[ CAS No. 51285-26-8 ] {[proInfo.proName]}

Name: 51285-26-8|Picolinimidamide hydrochloride|97%
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SKU: A146124
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Quality Control of [ 51285-26-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 51285-26-8 ]

Product Details of [ 51285-26-8 ]

CAS No. :	51285-26-8	MDL No. :	MFCD00052271
Formula :	C₆H₈ClN₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GMHCEDDZKAYPLB-UHFFFAOYSA-N
M.W :	157.60	Pubchem ID :	12403615
Synonyms :

Calculated chemistry of [ 51285-26-8 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	42.47
TPSA :	62.76 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.52 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.04
Log Po/w (WLOGP) :	1.17
Log Po/w (MLOGP) :	0.33
Log Po/w (SILICOS-IT) :	0.65
Consensus Log Po/w :	0.64

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.85
Solubility :	2.22 mg/ml ; 0.0141 mol/l
Class :	Very soluble
Log S (Ali) :	-1.95
Solubility :	1.77 mg/ml ; 0.0113 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.71
Solubility :	3.07 mg/ml ; 0.0195 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.41

Safety of [ 51285-26-8 ]

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 [ 51285-26-8 ]

* 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 [ 51285-26-8 ]
Downstream synthetic route of [ 51285-26-8 ]

[ 51285-26-8 ] Synthesis Path-Upstream 1~6

1
[ 51285-26-8 ]
[ 1005-02-3 ]

Reference： [1] Patent: WO2004/5291, 2004, A1, . Location in patent: Page/Page column 42; 43

2
[ 51285-26-8 ]
[ 64264-15-9 ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: With sodium ethanolate In ethanol for 18 h; Heating / reflux Stage #2: With hydrogenchloride In water	2-Pyridin-2-vl-3H-pyrimidin-4-one; Pyridine-2-carboxamidine hydrochloride (1.0 g, 6.5 mmol), sodium (lE)-3-ethoxy-3-oxoprop-l- en-1-olate (3.5 g, 25 mmol) and sodium ethoxide (0.45 g, 6.5 mmol) were added to ethanol (50 mL, 99.5 percent) and the reaction mixture was refluxed under nitrogen atmosphere for 18 h, filtered hot and concentrated. The residue was dissolved in water (20 mL), neutralised with hydrochloric acid (1 M) and purified with reversed phase preparative HPLC This gave 0.68 g (60 percent) of the title compound. 'H NMR (400 MHz, dmso-d6) 8 12.07 (br s, 1 H), 8.73 (m, 1 H), 8.29 (m, 1 H), 8.06-7. 97 (m, 2 H), 7.63 (m, 1 H), 6.34 (d, J=6. 8 Hz, 1 H).

Reference： [1] Patent: WO2005/82884, 2005, A2, . Location in patent: Page/Page column 10
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 9, p. 2467 - 2469

3
[ 100-70-9 ]
[ 51285-26-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: at 20℃; for 22 h; Stage #2: for 6 h;	Compound 1 (26.01) was stirred with sodium methoxide solution at room temperature for 22 hours, then ammonium chloride (28-01) was added for 6 hours, and unreacted ammonium chloride was removed by filtration, The filtrate was spin-dried to remove the methanol solvent to give a pale yellow solid powder which was then washed three times with diethyl ether to remove unreacted compound 1 and recrystallized from a mixed solvent of ethanol-ether to give compound 2 as a white product. Yield: 83percent.
83%	Stage #1: With sodium methylate In methanol at 20℃; for 22 h; Stage #2: With ammonium chloride In methanol at 20℃; for 6 h;	Prepare fresh sodium methoxide solution in a single mouth bottle, anhydrous methanol 20 mL asolution of 50 mg of sodium wire was added with stirring and the mixture was allowed to react completely with sodium, followed by 2-cyanopyridine (2.67 g, 26 mmol) and stirred at room temperature for 22 hours to form a homogeneous solution. After addition of ammonium chloride (1.1 g, 28 mmol), stirring was continued at room temperature for 6 hours. The unreacted ammonium chloride was removed by filtration and the filtrate was spin dried to remove the methanol solvent to give a pale yellow solid which was washed three times with ether to remove unreacted 2-cyanopyridine and recrystallized from ethanol-diethyl ether to give the product Py-NH2 as a white product. Yield: 83percent. ¹H NMR (400MHz, DMSO) δ=9.69(s,4H), 8.85–8.73(m,1H), 8.45(d,J=8.0Hz,1H), 8.14(td,J=7.8,1.7Hz,1H), 7.85–7.71(m,1H). ¹³C NMR(101MHz,DMSO)δ=162.67 ,150.33, 144.37, 138.76, 129.01, 124.00
66%	Stage #1: With sodium methylate In methanol at 20℃; for 24 h; Inert atmosphere Stage #2: With ammonium chloride In methanol at 20℃; for 4 h;	Synthesis of 10-1Step A: Picolinamidine hydrochloride (10-b)To a solution of 2-cyanopyridine (10-a) (Sigma-Aldrich) (lOOg, 0.95mol) in methanol (1.5L) under nitrogen was added sodium methoxide (2.5g, 44mmol). The reaction mixture was stirred at room temperature for 24 hours. Ammonium chloride (53.5g, lmol) was added to the reaction mixture. The mixture was stirred at room temperature for 4h and the solvent was removed in vacuo. The residue was washed with ipropanol/ethyl acetate=l/10 and dried in vacuo to provide compound 10-b (lOOg, 66percent).

