[ CAS No. 4214-73-7 ] {[proInfo.proName]}

Name: 4214-73-7|2-Amino-5-cyanopyridine|98%
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SKU: A453612
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Quality Control of [ 4214-73-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 4214-73-7 ]

CAS No. :	4214-73-7	MDL No. :	MFCD00128902
Formula :	C₆H₅N₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KDVBYUUGYXUXNL-UHFFFAOYSA-N
M.W :	119.12	Pubchem ID :	818260
Synonyms :

Calculated chemistry of [ 4214-73-7 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	33.36
TPSA :	62.7 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.87 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.92
Log Po/w (XLOGP3) :	0.22
Log Po/w (WLOGP) :	0.54
Log Po/w (MLOGP) :	-0.43
Log Po/w (SILICOS-IT) :	0.62
Consensus Log Po/w :	0.37

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.21
Solubility :	7.34 mg/ml ; 0.0616 mol/l
Class :	Very soluble
Log S (Ali) :	-1.1
Solubility :	9.55 mg/ml ; 0.0801 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.7
Solubility :	2.37 mg/ml ; 0.0199 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.63

Safety of [ 4214-73-7 ]

Signal Word:	Danger	Class:	9
Precautionary Statements:	P261-P273-P301+P310-P311-P501	UN#:	3077
Hazard Statements:	H301-H331-H410	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 4214-73-7 ]

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

Upstream synthesis route of [ 4214-73-7 ]
Downstream synthetic route of [ 4214-73-7 ]

[ 4214-73-7 ] Synthesis Path-Upstream 1~9

1
[ 4214-73-7 ]
[ 69879-22-7 ]

Yield	Reaction Conditions	Operation in experiment
73.16%	With lithium aluminium tetrahydride In tetrahydrofuran for 1.5 h;	To a solution of compound 53.9 (10 g, 83.95 mmol, 1 eq) in THF (150 mL) wasadded LAH (6.37 g, 167.90 mmol, 2 eq) at 0°C. The mixture was stirred at 0°C for 1.5 hours.The reaction mixture was quenched by addition saturated sodium sulfate at 0 °C and added100 ml H20 then extracted with ethyl acetate (100 mL x 3). The combined organic layerswere washed with saturated brines (30 mL x 1), dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to give the product compound 53.8 (7.50 g, 61.42mmol, 73.16percent yield) as a yellow oil. LCMS (ESI): m/z: [M + H] called for C6H6N20: 123;found 123; RT=0.099 mm.
30%	With diisobutylaluminium hydride In tetrahydrofuran; hexane at 0℃;	4.1.1 Synthesis of 6-aminopyridine-3-carboxaldehyde A 1M solution of diisobutylaluminum hydride (DIBAL) in hexane (10 mL) was added to a solution of 6-amino-5-cyanopyridine (10 mmol) in dry THF (50 mL) cooled at 0 °C. The ice-bath was removed, and additional 7.1 mL of a 1M solution of DIBAL in hexane were added in two successive portions. After stirring for additional 30 min, the reaction was quenched by the dropwise addition of dry MeOH (15 mL). The mixture was partitioned between 100 mL of AcOEt and 70 mL of 2N HCl. The aqueous layer was treated with 75 mL of 2N NaOH and extracted with AcOEt. The organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with CHCl₃/AcOEt 1:4. Yield: 30percent, mp = 174-175 °C. IR (KBr): 3366, 3121, 1659 cm^-1. ¹H NMR (CD₃OD, 400 MHz): δ (ppm) 9.67 (s, 1H, CHO), 8.41 (d, 1H, H2, J_2-4 = 1.6 Hz), 7.87 (dd, 1H, H4, J_4-5 = 8.8 Hz, J_2-4 = 1.6 Hz), 6.63 (d, 1H, H5, J_4-5 = 8.8 Hz), 3.31 (s, 2H, NH₂). ¹³C NMR (CDCl₃, 100 MHz): δ (ppm) 191.15, 164.46, 155.78, 137.39, 123.92, 109.99.

Reference： [1] Patent: WO2018/209132, 2018, A1, . Location in patent: Paragraph 0458; 0489
[2] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 292 - 300
[3] Patent: US2009/143420, 2009, A1, . Location in patent: Page/Page column 7
[4] Patent: EP1724263, 2006, A1, . Location in patent: Page/Page column 55
[5] Patent: EP3305785, 2018, A1, . Location in patent: Paragraph 0177; 0178

2
[ 4214-73-7 ]
[ 468068-28-2 ]
[ 329-89-5 ]

Yield	Reaction Conditions	Operation in experiment
22%	With hydroxylamine hydrochloride; sodium carbonate In ethanol; water for 6 h; Heating / reflux	A stirred mixture of commercially available 2-amino-5-cyano-pyridine [CAS-No. 4214-73-7] (5.0 g, 42 mmol), hydroxylamine hydrochloride (17.5 g, 0.25 mol) and sodium carbonate (31.1 g, 0.29 mol) in water (95 mL) and ethanol (21 mL) was heated under reflux conditions for 6 h. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (4.x.100 mL). The combined organic layers were washed with brine (150 mL), dried (MgSO₄) and evaporated.The crude product was purified by column chromatography on silica gel (ethyl acetate/MeOH/NH₄OH 4:1:0.5) and crystallization (ethyl acetate/MeOH/hexane) to yield 6-amino-nicotinamide (1.39 g) and the title compound (1.42 g, 22percent) as an off-white solid. MS (EI) 152.1 [(M)⁺]; mp 300° C.

Reference： [1] Patent: US2007/232583, 2007, A1, . Location in patent: Page/Page column 43

3
[ 4214-73-7 ]
[ 329-89-5 ]

Yield	Reaction Conditions	Operation in experiment
22%	With hydroxylamine hydrochloride; sodium carbonate In ethanol; water for 6 h; Heating / reflux	Example B.4 6-Amino-N-hydroxy-nicotinamidine; A stirred mixture of commercially available 2-amino-5-cyano-pyridine [CAS-No. 4214-73-71 (5.0 g, 42 mmol), hydroxylamine hydrochloride (17.5 g, 0.25 mol) and sodium carbonate (31.1 g, 0.29 mol) in water (95 ml) and ethanol (21 ml) was heated under reflux conditions for 6h. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (4.x.100 ml). The combined organic layers were washed with brine (150 ml), dried (MgSO₄) and evaporated. The crude product was purified by column chromatography on silica gel (ethyl acetate/MeOH/NH₄OH 4:1:0.5) and crystallization (ethyl acetate/MeOH/hexane) to yield 6-amino-nicotinamide (1.39 g) and the title compound (1.42 g, 22percent) as an off-white solid. MS (EI) 152.1 [(M)⁺]; mp 300° C.

Reference： [1] Patent: US2007/72879, 2007, A1, . Location in patent: Page/Page column 14

4
[ 4214-73-7 ]
[ 329-89-5 ]

Reference： [1] Journal of the American Chemical Society, 1947, vol. 69, p. 1147,1148
[2] Journal of the American Chemical Society, 1944, vol. 66, p. 1479,1482
[3] Chemicke Listy, 1952, vol. 46, p. 770[4] Chem.Abstr., 1953, p. 11191

5
[ 52334-81-3 ]
[ 4214-73-7 ]
[ 74784-70-6 ]

Reference： [1] Heterocycles, 1984, vol. 22, # 1, p. 117 - 124

6
[ 4214-73-7 ]
[ 477871-32-2 ]

Yield	Reaction Conditions	Operation in experiment
65%	at 20℃; for 2 h;	Example 36; 8- [ (3-Methyl-butylamino)-methyl]-10, 11-dihydro-5-oxa-4-aza- dibenzo [a, d] cycloheptene-2-carboxylic acid amide; Step 1; 6-Amino-5-bromo-nicotinonitrile; To a solution of 6-Amino-nicotinonitrile (102 mg, 0.86 mmol) in AcOH (2 mL) add a solution of Br2 l. OM in AcOH (0.86 mmol). Stir the mixture at room temperature for 2 hours. Eliminate the solvent. Purify by flash chromatography on silica gel (eluent: hexane/EtOAc 3/1) to afford the title compound (110 mg, 65percent). 'H-NMR (DMSO, 300 MHz): 8.26 (d, 1 H, J= 2.0 Hz), 8.10 (d, 1H, J= 2.0 Hz), 7.24 (bs 2H). MS (APCI Neg) : 196,198
11.2 g	With N-Bromosuccinimide In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere; Schlenk technique	To a well stirred solution of 6-aminopyridine-3-carbonitrile (8.0 g, 67.15 mmol) in tetrahydrofuran (100 ml) was added N-bromosuccinimide (17.92 g, 100.72 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2 x 200 ml). The combined organic layers were washed with 2N sodium hydroxide solution (100 ml) and brine (100 ml). The mixture was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue obtained was crystallized from a mixture of diethyl ether and n-pentane to yield 11.2 g of product as a white solid.
8.2 g	at 10 - 35℃; for 72 h; Cooling with ice	To a solution of 6-aminonicotinonitrile (5.0 g) in acetic acid (50 mL) was added bromine (4.3 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 days, and the precipitate was collected by filtration. The obtained solid was suspended in ethyl acetate and IPE, and collected by filtration to give the title compound (8.2 g). ¹H NMR (300 MHz, DMSO-d₆) δ 7.31 (2H, brs), 8.19 (1H, d, J 1.9 Hz), 8.36 (1H, d, J=1.9 Hz).

15.8 g

With bromine In chloroform; water at 0 - 20℃; for 2.5 h;

Reference Example 341
2-amino-3-bromo-5-cyanopyridine
To a chloroform solution (160 mL) of 2-amino-5-cyanopyridine (10.0 g) were added bromine (4.50 mL) and water (40.0 mL) at 0°C, and the reaction mixture was stirred at room temperature for 2.5 h
Aqueous sodium thiosulfate solution and aqueous sodium hydrogen carbonate solution were added and the mixture was extracted twice with chloroform.
The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (15.8 g).
MS(ESI)m/z; 198,200[M+H]⁺

Reference： [1] Patent: WO2005/90337, 2005, A1, . Location in patent: Page/Page column 42-43
[2] Patent: WO2008/60907, 2008, A2, . Location in patent: Page/Page column 38
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 9, p. 2073 - 2078
[4] Patent: US2015/266872, 2015, A1, . Location in patent: Paragraph 0783; 0784
[5] Patent: EP3372601, 2018, A1, . Location in patent: Paragraph 0743; 0744

7
[ 4214-73-7 ]
[ 943845-23-6 ]

Reference： [1] Patent: WO2011/79804, 2011, A1,
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 18, p. 7577 - 7589

8
[ 4214-73-7 ]
[ 1187322-51-5 ]

Yield	Reaction Conditions	Operation in experiment
6.6 g	Stage #1: With silver trifluoroacetate In 1,2-dichloro-ethane for 5 h; Reflux Stage #2: With iodine In 1,2-dichloro-ethane for 18 h; Reflux	Synthesis of 6-amino-5-iodonicotinonitrile 6-Amino-3-pyridinecarbonitrile (10.0 g, 0.081 mol), silver trifluoroacetate (25.5 g, 0.115 mol) and 160 ml of 1,2-dichloroethane are combined in a flask and heated under reflux for 5 h. Iodine (29.5 g, 0.116 mol) is added, and the mixture is heated for a further 18 h. After cooling, the mixture is filtered and partitioned between water and dichloroethane. Organic and aqueous phase are filtered through Celite. The aqueous phase is extracted to exhaustion, and the combined organic phases are combined, dried and evaporated. The residue is dissolved in ethyl acetate and washed with sodium thiosulfate solution. Removal of the solvent gives 6.6 g of yellowish crystals product. These are reacted further without further purification; HPLC: 2.57 min; LCMS: 246 [M+H]⁺.

