pyridine; In dichloromethane; at 0 - 20℃; for 15h;	Step 1 3-Amino-5-bromo pyridine (V) (1 eq) was dissolved in DCM and cooled to 0 C. before adding pyridine (2.2 eq) and isobutyryl chloride (VI) (1.1 eq). The reaction mixture was stirred at r.t. for 15 h until TLC showed the reaction was complete. The reaction mixture was diluted with DCM and washed with water. The organic extract was dried, concentrated and purified by column chromatography using silica gel (100-200 mesh) to afford N-(5-bromopyridin-3-yl)isobutyramide (VII) as an off-white solid, (71% yield). 1H NMR (CDCl3) delta ppm 8.55-8.35 (m, 3H), 7.32 (s, 1H), 2.59-2.48 (m, 1H), 1.28-1.27 (d, 6H); ESIMS found C9H11BrN2O m/z 243.05 (M+H).

71%

With pyridine; In dichloromethane; at 0 - 20℃; for 15h;

Step 1;3-Amino-5-bromo pyridine (XVIII) (1 eq) was dissolved in DCM and cooled to 0C before adding pyridine (2.2 eq) and isobutyryl chloride (XIX) (1.1 eq). The reaction mixture was stirred at r.t. for 15 h until TLC showed the reaction was complete. The reaction mixture was diluted with DCM and washed with water. The organic extract was dried, concentrated and purified by column chromatography using silica gel (100-200 mesh) to afford N-(5-bromopyridin-3-yl)isobutyramide (XX) as a off white solid, (71% yield). 1H NMR (CDCl3) delta ppm 8.55-8.35 (m, 3H), 7.32 (s, 1H), 2.59-2.48 (m, 1H), 1.28-1.27 (d, 6H); ESIMS found C9H11BrN2O m/z 243.05(M+H).

Reference： [1]Patent: WO2011/84486,2011,A1 .Location in patent: Page/Page column 115
[2]Patent: US2013/267495,2013,A1 .Location in patent: Paragraph 0420-0421
[3]Patent: US2014/194441,2014,A1 .Location in patent: Paragraph 0400
[4]Patent: EP2464232,2015,B1 .Location in patent: Paragraph 0093; 0094

34
[ 13535-01-8 ]
[ 68947-43-3 ]
[ 1314734-62-7 ]

Yield	Reaction Conditions	Operation in experiment
43%		Steps 1-2[00200] Oxalyl chloride (8.67 mmol) followed by DMF ( 2drops) was added to a solution of 1 -methyl piperidine-4-carboxylic acid (XLIII) (5.78 mmol) in DCM and stirred 30 min at room temperature under argon. The volatiles were evaporated under vacuum by avoiding contact with air. Pyridine was added to the residue followed by addition of 3-amino-5-bromopyridine (XL) (5.20 mmol). The solution was further stirred at room temperature for 3 h under argon. The pyridine was evaporated under vacuum. The residue was treated with water, basified by saturated NaHC03 solution and washed with DCM. The aqueous layer was extracted with n-butanol. The combined organic layer was evaporated. The residue was dissolved in DCM with the addition of few drops of MeOH. The insoluble inorganic solids were filtered off. The filtrate was concentrated under vacuum to get N-(5-bromopyridin-3-yl)-l-methylpiperidine-4-carboxamide (XLIV) as a brown viscous liquid (0.74 g, 43percent yield). 1H NMR (DMSO-d6) 1.61-1.69 (m, 2H), 1.77-1.79 (m, 2H), 1.93-1.97 (m, 2H), 2.20 (s, 3H), 2.29-2.35 (m, 1H), 2.84- 2.87 (m, 2H), 8.36 (d, J = 1.6 Hz, 1H), 8.39 (m, 1H), 8.66 (d, J = 1.6 Hz, 1H), 10.33 (s, 1H); ESIMS found Ci2Hi6BrN30 mlz 299 (M+H).

Reference： [1]Patent: WO2011/84486,2011,A1 .Location in patent: Page/Page column 118-119

35
[ 13535-01-8 ]
[ 591-50-4 ]
[ 73183-34-3 ]
[ 142137-17-5 ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 1923 - 1933

36
[ 13535-01-8 ]
[ 768-35-4 ]
[ 1214384-10-7 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 180.0℃; for 1.0h;Microwave irradiation; Inert atmosphere;	To a microwave vial was added <strong>[13535-01-8]3-amino-5-bromopyridine</strong> (LII) (0.400 g, 2.31 mmol), 3 -fluorophenyl boronic acid (XLIX) (0.356 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.133 g, 0.116 mmol), potassium phosphate (0.736 g, 3.47 mmol), water (1 mL), and DMF (5 niL). The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180C. The solution was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by column chromatography (4:6 EtOAc:hexanes ? 7:3 EtOAc:hexanes) to afford the 5-(3-fluorophenyl)pyridin-3-amine (LIII) (0.360 g, 1.92 mmol, 83%> yield) as a yellow-white solid. ESIMS found for CnH9FN2 mlz 189.1 (M+H).
83%	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 180.0℃; for 1.0h;Microwave irradiation; Inert atmosphere; Sealed tube;	To a microwave vial was added <strong>[13535-01-8]3-amino-5-bromopyridine</strong> (LII) (0.400 g, 2.31 mmol), 3 -fluorophenyl boronic acid (XLIX) (0.356 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.133 g, 0.116 mmol), potassium phosphate (0.736 g, 3.47 mmol), water (1 mL), and DMF (5 mL). The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180C. The solution was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by column chromatography (4:6 EtOAc:hexanes ? 7:3 EtOAc:hexanes) to afford the 5-(3- fluorophenyl)pyridin-3 -amine (LIII) (0.360 g, 1.92 mmol, 83% yield) as a yellow -white solid. ESIMS found for CnH9FN2 mlz 189.1 (M+H).

Reference： [1]Patent: WO2013/40215,2013,A1 .Location in patent: Paragraph 00274
[2]Patent: WO2018/75858,2018,A1 .Location in patent: Paragraph 0306; 0307

37
[ 13535-01-8 ]
[ 16841-19-3 ]
[ 1433904-98-3 ]

Yield	Reaction Conditions	Operation in experiment
		.2 mL (25.9 mmol, 9 eq) of oxalyl chloride were added, drop-by-drop, to a solution, cooled to 0C, of 1 .13 g (8.7 mmol, 3 eq) of 1 -hydroxy-cyclopentanecarboxylic acid in 20 mL of tetrahydrofuran. The solution was agitated at 0C for 1 hour, and then at ambient temperature for 16 hours. The reaction mixture was evaporated dry. The residue was absorbed in dichloromethane and added to a solution of 500 mg (2.80 mmol, 1 eq) of 5- bromo-pyridin-3-ylamine in 20 ml of dichloromethane. 1.2 mL (8.6 mmol, 3 eq) of triethylamine was then added. The mixture was agitated at ambient temperature for 30 minutes. No initial product remained. The reaction mixture was poured into a frozen mixture of sodium and dichloromethane. The organic phase was extracted indichloromethane and then washed in water twice, then dried over sodium sulphate, and dry concentrated under vacuum. The residue was precipitated in dichloromethane and heptanes. 1 -hydroxy-cyclopentanecarboxylic acid (2-bromo-pyridin-4-yl)-amide was obtained in the form of a white solid.Melting point = 153C. NMR (1H, DMSO): 1.70-1 .76 (m, 6 H), 1 .95-2.03 (m, 2 H), 5.74 (s, 1 H), 7.81 -7.83 (dd, 1 H, J = 5.7, 1.9 Hz), 8.14 (d, 1 H, J = 1 .8 Hz), 8.23 (d, 1 H, J = 5.7 Hz), 10.35 (s, 1 H).

Reference： [1]Patent: WO2013/64681,2013,A1 .Location in patent: Page/Page column 73

38
[ 13535-01-8 ]
[ 73183-34-3 ]
[ 1073354-99-0 ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; HK(1+)*C2H3O2(1-); In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;	5-Bromo-pyridin-3-ylamine (1.0 g, 5.8 mmol), bis(pinacolato)diboron (1.46 g, 5.7 mmol), Pd(dppf)Cl2 (200 mg), AcOK (1.1 g, 11.4 mmol) were stirred in 1,4-dioxane (15 mL) at 100C under N2 for 4 h. After cooled to room temperature, to the mixture was added 2- bromo-pyridine (0.91 g, 5.7 mmol), Cs2C03 (7.4 g, 22.8 mmol), Pd(PPh3)4 (200 mg), water (3 mL). The mixture was then heated to 100 C under N2 for 2 h. The solvent was concentrated under reduced pressure. The residue was dissolved in water and the aqueous phase was extracted with EtOAc (30 mL x3). The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated to dryness under reduced pressure. The crude was purified via silic gel column (DCM/MeOH, 20/1) to afford 300 mg (2-step yield: 30%) of [2,3]Bipyridinyl-5- ylamine. MS: m/z 172.0 (M+H+).
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; for 2h;Reflux; Inert atmosphere;	General procedure: A mixture of 5mmol of the appropriate amino-5-bromo pyridine and 1.96gm (20mmol) of potassium acetate and 0.18gm (0.25mmol) of Pd(dppf)Cl2 and 5.08gm (20mmol) of bis(pinacolato)diboron in dioxane was heated to reflux under argon for 2h to yield compounds A and B. The mixture was left to attain room temperature and then filtered under vacuum. Without further purification, a reaction flask containing the filtrate was charged with 6.5gm (20mmol) of Cs2CO3, 0.29gm (0.25mmol) of palladium-tetrakis(triphenylphosphine) and 6mmol of 2,4-dibromothiophene together with 30% water in a Suzuki coupling reaction. The reaction was left to reflux under argon for 3.5h. The mixture was concentrated in vacuo. The residue was partitioned between 150mL ethyl acetate and 50mL brine solution and then the aqueous layer was re-extracted using 3 portions of 100mL ethyl acetate. The organic layers were collected and the volume was reduced under reduced pressure. Afterwards the product was purified by CC to yield compounds C-D.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; for 2h;Reflux; Inert atmosphere;	A mixture of 5 mmol of the 3-amino-5-bromo pyridine and1.96 gm (20 mmol) of potassium acetate and 0.18 gm (0.25 mmol)of Pd (dppf)Cl2 and 5.08 gm(20 mmol) of bis(pinacolato)diboron indioxane was heated to reflux under argon for 2 h to yield compoundsA. The mixture was left to attain room temperature andthen filtered under vacuum. Without further purification, a reactionflask containing the filterate was charged with 6.5 gm(20 mmol) of Cs2CO3, 0.29 gm (0.25 mmol) of palladium-tetrakis(triphenylphosphine) and 6 mmol of the appropriate bromothiophenetogether with 30% water in a Suzuki coupling reaction. Thereaction was left to reflux under argon for 3.5 h. The mixture wasconcentrated in vacuo. The residue was partitioned between150 mLs ethyl acetate and 50 mLs brine solution and then theaqueous layer was re-extracted using 3 portions of 100 mLs ethylacetate. The organic layers were collected and the volume wasreduced under reduced pressure. Afterwards the product was purifiedby CC to yield compounds B, H.