66%	Stage #1: With sodium methylate In methanol at 20℃; for 24 h; Inert atmosphere Stage #2: With ammonium chloride In methanol at 20℃; for 4 h;	SSSBLAI Pfco)in3/4mjd_-ne hydrochloride flo-b)To a solution of 2-cyanopyridine (10-a) (Sigma-Aldrich) (lOOg, 0.95mol) in methanol (1.5L) under nitrogen was added sodium methoxide (2.5g, 44mmoJ). The reaction mixture was stirred at room temperature for 24 hours. Ammonium chloride (53.5g, lmol) was added to the reaction mixture. The mixture was stirred at room temperature for 4h and the solvent was removed in vacuo. The residue was washed with ipropanol/ethyl acetate=l/10 and dried in vacuo to provide compound 10-b (lOOg, 66percent).
66%	Stage #1: With sodium methylate In methanol at 20℃; for 24 h; Inert atmosphere Stage #2: With ammonium chloride In methanol at 20℃; for 4 h;	Sodium methoxide (2.5g, 44mmol) was added to a solution of 2-cyanopyridine (lOOg, 0.95mol) in methanol (1.5L) under nitrogen. The reaction mixture was stirred at room temperature for 24 hours. Then ammonium chloride (53.5g, lmol) was added. The mixture was stirred at room temperature for 4h and the solvent was removed in vacuo. The residue was washed with ipropanol/ethyl acetate=l/10 and dried in vacuo to provide the product, 1-1-g, (100g, 66percent).
66%	Stage #1: With sodium methylate In methanol at 20℃; for 24 h; Inert atmosphere Stage #2: With ammonium chloride In methanol at 20℃; for 4 h; Inert atmosphere	Step D: Picolinamidine hydrochloride (1-1-g) Sodium methoxide (2.5g, 44mmol) was added to a solution of 2-cyanopyridine (1 OOg, 0.95mol) in methanol (1.5L) under nitrogen. The reaction mixture was stirred at room temperature for 24 hours. Then ammonium chloride (53.5g, lmol) was added. The mixture was stirred at room temperature for 4h and the solvent was removed in vacuo. The residue was washed with ipropanol/ethyl acetate=l/10 and dried in vacuo to provide the product, 1-1-g, (lOOg, 66percent).
87%	With ammonium chloride; sodium methylate In methanol	EXAMPLE 27 2-Pyridinecarboxamidine hydrochloride To a solution of 2-cyanopyridine (20.0 g, 0.19 mol) in methanol (300 ml) under argon was added sodium methoxide (0.5 g). The reaction mixture was stirred at room temperature for 24 hours, then ammonium chloride (10.7 g, 0.2 mol) was added. The mixture was stirred at room temperature for 3.5 hours and the solvent was removed in vacuo. The residue was diluted with isopropanol (20 ml) and ether (400 ml) and a solid was collected by filtration to afford 28.2 g (87percent) of 2-pyridinecarboxamidine hydrochloride as a white solid, m.p. 141°-142° C. when dried at 40° C. in high vacuum.
3.99 g	Stage #1: With sodium methylate In ethanol at 20℃; for 4 h; Inert atmosphere Stage #2: With ammonium chloride In ethanol for 6 h; Reflux; Inert atmosphere	A mixture of 2-cyanopyridine (3.15 g, 30.3 mmol) and NaOCH3 (0.16 g, 3 mmol) is prepared in 10 mL ethanol and stirred at RT for 4 h under inert atmosphere. After 4 h, NH 4CI (1.81 g,33.8 mmol) is added to the solution. The mixture is refluxed for 6 hours, cooled down and filtered to remove excess salt. Ethanol is removed and a white solid of 2-pyridinecarboximidamide hydrochloride (3.99 g, 25.2 mmol) is obtained.

Reference： [1] Patent: CN105399775, 2016, A, . Location in patent: Paragraph 0026-0028
[2] Patent: CN103936795, 2016, B, . Location in patent: Paragraph 0032-0035
[3] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 9, p. 2600 - 2617
[4] Patent: WO2011/130908, 2011, A1, . Location in patent: Page/Page column 53
[5] Patent: WO2011/133444, 2011, A1, . Location in patent: Page/Page column 52
[6] Patent: WO2013/40790, 2013, A1, . Location in patent: Page/Page column 33; 102; 103
[7] Patent: WO2013/43624, 2013, A1, . Location in patent: Page/Page column 32; 33; 102; 103
[8] Journal of Medicinal Chemistry, 1990, vol. 33, # 4, p. 1230 - 1241
[9] Patent: US5294612, 1994, A,
[10] Journal of Medicinal Chemistry, 2008, vol. 51, # 6, p. 1719 - 1729
[11] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 1, p. 299 - 301
[12] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 1, p. 111 - 118
[13] Dyes and Pigments, 2013, vol. 99, # 1, p. 67 - 73
[14] Patent: KR2015/13888, 2015, A, . Location in patent: Paragraph 0237; 0238; 0239; 0240
[15] Angewandte Chemie - International Edition, 2016, vol. 55, # 34, p. 9947 - 9951[16] Angew. Chem., 2016, vol. 128, p. 10101 - 10105,5
[17] Tetrahedron, 2016, vol. 72, # 50, p. 8335 - 8341