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 3, p. 1160 - 1170
[2] Patent: US2015/218155, 2015, A1, . Location in patent: Paragraph 0300
[3] Patent: WO2009/112139, 2009, A1, . Location in patent: Page/Page column 25

9
[ 4214-73-7 ]
[ 943894-99-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 18, p. 7577 - 7589

[ 4214-73-7 ] Synthesis Path-Downstream 1~68

1
[ 4318-76-7 ]
[ 4214-73-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid Diazotization_.Eintragen der Diazoloesung in eine mit etwas Natronlauge versetzte Kaliumkupfer(I)-cyanid-Loesung bei 90grad;

Reference： [1]Raeth; Prange [Justus Liebigs Annalen der Chemie, 1928, vol. 467, p. 4]

2
[ 4214-73-7 ]
[ 329-89-5 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 1147,1148
[2]Journal of the American Chemical Society,1944,vol. 66,p. 1479,1482

3
[ 4214-73-7 ]
[ 94805-52-4 ]

Yield	Reaction Conditions	Operation in experiment
55%	With sulfuric acid; sodium nitrite; at 0℃; for 2h;Inert atmosphere; Schlenk technique;	A mixture of 2-amino-5-bromopyridine (692 mg, 4.0mmol) and CuCN (430 mg, 4.8 mmol) in DMF (1.5 mL) was refluxed for 4 h. After the mixturewas cooled to room temperature, aq. 10percent NaCN (16.3 mmol) solution was added and themixture was extracted by CH2Cl2. After the solvent was removed under vacuo, the residue waschromatographed on silica gel (AcOEt/hexane = 1 : 1) to give <strong>[4214-73-7]2-amino-5-cyanopyridine</strong> (258mg, 52percent). To a solution of <strong>[4214-73-7]2-amino-5-cyanopyridine</strong> and aq. 15percent H2SO4 (7 mL) was addedNaNO2 (281 mg, 4.0 mmol) at 0 °C and the mixture was stirred for 2 h at 0 °C. The mixture wasextracted by AcOEt and dried (Na2SO4). After the solvent was removed under vacuo, the residuechromatographed on silica gel (AcOEt) and recrystallization from MeOH to give 1ad (134 mg,55percent).1H NMR (400MHz, DMSO): delta 8.23 (s, 1H, Ar), 7.64 (d, 1H, J = 9.6 Hz, Ar), 6.41 (d, 1H,J = 9.6 Hz, Ar); 13C NMR (100.5 MHz, CD3OD): delta 170.5, 153.9, 149.6, 129.8, 98.5.

Reference： [1]Bioscience, Biotechnology and Biochemistry,1995,vol. 59,p. 572 - 575
[2]Journal of Organometallic Chemistry,2017,vol. 843,p. 14 - 19
[3]Justus Liebigs Annalen der Chemie,1931,vol. 487,p. 127,129

4
[ 1072-97-5 ]
[ 143-33-9 ]
[ 4214-73-7 ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 2890 - 2891
[2]Journal of Medicinal Chemistry,1996,vol. 39,p. 4261 - 4274

5
[ 4214-73-7 ]
[ 69807-81-4 ]
1-(5-Cyano-pyridin-2-yl)-3-[2-(1-methyl-1H-pyrrol-2-yl)-ethyl]-thiourea [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 4261 - 4274

6
[ 1072-97-5 ]
potassium ferrocyanide [ No CAS ]
[ 4214-73-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	With caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 8h;Inert atmosphere; Sealed tube;	General procedure: Under a dry nitrogen atmosphere, a mixture of aryl bromide(1.0 mmol), K4Fe(CN)6 (0.22 mmol), base (1.0 mmol) and Pd(0)-EGCG-CF (2.0 molpercent) in DMF (5 mL) was stirred at 130 °C for 8 h (Table 2). After completion (as monitoredby TLC), H2O was added and the organic layer was extracted with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography. All of the desired product(s) were characterized by comparison of their physical data with those of known compounds [4,5c,7]. The formation of aryl nitriles was confirmed by IR spectra, which showed one characteristic peak for the CN stretching band between 2225-2360 cm-1.
87%	With copper(II) acetate monohydrate; sodium carbonate; 1,3-phenylene-bis-(1H)-tetrazole; potassium iodide; In N,N-dimethyl-formamide; at 130℃; for 8h;Inert atmosphere;	General procedure: Under a dry nitrogen atmosphere, a mixture of copper acetate (0.2 mmol) and 2 (0.2 mmol) in DMF (2 mL) was stirred at room temperature for 10 min to give a homogeneous solution. Next the aryl halide (1 mmol), base (0.25mmol), KI (0.5 mmol), K4Fe(CN)6 (0.22 mmol) and DMF (2mL) were added and the mixture was stirred at 130 °C for 8h (Table 2). The reaction mixture was cooled at room temperature,diluted with H2O (15 mL), extracted with ethylacetate (3 15 mL), washed with brine (15 mL) and dried(MgSO4). The reaction mixture was filtered. The filtrate was evaporated under reduced pressure and the residue was subjected to gel permeation chromatography to afford pure products. The physical data (mp, IR, NMR) of the products were found to be identical with those reported in the literature[6-11,14,15].
86%	With copper(l) iodide; 3,3'-(1,4-phenylene)bis-(2-imino-2,3-dihydrobenzo[d]-oxazol-5-ol); caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 130℃; for 8h;Inert atmosphere;	General procedure: To a mixture of copper salt (0.3 mmol) and ligand 3 (0.8mmol) in DMF (2.5 mL), aryl halide (1.0 mmol), base (0.25mmol), KI (0.5 mmol), K4Fe(CN)6 (0.2 mmol) and DMF (2.5 mL) were added and the mixture was vigorously stirredat 130 C for 8 h under a dry nitrogen atmosphere. Aftercompletion (as monitored by TLC with EtOAc and nhexane),H2O was added and the organic layer was extractedwith EtOAc, washed with brine, dried over MgSO4, filteredand evaporated under reduced pressure. The residue waspurified by column chromatography. The purity of the compoundswas checked by 1H NMR and yields are based onaryl bromide. All the products are known and the spectroscopicdata (FT-IR and NMR) and melting points were consistentwith those reported in the literature [3-8].

82%

With 5,5?-(1,2-phenylene)bis(1H-tetrazole); copper(I) iodide; caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 130℃; for 20h;Inert atmosphere;

General procedure: A mixture of copper salt (0.3 mmol) and 2 (0.8 mmol) in DMF (2 mL)was stirred at room temperature under a dry nitrogen atmospherefor 10 min to give a homogeneous solution. Next the aryl bromide(1 mmol), base (1.0 mmol), KI (0.5 mmol), K4Fe(CN)6 (0.22 mmol)and DMF (2 mL) were added and the mixture stirred at 130 °C for 10 h(Table 2). After completion (as monitored by TLC), H2O (15 mL) was added and the organic layer was extracted with EtOAc (3 × 15 mL),washed with brine (15 mL), dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by columnchromatography. All the products are known and were characterisedby IR, NMR and melting points and their spectroscopic data identicalto that reported in the literature.

Reference： [1]Letters in Organic Chemistry,2013,vol. 10,p. 523 - 526
[2]Letters in Organic Chemistry,2014,vol. 11,p. 519 - 523
[3]Letters in Organic Chemistry,2014,vol. 11,p. 136 - 140
[4]Journal of Chemical Research,2014,vol. 38,p. 291 - 294
[5]Synlett,2007,p. 555 - 558
[6]Synthesis,2008,p. 3351 - 3355

7
[ 4214-73-7 ]
2-amino-3-chloro-5-cyanopyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With N-chloro-succinimide; In N,N-dimethyl-formamide; at 80℃; for 4h;	6-Amino-5-chloro-nicotinonitrileA solution of <strong>[4214-73-7]6-amino-nicotinonitrile</strong> (1.0 g, 8.2 mmol) in DMF (10 ml) was treated with N- chlorosuccinimide (1.26 g, 9.1 mmol) and the mixture was heated to 80°C for 4 h. It was then allowed to cool to rt. The mixture was then poured onto ice/water and the precipitate was filtered. The filter cake was washed with water and then dried in HV to give pure 6-amino-5- chloro-nicotinonitrile (1.1 g, 87percent). UPLC (5-100percent CH3CN): RT = 0.790 min.

Reference： [1]Patent: WO2007/113276,2007,A1 .Location in patent: Page/Page column 27
[2]Angewandte Chemie - International Edition,2013,vol. 52,p. 9755 - 9758

8
[ 4214-73-7 ]
[ 468068-28-2 ]
[ 329-89-5 ]

Yield	Reaction Conditions	Operation in experiment
22%	With hydroxylamine hydrochloride; sodium carbonate; In ethanol; water; for 6h;Heating / reflux;	A stirred mixture of commercially available 2-amino-5-cyano-pyridine [CAS-No. 4214-73-7] (5.0 g, 42 mmol), hydroxylamine hydrochloride (17.5 g, 0.25 mol) and sodium carbonate (31.1 g, 0.29 mol) in water (95 mL) and ethanol (21 mL) was heated under reflux conditions for 6 h. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (4.x.100 mL). The combined organic layers were washed with brine (150 mL), dried (MgSO4) and evaporated.The crude product was purified by column chromatography on silica gel (ethyl acetate/MeOH/NH4OH 4:1:0.5) and crystallization (ethyl acetate/MeOH/hexane) to yield 6-amino-nicotinamide (1.39 g) and the title compound (1.42 g, 22percent) as an off-white solid. MS (EI) 152.1 [(M)+]; mp 300° C.

Reference： [1]Patent: US2007/232583,2007,A1 .Location in patent: Page/Page column 43

9
[ 4214-73-7 ]
[ 37904-72-6 ]
2-(4-(dimethylamino)phenyl)-imidazo[1,2-a]pyridine-6-carbonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 4746 - 4758

10
[ 4214-73-7 ]
[ 2065-75-0 ]
3-formylimidazo[1,2-a]pyridine-6-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	In ethanol; water; at 110℃; for 0.166667h;Inert atmosphere; Microwave irradiation; Green chemistry;	General procedure: 6-bromo-2-aminopyridine (0.208 g, 1.2 mmol, 1 eq.) and 2-bromomalonaldehyde (0.272 g, 1.8 mmol, 1.5 eq.) were dissolved in the mixture of ethanol and water (v/v 1:1, total 2 ml) and placed in the pressure vial, equipped with a magnetic bar. The mixture was stirred for 1 min and purge with argon via syringe. Then microwave (MW) irradiation (with initial 150 W power) was applied. Depending on the substituents present in 2-aminopyridine 1, the following conditions were applied: a) for 2-aminopyridines substituted with halogen, or nitro or cyano groups: 10 min, 110 C; or b) for 2-aminopyridines substituted with methyl or phenyl groups: 20 min, 100 C. Afterwards, the reaction mixture was evaporated. Next the reaction mixture was neutralized with TEA, diluted with DCM (10 mL), and adsorbed on silica gel (~3 g).* The solvent was evaporated, and the residue was subjected to column chromatography using gradient DCM/acetone (100:0 => 75:25) as eluent to give product as yellow powder.