With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;

To a stirred solution of 5-bromopyridin-3-amine (MANCHESTER ORGANICS, 1 g, 5.78 mmol) in 1 ,4-dioxane (15 mL) were added 4,4,4',4', 5,5,5', 5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (ALFA-AESAR, 1.46 g, 5.78 mmol), potassium acetate (AVRA, 1.1 g, 1 1.56 mmol) and the reaction mixture was degassed with argon for 10 min. Followed by the addition of Pd(dppf)CI2.CH2Cl2 (ALFA-AESAR, 200 mg, 0.289 mmol). The reaction mixture was heated to 100 C and stirred for 4 h. The reaction mixture was cooled to 27 C and proceeded to next step without further purification. 1H NMR (400 MHz, CDCI3) delta ppm: 8.36 (s, 1 H), 8.22-8.13 (m, 1 H), 8.10-7.95 (m, 1 H), 7.36 (br s, 2H), 1.27 (s, 12H).

Reference： [1]Patent: WO2013/126608,2013,A1 .Location in patent: Paragraph 00394
[2]European Journal of Medicinal Chemistry,2018,vol. 157,p. 1031 - 1050
[3]European Journal of Medicinal Chemistry,2018,vol. 158,p. 270 - 285
[4]Patent: WO2019/34701,2019,A1 .Location in patent: Page/Page column 53

39
[ 13535-01-8 ]
[ 628692-15-9 ]
[ 1258620-56-2 ]

Yield	Reaction Conditions	Operation in experiment
47.5%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 120℃;Inert atmosphere;	The mixture of 5-bromo-pyriden-3-ylamine (2.6 g, 15 mmol), boronic acid (1.9 g, 12.5 mmol), Pd(PPh3)4 (1.45g, 1.25 mmol), K2C03 (5.18 g, 37.5 mmol) in DMF (50 mL) was stirred at 120°C under N2 overnight. The reaction mixture was concentrated in vacuum. The residue was purified by chromatography on silica gel eluting with EA, to give 1.2 g (yield: 47.5percent) of 5-(2-methoxypyrimidn-5-yl)-3-pyridylamine as yellow solid. [00824] 1H NMR (CDC13, 400 MHz): delta = 8.70 (2H, s), 8.17 (IH, d), 8.13 (IH, d), 7.07 (IH, dd), 4.07 (3H, s).

Reference： [1]Patent: WO2013/126608,2013,A1 .Location in patent: Paragraph 00823-00824

40
[ 13535-01-8 ]
[ 628692-15-9 ]
[ 1451274-22-8 ]

Reference： [1]Patent: WO2013/126608,2013,A1

41
[ 13535-01-8 ]
[ 3282-30-2 ]
[ 873302-39-7 ]

Yield	Reaction Conditions	Operation in experiment
73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XXV) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XXVIII) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXIX) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). 1H NMR (DMSO-d6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2 Hz, 1H), 8.39 (t, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.58 (brs, 1H); ESIMS found C10H13BrN2O m/z 257.0 (M+H).
73.1%	With pyridine; at 20℃; for 3h;	Step 1 (0800) To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). 1H NMR (DMSO-d6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2 Hz, 1H), 8.39 (t, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.58 (brs, 1H); ESIMS found C10H13BrN2O m/z 258.9 (Br81M+H).
73.1%	In pyridine; at 20℃; for 3h;	Step 1 To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XXI) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXII) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). 1H NMR (DMSO-d6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2 Hz, 1H), 8.39 (t, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.58 (brs, 1H); ESIMS found C10H13BrN2O m/z 258.9 (Br81M+H).

73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XXI) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXII) as an off- white solid (1.082 g, 4.22 mmol, 73.1% yield). 1H NMR (DMSO-d6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found C10H13BrN2O m/z 258.9 (Br81M+H).
73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XVIII) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XIX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 mm. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3- yl)pivalamide (XX) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). ?H NMR (DMSOd 6, 500 MHz) ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found C,0H,3BrN2O m/z 258.9 (Br8?M+H).
73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 mm. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an off- white solid (1.082 g, 4.22 mmol, 73.1% yield). ?H NMR(DMSO-d6, 500 MHz) ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found C,0H,3BrN2O m/z 258.9 (Br8?M+H).
73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 mm. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyndin-3-yl)pivalamide (XXI) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). ?H NMR (DM50-cl6, 500 MHz) ppm 1.23 (s, 9H), 8.37 (d, J2Hz, 1H), 8.39 (t, J2Hz, 1H), 8.80 (d, J2Hz, 1H), 9.58 (brs, 1H); ESIMS found C,0H,3BrN2O m/z 258.9 (Br8?M+H).
73.1%	With pyridine; at 20℃; for 3h;	j0635j To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XXXVI) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XXXVII) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 mm. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXXVIII) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). ?H NMR(DMSO-d6, 500 MHz) ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found C,0H,3BrN2O m/z 258.9 (Br8?M+H).
73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCC mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an off- white solid (1.082 g, 4.22 mmol, 73.1% yield). NMR (DIVISOR, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found Ci0Hi3BrN2O mlz 258.9 (Br81M+H).
73.1%	With pyridine; at 20℃; for 3h;	j0612j To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XVIII) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XIX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 mm. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XX) as an off- white solid (1.082 g, 4.22 mmol, 73.1% yield). ?H NMR(DMSO-d6, 500 MHz) ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found C,0H,3BrN2O m/z 258.9 (Br8?M+H).
73.1%	With pyridine; at 20℃; for 3h;	[0635] To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XXXVI) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XXXVII) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCC mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXXVIII) as an off-white solid ( 1.082 g, 4.22 mmol, 73.1% yield). NMR DMSO-d6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, IH), 8.39 (t, J=2Hz, IH), 8.80 (d, J=2Hz, IH), 9.58 (brs, IH); ESIMS found Ci0Hi3BrN2O mlz 258.9 (Br81M+H).
73.1%	With pyridine; at 25℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHC03 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). NMR (DMSO-£/tf, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found Ci0Hi3BrN2O mlz 258.9 (Br81M+H).
73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCC mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an off- white solid (1.082 g, 4.22 mmol, 73.1% yield). NMR (DMSO- e, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, lH); ESIMS found
73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHC03 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). NMR (DMSO- 6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found Ci0Hi3BrN2O mlz 258.9 (Br81M+H).
73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XXXVI) (1.0 g, 5.78 mmol) in dry pyridine (10 inL) was added pivaloyl chloride (XXXVII) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCC mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXXVIII) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). NMR (DMSO- tf, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found CioHi3BrN20 mlz 258.9 (Br81M+H).
73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 mm. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). ?H NMR (DM50-cl6, 500 MHz) ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found C,0H,3BrN2O m/z 258.9 (Br8?M+H).
73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XXXVI) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XXXVII) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCC mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXXVIII) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). NMR (DMSO- 6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, IH), 8.39 (t, J=2Hz, IH), 8.80 (d, J=2Hz, IH), 9.58 (brs, IH); ESIMS found Ci0Hi3BrN2O mlz 258.9 (Br81M+H).
73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XVIII) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XIX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHC03 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XX) as an off- white solid (1.082 g, 4.22 mmol, 73.1% yield). NMR (DMSO- e, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, IH), 8.39 (t, J=2Hz, IH), 8.80 (d, J=2Hz, IH), 9.58 (brs, IH); ESIMS found
73.1%	With pyridine; at 20℃; for 3h;	Step 1 [0615] To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHC03 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). NMR (DMSO- tf, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, IH), 8.39 (t, J=2Hz, IH), 8.80 (d, J=2Hz, IH), 9.58 (brs, IH); ESIMS found CioHi3BrN20 mlz 258.9 (Br81M+H).
73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine ( 10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). 1H NMR DMSO-d6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, IH), 8.39 (t, J=2Hz, IH), 8.80 (d, J=2Hz, IH), 9.58 (brs, IH); ESIMS found C10H13BrN2O m/z 258.9 (Br81M+H).
73.1%	With pyridine; at 20℃; for 3h;	Step 1 [0616] To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHC03 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). NMR (DMSO- tf, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found Ci0Hi3BrN2O mlz 258.9 (Br81M+H).
73.1%	With pyridine; at 25℃; for 3h;	[0612] To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XVIII) (1.0 g, 5.78 mmol) in dry pyridine (10 inL) was added pivaloyl chloride (XIX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCC mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XX) as an off- white solid (1.082 g, 4.22 mmol, 73.1% yield). NMR (OMSO-d6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, IH), 8.39 (t, J=2Hz, IH), 8.80 (d, J=2Hz, IH), 9.58 (brs, IH); ESIMS found CioHi3BrN20 mlz 258.9 (Br81M+H).
73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCC mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). NMR DMSO-d6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found CioHi3BrN20 mlz 258.9 (Br81M+H).
73.1%	With pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 mm. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an offwhite solid (1.082 g, 4.22 mmol, 73.1% yield). ?H NMR(DMSO-d6, 500 MHz) ppm 1.23 (s, 9H),8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found C,0H,3BrN2O mlz 258.9 (Br8?M+H)
73.1%	With pyridine; In pyridine; at 20℃; for 3h;	To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XXXIV) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XXXV) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXXVI) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). 1H NMR (DMSO-d6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2 Hz, 1H), 8.39 (t, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.58 (brs, 1H); ESIMS found C10H13BrN2O m/z 258.9 (Br81M+H).
73.1%	With pyridine; at 20℃; for 3h;	Step 1 To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). 1H NMR (DMSO-d6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2 Hz, 1H), 8.39 (t, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.58 (brs, 1H); ESIMS found C10H13BrN2O m/z 258.9 (Br81M+H).
73.1%	With pyridine; at 20℃; for 3h;	Preparation of intermediate N-(5-bromopyridin-3-yl)pivalamide (XXI) is depicted below in Scheme 4. Step 1 (0800) To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). 1H NMR (DMSO-d6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2 Hz, 1H), 8.39 (t, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.58 (brs, 1H); ESIMS found C10H13BrN2O m/z 258.9 (Br81M+H).
73.1%	With pyridine; at 20℃; for 3h;	Step 1 (0802) To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XIX) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXI) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). 1H NMR (DMSO-d6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2 Hz, 1H), 8.39 (t, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.58 (brs, 1H); ESIMS found C10H13BrN2O m/z 258.9 (Br81M+H).
73.1%	With pyridine; at 20℃; for 3h;	Step 1 (0824) To a solution of <strong>[13535-01-8]3-amino-5-bromo pyridine</strong> (XXXIV) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XXXV) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXXVI) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). 1H NMR (DMSO-d6, 500 MHz) delta ppm 1.23 (s, 9H), 8.37 (d, J=2 Hz, 1H), 8.39 (t, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.58 (brs, 1H); ESIMS found C10H13BrN2O m/z 258.9 (Br81M+H).