4
[ 19547-38-7 ]
[ 51285-26-8 ]

Reference： [1] Journal of Medicinal Chemistry, 1990, vol. 33, # 4, p. 1230 - 1241
[2] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 3, p. 372 - 375
[3] Dyes and Pigments, 2013, vol. 99, # 1, p. 67 - 73

5
[ 52313-50-5 ]
[ 51285-26-8 ]

Reference： [1] Patent: WO2005/40133, 2005, A1, . Location in patent: Page/Page column 126

6
[ 41050-95-7 ]
[ 51285-26-8 ]

Reference： [1] Patent: WO2005/79798, 2005, A1, . Location in patent: Page/Page column 147

[ 51285-26-8 ] Synthesis Path-Downstream 1~74

1
[ 19547-38-7 ]
[ 51285-26-8 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; at 20℃; for 16h;	Picolinonitrile and sodium methoxide (10:1) resolved in methanol was stirred under nitrogen at room temperature for 12 h. Then, NH4Cl was added. After stirred at room temperature for 16 h, the mixture was heated to reflux for 4 h. The solvent was removed at room temperature by vacuum. The product was washed in ether for many times in order to remove residual NH4Cl. 2-Iminazole pyridine hydrochloride were obtained.

Reference： [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 1230 - 1241
[2]Chemical and Pharmaceutical Bulletin,2007,vol. 55,p. 372 - 375
[3]Dyes and Pigments,2013,vol. 99,p. 67 - 73

2
[ 51285-26-8 ]
sodium (E)-3-ethoxy-3-oxoprop-1-en-1-olate [ No CAS ]
[ 64264-15-9 ]

Yield	Reaction Conditions	Operation in experiment
60%		2-Pyridin-2-vl-3H-pyrimidin-4-one; Pyridine-2-carboxamidine hydrochloride (1.0 g, 6.5 mmol), sodium (lE)-3-ethoxy-3-oxoprop-l- en-1-olate (3.5 g, 25 mmol) and sodium ethoxide (0.45 g, 6.5 mmol) were added to ethanol (50 mL, 99.5 %) and the reaction mixture was refluxed under nitrogen atmosphere for 18 h, filtered hot and concentrated. The residue was dissolved in water (20 mL), neutralised with hydrochloric acid (1 M) and purified with reversed phase preparative HPLC This gave 0.68 g (60 %) of the title compound. 'H NMR (400 MHz, dmso-d6) 8 12.07 (br s, 1 H), 8.73 (m, 1 H), 8.29 (m, 1 H), 8.06-7. 97 (m, 2 H), 7.63 (m, 1 H), 6.34 (d, J=6. 8 Hz, 1 H).

Reference： [1]Patent: WO2005/82884,2005,A2 .Location in patent: Page/Page column 10
[2]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2467 - 2469

3
[ 13134-31-1 ]
[ 51285-26-8 ]
2-pyridin-2-yl-1<i>H</i>-imidazo[4,5-<i>b</i>]pyrazine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 511 - 522

4
[ 13754-19-3 ]
[ 51285-26-8 ]
[ 15846-75-0 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 511 - 522

5
[ 100-70-9 ]
[ 51285-26-8 ]