Reference： [1]Tetrahedron Letters,2019,vol. 60
[2]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 5837 - 5844
[3]Chinese Chemical Letters,2015,vol. 26,p. 118 - 120
[4]Beilstein Journal of Organic Chemistry,2020,vol. 16,p. 15 - 21

11
[ 329-89-5 ]
[ 4214-73-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 5837 - 5844

12
[ 69045-78-9 ]
[ 4214-73-7 ]

Reference： [1]Heterocycles,1984,vol. 22,p. 117 - 124

13
[ 4214-73-7 ]
[ 1885-14-9 ]
[ 862011-06-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	With pyridine; In tetrahydrofuran; at 0℃; for 0.5h;	Step 1 (5-Cyano-pyridin-2-yl)-carbamic acid phenyl ester Phenylchloroformate (10.5 mL, 83.9 mmol) was added dropwise to a solution of <strong>[4214-73-7]2-amino-5-cyanopyridine</strong> (10.0 g, 83.9 mmol) in THF (200 mL) and pyridine (8.47 mL, 105 mmol) at 0° C. The reaction was stirred under an atmosphere of nitrogen for 30 minutes. The precipitate was filtered, washed with water several times followed by diethyl ether, and then air dried to yield a white solid (19.5 g, 97percent). 1H NMR (400 MHz, DMSO-d6) delta 8.79 (s, 1H), 8.25 (d, 1H), 7.94 (d, 1H), 7.45 (t, 2H), 7.24-7.26 (m, 3H). LCMS: method A, Rt=2.94 min, [MH+=240].
	With pyridine; In tetrahydrofuran; for 0.5h;Cooling with ice;	Intermediate 59: phenyl (5-cyanopyridin-2-yl)carbamate. Phenyl chloroformate (0.53 ml, 4.20 mmol) was added dropwise to a stirred solution of 6- aminonicotinonitrile (0.50 g, 4.20 mmol) and pyridine (0.39 ml, 4.83 mmol) in THF (10 ml) cooled with an ice bath. After 30 minutes the reaction mixture was filtered, the solid washed 3x with Et20 and the filtrate evaporated to give the title compound. (UPLC-MS 6) tR 0.92 min; ESI-MS 240.1 [M+H]+.

Reference： [1]Patent: US2005/176733,2005,A1 .Location in patent: Page/Page column 45
[2]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 215 - 220
[3]Patent: WO2016/151499,2016,A1 .Location in patent: Page/Page column 83

14
[ 4214-73-7 ]
[ 156973-09-0 ]

Yield	Reaction Conditions	Operation in experiment
	With borane; In tetrahydrofuran; at 0 - 20℃; for 1h;	To a solution of <strong>[4214-73-7]6-aminonicotinonitrile</strong> 117-A (5. 0g, 42 mmol) was added a solution of 1 M BH3-THF (294 mL, 294 mmol) at 0 C (prepared as in J. Org. Chem., Vol. 38, No. 5,1973). The reaction was stirred at room temperature for 1 hour. The reaction mixture was then slowly pored into ice water. 100 mL 4N HCI was added and stirred for 20 min. The solution was basified with NH40H to pH of about 11, and then concentrated. THF (300mLX2) was added to the mixture followed by addition of solid KOH (excess). The suspension was stirred. The THF layer was collected by filtration and concentrated to give 5- (aminomethyl) pyridin-2-amine 117-B (4.3g).

Reference： [1]Patent: WO2005/63739,2005,A1 .Location in patent: Page/Page column 121
[2]Patent: WO2015/103317,2015,A1
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 7965 - 7983

15
[ 4214-73-7 ]
[ 477871-32-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-Bromosuccinimide; In acetonitrile; at 20℃;	A reaction was performed at room temperature while stirring 2.00 g (16.8 mmol, 1 equivalent) of Compound 4a and 1.2 equivalents of N-bromosuccinimide under an acetonitrile solvent. After the reaction was terminated, water was poured thereto. Extraction was performed by using chloroform, the extract was washed with Na2S2O3 (aq), and then the moisture was removed over anhydrous magnesium sulfate. 3.16 g (yield 95%) of Compound 4b could be obtained by concentrating the residue through distillation under reduced pressure.
65%	With bromine; acetic acid; at 20℃; for 2.0h;	Example 36; 8- [ (3-Methyl-butylamino)-methyl]-10, 11-dihydro-5-oxa-4-aza- dibenzo [a, d] cycloheptene-2-carboxylic acid amide; Step 1; 6-Amino-5-bromo-nicotinonitrile; To a solution of 6-Amino-nicotinonitrile (102 mg, 0.86 mmol) in AcOH (2 mL) add a solution of Br2 l. OM in AcOH (0.86 mmol). Stir the mixture at room temperature for 2 hours. Eliminate the solvent. Purify by flash chromatography on silica gel (eluent: hexane/EtOAc 3/1) to afford the title compound (110 mg, 65%). 'H-NMR (DMSO, 300 MHz): 8.26 (d, 1 H, J= 2.0 Hz), 8.10 (d, 1H, J= 2.0 Hz), 7.24 (bs 2H). MS (APCI Neg) : 196,198
	With bromine; sodium acetate; In acetic acid; at 20℃; for 1.08333h;	A) To a solution of 6-aminonicotinonitrile (3.6 g, 300 mmol) in glacial acetic acid (50 mL) at RT was added sodium acetate (30 mmol). To the resulting well stirred mixture was added bromine (2.58 mL, 30 mmol) dropwise. After 5 min, a precipitate started to form and the mixture became very thick. Acetic acid (10 mL) was added and the mixture was stirred vigorously for 1 h, poured into cold water (100 mL). The mixture was filtered; the solid was washed with water and dried in vacuo to afford 6-amino-5-bromonicotinonitrile (4.25 g) as a solid. LC/MS; (M+eta)+ = 199. Additional solid precipitated from the filtrate after some time which upon filtration and drying gave less pure compound (1.2Ig).

11.2 g	With N-Bromosuccinimide; In tetrahydrofuran; at 20℃; for 1.0h;Inert atmosphere; Schlenk technique;	To a well stirred solution of 6-aminopyridine-3-carbonitrile (8.0 g, 67.15 mmol) in tetrahydrofuran (100 ml) was added N-bromosuccinimide (17.92 g, 100.72 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2 x 200 ml). The combined organic layers were washed with 2N sodium hydroxide solution (100 ml) and brine (100 ml). The mixture was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue obtained was crystallized from a mixture of diethyl ether and n-pentane to yield 11.2 g of product as a white solid.
8.2 g	With bromine; acetic acid; at 10 - 35℃; for 72.0h;Cooling with ice;	To a solution of 6-aminonicotinonitrile (5.0 g) in acetic acid (50 mL) was added bromine (4.3 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 days, and the precipitate was collected by filtration. The obtained solid was suspended in ethyl acetate and IPE, and collected by filtration to give the title compound (8.2 g). 1H NMR (300 MHz, DMSO-d6) delta 7.31 (2H, brs), 8.19 (1H, d, J 1.9 Hz), 8.36 (1H, d, J=1.9 Hz).
15.8 g	With bromine; In chloroform; water; at 0 - 20℃; for 2.5h;	Reference Example 341 2-amino-3-bromo-5-cyanopyridine To a chloroform solution (160 mL) of 2-amino-5-cyanopyridine (10.0 g) were added bromine (4.50 mL) and water (40.0 mL) at 0C, and the reaction mixture was stirred at room temperature for 2.5 h Aqueous sodium thiosulfate solution and aqueous sodium hydrogen carbonate solution were added and the mixture was extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (15.8 g). MS(ESI)m/z; 198,200[M+H]+

Reference： [1]Patent: US2020/95265,2020,A1 .Location in patent: Paragraph 0140-0141
[2]Patent: WO2005/90337,2005,A1 .Location in patent: Page/Page column 42-43
[3]Patent: WO2008/60907,2008,A2 .Location in patent: Page/Page column 38
[4]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 2073 - 2078
[5]Patent: US2015/266872,2015,A1 .Location in patent: Paragraph 0783; 0784
[6]Patent: EP3372601,2018,A1 .Location in patent: Paragraph 0743; 0744

16
[ 4214-73-7 ]
[ 144-55-8 ]
propyl 6-amino-3-pyridinecarboximidate [ No CAS ]
propyl N-cyano-6-amino-3-pyridinecarboximidate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrogenchloride; In propan-1-ol;	After <strong>[4214-73-7]6-amino-3-cyanopyridine</strong> (1.0 g, 8.4 mmol) was dissolved in 1-propanol (50 ml) and hydrogen chloride gas was passed into the solution at a temperature of 0°-10° C. for 30 minutes, the reactor was tight sealed for stirring the mixture at 0° C. for 21 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the concentrated mixture to adjust the pH to alkaline. The mixture was extracted with chloroform (50 ml*3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of propyl 6-amino-3-pyridinecarboximidate (1.56 g). The crude product was then dissolved in a mixture of acetonitrile (6 ml) and DMF (2 ml), and an aqueous solution (20 ml) NaH2 PO4 -2H20 (5.24 g, 33.6 mmol), mmol) was added to the solution. The mixture was stirred at room temperature for 18 hours. After the completion of the reaction, colorless powder deposited was collected by filtration and washed with water to give propyl N-cyano-6-amino-3-pyridinecarboximidate (1.45 g, yield 85percent). Mp 150° C. IR (KBr) cm-1:3380, 2180, 1650, 1580, 1295. 1 H-NMR (500 MHz, DMSO): delta (ppm). 8.74(1H, d, J=2.4Hz, H-6), 8.04(1H, dd, J=2.4, 9.2Hz, H-4), 7.20(1H, brs, NH2), 6.53(1H, d, J=9.2Hz, H-3), 4.27 (2H, t, J=6.7Hz, OCH2 CH2 CH3), 1.7 5 (2H, m, OCH2 CH2 CH3), 0.97 (3H, t, J=7.3Hz, OCH2 CH2 CH3).

Reference： [1]Patent: US5508293,1996,A

17
[ 4214-73-7 ]
[ 5424-21-5 ]
[ 912673-59-7 ]

Yield	Reaction Conditions	Operation in experiment
10%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 8.16667h;	The 2-chloro-6-methyl-4-(5-cyanopyrid-2-ylamino)pyrimidine starting material was prepared as follows: A mixture of 2,4-dichloro-6-methylpyrimidine (2.Og, 12.3mmol), 2-amino-5- cyanopyridine (l.lg, 9.48mmol) and cesium carbonate (4.3g, 13.2mmol) in 1,4-dioxane (20ml) was purged with nitrogen for 10 minutes. 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (470mg, 0.8mmol), tris(dibenzylideneacetone) dipalladium(O) (470mg, 0.53mmol) were added and heated to 100°C for 8 hours. The mixture was allowed to cool, filtered through diatomeous earth the filter pad washed with methanol and the solvent removed from the filtrate by evaporation. The residue was dissolved in EtOAc, washed with water and dried (Na2SO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica gel eluting with EtOAc / isohexane (40:60) to give 2-chloro-6-methyl-4-(5-cyanopyrid-2-ylamino)pyrimidine (370mg,10percent); NMR Spectrum 2.41 (s, 3H), 7.67 (d, IH), 7.74 (s, IH), 8.22 (dd, IH), 8.79 (d, IH), 11.06 (s, IH); Mass Spectrum 245 [MH]+.