Reference： [1]Patent: US2013/296302,2013,A1 .Location in patent: Paragraph 0517
[2]Patent: US2016/68548,2016,A1 .Location in patent: Paragraph 0800
[3]Patent: US2016/68550,2016,A1 .Location in patent: Paragraph 1066
[4]Patent: WO2016/40193,2016,A1 .Location in patent: Paragraph 0712-0713
[5]Patent: WO2017/23989,2017,A1 .Location in patent: Paragraph 0611; 0612
[6]Patent: WO2017/23975,2017,A1 .Location in patent: Paragraph 0615; 0616
[7]Patent: WO2017/23993,2017,A1 .Location in patent: Paragraph 0620; 0621
[8]Patent: WO2017/24021,2017,A1 .Location in patent: Paragraph 0634; 0635
[9]Patent: WO2017/23987,2017,A1 .Location in patent: Paragraph 0615; 0616
[10]Patent: WO2017/23972,2017,A1 .Location in patent: Paragraph 0611; 0612
[11]Patent: WO2017/24013,2017,A1 .Location in patent: Paragraph 0634; 0635
[12]Patent: WO2017/24004,2017,A1 .Location in patent: Paragraph 0616
[13]Patent: WO2017/24025,2017,A1 .Location in patent: Paragraph 0616
[14]Patent: WO2017/24003,2017,A1 .Location in patent: Paragraph 0615; 0616
[15]Patent: WO2017/24010,2017,A1 .Location in patent: Paragraph 018; 019
[16]Patent: WO2017/23981,2017,A1 .Location in patent: Paragraph 0615; 0616
[17]Patent: WO2017/23986,2017,A1 .Location in patent: Paragraph 0638; 0639
[18]Patent: WO2017/24015,2017,A1 .Location in patent: Paragraph 011
[19]Patent: WO2017/23984,2017,A1 .Location in patent: Paragraph 0615
[20]Patent: WO2017/23973,2017,A1 .Location in patent: Paragraph 0636-0637
[21]Patent: WO2017/23980,2017,A1 .Location in patent: Paragraph 0616
[22]Patent: WO2017/23988,2017,A1 .Location in patent: Paragraph 0612
[23]Patent: WO2017/23996,2017,A1 .Location in patent: Paragraph 0616
[24]Patent: WO2017/24026,2017,A1 .Location in patent: Paragraph 0619; 0620
[25]Patent: US2016/75701,2016,A1 .Location in patent: Paragraph 0823; 0824
[26]Patent: US2016/68547,2016,A1 .Location in patent: Paragraph 0801; 0802
[27]Patent: US2016/68551,2016,A1 .Location in patent: Paragraph 0799-0800
[28]Patent: US2016/68529,2016,A1 .Location in patent: Paragraph 0802
[29]Patent: US2016/90380,2016,A1 .Location in patent: Paragraph 0824

42
[ 13535-01-8 ]
[ 67-64-1 ]
[ 1201643-57-3 ]

Yield	Reaction Conditions	Operation in experiment
47%		To a solution of 5-bromopyridin-3-amine (XXII) (535 mg, 3.09 mmol) in MeOH (62 mL) was added acetone (296 muL, 4.02 mL) The pH was adjusted to 4 using HOAc and stirred for 30 min. NaCNBH3 (272 mg, 4.33 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% hexane?90:10 hexane:EtOAc) to produce 5-bromo-N-isopropylpyridin-3-amine (XLIV) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield). 1H NMR (DMSO-d6, 500 MHz) delta ppm 1.12 (d, J=6.3 Hz, 6H), 3.55-3.59 (m, 1H), 6.03 (d, J=7.9 Hz, 1H), 7.05-7.06 (m, 1H), 7.75 (d, J=2 Hz, 1H), 7.90 (d, J=2 Hz, 1H); ESIMS found C8H11BrN2 m/z 215 (M+H).
47%		Steps 1 To a solution of 5-bromopyridin-3-amine (XXII) (535 mg, 3.09 mmol) in MeOH (62 mL) was added acetone (296 muL, 4.02 mL). The pH was adjusted to 4 using HOAc and stirred for 30 min. NaCNBH3 (272 mg, 4.33 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% hexane 90:10 hexane:EtOAc) to produce 5-bromo-N-isopropylpyridin-3-amine (XXIII) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield).
47%		Step 1 To a solution of 5-bromopyridin-3-amine (XX) (535 mg, 3.09 mmol) in MeOH (62 mL) was added acetone (296 muL, 4.02 mL). The pH was adjusted to 4 using HOAc and stirred for 30 min. NaCNBH3 (272 mg, 4.33 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% hexane?90:10 hexane:EtOAc) to produce 5-bromo-N-isopropylpyridin-3-amine (XXXVIII) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield). 1H NMR (DMSO-d6, 500 MHz) delta ppm 1.12 (d, J=6.3 Hz, 6H), 3.55-3.59 (m, 1H), 6.03 (d, J=7.9 Hz, 1H), 7.05-7.06 (m, 1H), 7.75 (d, J=2 Hz, 1H), 7.90 (d, J=2 Hz, 1H); ESIMS found C8H11BrN2 m/z 215.1 (M+H).

47%		To a solution of 5-bromopyridin-3-amine (XX) (535 mg, 3.09 mmol) in MeOH (62 mL) was added acetone (296 muL, 4.02 mL). The pH was adjusted to 4 using HOAc and stirred for 30 min. NaCNBH3 (272 mg, 4.33 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between EtOAc and saturated aqueous NaHC03. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% hexane ? 90: 10 hexane:EtOAc) to produce 5-bromo-N-isopropylpyridin-3-amine (XXXVIII) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield). 1H NMR (DMSO-d6, 500 MHz) delta ppm 1.12 (d, J=6.3Hz, 6H), 3.55-3.59 (m, 1H), 6.03 (d, J=7.9Hz, 1H), 7.05-7.06 (m, 1H), 7.75 (d, J=2Hz, 1H), 7.90 (d, J=2Hz, 1H); ESIMS found C8H11BrN2 m/z 215.1 (M+H).
47%		To a solution of 5-bromopyridin-3-amine (XVIII) (535 mg, 3.09 mmol) in MeOH (62 mL) was added acetone (296 .iL, 4.02 mL). The pH was adjusted to 4 using HOAc and stirred for 30 mm. NaCNBH3 (272 mg, 4.33 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over Mg504 and evaporated under vacuum. The cmde product was purified on a silica gel column (100% hexane-* 90:10 hexane : EtOAc) to produce 5 -bromo-N-isopropylpyridin-3 -amine (XXXVI) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield). ?H NMR (DMSO-d6, 500 MHz) ppm 1.12 (d, J6.3Hz, 6H), 3.55-3.59 (m, 1H), 6.03 (d, J7.9Hz, 1H), 7.05-7.06 (m, 1H), 7.75 (d, J2Hz, 1H), 7.90 (d, J2Hz, 1H); ESIMS found C8H,,BrN2 mlz 215.1 (M+H).
47%		To a solution of 5-bromopyridin-3-amine (XIX) (535 mg, 3.09 mmol) in MeOH (62 mL) was added acetone (296 tL, 4.02 mL). The pH was adjusted to 4 using HOAc and stirred for 30 mi NaCNBH3 (272 mg, 4.33 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over Mg504 and evaporated under vacuum. The cmde product was purified on a silica gel column (100% hexanes -* 90:10 hexanes:EtOAc) to produce 5-bromo-N-isopropylpyridin-3-amine (XXXVII) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield). ?H NMR (DMSO-d6, 500 MHz) ppm 1.12 (d, J6.3Hz, 6H), 3.55-3.59 (m, 1H), 6.03 (d, J7.9Hz, 1H), 7.05-7.06 (m, 1H), 7.75 (d, J2Hz, 1H), 7.90 (d, J2Hz, 1H); ESIMS found C8H,,BrN2 mlz 215.1 (M+H).
47%		To a solution of 5-bromopyridin-3-amine (XIX) (535 mg, 3.09 mmol) in MeOH (62 mL) was added acetone (296 .iL, 4.02 mL). The pH was adjusted to 4 using HOAc and stirred for 30 mi NaCNBH3 (272 mg, 4.33 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over Mg504 and evaporated under vacuum. The crude product was purified on a silica gel column (100% hexanes-* 90:10 hexanes:EtOAc) to produce 5-bromo-N-isopropylpyridin-3-amine (XXXVII) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield). ?H NMR (DMSO-d6, 500 MHz) ppm 1.12 (d, J=6.3Hz, 6H), 3.55-3.59 (m, 1H), 6.03 (d, J=7.9Hz, 1H), 7.05-7.06 (m, 1H), 7.75 (d, J2Hz, 1H), 7.90 (d, J=2Hz, 1H); ESIMS found C8H11BrN2 mlz 215.1 (M+H).