Yield	Reaction Conditions	Operation in experiment
83%		Compound 1 (26.01) was stirred with sodium methoxide solution at room temperature for 22 hours, then ammonium chloride (28-01) was added for 6 hours, and unreacted ammonium chloride was removed by filtration, The filtrate was spin-dried to remove the methanol solvent to give a pale yellow solid powder which was then washed three times with diethyl ether to remove unreacted compound 1 and recrystallized from a mixed solvent of ethanol-ether to give compound 2 as a white product. Yield: 83%.
83%		Prepare fresh sodium methoxide solution in a single mouth bottle, anhydrous methanol 20 mL asolution of 50 mg of sodium wire was added with stirring and the mixture was allowed to react completely with sodium, followed by 2-cyanopyridine (2.67 g, 26 mmol) and stirred at room temperature for 22 hours to form a homogeneous solution. After addition of ammonium chloride (1.1 g, 28 mmol), stirring was continued at room temperature for 6 hours. The unreacted ammonium chloride was removed by filtration and the filtrate was spin dried to remove the methanol solvent to give a pale yellow solid which was washed three times with ether to remove unreacted 2-cyanopyridine and recrystallized from ethanol-diethyl ether to give the product Py-NH2 as a white product. Yield: 83%. 1H NMR (400MHz, DMSO) delta=9.69(s,4H), 8.85-8.73(m,1H), 8.45(d,J=8.0Hz,1H), 8.14(td,J=7.8,1.7Hz,1H), 7.85-7.71(m,1H). 13C NMR(101MHz,DMSO)delta=162.67 ,150.33, 144.37, 138.76, 129.01, 124.00
66%		Synthesis of 10-1Step A: Picolinamidine hydrochloride (10-b)To a solution of 2-cyanopyridine (10-a) (Sigma-Aldrich) (lOOg, 0.95mol) in methanol (1.5L) under nitrogen was added sodium methoxide (2.5g, 44mmol). The reaction mixture was stirred at room temperature for 24 hours. Ammonium chloride (53.5g, lmol) was added to the reaction mixture. The mixture was stirred at room temperature for 4h and the solvent was removed in vacuo. The residue was washed with ipropanol/ethyl acetate=l/10 and dried in vacuo to provide compound 10-b (lOOg, 66%).

66%		SSSBLAI Pfco)in¾mjd-ne hydrochloride flo-b)To a solution of 2-cyanopyridine (10-a) (Sigma-Aldrich) (lOOg, 0.95mol) in methanol (1.5L) under nitrogen was added sodium methoxide (2.5g, 44mmoJ). The reaction mixture was stirred at room temperature for 24 hours. Ammonium chloride (53.5g, lmol) was added to the reaction mixture. The mixture was stirred at room temperature for 4h and the solvent was removed in vacuo. The residue was washed with ipropanol/ethyl acetate=l/10 and dried in vacuo to provide compound 10-b (lOOg, 66%).
66%		Sodium methoxide (2.5g, 44mmol) was added to a solution of 2-cyanopyridine (lOOg, 0.95mol) in methanol (1.5L) under nitrogen. The reaction mixture was stirred at room temperature for 24 hours. Then ammonium chloride (53.5g, lmol) was added. The mixture was stirred at room temperature for 4h and the solvent was removed in vacuo. The residue was washed with ipropanol/ethyl acetate=l/10 and dried in vacuo to provide the product, 1-1-g, (100g, 66%).
66%		Step D: Picolinamidine hydrochloride (1-1-g) Sodium methoxide (2.5g, 44mmol) was added to a solution of 2-cyanopyridine (1 OOg, 0.95mol) in methanol (1.5L) under nitrogen. The reaction mixture was stirred at room temperature for 24 hours. Then ammonium chloride (53.5g, lmol) was added. The mixture was stirred at room temperature for 4h and the solvent was removed in vacuo. The residue was washed with ipropanol/ethyl acetate=l/10 and dried in vacuo to provide the product, 1-1-g, (lOOg, 66%).
28.2 g (87%)	With ammonium chloride; sodium methylate; In methanol;	EXAMPLE 27 2-Pyridinecarboxamidine hydrochloride To a solution of 2-cyanopyridine (20.0 g, 0.19 mol) in methanol (300 ml) under argon was added sodium methoxide (0.5 g). The reaction mixture was stirred at room temperature for 24 hours, then ammonium chloride (10.7 g, 0.2 mol) was added. The mixture was stirred at room temperature for 3.5 hours and the solvent was removed in vacuo. The residue was diluted with isopropanol (20 ml) and ether (400 ml) and a solid was collected by filtration to afford 28.2 g (87%) of 2-pyridinecarboxamidine hydrochloride as a white solid, m.p. 141-142 C. when dried at 40 C. in high vacuum.
3.99 g		A mixture of 2-cyanopyridine (3.15 g, 30.3 mmol) and NaOCH3 (0.16 g, 3 mmol) is prepared in 10 mL ethanol and stirred at RT for 4 h under inert atmosphere. After 4 h, NH 4CI (1.81 g,33.8 mmol) is added to the solution. The mixture is refluxed for 6 hours, cooled down and filtered to remove excess salt. Ethanol is removed and a white solid of 2-pyridinecarboximidamide hydrochloride (3.99 g, 25.2 mmol) is obtained.
		a. A mixture solution of picolinonitrile (1.0 g, 10 mmol), sodium methoxide (0.05 g, 1 mmol), and methanol (20 mL) was stirred for 10 h at room temperature under nitrogen atmosphere. Then NH4Cl (0.5 g, 10 mmol) be added and reacted other 20 h at room temperature. The mixture was heated to reflux for 4 h. After cooling to room temperature, the mixture was added a lot of diethyl ether and then filtered. The white crystals of pyridine-2-carboximidamide hydrochloride were obtained.