Reference： [1]Patent: WO2006/109026,2006,A1 .Location in patent: Page/Page column 96

18
[ 4214-73-7 ]
[ 912673-53-1 ]
S-6-methyl-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-cyanopyrid-2-ylamino)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 60℃; for 18h;	Example 14; S-6-Methyl-2-{2-r3-(pyrid-2-vI)isoxazoI-5-vnpyrrolidin-l-yl}-4-(5-cyanopyrid-2- ylamino)pyrimidine; Tris(dibenzylideneacetone)dipalladium(0) (20mg, 0.022mmol), and 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (20mg, 0.034mmol) were added to a mixture of 2-amino-5- cyanopyridine (60mg, 0.5mmol), S-4-chloro-6-methyl-2-{2-[3-(pyridin-2-yl)isoxazol-5- yl]pyrrolidin-l-yl}pyrimidine (188mg, 0.55mmol) and cesium carbonate (326mg, l.Ommol) in 1,4-dioxane (4ml) under nitrogen and the reaction mixture heated at 6O0C under nitrogen EPO <DP n="96"/>for 18 hours. The mixture was allowed to cool, the insoluble material removed by filtration, the solvent was removed from the filtrate by evaporation. The residue was purified by column chromatography on silica gel eluting with EtOAc / DCM (10:90) to give the title compound (33mg, 16percent) as a white solid; NMR Spectrum 2.05-2.20 (m, 3H), 2.22 (s, 3H), 2.32-2.47 (m, IH), 3.68-3.78 (m, IH), 3.78-3.88 (m, IH), 5.45-5.50 (d, IH), 6.56 (s, IH), 6.70 (s, IH), 7.40-7.47 (m, IH), 7.85-7.90 (m, IH), 7.90-8.00 (m, 2H), 8.00-8.07 (d, IH), 8.57 (s, IH), 8.62-8.66 (d, IH), 9.85(s, IH). Mass Spectrum 425 [MH]+.

Reference： [1]Patent: WO2006/109026,2006,A1 .Location in patent: Page/Page column 94-95

19
[ 4214-73-7 ]
[ 69879-22-7 ]

Yield	Reaction Conditions	Operation in experiment
73.16%	With lithium aluminium tetrahydride; In tetrahydrofuran; for 1.5h;	To a solution of compound 53.9 (10 g, 83.95 mmol, 1 eq) in THF (150 mL) wasadded LAH (6.37 g, 167.90 mmol, 2 eq) at 0C. The mixture was stirred at 0C for 1.5 hours.The reaction mixture was quenched by addition saturated sodium sulfate at 0 C and added100 ml H20 then extracted with ethyl acetate (100 mL x 3). The combined organic layerswere washed with saturated brines (30 mL x 1), dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to give the product compound 53.8 (7.50 g, 61.42mmol, 73.16% yield) as a yellow oil. LCMS (ESI): m/z: [M + H] called for C6H6N20: 123;found 123; RT=0.099 mm.
30%	With diisobutylaluminium hydride; In tetrahydrofuran; hexane; at 0℃;	4.1.1 Synthesis of 6-aminopyridine-3-carboxaldehyde A 1M solution of diisobutylaluminum hydride (DIBAL) in hexane (10 mL) was added to a solution of 6-amino-5-cyanopyridine (10 mmol) in dry THF (50 mL) cooled at 0 C. The ice-bath was removed, and additional 7.1 mL of a 1M solution of DIBAL in hexane were added in two successive portions. After stirring for additional 30 min, the reaction was quenched by the dropwise addition of dry MeOH (15 mL). The mixture was partitioned between 100 mL of AcOEt and 70 mL of 2N HCl. The aqueous layer was treated with 75 mL of 2N NaOH and extracted with AcOEt. The organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with CHCl3/AcOEt 1:4. Yield: 30%, mp = 174-175 C. IR (KBr): 3366, 3121, 1659 cm-1. 1H NMR (CD3OD, 400 MHz): delta (ppm) 9.67 (s, 1H, CHO), 8.41 (d, 1H, H2, J2-4 = 1.6 Hz), 7.87 (dd, 1H, H4, J4-5 = 8.8 Hz, J2-4 = 1.6 Hz), 6.63 (d, 1H, H5, J4-5 = 8.8 Hz), 3.31 (s, 2H, NH2). 13C NMR (CDCl3, 100 MHz): delta (ppm) 191.15, 164.46, 155.78, 137.39, 123.92, 109.99.
		To a suspension of 1 g of 6-aminopyridine-3-carbonitrile in 20 mL of toluene cooled to -78 C. are added dropwise 15 mL of a 1.2 M solution of diisobutylaluminum hydride in toluene. The reaction medium is stirred for 30 minutes at -78 C. and is then allowed to warm slowly to 20 C. After cooling again to -78 C., 6 mL of water are added slowly and the resulting mixture is stirred for 1 hour at -78 C. The reaction medium is stirred for 16 hours at 20 C., treated with 20 mL of 2.5 N hydrochloric acid, stirred for 20 minutes, basified by addition of concentrated sodium hydroxide and extracted three times with 100 mL of dichloromethane. The combined organic phases are dried and concentrated to dryness under reduced pressure. The residue is taken up in 40 mL of ethyl acetate and 40 mL of saturated sodium bisulfite solution. The aqueous phase is washed twice with 40 mL of ethyl acetate, basified to about pH 14 by addition of concentrated sodium hydroxide, and extracted three times with 50 mL of dichloromethane. The combined organic phases are dried and concentrated to dryness under reduced pressure to give 200 mg of crude 6-aminopyridine-3-carboxaldehyde in the form of a yellow powder, which is used without further purification.

		2-Amino-5-cyanopyridine (1.02 g) was dissolved in THF (40 ml) and added with Lithium aluminum hydride (637 mg) and the whole was stirred at room temperature for 2 hours. Water was added thereto to stop the reaction, and the whole was added with a saturated sodium sulfate aqueous solution and subjected to filtration through Celite. The residue obtained by concentration of the filtrate was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.04 g) as a yellow solid. MS(EI):m/z=122[M]+ 1H-NMR(500MHz,DMSO-d6):delta=6.51(1H,dd,J=0.7,8.9Hz),7.19(2H,br),7.75(1H,dd,J=2.4,8.9Hz),8.43(1H,dd,J=0.5,2.2Hz),9.66(1H,s).
	With diisobutylaluminium hydride; In tetrahydrofuran; toluene; at -78 - 20℃; for 2h;	6-Aminopyridine-3-carbonitrile (1.9 g, 16 mmol) was dissolved in THF (160 mL) and cooled to -78C with stir. Diisobutylaluminium hydride (106.5 mL, 1.5M toluene solution) was slowly added dropwise to the solution at - 78C and the mixture was allowed to warm to 20C with stir, followed by further stirring for two hours. The reaction was quenched by addition of ice water (100 mL) to the resultant reaction mixture, and the mixture was extracted three times with dichloromethane (50 mL). The resultant organic phases were combined together and then washed once with brine (100 mL) and dried over anhydrous sodium sulfate. The solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was roughly purified by silica gel column chromatography to yield a crude product of the title compound (1.7 g). The crude product was used for the subsequent reaction without further purification
	With diisobutylaluminium hydride; In tetrahydrofuran; at -78 - 20℃; for 2h;	6-Aminopyridine-3-carbonitrile (1.9 g, 16 mmol) was dissolved in THF (160 mL). The solution was cooled to -78C with stirring. Diisobutylaluminum hydride (106.5 mL, 1.5 M toluene solution) was slowly added dropwise to the solution at -78C. The solution was allowed to warm to 20C with stirring and further stirred for two hours. The reaction was quenched by addition of iced water (100 mL). The solution was extracted with dichloromethane (50 mL) three times. The extracted organic phases were combined, washed with brine (100 mL) once, and dried over anhydrous sodium sulfate. The solid was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a crude product (1.7 g) of the title compound.

Reference： [1]Patent: WO2018/209132,2018,A1 .Location in patent: Paragraph 0458; 0489
[2]European Journal of Medicinal Chemistry,2016,vol. 117,p. 292 - 300
[3]Patent: US2009/143420,2009,A1 .Location in patent: Page/Page column 7
[4]Patent: EP1724263,2006,A1 .Location in patent: Page/Page column 55
[5]Patent: EP3305785,2018,A1 .Location in patent: Paragraph 0177; 0178
[6]Patent: EP3546458,2019,A1 .Location in patent: Paragraph 0180; 0181

20
[ 4214-73-7 ]
6-amino-N-hydroxy-nicotinamidine [ No CAS ]
[ 329-89-5 ]

Yield	Reaction Conditions	Operation in experiment
22%	With hydroxylamine hydrochloride; sodium carbonate; In ethanol; water; for 6h;Heating / reflux;	Example B.4 6-Amino-N-hydroxy-nicotinamidine; A stirred mixture of commercially available 2-amino-5-cyano-pyridine [CAS-No. 4214-73-71 (5.0 g, 42 mmol), hydroxylamine hydrochloride (17.5 g, 0.25 mol) and sodium carbonate (31.1 g, 0.29 mol) in water (95 ml) and ethanol (21 ml) was heated under reflux conditions for 6h. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (4.x.100 ml). The combined organic layers were washed with brine (150 ml), dried (MgSO4) and evaporated. The crude product was purified by column chromatography on silica gel (ethyl acetate/MeOH/NH4OH 4:1:0.5) and crystallization (ethyl acetate/MeOH/hexane) to yield 6-amino-nicotinamide (1.39 g) and the title compound (1.42 g, 22percent) as an off-white solid. MS (EI) 152.1 [(M)+]; mp 300° C.