Reference： [1]Patent: US2013/267495,2013,A1 .Location in patent: Paragraph 0444-0445
[2]Patent: US2014/194441,2014,A1 .Location in patent: Paragraph 0417
[3]Patent: US2016/68550,2016,A1 .Location in patent: Paragraph 1083-1084
[4]Patent: WO2016/40193,2016,A1 .Location in patent: Paragraph 0730-0731
[5]Patent: WO2017/23989,2017,A1 .Location in patent: Paragraph 0629; 0630
[6]Patent: WO2017/23975,2017,A1 .Location in patent: Paragraph 0633; 0634
[7]Patent: WO2017/23993,2017,A1 .Location in patent: Paragraph 0638; 0639
[8]Patent: WO2017/24021,2017,A1 .Location in patent: Paragraph 0652; 0653
[9]Patent: WO2017/23987,2017,A1 .Location in patent: Paragraph 0633; 0634
[10]Patent: WO2017/23972,2017,A1 .Location in patent: Paragraph 0629; 0630
[11]Patent: WO2017/24013,2017,A1 .Location in patent: Paragraph 0652; 0653
[12]Patent: WO2017/24004,2017,A1 .Location in patent: Paragraph 0634
[13]Patent: WO2017/24025,2017,A1 .Location in patent: Paragraph 0634
[14]Patent: WO2017/24003,2017,A1 .Location in patent: Paragraph 0633; 0634
[15]Patent: WO2017/24010,2017,A1 .Location in patent: Paragraph 036; 037
[16]Patent: WO2017/23981,2017,A1 .Location in patent: Paragraph 0633; 0634
[17]Patent: WO2017/23986,2017,A1 .Location in patent: Paragraph 0656; 0657
[18]Patent: WO2017/24015,2017,A1 .Location in patent: Paragraph 029
[19]Patent: WO2017/23984,2017,A1 .Location in patent: Paragraph 0633
[20]Patent: WO2017/23973,2017,A1 .Location in patent: Paragraph 0654-0655
[21]Patent: WO2017/23980,2017,A1 .Location in patent: Paragraph 0634
[22]Patent: WO2017/23988,2017,A1 .Location in patent: Paragraph 0630
[23]Patent: WO2017/23996,2017,A1 .Location in patent: Paragraph 0633-0634
[24]Patent: WO2017/24026,2017,A1 .Location in patent: Paragraph 0637; 0638
[25]Patent: US2016/75701,2016,A1 .Location in patent: Paragraph 0841; 0842
[26]Patent: US2016/68547,2016,A1 .Location in patent: Paragraph 0819; 0820
[27]Patent: US2016/68551,2016,A1 .Location in patent: Paragraph 0817-0818
[28]Patent: US2016/68529,2016,A1 .Location in patent: Page/Page column 0820
[29]Patent: US2016/90380,2016,A1 .Location in patent: Paragraph 0842

43
[ 39620-02-5 ]
[ 13535-01-8 ]

Reference： [1]ChemMedChem,2014,vol. 9,p. 217 - 232

44
[ 13535-01-8 ]
[ 97267-61-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 1.5 h / 90 °C 1.2: 0.67 h / 60 - 70 °C 2.1: Dowtherm A / 0.17 h / 235 - 240 °C 3.1: trichlorophosphate / 2 h / Inert atmosphere; Reflux
	Multi-step reaction with 3 steps 1: glycerol; ferrous(II) sulfate heptahydrate; boric acid; sulfuric acid; sodium 3-nitrobenzenesulfonate / 18 h / 135 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 18 h / 20 °C 3: trichlorophosphate / dichloromethane / 2.5 h / Reflux
	Multi-step reaction with 5 steps 1: toluene / 3 h / Reflux 2: diphenylether / 1 h / Reflux 3: sodium hydroxide / water / 1 h / Reflux 4: quinoline / 1 h / Reflux 5: trichlorophosphate / 5 h / Reflux

	Multi-step reaction with 5 steps 1.1: toluene / 3 h / Heating / reflux 2.1: diphenylether / 1 h / Heating / reflux 3.1: sodium hydroxide; water / 1 h / Heating / reflux 3.2: pH 4 4.1: quinoline / 1.17 h / Heating / reflux 5.1: trichlorophosphate / 5 h / Heating / reflux 5.2: 0 °C
	Multi-step reaction with 3 steps 1.1: 1 h / 90 °C 1.2: 0.67 h / 70 °C 2.1: diphenyl ether-biphenyl eutectic / 1.08 h / 240 °C 3.1: trichlorophosphate / 1 h / 105 °C

Reference： [1]Defaux, Julien; Antoine, Maud; Le Borgne, Marc; Schuster, Tilmann; Seipelt, Irene; Aicher, Babette; Teifel, Michael; Guenther, Eckhard; Gerlach, Matthias; Marchand, Pascal [ChemMedChem, 2014, vol. 9, # 1, p. 217 - 232]
[2]Defaux, Julien; Antoine, Maud; Logé, Cédric; Le Borgne, Marc; Schuster, Tilmann; Seipelt, Irene; Aicher, Babette; Teifel, Michael; Günther, Eckhard; Gerlach, Matthias; Marchand, Pascal [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 16, p. 3748 - 3752]
[3]Current Patent Assignee: AMGEN INC - US2014/336182, 2014, A1
[4]Current Patent Assignee: AMGEN INC - WO2008/124083, 2008, A2
[5]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2020/150114, 2020, A1

45
[ 13535-01-8 ]
[ 1309774-03-5 ]
[ 97267-61-3 ]

Reference： [1]ChemMedChem,2014,vol. 9,p. 217 - 232

46
[ 13535-01-8 ]
[ 56-81-5 ]
[ 17965-71-8 ]

Yield	Reaction Conditions	Operation in experiment
	With ferrous(II) sulfate heptahydrate; sulfuric acid; boric acid; sodium 3-nitrobenzenesulfonate; In water; at 135℃;	Procedure: To a stirred solution of FeSO4.7H2O( 0.97 g, 3.46 mmol) in cone. H2SO4 (25 mL), sodium 3-nitrobenesulfonate (13.01 g, 57.80 mmol) and B(OH)3 (2.7 g, 43.35 mmol) were added at rt, and the reaction mixture was stirred at rt 1 h. Then to this reaction mixture glycerol (12.0 g, 130.05 mmol), 3-amino-5-bromopyridine (5.0 g, 28.90 mmol) and H2O (25 mL) were added at rt and the reaction mixture was stirred at 135 C overnight. The reaction mixture was cooled to rt and basified with 8 M NaOH until the mixture reached pH 14 and was extracted with DCM (2 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2S04 and concentrated. The crude product was purified by flash column chromatography to afford the title compound (yellow solid). 1H NMR (400 MHz, DMSO-d6): delta 9.09 (d, J = 2.0 Hz, 1 H), 9.04 (dd, J = 1.6, 4.0 Hz, 1 H), 8.76 (d, J = 1.6 Hz, 1 H), 8.47 (d, J = 8.4 Hz, 1 H), 7.86-7.83 (m, 1 H).

Reference： [1]ChemMedChem,2014,vol. 9,p. 217 - 232
[2]Patent: WO2017/144639,2017,A1 .Location in patent: Page/Page column 105

47
[ 13535-01-8 ]
[ 1180678-40-3 ]

Yield	Reaction Conditions	Operation in experiment
42%	With N-iodo-succinimide; acetic acid;Reflux;	General procedure: NIS (24.75 g, 110.0 mmol) was added to a solution of 2-chloropyridin-4-ylamine (12.85 g, 100.0 mmol) in MeCN (400 mL),and the mixture was stirred and held at reflux overnight. Uponcooling to r.t. the solvent was removed in vacuo and the residuepartitioned between EtOAc (250 mL), sat. Na2S2O3 (100 mL), andH2O (250 mL). The organic layer was separated, washed withH2O (2 × 250 mL), separated, and the solvent removed in vacuoto afford an orange oil that was subjected to column chromatographyon silica gel. Elution with 30-50% EtOAc in PE afforded apale orange solid that was rinsed with 25% EtOAc in PE (80 mL).The solids were collected by filtration and sucked dry to afford2-chloro-5-iodopyridin-4-ylamine (7.32 g) as an off-white solid.The mother liquors were concentrated to dryness in vacuo andthe residues subjected to column chromatography on silica.Elution with 30-50% EtOAc in PE afforded further pure material(1.90 g)
11.5 g	With N-iodo-succinimide; acetic acid; at 20℃;Inert atmosphere;	3-Amino-5-bromopyridine (13.8 g, 79.8 mmol) was dissolved in acetic acid (440 mL) and placed under a nitrogen atmosphere. N-lodosuccinimide (16.15 g, 71.8 mmol) was charged to the reaction which was stirred at room temperature overnight. The reaction wasconcentrated and the residue partitioned between EtOAc (200 mL) and saturated aqueous sodium hydrogen carbonate (200 mL). The layers were separated and the organic phase was washed with saturated aqueous sodium hydrogen carbonate (200 mL). The aqueous phase was extracted with EtOAc (3 x 200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated. Chromatography (silica; 1.4 Kg packed in70% DCM:30% heptane, eluting with 70-100% DCM in heptane) gave the title compound (11.5 g). 1H NMR (270 MHz, CDCI3): 7.83 (1H, m), 7.04 (1H, m), 4.33 (2H, brs).
11.5 g	With N-iodo-succinimide; acetic acid; at 20℃;Inert atmosphere;	Preparation 14: 5-Bromo-2-iodo-pyridin-3-ylamine 3-Amino-5-bromopyridine (13.8 g, 79.8 mmol) was dissolved in acetic acid (440 mL) and placed under a nitrogen atmosphere. N-lodosuccinimide (16.15 g, 71.8 mmol) was charged to the reaction which was stirred at room temperature overnight. The reaction was concentrated andthe residue partitioned between EtOAc (200 mL) and saturated aqueous sodium hydrogen carbonate (200 mL). The layers were separated and the organic phase was washed with saturated aqueous sodium hydrogen carbonate (200 mL). The aqueous phase was extracted with EtOAc (3 x 200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated. Chromatography (silica; 1.4 Kg packed in 70% DCM:30% heptane, eluting with70-100% DCM in heptane) gave the title compound (11.5 g). 1H NMR (270 MHz, CDCI3): 7.83 (1H, m), 7.04 (1H, m), 4.33 (2H, brs).