Reference： [1]Patent: CN105399775,2016,A .Location in patent: Paragraph 0026-0028
[2]Patent: CN103936795,2016,B .Location in patent: Paragraph 0032-0035
[3]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 2600 - 2617
[4]Patent: WO2011/130908,2011,A1 .Location in patent: Page/Page column 53
[5]Patent: WO2011/133444,2011,A1 .Location in patent: Page/Page column 52
[6]Patent: WO2013/40790,2013,A1 .Location in patent: Page/Page column 33; 102; 103
[7]Patent: WO2013/43624,2013,A1 .Location in patent: Page/Page column 32; 33; 102; 103
[8]Journal of Medicinal Chemistry,1990,vol. 33,p. 1230 - 1241
[9]Patent: US5294612,1994,A
[10]Journal of Medicinal Chemistry,2008,vol. 51,p. 1719 - 1729
[11]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 299 - 301
[12]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 111 - 118
[13]Dyes and Pigments,2013,vol. 99,p. 67 - 73
[14]Patent: KR2015/13888,2015,A .Location in patent: Paragraph 0237; 0238; 0239; 0240
[15]Angewandte Chemie - International Edition,2016,vol. 55,p. 9947 - 9951
Angew. Chem.,2016,vol. 128,p. 10101 - 10105,5
[16]Tetrahedron,2016,vol. 72,p. 8335 - 8341

6
[ 5652-84-6 ]
[ 51285-26-8 ]
[ 657411-85-3 ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium methylate; In methanol; at 20℃; for 2.33333h;	A solution of 17.0 g (0.32 mol) of sodium methoxide in 60 ml of methanol is added dropwise, at room temperature, to a solution of 50.0 g (0.32 mol) of pyrid-2-ylamidine hydrochloride in 240 ml of methanol. After stirring for 20 minutes, filtration is carried out and the solution is then added dropwise to 31.4 g (0.32 mol) of [METHYL-N-CYANOETHANIMIDATE, WITH] stirring. After stirring for 2 hours at room temperature, cooling to [0C] is carried out and the precipitate is subsequently filtered off. The compound of formula (101) is purified by re-crystallisation from ethanol. Yield: 30. 0 g (50 % of theory) H NMR [(CDC13)] : 7. 35-8. 75 (m, 4H, arom. H), 6.00 (s, 2H, NH2), 2.50 (s, 3H, CH3) ['3C] NMR [(CDCI3)] : [177. 8/171.] 0/167.7 (triazine C's), 153.9/150. [4/137.] 7/126.4/124. 6 (pyridine C's), 26.0 [(CH3)] [M/Z= 187] (GC/MS)

Reference： [1]Patent: WO2004/13124,2004,A1 .Location in patent: Page 11

7
[ 851382-72-4 ]
[ 51285-26-8 ]
4-amino-6-(3-methoxyphenyl)-2-pyridin-2-ylpyrimidine-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In ethanol; at 20℃; for 0.25h;	Step 2: Preparation of 4-amino-6- (3-methoxyphenyl)-2-pyridin- 2-ylpyrimidine-5-carbonitrile NH2 CN N CH3 N N O [00323] I (structure from ChemLink) [00324] To a suspension of pyridine-2-carboximidamide (Example 15, 307 mg, 1.95 mmol) and the product obtained in Step 1 (500 mg, 2.33 mmol) in ethanol (20 mL) was added sodium methoxide (421 mg, 7. 80 mmol) and stirred for 15 min at room temperature. The reaction mixture was then filtered and the remaining solid was washed with a solution of 9: 1 ethanol/water. Purification by preparative HPLC yielded the desired product, a portion of which was then dissolved in DMF and filtered. To the filtrate was added water and the title compound precipitated from solution as a white solid. mp 231-235C.'H NMR (500 MHz, DMSO-d,) : No. 8.74 (d, J = 4.0 Hz, 1 H), 8.55-7. 65 (br s, 2H), 8.40 (d, J = 8.0 Hz, 1 H), 7.98 (dt, J = 3.9, 1.8 Hz, 1 H), 7.57-7. 49 (m, 4H), 7.20-7. 18 (m, 1 H), 3. 85 (s, 3H). ESI MS m/z 304 [M+H] +. Anal. Calcd for C, 7H, 3NsO : C, 67.32 ; H, 4.32 ; N, 23.09. Found: C, 67.24 ; H, 4.12 ; N, 22.82.

Reference： [1]Patent: WO2005/40133,2005,A1 .Location in patent: Page/Page column 130

8
[ 52313-50-5 ]
[ 51285-26-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol;	Example 15: <strong>[52313-50-5]pyridine-2-carboximidamide</strong> [00305] To a slurry of NH, C . (4.62 g, 86.4 mmol) in toluene (34 mL) at 0C was added dropwise a solution of AI (CH3) 3 (7.6 mL, 79.7 mmol) in toluene (32 mL). The reaction mixture was warmed to room temperature and stirred for 2 h prior to the addition of a solution of 2-cyanopyridine (5.0 g, 48.0 mmol) in toluene (15.0 mL). The resulting solution was heated to 80C for 20 h. The cooled reaction mixture was poured into a slurry of silica gel (24.0 g) in CHCI3 (80 mL), followed by vigorous stirring for 10 min. The silica gel was filtered off and the cake was rinsed in turn with methanol and an aqueous solution of 2N NaOH (100 mL). The combined filtrates were extracted with CHCI3 (3 x 300 mL), then concentrated to dryness under reduced pressure, diluted with a small amount of methanol, and treated with a 2N HCI solution in methanol. The precipitate that formed was isolated by filtration and dried in a vacuum oven to afford the title compound as an off-white HCI salt.'H NMR (500 MHz, DMSO- d6) 5 9.66 (s, 2H), 9.52 (s, 2H), 8.85-8. 81 (m, 1 H), 8.37 (d, J = 7.9 Hz, 1 H), 8.17 (td, J= 1.8, 1.6 Hz, 1H), 7.80 (ddd, J= 7.7, 4.7, 0.9 Hz, 1H).