Reference： [1]Patent: US2007/72879,2007,A1 .Location in patent: Page/Page column 14

21
[ 4214-73-7 ]
[ 2960-66-9 ]
[ 1034309-63-1 ]

Yield	Reaction Conditions	Operation in experiment
29%	In acetonitrile at 90℃; for 14h;	26 2-Amino-5-cyanopyridine (5.0 g, 39.9 mmol) and ethyl-(E)-4-oxobutenoate (5.92 g, 43.9 mmol, 1.1 equiv) are dissolved in acetonitrile (25 ml). The solution is heated for 14 hours at 90 0C. After cooling, volatiles are removed in vacuo, and the residue is purified by flash chromatography (gradient hexane / EtOAc 100 : 0 to 50 : 50) to afford the title compound (2.77 g, 29%). 1H NMR (400 MHz, d6-DMSO): δ = 9.17 - 9.15 (m, 1 H), 7.60 (dd, J = 9.3 / 1.0 Hz, 1 H), 7.54 (s, 1 H), 7.37 (dd, J = 9.3 / 1.7 Hz, 1 H), 4.07 (s, 2H), 3.99 (q, J = 7.4 Hz, 2H), 1.07 (t, J = 7.1 Hz, 3H). MS (ES+): 230 (M+H)+.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2008/74752, 2008, A2 Location in patent: Page/Page column 24

22
[ 107-20-0 ]
[ 4214-73-7 ]
[ 885276-13-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-chloroethanal; 6-aminonicotinonitrile With sodium hydrogencarbonate In water Stage #2: With N-iodo-succinimide In acetonitrile

Reference： [1]Location in patent: scheme or table Buckley, George M.; Fosbeary, Richard; Fraser, Joanne L.; Gowers, Lewis; Higueruelo, Alicia P.; James, Lynwen A.; Jenkins, Kerry; Mack, Stephen R.; Morgan, Trevor; Parry, David M.; Pitt, William R.; Rausch, Oliver; Richard, Marianna D.; Sabin, Verity [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 12, p. 3656 - 3660]

23
[ 4214-73-7 ]
[ 79-36-7 ]
[ 1116016-13-7 ]

Yield	Reaction Conditions	Operation in experiment
35%	With triethylamine; In dichloromethane; at 0 - 20℃; for 49h;	To a suspension of <strong>[4214-73-7]2-amino-5-cyanopyridine</strong> (0.500 g, 4.2 mmol) in dry dichloromethane (20 ml_) was added triethylamine (0.830 g, 6.3 mmol) and the mixture stirred at 0 0C. To the reaction mixture 2,2-dichloroacetyl chloride (0.923 g,6.3 mmol) was added dropwise and the mixture was stirred at 0 0C for about 1 hour and then at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane (100 ml_) and washed with water (150 ml_). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 25-30 percent ethyl acetate in petroleum ether as an eluent) to obtain the title compound.Yield: 0.305 g (35 percent); 1H NMR (DMSOd6, 300MHz): 5 6.7 (s, 1 H), 8.18-8.20 (d, 1 H), 8.35-8.37(d, 1 H), 8.87 (s, 1 H); MS m/e: 229.05 (M-1 ).

Reference： [1]Patent: WO2009/19656,2009,A1 .Location in patent: Page/Page column 48
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2949 - 2952

24
[ 4214-73-7 ]
[ 79-04-9 ]
[ 875315-36-9 ]

Yield	Reaction Conditions	Operation in experiment
65%	With triethylamine; In chloroform; at 0 - 20℃; for 13h;	To a suspension of <strong>[4214-73-7]2-amino-5-cyanopyridine</strong> (2.0 g, 16.8 mmol) in dry chloroform (40 ml_) was added triethylamine (2.54 g, 25.21 mmol) with stirring at 0 0C. To the reaction mixture chloroacetyl chloride (2.08g, 18.48 mmol) was added dropwise, and stirred at 0 0C for 1 hour and then at room temperature for 12 hours. The reaction mixture was diluted with chloroform (100 ml_) and washed with water (150 ml_). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was recrystallized from chloroform and petroleum ether to obtain the title compound.Yield: 2.15 g (65 percent); 1 H NMR (DMSOd6, 300MHz): 5 4.39 (s, 2H), 8.17-8.18 (d, 1 H), 8.27-8.29 (m, 1 H), 8.8 (s, 1 H), 1 1 .32 (s, 1 H); MS m/e: 195.96 (M+1 ).
	With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;	a)2-Chloro-N-(5-cyano-pyridin-2-yl)-acetamideA solution of 2-amino-5-cyano pyridine (2.0 g) in dry dichloromethane (17 mL) under nitrogen at 0° C. was treated with triethylamine (2.6 mL) followed by slow addition of chloroacetyl chloride (1.5 mL).The reaction mixture was allowed to warm up to room temperature.After 2 h, the mixture was partitioned between dichloromethane and water.The phases were separated and the aqueous layer was extracted with dichloromethane (*2).The combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 50percent EtOAc/cyclohexane.The relevant fractions were combined and evaporated to give the title compound (2.17 g) as a light brown solid.1H NMR (400 MHz, CDCl3): delta 8.99 (s, 1H), 8.61 (dd, 1H), 8.36 (dd, 1H), 8.00-7.97 (m, 1H), 4.23 (s, 2H).
	With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;	Example 51: (/f)-l-[(5-Cyano-pyridin-2-ylcarbamoyl)-methyl]-3-(l-phenyl- cycloheptanecarbonyloxy)-l-azonia-bicyclo[2.2.2]octane chloride <n="103"/>a) 2-Chloro-./V-(5-cyano-pyridin-2-yl)-acetamide A solution of 2-amino-5-cyano pyridine (2.0 g) in dry dichloromethane (17 mL) unda nitrogen at O0C was treated with triethylamine (2.6 mL) followed by slow addition of chloroacetyl chloride (1.5 mL). The reaction mixture was allowed to warm up to roorr temperature. After 2h, the mixture was partitioned between dichloromethane and wate The phases were separated and the aqueous layer was extracted with dichloromethane The combined organic layer was washed with brine, dried over sodium sulphate, filter and concentrated to give the crude product which was purified by silica gel chromatography eluting with 50percent EtOAc/cyclohexane. The relevant fractions were combined and evaporated to give the title compound (2.17g) as a light brown solid.1H NMR (400 MHz, CDCl3): delta 8.99 (s, IH), 8.61 (dd, IH), 8.36 (dd, IH), 8.00-7.97 IH), 4.23 (s, 2H).

Reference： [1]Patent: WO2009/19656,2009,A1 .Location in patent: Page/Page column 45
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2949 - 2952
[3]Patent: US2011/172237,2011,A1 .Location in patent: Page/Page column 39
[4]Patent: WO2009/138707,2009,A1 .Location in patent: Page/Page column 101-102

25
[ 4214-73-7 ]
[ 7623-09-8 ]
[ 1116016-11-5 ]

Yield	Reaction Conditions	Operation in experiment
35%	With triethylamine; In dichloromethane; at 0 - 20℃; for 49h;	To a suspension of <strong>[4214-73-7]2-amino-5-cyanopyridine</strong> (0.500 g, 4.2 mmol) in dry dichloromethane (20 ml_) was added triethylamine (0.830 g, 6.3 mmol) and the mixture was stirred at 0 0C. To the reaction mixture, 2-chloropropionyl chloride (0.800 g, 6.3 mmol) was added dropwise, and the reaction mixture was stirred at O0C for an hour and then at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane (100 ml_) and was washed with water (150 ml_). The reaction mixture was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 15-20 percent ethyl acetate in petroleum ether as an eluent) to obtain the title compound. Yield: 0.305 g (35 percent); 1 H NMR (DMSOd6, 300MHz): delta 1 .57-1 .59 (d, 3H), 4.80-4.86 (m, 1 H), 8.18-8.20 (d, 1 H), 8.26-8.30 (m, 1 H), 8.8 (s, 1 H), 1 1 .37 (s, 1 H).

Reference： [1]Patent: WO2009/19656,2009,A1 .Location in patent: Page/Page column 47
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2949 - 2952

26
[ 4214-73-7 ]
[ 187834-88-4 ]
C₁₇H₂₄N₆O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4191 - 4194

27
[ 4214-73-7 ]
[ 1187322-51-5 ]

Yield	Reaction Conditions	Operation in experiment
6.6 g		Synthesis of 6-amino-5-iodonicotinonitrile 6-Amino-3-pyridinecarbonitrile (10.0 g, 0.081 mol), silver trifluoroacetate (25.5 g, 0.115 mol) and 160 ml of 1,2-dichloroethane are combined in a flask and heated under reflux for 5 h. Iodine (29.5 g, 0.116 mol) is added, and the mixture is heated for a further 18 h. After cooling, the mixture is filtered and partitioned between water and dichloroethane. Organic and aqueous phase are filtered through Celite. The aqueous phase is extracted to exhaustion, and the combined organic phases are combined, dried and evaporated. The residue is dissolved in ethyl acetate and washed with sodium thiosulfate solution. Removal of the solvent gives 6.6 g of yellowish crystals product. These are reacted further without further purification; HPLC: 2.57 min; LCMS: 246 [M+H]+.
		Example 1rOObetan Synthesis of 5-{4-[4-(5-Cyano-1 H-pyrrolo[2,3-b]pyridine-3-yl)-butyl]- piperazin-1-yl}-benzofuran-2-carboxylic acid amide: a.: 67 g of 6-amino-nicotinonitrile were dissolved in 1 L 1 ,2-dichloroethane, 125 g argentic trifluoro acetate were added and the mixture was refluxed for 7 h. After cooling to room temperature (RT), 143 g of iodine were added. The mixture was heated again for 12 h. Then the temperature was lowered to RT and the salts removed by filtration. The reaction phase was treated with 1 L of water. The aqueous phase was extracted with dichloromethane and the combined organic layers were dried over magnesium sulfate, evaporated and purified by chromatography over silica gel yielding 41 g yellowish crystals 6- amino-5-iodo-nicotinonitrile. [M+H]+: 246
	With N-iodo-succinimide; trifluoroacetic acid; In N,N-dimethyl-formamide; at 50℃; for 3h;	To a solution of 2-amino-5-cyanopyridine (500 mg, 4.2 mmol) in DMF (5 mL), trifluoroacetic acid (574 nig, 386 uL, 1.2 mol equivalents) was added. At room temperature iV- iodosuccinimide (1.04 g, 4.62 mmol, 1.1 mol equivalents) was added and the reaction mixture was heated at 50 C for 3 hours. Complete conversion was Indicated by TLC. After cooling the reaction mixture to room temperatures the product was precipitated by adding the reaction mixture to water. After neutralization with NarSiCh and 1 N NaOH the title compound (660 mg) was collected by filtration as a brown solid. It was used in the next step without any purification.

With N-iodo-succinimide; trifluoroacetic acid; In N,N-dimethyl-formamide; at 50℃; for 3h;

To a solution of 2-amino-5-cyanopyridine (500 mg, 4 2 mmol) in DMF (5 tnL), TFA (574 mg, 386 pL, 1.2 mol equivalents) was added. At room temperature A-iodosuccinimide (1.04 g, 4.62 mmol, 1.1 mol equivalents) was added, and the reaction mixture was heated at 50 C for 3 hours. Complete conversion was indicated by TLC. After cooling the reaction mixture to room temperature, the product was precipitated by adding the reaction mixture to water. After neutralization with Na2S2C>3 and 1 N NaOH, 6-amino-5-iodopyridine-3- carbonitrile (660 mg) was collected by filtration as a brown solid. It was used in the next step without any purification.