11.5 g

With N-iodo-succinimide; acetic acid; at 20℃;Inert atmosphere;

Preparation II: 5-Bromo-2-iodo-pyridin-3-ylamine H2N3-Amino-5-bromopyridine (13.8 g, 79.8 mmol) was dissolved in acetic acid (440 mL) and placed under a nitrogen atmosphere. N-lodosuccinimide (16.15 g, 71.8 mmol) was charged to the reaction which was stirred at room temperature overnight. The reaction wasconcentrated and the residue partitioned between EtOAc (200 mL) and saturated aqueous sodium hydrogen carbonate (200 mL). The layers were separated and the organic phase was washed with saturated aqueous sodium hydrogen carbonate (200 mL). The aqueous phase was extracted with EtOAc (3 x 200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated. Chromatography (silica; 1.4 Kg packed in70% DCM:30% heptane, eluting with 70-100% DCM in heptane) gave the title compound (11.5g). 1H NMR(27OMHz, CDCI3): 7.83(1H, m), 7.04(1H, m),4.33(2H, brs).

Reference： [1]Synlett,2015,vol. 26,p. 2570 - 2574
[2]Patent: WO2014/60768,2014,A1 .Location in patent: Page/Page column 94; 95
[3]Patent: WO2014/60767,2014,A1 .Location in patent: Page/Page column 107
[4]Patent: WO2014/60770,2014,A1 .Location in patent: Page/Page column 126
[5]Journal of Organic Chemistry,2015,vol. 80,p. 10806 - 10816

48
[ 13535-01-8 ]
[ 411235-57-9 ]
[ 1314353-68-8 ]

Yield	Reaction Conditions	Operation in experiment
56%	With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 15h;	To a solution of 5-bromopyridin-3-amine (4.75 g, 27.45 minol) in dioxane (45 mL) was added cyclopropylboronic acid (4.75 g, 55.30 minol), C52CO3(28 g, 85.67 minol), tetrakis(triphenylphosphane) palladium(1.66 g, 1.44 minol) and water (5 mL) at room temperature. The resultingminxture was then stirred for 15 h at 100 C. After cooling to room temperature, the reaction mxiture was diluted with water (200 mL). The resultingminxture was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 100% gradient) to yield 5-cyclopropylpyridin-3-amine as light brown oil (2.08 g, 56%). MS: m/z = 135.0 [M+Hj .
	With palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃; for 11h;	(Step 1) A solution of cyclopropyl boronic acid (497 mg), palladium acetate (II) (65 mg), tricyclohexylphosphine (162 mg), and potassium phosphate (2.5 g) in toluene (9 mL) and water (0.45 mL) was added to 5-bromopyridin-3-amine (500 mg), and the mixture was stirred at 100C for 11 hours. Ethyl acetate and water were added, the organic layer was separated, and the resultant was washed with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent: hexane/ethyl acetate) to obtain 3-amino-5-cyclopropylpyridine.
314 mg	With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 5h;Inert atmosphere; Sealed tube;	Reference Example 45 Cyclopropylboronic acid (360 mg), cesium carbonate (1.4 g), and Pd(PPh3)4 (166 mg) were added to a 1,4-dioxane/water (4.5 ml/0.5 ml) solution containing 5-bromopyridin-3-amine (500 mg) in a nitrogen atmosphere, followed by stirring in a sealed tube at 100 C. for 5 hours. The reaction solution was adjusted to room temperature and water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform:MeOH=1:0 to 30:1). A brown solid of 5-cyclopropyl pyridin-3-amine (314 mg) was thus obtained. MS (ESI m/z): 135 (M+H)

Reference： [1]Patent: WO2017/106607,2017,A1 .Location in patent: Paragraph 00477
[2]Patent: EP2762476,2014,A1 .Location in patent: Paragraph 0174
[3]Patent: US2014/309225,2014,A1 .Location in patent: Paragraph 0700; 0701; 0702; 0703

49
[ 13535-01-8 ]
[ 17965-71-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3748 - 3752

50
[ 13535-01-8 ]
[ 1309774-03-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3748 - 3752

51
[ 13535-01-8 ]
[ 1309774-04-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: glycerol; ferrous(II) sulfate heptahydrate; boric acid; sulfuric acid; sodium 3-nitrobenzenesulfonate / 18 h / 135 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 18 h / 20 °C 3: trichlorophosphate / dichloromethane / 2.5 h / Reflux 4: ammonium hydroxide / 1,4-dioxane / 24 h / 140 °C / Sealed tube

Reference： [1]Defaux, Julien; Antoine, Maud; Logé, Cédric; Le Borgne, Marc; Schuster, Tilmann; Seipelt, Irene; Aicher, Babette; Teifel, Michael; Günther, Eckhard; Gerlach, Matthias; Marchand, Pascal [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 16, p. 3748 - 3752]

52
[ 13535-01-8 ]
[ 75-36-5 ]
[ 15862-46-1 ]

Yield	Reaction Conditions	Operation in experiment
91%		To a stirred suspension of 5-bromopyridin-3-amine (500 mg, 2.89 mmol) in DCM (10 mL), was added pyridine (0.467 mL, 5.78 mmol). The mixture was stirred for 20 min and acetyl chloride (0.236 mL, 3.32 mmol) was added. The mixture was stirred for 3 h. The mixture was diluted with water (20 mL) and DCM (20 mL). The layers were separated and the aqueous layer was re-extracted with DCM (3 x 20 mL). The combined organics were washed with brine (20 mL), dried using a hydrophobic frit and concentrated in vacuo to give A/-(5-bromopyridin-3- yl)acetamide as an orange solid (563 mg, 91 %). LCMS (2 min, Formic): Rt = 0.59 min, MH+ 215/217

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 730 - 734
[2]Patent: WO2014/140077,2014,A1 .Location in patent: Page/Page column 55

53
[ 13535-01-8 ]
[ 1201645-46-6 ]

Reference： [1]Patent: WO2014/140077,2014,A1

54
[ 13535-01-8 ]
[ 152684-25-8 ]

Reference： [1]Patent: EP2873669,2015,A1
[2]Patent: EP2848618,2015,A1
[3]Patent: US9242996,2016,B2
[4]Patent: WO2017/7756,2017,A1

55
[ 13535-01-8 ]
[ 1476730-34-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: pyridine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: nitric acid; sulfuric acid / 72 h / 0 - 20 °C / Inert atmosphere 3: methanol / 4 h / 65 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: pyridine / tetrahydrofuran / 0 - 35 °C / Inert atmosphere 2: sulfuric acid; nitric acid / 72 h / 0 - 35 °C / Inert atmosphere 3: methanol / 4 h / 65 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2873669, 2015, A1
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED; ENERSYS - EP2848618, 2015, A1

56
[ 13535-01-8 ]
[ 72482-64-5 ]
N-(5-bromopyridin-3-yl)-2,4-difluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With pyridine; In dichloromethane; at 0℃;Inert atmosphere;	[00417] A flask containing 3-amino-5-bromopyridine (0.500 g, 2.89 mmol) was evacuated and backfilled with argon. Pyridine (0.70 niL) and DCM (8 niL) were added and the mixture was allowed to stir at 0C. <strong>[72482-64-5]2,4-difluorobenzoyl chloride</strong> (0.5 10 g, 2.89 mmol) was dissolved in DCM (3 mL) and added dropwise to the reaction mixture. The reaction mixture was allowed to stir at the same temperature until the starting material was consumed. The reaction mixture was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The crude compound was purified by column chromatography as a pale yellow powder (0.83 g, 9 1%). LCMS (FA):m/z= 314.0 (M+H).
91%	With pyridine; In dichloromethane; at 0℃;Inert atmosphere;	Step 1: N-(5-bromopyridin-3-yl)-2,4-difluorobenzamide A flask containing 3-amino-5-bromopyridine (0.500 g, 2.89 mmol) was evacuated and backfilled with argon. Pyridine (0.70 mL) and DCM (8 mL) were added and the mixture was allowed to stir at 0 C. <strong>[72482-64-5]2,4-difluorobenzoyl chloride</strong> (0.510 g, 2.89 mmol) was dissolved in DCM (3 mL) and added dropwise to the reaction mixture. The reaction mixture was allowed to stir at the same temperature until the starting material was consumed. The reaction mixture was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The crude compound was purified by column chromatography as a pale yellow powder (0.83 g, 91%). LCMS (FA): m/z=314.0 (M+H).
84.0%	With pyridine; at 20℃; for 16h;	Step 2 To a solution of <strong>[72482-64-5]2,4-difluorobenzoyl chloride</strong> (XXI) in pyridine (20 mL) then 3-amino-5-bromopyridine (XXII) (2.63 g, 15.18 mmol, 1.21 eq) was added and stirred at room temperature for 16 h. The reaction was then quenched with water (10 mL) and the the solvent was concentrated in vacuo. The residue was purified by chromatography on silica gel (Hexanes:EtOAc=4:1) to afford N-(5-bromopyridin-3-yl)-2,4-difluorobenzamide (XXIII) (3.3 g, 10.6 mmol, 84.0% yield) as a tan solid. ESIMS found for C12H7BrF2N2O m/z 312.8 (M+H).