Reference： [1]Patent: WO2005/40133,2005,A1 .Location in patent: Page/Page column 126

9
[ 615-09-8 ]
[ 51285-26-8 ]
[ 856173-46-1 ]

Yield	Reaction Conditions	Operation in experiment
25%	With potassium tert-butylate; In butan-1-ol; at 135℃; for 5h;	To a solution of potassium tertbutoxide (0.87 g, 7. 79 mmol) in butanol (3 ml) were added Intermediate 35 (1.00 g, 5.49 mmol) and pyridine-2-carboxamidine (HCI) (1.08 g, 6.86 mmol). The mixture was heated at 135C for 5 hours. The resulting solid was filtered and washed with n-pentane. Purification by flash chromatography with silica gel and methylene chloride/methanol (from 1% to 3%) as eluent gave 6- (2-furyl)-2-pyridin-2- ylpyrimidin-4-ol (0.33 g, 25%) as an off-white solid. No. (200 MHz, Ceci3) : 6.58 (s, 1H) ; 6.75 (dd, J1=3. 4 Hz, J2=1.7 Hz, 1H) ; 7.39 (d, J=3. 4 Hz, 1H) ; 7.66-7. 72 (m, 1H) ; 7.97 (s, 1H) ; 8.06-8. 14 (m, 1H) ; 8.49 (d, J=7.7 Hz, 1H) ; 8.77 (d, J=4. 7 Hz, 1 H).

Reference： [1]Patent: WO2005/58883,2005,A1 .Location in patent: Page/Page column 95

10
[ 41050-95-7 ]
[ 51285-26-8 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; In ethanol; for 4h;Heating / reflux;	Ethyl 2-pyridylimidate (45g, 0.3 mol) and ammonium chloride (19.3g, 0.36 mol) were suspended in ethanol (150ml) and the mixture was refluxed for 4 hours. After finishing the reaction, the reaction solution was concentrated to about 1/3 of the volume under reduced pressure. The precipitation, formed by adding diethyl ether (100ml) thereto, was filtered, washed with diethyl ether and then with acetone, and dried in a desiccator to obtain 2-amidinopyridine hydrochloride (42.15g).

Reference： [1]Patent: WO2005/79798,2005,A1 .Location in patent: Page/Page column 147

11
[ 905300-62-1 ]
[ 51285-26-8 ]
C₂₀H₁₈ClN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; In water; acetonitrile; at 20℃; for 15h;	Step 3: EXAMPLE 155 ;To a mixture of <strong>[51285-26-8]2-amidinopyridinium hydrochloride</strong> (0.51 g, 3.2 mmol) and potassium carbonate (1.48 g, 10.7 mmol) in 25% aqueous acetonitrile (20 mL) at rt was added a solution of Preparation 26 in acetonitrile (20 mL) and the resulting mixture was stirred at rt for 15 h. The mixture was concentrated on a rotary evaporator to remove the acetonitrile and the mixture was partitioned between methylene chloride (30 mL) and water (15 mL). The separated aqueous portion was extracted with additional methylene chloride (2×10 mL) and the combined organic portions were washed with brine (20 mL), dried over anhyd sodium sulfate, filtered, and concentrated in vacuo to initially give a foam which eventually solidified to afford 1.1 g (99%) of Example 155 as a yellow semi-solid. This material was directly used without any further purificationHPLC Ret. time: 3.66 min. 1H NMR: (d4-MeOH, 400 MHz) delta 8.77 (m, 1H), 8.69 (d, 1H), 8.33 (s, 1H), 8.08 (t, 1H), 7.91 (m, 1H), 7.63 (m, 2H), 7.56 (m, 2H), 1.70 (s, 9H).