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 1160 - 1170
[2]Patent: US2015/218155,2015,A1 .Location in patent: Paragraph 0300
[3]Patent: WO2009/112139,2009,A1 .Location in patent: Page/Page column 25
[4]Patent: WO2020/12422,2020,A1 .Location in patent: Page/Page column 54
[5]Patent: WO2020/12424,2020,A1 .Location in patent: Page/Page column 80

28
[ 4214-73-7 ]
[ 24424-99-5 ]
[ 400720-77-6 ]

Yield	Reaction Conditions	Operation in experiment
73%	With sodium tetrahydroborate;nickel(II) chloride hexahydrate; In methanol; at 0 - 20℃; for 18h;	2-Amino-5-cyanopyridine (2.Og, 16.8mmol) was dissolved in methanol (100ml). This solution was cooled to 00C. Nickel (II) chloride hexahydrate (0.4g, 1.67mmol) and di- tertbutyl dicarbonate (7.33g, 33.6mmol) were added followed by sodium borohydride (4.49g, 117mmol) portionwise. The reaction mixture was stirred at O0C to room temp for 18hrs. The MeOH was removed by evaporation. The residue was dissolved in EtOAc (100ml), washed with sat NaHCO3 (lx50mls), water (lx50mls), brine (lx50mls), dried (Na2SO4) and evaporated in vacuo to give a brown oil. Purified by flash chromatography, eluant 3percent MeOH, 97percent CHCl3 to give an orange oil identified as the title compound.Yield = 2.74g, 12.25mmol, 73percent [M+H]+ = 224.1
19%		To a stirred solution of <strong>[4214-73-7]6-aminopyridine-3-carbonitrile</strong> (24, 500 mg, 4.2 mmol), ditertbutyl dicarbonate (1.92 mL, 8.4 mmol) and NiCI2.6H20 (100 mg, 0.42 mmol) inmethanol (25 mL) was added sodium borohydride (1 .11 g, 29.4 mmcl) at 0°C in portions. The resulting solution was then slowly warmed to room temperature and then stirred for 1 hour. Di-ethylene triamine (0.45 mL, 4.2 mmol) was then added to the reaction mixture and stirred for further 1 hour. After completion (monitored by TLC, 5percent MeOH in DCM, Rf 0.5), the reaction mixture was concentrated under vacuo and theresidue was partitioned between saturated aq. NaHCO3 (50 mL) and ethyl acetate (100 mL). Organic part was separated and washed with brine, dried over sodium sulfate and concentrated under vacuo. The crude residue was purified by column chromatography (1 00-200 mesh silica, gradient elution of 100percent DCM to 2percent MeOH in DCM) to afford tert-butyl [(6-aminopyridin-3-yl)methyl]carbamate (25) as a gum. Yield: 180 mg(19percent).1H NMR (400 MHz, DMSO-d6) O 7.75 (brs, 1H), 7.24 (dd, 1H), 7.20 (t, 1H), 6.37 (d, 1 H), 5.76 (br s, 2H), 3.89 (d, 2H), 1.37 (5, 9H), LCMS [M+H]: 224.0

Reference： [1]Patent: WO2009/133348,2009,A1 .Location in patent: Page/Page column 74
[2]Patent: WO2016/193844,2016,A1 .Location in patent: Page/Page column 108; 109

29
[ 4214-73-7 ]
2-amino-5-aminomethylpyridine dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With hydrogenchloride;palladium on activated charcoal; In water; under 517.1619999999999 Torr; for 18h;	6-Amino-3-pyridinecarbonitrile (12.5g, 104mmol) was dissolved (25OmIs), 6M HCl (35mls, 210mmol) was added. 10percent Pd/C (2.5g) was added. The reaction mixture was <n="80"/>shaken at lOpsi for 18hours after which time the catalyst was filtered off through celite and the residue washed with methanol (20OmIs) and water (2OmIs). The combined filtrates were evaporated in vacuo to give a white solid. Recrystallised from MeOH/diethyl ether to give a white solid identified as the title compound Yield = 15.52g, 79.2mmol, 75percent [M+H]+ = 124.17
69%	With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In water; under 517.1619999999999 Torr; for 18h;	EXAMPLE 1(R)-N-[(S)-l-K6-Amino-pyridin-3-ylmethyl)-carbamoyll-2-(3,4-difluoro-phenvn- ethvH-2-hydroxy-3-phenyl-propionamideA. 5-AminomethyI-pyridin-2-ylamine dihydrochloride6-Amino-3-pyridinecarbonitrile (12.5g, 21.0mmol) was dissolved (250mls), 6M HC1 (35mls, 210mmol) was added. 10percent Pd/C (2.5g) was added. The reaction mixture was shaken at lOpsi for 18 hours after which time the catalyst was filtered off through celite and the residue washed with methanol (lOOmls) and water (20mls). The combined filtrates were evaporated in vacuo to give a white solid. Recrystalised from MeOH diethyl ether to give a white solid identified as the title compoundYield = 14.28g, 72.8mmol, 69percent[M+H]+ = 124.1

Reference： [1]Patent: WO2009/133348,2009,A1 .Location in patent: Page/Page column 78-79
[2]Patent: WO2011/51671,2011,A1 .Location in patent: Page/Page column 60
[3]Patent: WO2009/133348,2009,A1

30
[ 4214-73-7 ]
[ 300356-14-3 ]
[ 710322-11-5 ]

Yield	Reaction Conditions	Operation in experiment
86%		Example 2 2 (R)- (3-CHLORO-4-METHANESULFONYL-PHENYL)-3-CYCLOPENTYL-N- [5- (N- hydroxycarbamimidoyl)-pyridin-2-yl]-propionamide [000137] A solution of 2 (R)- (3-CHLORO-4-METHANESULFONYL-PHENYL)-3-CYCLOPENTYL- propionic acid (prepared as in Example 1, 300 mg, 0.91 mmol) in methylene chloride (10 ML) and N, N DIMETHYLFORMAMIDE (1 drop) cooled to 0°C was treated with a 2. 0M solution of oxalyl chloride in methylene chloride (0.52 mL, 1.04 mmol). The reaction was stirred at 0°C for 30 min. At this time, the reaction was concentrated in vacuo to give a light yellow oil. The residue was then treated with a solution of 2-amino-5- cyanopyridine (216 mg, 1.80 mmol) in tetrahydrofuran (5 ML) and pyridine (0.37 ML, 4.5 mmol). The reaction was then stirred at 25°C for 16 h. At this time, the reaction was diluted with water (15 ML) and extracted with methylene chloride (3 x 25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 70/30 hexanes/ethyl acetate) afforded 2 (R)- (3-CHLORO-4-METHANESULFONYL-PHENYL)-N- (5-CYANO-PYRIDIN-2-YL)-3- cyclopentyl-propionamide (53 mg, 86percent) as a colorless oil: (ES) +-HRMS M/E calcd for C21H22CLN303S (M+H) + 432. 1143, found 432.1147.

Reference： [1]Patent: WO2004/52869,2004,A1 .Location in patent: Page 78 - 79

31
[ 4214-73-7 ]
[ 1207830-37-2 ]
[ 1207830-40-7 ]

Yield	Reaction Conditions	Operation in experiment
94%		Trimethylaluminium (2M in toluene) (0.638 mL, 1.28 mmol) was added to <strong>[4214-73-7]6-aminonicotinonitrile</strong> (152 mg, 1.28 mmol) in toluene (2 mL) under nitrogen. The resulting solution was stirred at room temperature for 15 minutes. (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AR1) (425 mg, 0.64 mmol) in toluene (8 mL) was added sealed into a 20 mL microwave tube. The reaction was heated to 120° C. for 4 hours in the microwave reactor and cooled to RT. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water (30 mL) and extracted with EtOAc (2.x.50 mL). The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50percent EtOAc in isohexane to afford (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-cyanopyridin-2-yl)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (450 mg, 94percent).m/z (ES+) (M+H)+=752; HPLC tR=3.74 min.

Reference： [1]Patent: US2010/93757,2010,A1 .Location in patent: Page/Page column 91-92

32
[ 107-20-0 ]
[ 4214-73-7 ]
[ 106850-34-4 ]

Yield	Reaction Conditions	Operation in experiment
95%		Preparation 77 Imidazo[1,2-a]pyridine-6-carbonitrile A solution of <strong>[4214-73-7]6-aminonicotinonitrile</strong> (10g, 0.08mol) in CH3CN (300 mL) was treated with the 2-chloroacetaldehyde solution (26.4ml, 0.21mol) and the mixture warm to reflux for 6h. The mixture was cooled down to r.t. overnight. The crystalline precipitate was filtered and washed with a little CH3CN. The solid was treated with aq. NaHCO3 solution until pH = 7 then extracted with DCM. The organic layer was dried (MgSO4) and evaporated to give a pale yellow solid. Yield=95percent m/z 144 (M+1)+ Retention time: 0.65min (Method B)
94%		A solution of <strong>[4214-73-7]6-aminonicotinonitrile</strong> (10 g, 80 mmol) in acetonitrile (300 mL) was treated with a 50percent aqueous solution of 2-chloroacetaldehyde (26.4 mL, 210 mmol). The mixture was stirred and heated to reflux. After 6 hours, the mixture was cooled to room temperature. The mixture was concentrated to low bulk (approx. 100 mL), treated with saturated aqueous sodium hydrogencarbonate solution to neutral pH, and then extracted with dichloromethane (2 x 300 mL). The organic layer was dried (MgS04) and evaporated and the residue was stirred with diethyl ether (200 mL), filtered and dried in vacuum to give the title compound (22.54 g, 94percent) as a pale brown solid.LRMS (m/z): 144 (M+1)+.1H-NMR delta (CDCI3): 7.29 (dd, 1 H), 7.71 (d, 1 H), 7.73 (d, 1 H), 7.80 (d, 1 H), 8.61- 8.62 (m, 1 H).
94%	In water; acetonitrile; for 6h;Reflux;	<strong>[4214-73-7]6-aminonicotinonitrile</strong> (10 g, 80 mmol) in acetonitrile (300 mL) was treated with a 50percent aqueous solution of 2-chloroacetaldehyde (26.4 mL, 210 mmol). The mixture was stirred and heated to reflux. After 6 hours, the mixture was cooled to room temperature. The mixture was concentrated to low bulk (approx. 100 mL), treated with saturated aqueous sodium hydrogencarbonate solution to neutral pH, and then extracted with dichloromethane (2 x 300 mL). The organic layer was dried (MgSO4) and evaporated and the residue was stirred with diethyl ether (200 mL), filtered and dried in vacuum to give the title compound (22.54 g, 94percent) as a pale brown solid.LRMS (m/z): 144 (M+1)+.1H-NMR delta (CDCI3): 7.29 (dd, 1 H), 7.71 (d, 1 H), 7.73 (d, 1 H), 7.80 (d, 1 H), 8.61-8.62 (m, 1 H)

89%		PREPARATION 1 Imidazo[1,2-a]pyridine-6-carbonitrile A 50percent aqueous solution of 2-chloroacetaldehyde (26.40 mL, 210 mmol) was added to a solution of 2-aminonicotinonitrile (10 g, 80 mmol) in acetonitrile (300 mL) and the mixture was stirred and heated to reflux. After 20 hours, aqueous saturated sodium hydrogencarbonate solution was added, the mixture was partially concentrated and further aqueous saturated sodium hydrogencarbonate solution was added until the pH reached 7. The mixture was extracted with dichloromethane and the organic layer was dried (MgSO4) and evaporated and the residue was triturated with diethyl ether to yield the title compound (10.75 g, 89percent) as a brown solid. LRMS (m/z): 144 (M+1)+.1H NMR (300 MHz, DMSO-d6) deltappm 7.49 (dd, 1H), 7.72 (s, 1H), 7.75 - 7.78 (m, 1H), 8.07 (s, 1H), 9.37 (s, 1H).
	In ethanol; water; for 4h;Reflux;	To a solution of 6-aminonicotinonithle (K-1 ) (4.0 g, 33.6 mmol) in anhydrous EtOH (160 ml_) was added 2-chloroacetaldehyde (40percent in H20, 27.5 ml_, 68 mmol). The reaction was refluxed for 4h, and then concentrated. The resulting residue was dissolved in water and adjusted to pH > 7 with a saturated NaHC03 solution. The precipitate was collected and dried to afford the title compound (4.80 g).
	In ethanol; water; for 4h;Reflux;	H-Imidazo[1,2-a]pyridine-6-carbonitrile (K-2)To a solution of <strong>[4214-73-7]6-aminonicotinonitrile</strong> (K-1) (4.0 g, 33.6 mmol) in anhydrous EtOH (160 mL) was added 2-chloroacetaldehyde (40percent in H2O, 27.5 mL, 168 mmol).The reaction was refluxed for 4 h, and then concentrated.The resulting residue was dissolved in water and adjusted to pH>7 with a saturated NaHCO3 solution.The precipitate was collected and dried to afford the title compound (4.80 g).