Reference： [1]Patent: WO2015/108861,2015,A1 .Location in patent: Paragraph 00417
[2]Patent: US2015/225422,2015,A1 .Location in patent: Paragraph 0576-0577
[3]Patent: US2015/266825,2015,A1 .Location in patent: Paragraph 1245; 1247

57
[ 13535-01-8 ]
[ 832114-00-8 ]
5-(3,5-dimethylisoxazol-4-yl)pyridin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 80℃; for 1h;Inert atmosphere;	Step 1: 5-(3,5-Dimethylisoxazol-4-yl)pyridin-3-amineTo a 40 mL vial containing 5-bromopyridin-3-amine (Aldrich, 200 mg, 1.16 mmol) and 3,5 -dimethyl-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)isoxazole(Aldrich, 516 mg, 2.31 mmol) in THF (10 mL) was added aq. tripotassium phosphate (2M, 1.7 mL, 3.47 mmol) to give a yellow suspension. Pd(dppf)C12-CH2C12 (94 mg, 0.12 mmol) was then added and N2 was bubbled into the mixture for 2 mm. The resulting reaction mixture was heated at 80 C for 1 h, concentrated and purified using ISCO silica gel chromatography (40 g column, gradient from 0% to 10% MeOH/CH2C12) to give the title compound (213 mg, 97%) as a pale orange solid. LCMS (M+H) = 190; HPLC RT = 0.51 mm (Column: Chromolith ODS S5 4.6 x 50mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40 C; Gradient: 0-100% B over 4 mm; Flow: 4 mL/min).
97%	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 80℃; for 1h;Inert atmosphere;	To a 40 mL vial containing 5-bromopyridin-3-amine (Aldrich, 200 mg, 1.16 mmol) and <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (Aldrich, 516 mg, 2.31 mmol) in THF (10 mL) was added aq. tripotassium phosphate (2M, 1.7 mL, 3.47 mmol) to give a yellow suspension. Pd(dppf)Cl2-CH2Cl2 (94 mg, 0.12 mmol) was then added and N2 was bubbled into the mixture for 2 min. The resulting reaction mixture was heated at 80 C. for 1 h, concentrated and purified using ISCO silica gel chromatography (40 g column, gradient from 0% to 10% MeOH/CH2Cl2) to give the title compound (213 mg, 97%) as a pale orange solid. LCMS (M+H)=190; HPLC RT=0.51 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40 C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Reference： [1]Patent: WO2015/100282,2015,A1 .Location in patent: Page/Page column 98; 99
[2]Patent: US2016/176864,2016,A1 .Location in patent: Paragraph 0423; 0424

58
[ 13535-01-8 ]
[ 776-04-5 ]
N-(5-bromopyridin-3-yl)-2-(trifluoromethyl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With pyridine; In acetonitrile; at 20℃; for 24h;	Method 3; To a solution of 2-(trifluoromethyl)benzenesulfonyl chloride (1 g, 4.09 mmol) and 5-bromopyridin-3-amine (707 mg, 4.09 mmol) in acetonitrile (15 mL) was added pyridine (660 muL, 8.18 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water (25 mL) and extracted into EtOAc (2 x 40 mL). The organic layers were combined, washed with saturated aqueous ammonium chloride solution (20 mL), brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was triturated with DCM to afford the title compound as a white solid (335 mg, 21 %). 1 H NMR (400MHz, DMSO-d6): delta ppm 7.65 (t, 1 H), 7.84-7.92 (m, 2H), 8.01 (dd, 1 H), 8.14 (dd, 1 H), 8.29 (d, 1 H), 8.38 (d, 1 H), 1 1 .24 (br s, 1 H); 19F NMR (400MHz, DMSO-d6): delta ppm -56 (s, 3F). MS m/z 381 [M+H]+

Reference： [1]Patent: WO2016/34971,2016,A1 .Location in patent: Page/Page column 54
[2]MedChemComm,2016,vol. 7,p. 1572 - 1579

59
[ 122918-25-6 ]
[ 13535-01-8 ]
[ 885518-49-0 ]
methyl 6-(5-aminopyridin-3-yl)-1-(6-cyanopyridin-2-yl)-1H-indazole-4-carboxylate [ No CAS ]
methyl 6-(5-aminopyridin-3-yl)-2-(6-cyanopyridin-2-yl)-2H-indazole-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/11390,2016,A1 .Location in patent: Page/Page column 97; 98; 99

60
[ 13535-01-8 ]
[ 885518-49-0 ]
[ 39890-95-4 ]
methyl 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate [ No CAS ]
methyl 6-(5-aminopyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)-2H-indazole-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/11390,2016,A1 .Location in patent: Page/Page column 99; 100

61
[ 13535-01-8 ]
[ 1201644-38-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: acetic acid / methanol / 0.5 h / pH 4 1.2: 25 °C 2.1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 85 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: BIOSPLICE THERAPEUTICS INC - WO2017/23988, 2017, A1

62
[ 13535-01-8 ]
[ 72040-64-3 ]
N-(4-((5-bromopyridin-3-yl)amino)-4-oxobutyl)-5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.4%		Thionyl chloride (20equiv) was added dropwise to dry solid 7 (1equiv) at 0°C. The solution was stirred overnight at room temperature. The thionyl chloride in excess was removed under reduced pressure. Then the product was dissolved in DCM and added dropwise to 3-amino-5-bromopyridine (1equiv) in DCM at 0°C. The resulting mixture was stirred overnight at room temperature. The product was filtered, washed with saturated solution of NaHCO3, and dried under vacuum.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3591 - 3594

63
[ 13535-01-8 ]
[ 2942-14-5 ]
5-(5-methoxybenzo[d]thiazol-2-yl)pyridin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With tri-tert-butyl phosphine; palladium diacetate; caesium carbonate; copper(I) bromide; In N,N-dimethyl-formamide; at 150℃; for 1.5h;Inert atmosphere;	<strong>[2942-14-5]5-Methoxybenzothiazol</strong>e (6.34 g, 38.4 mmol), 3-amino-5-bromopyridine (7.41 g, 42.8 mmol), cesium carbonate (12.5 g, 38.4 mmol), copper(l)bromide (1.12 g) and Pd(OAc)2 (0.56 g, 2.50 mmol) were suspended in dry DMF (200 ml) under argon. P(i-Bu)3 (1 .00 g, 4.94 mmol) dissolved in 10 ml dry DMF was added. The reaction mixture was heated at 150 C for 1 .5 hrs, cooled to room temperature and poured into EtOAc (100 ml). The organic phase was washed with water (100 ml) and the aqueous phase extracted with EtOAc (2 x 100 ml). The combined organic phase was washed with water, dried (MgS04), filtered and concentrated. Flash chromatography (Heptane : EtOAc 80 : 20 - 50 : 50 - EtOAc) afforded 4.09 g (41 %) of the title compound as a pale yellow solid. (0173) 1H NMR (300 MHz, DMSO-d6) delta 8.39 (s, 1 H), 8.08 (s, 1 H), 8.01 (d, J = 8.8, 1 H), 7.73 - 7.49 (m, 2H), 7.1 1 (dd, J = 8.8, 2.5, 1 H), 5.71 (s, 2H), 3.87 (s, 3H). MS (pos): 258 (M+H)

Reference： [1]Patent: WO2018/69468,2018,A1 .Location in patent: Page/Page column 52-53

64
[ 13535-01-8 ]
[ 65001-21-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; thionyl chloride; copper(l) chloride; sodium nitrite; In water; at 0 - 20℃; for 1.5h;	[0323] To a cooled (0 C) solution of 5-bromopyridin-3-amine (10 g, 57.80 mmol) in HC1 (122V, 78 mL) was added NaN02 (5.78 g, 52.63 mmol) in H20 (24 mL). In another flask, SOCl2 (24 mL) was mixed with H20 (150 mL) and the solution was cooled to 10 C. Then Cu(I)Cl (0.087 g, 0.878 mmol) was added in portions and the reaction mixture was stirred at 10 C for 1 hr. To this solution was added the diazotization mixture at 0 C. The reaction mixture was stirred at 0 C for 30 min, and then allowed to warm up to r.t. over a period of 1 hr. Then the reaction mixture was poured into crushed ice. The resultant solid was filtered and dried under reduced pressure to afford 5 g (34% yield) of crude 5-bromopyridine-3-sulfonyl chloride Int-28 as a pale brown solid. The crude product was taken to the next step without further purification. MS (ESI) m/z 257.96 [M+H]+.

Reference： [1]Patent: WO2018/85348,2018,A1 .Location in patent: Paragraph 0322-0323

65
[ 13535-01-8 ]
[ 120539-91-5 ]
N-benzyloxycarbonyl-3-(3'-amino-5'-pyridyl)-prop-2-ynyl-1-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23.7%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In acetonitrile at 80℃; for 3h; Inert atmosphere; Sealed tube;	4.33. N-Benzyloxycarbonyl-3-(3'-amino-5'-pyridyl)-prop-2-ynyl-1-amine (22e) To a solution of 21 (1.0 g, 5.28 mmol), CuI (0.1 g, 0.525 mmol), (PPh3)2PdCl2 (0.185 g, 0.264 mmol) and triethylamine (1.1 mL, 7.92 mmol) in acetonitrile (20 mL) was added 3-amino-5-bromopyridine (1.83 g, 10.58 mmol). The reaction mixture was recharged with argon and stirred at 80 °C for 3 h in a sealed tube. The mixture was extracted with ethyl acetate and the organic layer was washed successively with water and brine. The organic solvent was removed in vacuum. The residue was purified by column chromatography on silica gel (CH2Cl2/C2H5OH/NH3•H2O, 10:0.1:0.1) to afford 22e (0.3511 g, 1.25 mmol, 23.7%).1H NMR (CDCl3, 400 MHz), δ: 8.03 (d, J = 13.7 Hz, 2 H, H-pyridine), 7.41-6.88 (m, 6 H, H-pyridine, H-phenyl), 5.19 (s, 1 H, -NH-), 5.15 (s, 2 H,-CH2-O-), 4.21 (s, 2 H, -NH-CH2-), 3.32 (br, 2 H, -NH2).