Reference： [1]Patent: US2006/178388,2006,A1 .Location in patent: Page/Page column 96-97

12
[ 79424-03-6 ]
[ 51285-26-8 ]
[ 338404-77-6 ]

Yield	Reaction Conditions	Operation in experiment
31.2%	With potassium hydroxide; concentrated aqueous KOH; In ethanol; water;	a. 4-Hydroxy-2-(2-pyridinyl)-6-trifluoromethyl-pyrimidine. To a solution of <strong>[51285-26-8]pyridine-2-carboxamidine hydrochloride</strong> (5.0 g, 33.2 mmol) in 20 ml of water was added concentrated aqueous KOH and the resulting mixture was extracted with ethyl acetate (50 mL3). The extract was evaporated under vacuum to afford 4.0 g of free base. To a solution of the free base and 4,4,4-trifluoro-but-2-ynoic acid ethyl ester (6.0 g, 36 mmol) in ethanol (50 mL) at 0 C.~60 C. was added dropwise potassium hydroxide solution (1.68 g in 40 mL water) in twenty minutes. The solution was then refluxed 2.5 h. The solvent was evaporated under vacuum and the residue was extracted with ethyl acetate (30 ml3). The combined ethyl acetate extracts were dried with sodium sulfate, evaporated to give a solid. It was recrystallized with Hexane/methylene chloride/methanol: 6/211) to give the product as a white solid (2.50 g, 31.2%). 1H NMR (CD3OD): 8.63(d, J=4.8 Hz, 1H), 8.31 (d, J=7.8 Hz, 1H), 7.90 (t, J=7.8 Hz, 1H), 7.49 (m, 1H), 6.73 (s, 1H), 4.76 (s, 1H).

Reference： [1]Patent: US2003/69239,2003,A1

13
(β-dimethylaminovinyl)glyoxal dimethylacetal [ No CAS ]
[ 51285-26-8 ]
4-formyldimethylacetal-2-(2-pyridyl)-pyrimidine [ No CAS ]
[ 124237-06-5 ]

Yield	Reaction Conditions	Operation in experiment
27%	With sodium methylate; sodium; In methanol; dichloromethane;	EXAMPLE 3 4-Formyldimethylacetal-2-(2-pyridyl)-pyrimidine (compound 1.3) A solution of 40 g (0.25 mol) of 2-pyridylamidine hydrochloride in 100 ml of methanol is added to a solution of sodium methylate in methanol, prepared from 7 g (0.3 mol) of sodium and 200 ml of methanol, and stirring is carried out for 10 minutes at room temperature. Thereafter, a solution of 43.9 g (0.25 mol) of (beta-dimethylaminovinyl)glyoxal dimethylacetal in 100 ml of methanol is added dropwise and the mixture is refluxed. for 7 hours. The reaction mixture is then evaporated down under reduced pressure and neutralized with water/acetic acid. Extraction with three times 150 ml of dichloromethane, subsequent washing with water (3*50 ml), drying over sodium sulfate and removal of the solvent by distillation under reduced pressure give the title compound in the form of brownish crystals. Yield: 47% of theory, mp.=42 C. If 6-methyl-2-pyridylamidine hydrochloride is used instead of 2-pyridylamidine hydrochoride and diethoxyacetylacetone instead of (beta-dimethylaminovinyl)glyoxal dimethyl acetal, 4-formyldiethylacetal-6-methyl-2-(6-methyl-2-pyridyl)-pyrimidine (compound 4.3) is obtained in a corresponding manner. A yellow oil which slowly crystallizes on standing is obtained in a yield of 27% of theory. IR: 2975, 1581, 1372, 1112, 1062 cm-1.

Reference： [1]Patent: US5346899,1994,A

14
[ 24310-36-9 ]
[ 51285-26-8 ]
2-(2-Pyridyl)-1,4,5,6-tetrahydro-6-(4-methylbenzenesulfonyl)imidazo[4,5-d][ 1]benzazepine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; bromine; potassium carbonate; In chloroform;	Referential Example 1 2-(2-Pyridyl)-1,4,5,6-tetrahydro-6-(4-methylbenzenesulfonyl)imidazo[4,5-d][ 1]benzazepine In 30 mL of chloroform was dissolved 2.0 g of <strong>[24310-36-9]1,2,3,4-tetrahydro-1-(4-methylbenzenesulfonyl)-1-benzazepin-5-one</strong>, to which was then added dropwise a solution of 0.33 mL of bromine in 10 mL of chloroform. The mixture was stirred at room temperature for one hour. The reaction mixture was rinsed with saturated sodium hydrogencarbonate and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was dissolved in 30 mL of chloroform. To the solution were added 5.0 g of 2-amidinopyridinium hydrochloride hydrate and 5.3 g of potassium carbonate, and the mixture was refluxed upon heating for 10 hours. The reaction mixture was cooled, and the solvent was then distilled off. To the resulting residue was added 30 mL of a 1M hydrochloric acid aqueous solution, and a deposited solid was collected by filtration. The resulting solid was suspended in chloroform and rinsed with a 1M sodium hydroxide aqueous solution, and the chloroform layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was recrystallized from ethanol to obtain 1.70 g of the titled compound. 1H-NMR (DMSO-d6): delta2.12 (3H, s), 3.00 to 3.33 (4H, br), 7.13 (2H, d, J=8.1 Hz), 7.21 (1H, dt, J=1.4 Hz, 8.1 Hz), 7.29 to 7.43 (5H, m), 7.89 (1H, dt, J=1.4 Hz, 8.1 Hz), 8.07 (1H, d, J=8.1 Hz), 8.17 (1H, d, J=7.3 Hz), 8.60 (1H, d, J=4.4 Hz)