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 7577 - 7589
[2]Patent: EP2202232,2010,A1 .Location in patent: Page/Page column 55
[3]Patent: WO2011/76419,2011,A1 .Location in patent: Page/Page column 100
[4]Patent: EP2338888,2011,A1 .Location in patent: Paragraph 0103; 0104
[5]Patent: WO2011/157397,2011,A1 .Location in patent: Page/Page column 80
[6]Journal of Medicinal Chemistry,2019,vol. 62,p. 9045 - 9060
[7]Patent: WO2011/79804,2011,A1 .Location in patent: Page/Page column 34
[8]Patent: US2012/245178,2012,A1 .Location in patent: Page/Page column 19

33
[ 5271-67-0 ]
[ 4214-73-7 ]
[ 477871-47-9 ]

Yield	Reaction Conditions	Operation in experiment
14%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - 20℃; for 24h; Inert atmosphere;

Reference： [1]Ballard, T. Eric; Wang, Xia; Olekhnovich, Igor; Koerner, Taylor; Seymour, Craig; Hoffman, Paul S.; MacDonald, Timothy L. [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 12, p. 3537 - 3539]

34
[ 4214-73-7 ]
[ 468068-28-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	With hydroxylamine; In ethanol; water; at 80℃; for 8h;Sealed tube;	Intermediate 34: 6-amino-N'-hvdroxypyridine-3-carboximidamide; 25 To a solution of <strong>[4214-73-7]6-aminonicotinonitrile</strong> (Aldrich; 1.02 g, 8.57 mmol) in EtOH (10 mL) was added hydroxylamine (2.82 mL, 42.5 mmol) and the mixture stirred at 80 0C for 8 hours. The mixture was cooled to 0 0C and the precipitated solid was collected by filtration to give Intermediate 34 (1.15 g, 88 percent) as a brown solid. 1H NMR: (DMSO-d6, 400MHz) delta 9.36 (1 H, s), 8.23 (1 H, d, J = 2.4 Hz), 7.64 (1 H, dd, J = 8.6, 2.4 Hz), 6.43 (1 H, d, J = 8.6 Hz), 6.13 (230 H, s), 5.68 (2 H, s).

Reference： [1]Patent: WO2010/142628,2010,A1 .Location in patent: Page/Page column 89

35
[ 4214-73-7 ]
[ 33142-21-1 ]
[ 1313410-31-9 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; benzene; for 10h;Reflux;	2-Amino-5-cyanopyridine (15.5 g, 152 mmol) was dissolved in ethanol (500 mL) in 2 L round bottom flask. Ethyl 2-chloro-3-oxopropanoate (5% in benzene; 730 mL; Commercial solution from Toronto Research Chemicals Inc.) was added and the mixture was heated at reflux for 10 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica-gel chromatography to give ethyl 6-cyanoimidazo[l,2-a]pyridine-3- carboxylate as a pale yellow solid (13.9 g).
	In ethanol; benzene; for 10h;Reflux;	Step A: Preparation of ethyl 6-cvanoimidazori,2-a1pyridine-3-carboxylate: 2-Amino-5-cyanopyridine (15.5 g, 152 mmol) was dissolved in ethanol (500 mL) in 2 L round bottom flask. Ethyl 2-chloro-3-oxopropanoate (5% in benzene; 730 mL; Commercial solution from Toronto Research Chemicals Inc.) was added and the mixture was heated at reflux for 10 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica-gel chromatography to give ethyl 6-cyanoimidazo[l,2-a]pyridine-3-carboxylate as a pale yellow solid (13.9 g).

Reference： [1]Patent: WO2011/79076,2011,A1 .Location in patent: Page/Page column 147; 148
[2]Patent: WO2012/82689,2012,A1 .Location in patent: Page/Page column 112

36
[ 4214-73-7 ]
[ 137100-52-8 ]
[ 1334126-93-0 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium In tetrahydrofuran; hexane at 20℃;	1.) Synthesis of the urea derivatives General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.

Reference： [1]Monte, Fabio Lo; Kramer, Thomas; Boländer, Alexander; Plotkin, Batya; Eldar-Finkelman, Hagit; Fuertes, Ana; Dominguez, Juan; Schmidt, Boris [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5610 - 5615]

37
[ 4214-73-7 ]
[ 56651-60-6 ]
[ 1334126-89-4 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium In tetrahydrofuran; hexane at 20℃;	1.) Synthesis of the urea derivatives General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.

38
[ 4214-73-7 ]
[ 1378039-20-3 ]
[ 1378037-57-0 ]

Yield	Reaction Conditions	Operation in experiment
52%		Method 2:Example 3 :6-[2-(2,6-Dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-ylamino]nicotinonitrile Sodium hydride (12 mg, 0.30 mmol) was added to a solution of <strong>[4214-73-7]6-amino-3-pyridinecarbonitrile</strong> (36 mg, 0.30 mmol) in DMF (2 mL) and the resultant mixture was stirred for 5 minutes before 4-chloro-2-(2,6- dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (80 mg, 0.27 mmol) was added. The reaction vial was sealed, purged with nitrogen and irradiated in a microwave at 150 °C for 10 minutes. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (40percent ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (53 mg, 52percent yield). NMR (400 MHz, DMSO-d6): delta 9.57 (d, J = 0.9 Hz, 1H), 8.98 (dd, J = 2.3, 0.8 Hz, 1H), 8.47 (dd, J = 8.7, 2.3 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.89-7.83 (m, 2H), 7.77 (dd, J = 9.1, 7.2 Hz, 1H), 7.65-7.61 (m, 2H). LCMS (Method B): RT = 3.05 min, m/z: 381 [M+H+].

Reference： [1]Patent: WO2012/66061,2012,A1 .Location in patent: Page/Page column 82

39
[ 4214-73-7 ]
[ 106850-34-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 130 °C 2: hydroxylamine-O-sulfonic acid; pyridine / methanol / 20 °C

Reference： [1]Current Patent Assignee: HUTCHISON MEDIPHARMA LTD; HUTCHISON CHINA MEDITECH LTD. - US2012/245178, 2012, A1

40
[ 4214-73-7 ]
[ 88333-03-3 ]
[ 6630-33-7 ]
[ 1402350-32-6 ]

Yield	Reaction Conditions	Operation in experiment
89%	With perchloric acid; In methanol; at 20℃;	5.5 3-(Benzylamino)-2-(2-bromophenyl)imidazo[1,2-a]pyridine-6-carbonitrile (4e) Following the general Groebke-Bienaym? procedure with <strong>[4214-73-7]2-amino-5-cyanopyridine</strong>, 2-bromobenzaldehyde, and (isocyanomethyl)benzene. Column chromatography on silica gel with (AcOEt/Hexanes: 3/7) provided 3-(benzylamino)-2-(2-bromo-phenyl)imidazo[1,2-a]pyridine-6-carbonitrile 4e (302 mg, 89percent) as a yellow solid; mp=126 °C; numax (ATR) 3169, 2867, 2227, 1566, 1419, 699 cm-1; 1H NMR (400 MHz, CDC13) delta=8.47 (1H, s), 7.67 (1H, d, J 7.9 Hz), 7.56 (1H, d, J 9.3 Hz), 7.43 (1H, d, J 7.1 Hz), 7.38 (1H, dd, J 7.4, 7.2 Hz), 7.28 (1H, dd, J 8.4, 7.4 Hz), 7.21-7.19 (4H, m), 7.07 (2H, d, J 3.1 Hz), 3.95 (2H, d, J 4.7 Hz, CH2), 3.74 (1H, bs, NH); 13C NMR (100.6 MHz, CDCl3) delta=140.3, 138.9, 138.3, 134.6, 132.8, 132.5, 130.2, 129.2, 128.6, 128.6, 128.2, 128.2, 127.8, 127.6, 127.5, 123.6, 122.9, 118.6, 117.0, 98.0, 52.6; HRMS (ES+): MH+, calcd for C21H16N4Br 403.0558. Found 403.0549.

Reference： [1]Tetrahedron,2012,vol. 68,p. 9131 - 9138,8

41
[ 4214-73-7 ]
[ 1490-25-1 ]
[ 1427468-05-0 ]

Yield	Reaction Conditions	Operation in experiment
71%	With N,N-dimethyl-aniline; In tetrahydrofuran; for 12h;Reflux;	The <strong>[4214-73-7]6-amino-3-pyridinecarbonitrile</strong> (commercially available, 0.470 g, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL) then N,N-dimethylaniline (0.5 mL, 1.0 eq.) and methyl-4-chloro- 4-oxo-butanoate (0.54 mL, 1.1 eq.) were successively added. The mixture was reflux for 12 h. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2x). The combined organic layer was dried on magnesium sulfate and concentrated under vaccum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate to give methyl 4-[(5- cyano-2-pyridyl)amino]-4-oxo-butanoate Al (71percent). M.p. = 161-164 °C. 1H NMR (400 MHz, DMSO-d6) delta 8.78 (s, 1H), 8.20 (m, 2H), 3.58 (s, 3H), 2.74 (t, 2H), 2.61 (t, 2H) ppm. LC-MS (Method B): RT 1.19, 234 (M+H+)
71%	With N,N-dimethyl-aniline; In tetrahydrofuran; for 12h;Reflux;	The <strong>[4214-73-7]6-amino-3-pyridinecarbonitrile</strong> (Commercialy available, 0.470g, 1.0eq.)was dissolved in tetrahydrofurann (10 mL) then N,N-dimethylaniline (0.5 mL, 1.0 eq.) and methyl-4-chloro-4-oxo-butanoate (0.54 mL, 1.1 eq.) were successively added. The mixture was reflux for 12h. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2x). The combined organic layer were dried on magnesium sulfate and concentrated under vaccum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate to give methyl 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoate A1 (71percent). MP = 161-164°C. 1H NMR (400 MHz, DMSO-d6) delta 8.78 (s, 1H), 8.20 (m, 2H), 3.58 (s, 3H), 2.74 (t, 2H), 2.61 (t, 2H) ppm. LC-MS (Method B): RT 1.19, 234 (M+H+)
71%	With N,N-dimethyl-aniline; In tetrahydrofuran; for 12h;Reflux;	Example I: l-[5-(cyano)-2-pyridyl]pyrrolidine-2,5-dione (compound Al) Step 1 : Method A: methyl 4-oxo-4-[[5-(cyano)-2-pyridyl]amino]butanoate II.1 The <strong>[4214-73-7]6-amino-3-pyridinecarbonitrile</strong> (Commercialy available, 0.470 g, 1.0 eq.) was dissolved in tetrahydroiuran (10 mL) then N,N-dimethylaniline (0.5 mL, 1.0 eq.) and methyl-4-chloro- 4-oxo-butanoate (0.54 mL, 1.1 eq.) were successively added. The mixture was reflux for 12 h. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2x). The combined organic layer were dried on magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate to give methyl 4-[(5- cyano-2-pyridyl) amino]-4-oxo-butanoate 11.1 (71percent). Mp = 161-164°C. 1H NMR (400 MHz, DMSO-d6) delta 8.78 (s, 1H), 8.20 (m, 2H), 3.58 (s, 3H), 2.74 (t, 2H), 2.61 (t, 2H) ppm. LC-MS (Method B): RT 1.19, 234 (M+H+).