Reference： [1]Li, Xue-Meng; Lv, Wei; Guo, Si-Yang; Li, Ya-Xin; Fan, Bing-Zhi; Cushman, Mark; Kong, Fan-Sheng; Zhang, Jun; Liang, Jian-Hua [European Journal of Medicinal Chemistry, 2019, vol. 171, p. 235 - 254]

66
[ 13535-01-8 ]
[ 15026-17-2 ]
tert-butyl 4-((5-bromopyridin-3-yl)amino)-4-oxobutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 50℃; for 1h;	A mixture of 5 -bromopyri din-3 -amine (300 mg, 1.73 mmol), mono-tert-butyl succinic acid (301 mg, 1.73 mmol) and EDCI.HCl (365 mg, 1.90 mmol) in pyridine (5 mL) was heated at 50 C for 1 hour. An orange solution was formed. The mixture was concentrated and the residue was poured into water (20 mL) and stirred for 2 minutes. The aqueous layer was extracted with ethyl acetate (20 mL x3). The combined organic layer was washed with water (20 mL x2) and brine (20 mL), dried over anhydrous Na2SC>4, filtered and concentrated. The residue was triturated with pentane/EtOAC (3 mL, 3/1) to give tert-butyl 4- ((5-bromopyridin-3-yl)amino)-4-oxobutanoate(470 mg, yield: 82%) as a yellow solid. (1356) NMR (400 MHz DMSO-r/e) d 1.39 (9H, s), 2.52-2.55 (2H, m), 2.57-2.62 (2H, m), 8.30- 8.40 (2H, m), 8.62-8.65 (1H, m), 10.41 (1H, brs)

Reference： [1]Patent: WO2019/126730,2019,A1 .Location in patent: Paragraph 0478

67
[ 13535-01-8 ]
[ 1670-82-2 ]
N-(5-bromopyridin-3-yl)-1H-indole-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 50℃; for 1h;	A mixture of lH-<strong>[1670-82-2]indole-6-carboxylic acid</strong> (307mg, 1.90 mmol), 5-bromopyridin-3- amine (300 mg, 1.73 mmol) and EDCI.HCl (365 mg, 1.90 mmol) in pyridine (5 mL) was heated at 50 C for 1 hour. An orange solution was formed. LCMS (Rt = 0.733 min; MS Calcd: 315.0; MS Found: 315.9 [M+H]+). The mixture was concentrated and the residue was poured into water (20 mL) and stirred for 2 minutes. The aqueous layer was extracted with ethyl acetate (20 mL x3). The combined organic layer was washed with water (20 mL x2) and brine (20 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was triturated with pentane/EtOAC (3 mL, 3/1) to give N-(5-bromopyridin-3-yl)-lH-indole-6-carboxamide (440 mg, yield: 80%) as a light yellow solid. NMR (400 MHz DMSO-rie) d 6.55 (1H, t, J= 2.0 Hz), 7.60 (1H, t, J= 2.8 Hz), 7.68 (1H, s), 8.12 (1H, s), 8.43 (1H, d, J= 2.0 Hz), 8.49 (1H, s), 8.58 (1H, t, J= 2.1 Hz), 8.97 (1H, d, J = 2.3 Hz), 10.55 (1H, brs), 11.55 (1H, brs).

Reference： [1]Patent: WO2019/126730,2019,A1 .Location in patent: Paragraph 0484

68
[ 13535-01-8 ]
[ 2124-55-2 ]
N-(5-((5-methyl-8-(2-oxopyrrolidin-1-yl)-5H-chromeno[4,3-c]pyridin-3-yl)amino)pyridin-3-yl)-1H-indole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2019/126730,2019,A1

69
[ 13535-01-8 ]
[ 2124-55-2 ]
N-(5-bromopyridin-3-yl)-1H-indole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 50℃; for 1h;	A mixture of lH-<strong>[2124-55-2]indole-4-carboxylic acid</strong> (307 mg, 1.91 mmol), 5-bromopyridin- 3-amine (300 mg, 1.73 mmol) and EDCI.HC1 (366 mg, 1.91 mmol) in pyridine (5 mL) was heated at 50 C for 1 hour. An orange solution was formed. The mixture was concentrated and the residue was poured into water (20 mL) and stirred for 2 minutes. The aqueous layer was extracted with ethyl acetate (20 mL x3).The combined organic layer was washed with water (20 mL x2) and brine (20 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was triturated with pentane/EtOAC (3 mL, 3/1) to give N-(5-bromopyridin-3-yl)-lH- indole-4-carboxamide (470 mg, yield: 86%) as a yellow solid. NMR (400 MHz DMSO-rie) d 6.89 (1H, t, J= 2.0 Hz), 7.25 (1H, t , J= 7.7 Hz), 7.52 (1H, t, = 2.8 Hz), 7.62 (1H, d, = 6.8 Hz), 7.67 (1H, d, J= 8.3 Hz), 8.43 (1H, d, J= 2.0 Hz), (1552) 8.60 (1H, t, J= 2.1 Hz), 8.96 (1H, d, = 2.3 Hz), 10.58 (1H, brs), 11.45 (1H, brs).

Reference： [1]Patent: WO2019/126730,2019,A1 .Location in patent: Paragraph 0524

70
[ 13535-01-8 ]
[ 50681-25-9 ]
N-(5-((5-methyl-8-(2-oxopyrrolidin-1-yl)-5H-chromeno[4,3-c]pyridin-3-yl)amino)pyridin-3-yl)pyridazine-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2019/126730,2019,A1

71
[ 13535-01-8 ]
[ 50681-25-9 ]
N-(5-bromopyridin-3-yl)pyridazine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 50℃; for 1h;	A mixture of <strong>[50681-25-9]pyridazine-4-carboxylic acid</strong> (236 mg, 1.90 mmol), 5-bromopyridin- 3-amine (300 mg, 1.73 mmol) and EDCI.HC1 (365 mg, 1.90 mmol) in pyridine (5 mL) was heated at 50 C for 1 hour. A brown solution was formed. The mixture was concentrated and the residue was poured into water (20 mL) and stirred for 2 minutes. The aqueous layer was extracted with EtOAc (20 mL x3).The combined organic layer was washed with water (20 mL x2) and brine (20 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was triturated with pentane/EtOAC (3 mL, 3/1) to give N-(5-bromopyridin-3-yl)pyridazine-4- carboxamide (400 mg, yield: 74%) as a yellow solid. (1564) NMR (400 MHz DMSO-rie) d 8.14 (1H, dd, J= 5.4, 2.4 Hz), 8.48-8.53 (2H, m), 8.89 (1H, d, .7= 2.0 Hz), 9.55 (1H, dd, .7= 5.4, 1.1 Hz), 9.66 (1H, dd, .7= 2.3, 1.3 Hz), 11.08 (1H, brs).

Reference： [1]Patent: WO2019/126730,2019,A1 .Location in patent: Paragraph 0527

72
[ 13535-01-8 ]
[ 1009-67-2 ]
N-(5-bromopyridin-3-yl)-2-methyl-3-phenylpropanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 50℃; for 2h;	133.1 Step 7: Preparation ofN-(5-bromopyridin-3-yl)-2-methyl-3-phenylpropanamide A mixture of 5-bromopyridin-3-amine (300 mg, 1.73 mmol), 2-methyl-3- phenylpropanoic acid (426 mg, 2.60 mmol) and EDCI.HC1 (497 mg, 2.60 mmol) in pyridine (4 mL) was stirred at 50 °C for 2 h. The reaction mixture turned into brown solution from yellow. The reaction mixture was concentrated and the residue was diluted with water (25 mL), and then extracted with EtOAc (25 mL x3). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na2S04 and concentrated. The crude product was triturated with pentane/EtOAC (10 mL, 3/1) to give N-(5-bromopyridin-3-yl)-2-methyl-3- phenylpropanamide (480 mg, yield: 87%) as an off-white solid. (1624) NMR (400 MHz, CDCb) d 1.32 (3H, d, J= 6.8 Hz), 2.58-2.68 (1H, m), 2.79-2.85 (1H, m), 2.95-3.02 (1H, m), 6.91 (1H, brs), 7.16-7.20 (2H, m), 7.21-7.33 (3H, m), 8.12 (1H, d , J = 2.0 Hz), 8.32 (1H, t, J= 1.8 Hz), 8.35 (1H, d, J= 2.0 Hz).

Reference： [1]Current Patent Assignee: HIBERCELL INC - WO2019/126730, 2019, A1 Location in patent: Paragraph 0543

73
[ 13535-01-8 ]
[ 94-53-1 ]
N-(5-bromopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 50℃; for 2h;	136.1 Step 7: Preparation ofN-(5-bromopyridin-3-yl)tetrahydrofuran-2-carboxamide A mixture of 5 -bromopyri din-3 -amine (300 mg, 1.73 mmol), tetrahydrofuran-2- carboxylic acid (302 mg, 2.60 mmol) and EDCI.HC1 (497 mg, 2.60 mmol) in pyridine (4 mL) was stirred at 50 °C for 2 h. The reaction mixture turned into brown solution from yellow. The reaction mixture was concentrated and the residue was diluted with water (25 mL), and then extracted with EtOAc (25 mL x3). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na2SC>4 and concentrated. The residue was purified by Combi Flash (30% to 50% EtOAc in pentane) to give N-(5-bromopyridin-3-yl)tetrahydrofuran-2- carboxamide (380 mg, yield: 65%) as a yellow solid. (1644) NMR (400 MHz, CDCb) d 1.88-2.04 (2H, m), 2.12-2.21 (1H, m), 2.34-2.44 (1H, m), 3.93-4.00 (1H, m), 4.02-4.09 (1H, m), 4.48 (1H, dd, J = 8.3, 6.0 Hz), 8.42 (1H, d, J= 2.0 Hz), 8.49-8.50 (1H, m), 8.51-8.53 (1H, m), 8.57 (1H, brs).

Reference： [1]Current Patent Assignee: HIBERCELL INC - WO2019/126730, 2019, A1 Location in patent: Paragraph 0550

74
[ 13535-01-8 ]
[ 5768-39-8 ]
N-(5-((5-methyl-8-(2-oxopyrrolidin-1-yl)-5H-chromeno[4,3-c]pyridin-3-yl)amino)pyridin-3-yl)benzo[d][1,3]dioxole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2019/126730,2019,A1

75
[ 13535-01-8 ]
[ 5768-39-8 ]
N-(5-bromopyridin-3-yl)benzo[d][1,3]dioxole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 50℃; for 2h;	A mixture of 5-bromopyridin-3-amine (300 mg, 1.73 mmol), benzo[d][l,3]dioxole- 4-carboxylic acid (431 mg, 2.60 mmol) and EDCI.HC1 (497 mg, 2.60 mmol) in pyridine (4 mL) was stirred at 50 C for 2 h. The reaction mixture turned into brown solution from yellow. The reaction mixture was concentrated and the residue was diluted with water (25 mL), and then extracted with EtOAc (25 mL x3). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na2S04 and concentrated. The crude product was triturated with pentane/EtOAC (10 mL, 1/1) to give N-(5-bromopyridin-3-yl)benzo[d][l,3]dioxole-4- carboxamide (385 mg, yield: 69%) as a yellow solid. (1662) NMR (400 MHz, CDCb) d 6.20 (2H, s), 6.99-7.07 (2H, m), 7.64 (1H, d , J= 7.5, 1.8 Hz), 8.44 (1H, d, J= 2.0 Hz), 8.57 (1H, d, J= 2.3 Hz), 8.60-8.63 (1H, m), 8.83 (1H, brs).

Reference： [1]Patent: WO2019/126730,2019,A1 .Location in patent: Paragraph 0552

76
[ 13535-01-8 ]
[ 25177-85-9 ]
N-(5-((5-methyl-8-(2-oxopyrrolidin-1-yl)-5H-chromeno[4,3-c]pyridin-3-yl)amino)pyridin-3-yl)-2,3-dihydro-1H-indene-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2019/126730,2019,A1

77
[ 13535-01-8 ]
[ 25177-85-9 ]
N-(5-bromopyridin-3-yl)-2,3-dihydro-1H-indene-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 50℃; for 2h;	A mixture of 5 -bromopyri din-3 -amine (300 mg, 1.73 mmol), 2,3-dihydro-lH- indene-2-carboxylic acid (421 mg, 2.60 mmol) and EDCI.HC1 (497 mg, 2.60 mmol) in pyridine (1673) (4 mL) was stirred at 50 C for 2 h. The reaction mixture turned into brown solution from yellow. The reaction mixture was concentrated and the residue was diluted with water (25 mL), and then extracted with EtOAc/THF (25 mL x3, 1/1). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na2S04 and concentrated. The crude product was triturated with pentane/EtOAC (10 mL, 1/1) to give N-(5-bromopyridin-3-yl)-2,3-dihydro-lH- indene-2-carboxamide (500 mg, yield: 91%) as a yellow solid. (1674) NMR (400 MHz, CDCb) d 3.23-3.41 (5H, m), 7.18-7.26 (4H, m), 7.39 (1H, brs), 8.41 (1H, d, J= 2.0 Hz), 8.43 (1H, d, J= 2.3 Hz), 8.48-8.51 (1H, m).

Reference： [1]Patent: WO2019/126730,2019,A1 .Location in patent: Paragraph 0554

78
[ 13535-01-8 ]
[ 63237-88-7 ]
N-(5-((5-methyl-8-(2-oxopyrrolidin-1-yl)-5H-chromeno[4,3-c]pyridin-3-yl)amino)pyridin-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2019/126730,2019,A1

79
[ 13535-01-8 ]
[ 63237-88-7 ]
N-(5-bromopyridin-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 50℃; for 2h;	A mixture of 5-bromopyridin-3-amine (300 mg, 1.73 mmol), pyrazolo[l,5- a]pyridine-2-carboxylic acid (421 mg, 2.60 mmol) and EDCI.HC1 (497 mg, 2.60 mmol) in pyridine (4 mL) was stirred at 50 C for 2 h. The reaction mixture turned into brown solution from yellow. The reaction mixture was concentrated and the residue was diluted with water (25 mL), and then extracted with EtOAc/THF (25 mL x3, 3/1). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na2S04 and concentrated. The crude product was triturated with pentane/EtOAC (10 mL, 1/1) to give N-(5-bromopyridin-3- yl)pyrazolo[l,5-a]pyridine-2-carboxamide (498 mg, yield: 91%) as a yellow solid. (1686) NMR (400 MHz, DMSO-rie) d 7.12 (1H, td, J= 6.9, 1.3 Hz), 7.19 (1H, s), 7.36 (1H, ddd, J= 9.0, 6.8, 1.0 Hz), 7.86 (1H, d, J= 8.8 Hz), 8.45 (1H, d, J = 2.0 Hz), 8.62 (1H, t, J = 2.1 Hz), 8.76 (1H, dd, J= 7.0, 1.0 Hz), 9.05 (1H, d, J= 2.3 Hz), 10.92 (1H, brs).

Reference： [1]Patent: WO2019/126730,2019,A1 .Location in patent: Paragraph 0557

80
[ 13535-01-8 ]
[ 1914-60-9 ]
N-(5-((5-methyl-8-(2-oxopyrrolidin-1-yl)-5H-chromeno[4,3-c]pyridin-3-yl)amino)pyridin-3-yl)-2,3-dihydrobenzofuran-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2019/126730,2019,A1

81
[ 13535-01-8 ]
[ 1914-60-9 ]
N-(5-bromopyridin-3-yl)-2,3-dihydrobenzofuran-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 50℃; for 2h;	A mixture of 5-bromopyridin-3-amine (300 mg, 1.73 mmol), 2,3- dihydrobenzofuran-2-carboxylic acid (426 mg, 2.60 mmol) and EDCI.HC1 (497 mg, 2.60 mmol) in pyridine (4 mL) was stirred at 50 C for 2 h. The reaction mixture turned into brown solution from yellow. The reaction mixture was concentrated and the residue was diluted with water (25 mL), and then extracted with EtOAc (25 mL x3). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na2S04 and concentrated. The residue was purified by Combi Flash (20% to 50% EtOAc in pentane) to give N-(5-bromopyridin-3-yl)- 2,3-dihydrobenzofuran-2-carboxamide (500 mg, yield: 91%) as yellow gum. (1699) NMR (400 MHz, CDCb) d 3.49-3.57 (1H, m), 3.64-3.74 (1H, m), 5.28 (1H, dd, J= 10.8, (1700) 6.5 Hz), 6.94-7.01 (2H, m), 7.18-7.26 (2H, m), 8.39-8.49 (3H, m), 8.54 (1H, d, J= 2.3 Hz).

Reference： [1]Patent: WO2019/126730,2019,A1 .Location in patent: Paragraph 0560

82
[ 13535-01-8 ]
[ 833472-82-5 ]
methyl 3-(3-(5-aminopyridin-3-yl)phenyl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate In water; toluene at 110℃; for 0.5h; Inert atmosphere; Microwave irradiation;	1 Step 1 To the solution of (3-(3-methoxy-3-oxopropyl)phenyl)boronic acid (LXXXI) dioxane (421 mg, 2.02 mmol, Combi-Blocks Inc.) was added 5-bromopyridin-3-amine (LXXX) (446 mg, 2.06 mmol, Combi-Blocks Inc.), Pd(dppf)Cl2 (82.6 mg, 0.10 mmol), and a 2 M aqueous solution of K2CO3 (2.0 mL, 4.05 mmol). The solution was purged with argon and irradiated with microwave at 110oC for 30 minutes. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified on silica gel (010% 7N NH3 in MeOH/CHCl3) to give methyl 3-(3-(5-aminopyridin-3-yl)phenyl)propanoate (LXXXII) as a beige solid (560 mg, 2.18 mmol, 108% yield). ESIMS found for C15H16N2O2 m/z 257.1 (M+H).

Reference： [1]Current Patent Assignee: BIOSPLICE THERAPEUTICS INC - WO2019/241540, 2019, A1 Location in patent: Paragraph 0389-0390

83
[ 944392-68-1 ]
[ 13535-01-8 ]
C₁₅H₁₄N₂O₄ [ No CAS ]

Reference： [1]Dalton Transactions,2020,vol. 49,p. 3553 - 3561

84
[ 13535-01-8 ]
[ 1207529-93-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 12 h / 80 °C / Inert atmosphere 2: palladium 10% on activated carbon; ammonium hydroxide; hydrogen / methanol / 0.17 h / 20 °C / 775.74 Torr

Reference： [1]Current Patent Assignee: CORNELL UNIVERSITY - WO2020/117634, 2020, A1

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P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
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. 13535-01-8 ] {[proInfo.proName]}

Quality Control of [ 13535-01-8 ]

Related Doc. of [ 13535-01-8 ]

Product Details of [ 13535-01-8 ]

Calculated chemistry of [ 13535-01-8 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 13535-01-8 ]

Application In Synthesis of [ 13535-01-8 ]

[ 13535-01-8 ] Synthesis Path-Upstream 1~30

[ 13535-01-8 ] Synthesis Path-Downstream 1~84

Related Functional Groups of [ 13535-01-8 ]

Bromides

Amines

Related Parent Nucleus of [ 13535-01-8 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 13535-01-8 ]

Related Parent Nucleus of
[ 13535-01-8 ]