Reference： [1]Patent: WO2013/37755,2013,A1 .Location in patent: Page/Page column 25
[2]Patent: EP2570404,2013,A1 .Location in patent: Paragraph 0077; 0078
[3]Patent: WO2013/164245,2013,A1 .Location in patent: Page/Page column 26

42
[ 4214-73-7 ]
[ 103-40-2 ]
[ 1427468-26-5 ]

Yield	Reaction Conditions	Operation in experiment
96%		4-Benzyloxy-4-oxo-butanoic acid (commercially available, 2.097 g, 10.1 mmol, 1.2 eq.) was dissolved in dichloromethane then oxalyl dichloride (2.13 g, 1.4 mL, 16.8 mmol, 2.0 eq.) and one drop of N,N-dimethylformamide were added. The solution was stirred at roomtemperature for 1 h and then refluxed for 1 h. The solvent was removed and dry by vacuum. The residue was dissolved in 30 ml of tetrahydrofuran and was added in a mixture with 6- aminopyridine-3-carbonitrile (commercially available, 1.00 g, 8.39 mmol, 1.0 eq.) in tetrahydrofuran (30 mL) and pyridine (1.99 g, 2.03 mL, 25.2 mmol, 3.0 eq.). The solution was refluxed for 4 h. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2x). The combined organic layer was dried on magnesium sulfate and concentrated under vaccum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate (3 / 1) to give benzyl 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoate A23 (2.49 g, 96percent). LC-MS (Method A): RT 1.58, 310 (M-H+), 308 (M-H+).

Reference： [1]Patent: WO2013/37755,2013,A1 .Location in patent: Page/Page column 29; 30

43
[ 108-30-5 ]
[ 4214-73-7 ]
[ 1427468-06-1 ]

Yield	Reaction Conditions	Operation in experiment
18%	In tetrahydrofuran; at 100℃; for 12h;	The <strong>[4214-73-7]6-amino-3-pyridinecarbonitrile</strong> (commercially available, 1.0 g, 8.40 mmol) was dissolved in tetrahydrofuran (20 mL) then succinic anhydride (1.04 g, 10.5 mmol) was added, the mixture was stirred at 100 °C for 12 h. The reaction was stopped and the solution was washed with a saturated solution of sodium carbonate. The organic layer was concentrated under vaccum. The residue was purified by flash chromatography eluting with methanol-ethyl acetate (5/95) to give 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoic acid A2 (0.325 g, 18percent). M.p. = 220-221 °C, 1H NMR (400 MHz, DMSO-d6) delta 12.18 (bs, 1H), 11.04 (s, 1H), 8.78(s, 1H), 8.21 (m, 2H), 2.69 (t, 2H), 2.52 (m, 2H) ppm. LC-MS (Method B): RT 1.00, 218 (M-H+)
18%	In tetrahydrofuran; at 100℃; for 12h;	The <strong>[4214-73-7]6-amino-3-pyridinecarbonitrile</strong> (Commercialy available, 1g, 8.40 mmol) was dissolved in tetrahydrofurann (20 mL) then succinic anhydride (1.04g, 10.5 mmol) was added, the mixture was stirred at 100°C for 12h. The reaction was stopped and the solution was washed with a saturated solution of sodium carbonate. The organic layer was concentrated under vaccum. The residue was purified by flash chromatography eluting with methanol-ethyl acetate (5/95) to give 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoic acid A2 (0.325 g, 18percent). Mp= 220-221 °C, 1H NMR (400 MHz, DMSO-d6) delta 12.18 (bs, 1H), 11.04 (s, 1H), 8.78(s, 1H), 8.21 (m, 2H), 2.69 (t, 2H), 2.52 (m, 2H) ppm. LC-MS (Method B): RT 1.00, 218 (M-H+)
18%	In tetrahydrofuran; at 100℃; for 12h;	Step 2: Method A: 4-oxo-4-[[5-(cyano)-2-pyridyl] amino] butanoic acid 12.1 The <strong>[4214-73-7]6-amino-3-pyridinecarbonitrile</strong> (commercially available, 1 g, 8.40 mmol) was dissolved in tetrahydrofuran (20 mL) then succinic anhydride (1.04g, 10.5 mmol) was added, the mixture was stirred at 100 °C for 12 h. The reaction was stopped and the solution was washed with a saturated solution of sodium carbonate. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography eluting with methanol-ethyl acetate (5/95) to give 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoic acid A2 (0.325 g, 18percent). Mp= 220-221 °C, 1H NMR (400 MHz, DMSO-d6) delta 12.18 (bs, 1H), 11.04 (s, 1H), 8.78(s, 1H), 8.21 (m, 2H), 2.69 (t, 2H), 2.52 (m, 2H) ppm. LC-MS (Method B): RT 1.00, 218 (M-H+)

18%

In tetrahydrofuran; at 100℃; for 12h;

[4214-73-7]6-amino-3-pyridinecarbonitrile (commercially available, 1 .0 g, 8.40 mmol) was dissolved in tetrahydrofuran (20 ml_), then succinic anhydride (1 .04 g, 10.5 mmol) was added. The mixture was stirred at 100 °C for 12 hours. The reaction was stopped and the solution washed with a saturated solution of sodium carbonate. The organic layer was concentrated under vaccum. The residue was purified by flash chromatography eluting with methanol-ethyl acetate (5/95) to give 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoic acid (12.4) (0.325 g, 18percent). M.p. = 220-221 °C, 1H N MR (400 MHz, DMSO-d6) delta : 12.18 (bs, 1 H), 1 1 .04 (s, 1 H), 8.78(s, 1 H), 8.21 (m, 2H), 2.69 (t, 2H), 2.52 (m, 2H) ppm. LC-MS (Method B): RT 1.00, 218 (M-H+)

Reference： [1]Patent: WO2013/37755,2013,A1 .Location in patent: Page/Page column 27
[2]Patent: EP2570404,2013,A1 .Location in patent: Paragraph 0080; 0081
[3]Patent: WO2013/164245,2013,A1 .Location in patent: Page/Page column 29; 30
[4]Patent: WO2014/131732,2014,A2 .Location in patent: Page/Page column 33; 34

44
[ 4214-73-7 ]
[ 2058-74-4 ]
[ 1450663-25-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	With 1-butyl-3-methylimidazolium hydroxide; at 20℃; for 3h;	General procedure: Genereal procedure for synthesis of 4a: A mixture of N-methyl-isatin 1 (2.0 mmol), 2-aminopyridine 2a (2.0 mmol) and [bmIm]OH (0.4 mmol) was stirred at room temperature for 2?5 h. After completion of reaction as indicated by TLC, 20 mL of water was added to the reaction mixture and stirred well. The product was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4 to afford the crude product and recrystallized from ethanol to obtain analytically pure compound 4 (75?89percent). After isolation of the product, the remaining aqueous layer containing the ionic liquid was washed with ether (2 × 10 mL) to remove organic impurities and filtered. The filtrate was extracted with dichloromethane (2 × 10 mL), dried over MgSO4 and evaporated under reduced pressure to afford [bmIm]OH, which was recycled twice in subsequent runs without further purification.

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 5083 - 5086

45
[ 4214-73-7 ]
[ 1256790-78-9 ]

Yield	Reaction Conditions	Operation in experiment
34%		A round bottom flask was charged with <strong>[4214-73-7]6-aminonicotinonitrile</strong> (Arborchem, Mechanicsburg, PA, USA) (100 g, 839 mmol), N-chlorosuccinimide (Sigma-Aldrich, St. (0457) Louis, MO, USA) (123 g, 923 mmol), and acetonitrile (2 L). The reaction mixture was heated at 60 °C for 2 hours. After cooling to room temperature, copper (II) bromide (Sigma-Aldrich, St. Louis, MO, USA) (375 g, 1678 mmol) and isoamyl nitrite (Arborchem, Mechanicsburg, PA, USA) (230 mL, 1678 mmol) were added and the mixture was heated to 65 °C for 2 hours. After cooling to room temperature, the mixture was quenched with sat'd aqueous ammonium chloride solution (200 mL) and extracted with DCM (3 x 500 mL). The combined organic solution was dried over MgS04 and concentrated. The residue was purified by silica gel chromatography (10percent EtOAc in hexanes) to provide 8a (63 g, 34percent yield). MS (ESI, positive ion) m/z: no ionization. NMR (400 MHz, Chloroform- ) delta 8.68 - 8.49 (m, 1H), 8.19 - 7.84 (m, 1H).
34%		A round bottom flask was charged with <strong>[4214-73-7]6-aminonicotinonitrile</strong> (Arborchem, Mechanicsburg, PA, USA) (100 g, 839 mmol), N-chlorosuccinimide (Sigma-Aldrich, St. Louis, MO, USA) (123 g, 923 mmol), and acetonitrile (2 L). The reaction mixture was heated at 60 C for 2 h. After cooling to RT, copper (II) bromide (Sigma-Aldrich, St. Louis, MO, USA) (375 g, 1678 mmol) and isoamyl nitrite (Arborchem, Mechanicsburg, PA, USA) (230 mL, 1678 mmol) were added and the mixture was heated to 65 C for 2 h. It was cooled to RT and quenched with sat'd aqueous ammonium chloride solution (200 mL), extracted with DCM (3 x 500 mL). The combined organic solution was dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography (10percent EtOAc in hexanes) to provide 8a (63 g, 34percent yield). MS (ESI, positive ion) m/z: no ionization. 1H NMR (400 MHz, chloroform-d) _ 8.68- 8.49 (m, 1H), 8.19- 7.84 (m, 1H).

Reference： [1]Organic Letters,2014,vol. 16,p. 110 - 113
[2]Patent: WO2018/112084,2018,A1 .Location in patent: Page/Page column 61
[3]Patent: WO2018/112094,2018,A1 .Location in patent: Page/Page column 78
[4]Angewandte Chemie - International Edition,2013,vol. 52,p. 9755 - 9758

46
[ 4214-73-7 ]
[ 1225924-83-3 ]
[ 1586822-52-7 ]

Yield	Reaction Conditions	Operation in experiment
54%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	General procedure: To a stirred solution of the amine (0.169mmol), the carboxylic acid (5?22, 0.154mmol), and with or without DMAP (0.154mmol) in DCM (10mL) at room temperature was added EDCI (0.308mmol). The reaction mixture was stirred overnight and then concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc/hexane) to afford the desired product (23?152, 169, 170, 175, 176).