Reference： [1]Patent: EP1338597,2003,A1

15
3-amino-3-(6-morpholin-4-yl-pyridin-2-yl)-acrylonitrile [ No CAS ]
[ 51285-26-8 ]
[ 76-05-1 ]
[ 1061748-46-6 ]

Yield	Reaction Conditions	Operation in experiment
		Compound 4-1 : 2-(Pyridin-2-yl)-6-(6-morpholin-4-yl-pyridin-2-yl)-pyrimidin-4-yl- amine; A mixture of Intermediate 9 (230 mg, 1.0 mmol), pyridine-2- carboxamidine hydrochloride (302 mg, 2.0 mmol), sodium ethoxide solution (21 wt %, Aldrich, 0.98 ml, 3.0 mmol), and ethanol (1 ml) was heated with stirring in a microwave reactor at 160 0C for 30 min. Additional sodium ethoxide solution (0.5 ml, 1.5 eq) was added and the mixture was subjected to additional heating in the microwave reactor at 180 0C for 20 min. The solvent was evaporated, then water (2 ml) was added and the mixture was extracted with ethyl acetate. The combined organic extracts were concentrated, then the residue was purified by HPLC to provide the title compound as a TFA salt. LCMS (Method 1) m/z 334.9 [MH+], Tr = 4.17 min. TFA salt

Reference： [1]Patent: WO2008/116185,2008,A2 .Location in patent: Page/Page column 46

16
[ 134653-70-6 ]
[ 51285-26-8 ]
[ 1068974-85-5 ]

Yield	Reaction Conditions	Operation in experiment
88%		Step 2: Na0 (31.7 mmol) is added to anhydrous EtOH (100 mL) and stirred at rt for 15 min. Pyridine -2-carboxamidine hydrochloride (31.7 mmol) is added and the solution is stirred for 15 min. 2-Dimethylaminomethylene-3-oxo-butyric acid ethyl ester (31.7mmol) is added and the reaction mixture is heated at reflux under N2 for 1 h. The reaction is cooled to rt and concentrated in vacuo. The residue is dissolved in EtOAc (200 mL), washed with brine (2x100 mL), dried (Na2SO4), filtered, and concentrated to afford 4-methyl-2-pyridin-2-yl- Pyrimidine-5-carboxylic acid ethyl ester (6.77 g, 88%). MS: 261 (M+H); 1H 1H NMR (300 MHz, CDCl3): delta 1.44 (t, 3H), 2.97 (s, 3H), 4.44 (q, 2H), 7.44 (m, IH), 7.91 (m, IH), 8.60 (m, IH), 8.90 (m, IH), 9.31 (s, IH).

Reference： [1]Patent: WO2008/121670,2008,A1 .Location in patent: Page/Page column 57

17
[ 51285-26-8 ]
[ 141-97-9 ]
[ 55417-80-6 ]

Yield	Reaction Conditions	Operation in experiment
56%	With sodium ethanolate; for 24h;Reflux;	Compound 2 (5 mmol) and ethyl acetoacetate (5 mmol) were heated under reflux with sodium ethoxide over 24 hours,The solvent was removed by spin-drying and the solid was dissolved in 30 mL of deionized water,Adjust the pH value to 4-5, a large number of white solid precipitation,Filtration gave the white solid,And washed three times with ether and water,Compound 3 was obtained as a white solid. Yield: 56%
56%	With sodium alkoxide; In methanol; for 24h;Reflux;	Preparation of sodium methoxide solution, 10 mL of methanol was added 230 mg of sodium wire, stir to dissolve, Py-NH2605.3 mg (5 mmol) was added, ethyl acetoacetate 650.7mg (5mmol) was heated under reflux for 24 hours. The reaction was completed, the solvent was removed by dry-drying and the solid was dissolved in 30 mL of deionized water. The pH was adjusted to 4-5 with hydrochloric acid. A large amount of white solid was precipitated, washed with ether and water three times to give a white solid bpy-OH compound. Yield: 56%. 1H NMR (400MHz,DMSO) delta=11.89(s,1H), 8.69(d,J=4.4Hz,1H), 8.25(d,J=7.9Hz,1H), 8.00(td,J=7.8,1.2Hz,1H), 7.60(dd,J=6.9,5.1Hz,1H), 6.25(s,1H),2.26(s,3H).

Reference： [1]Patent: CN105399775,2016,A .Location in patent: Paragraph 0026; 0029; 0030
[2]Patent: CN103936795,2016,B .Location in patent: Paragraph 0032; 0036-0038
[3]Patent: EP1254903,2002,A1 .Location in patent: Page 14
[4]Angewandte Chemie - International Edition,2016,vol. 55,p. 9947 - 9951
Angew. Chem.,2016,vol. 128,p. 10101 - 10105,5

18
[ 51285-26-8 ]
[ 594-42-3 ]
[ 887623-91-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In dichloromethane; water; at 5℃; for 1.5h;	To solution of picolinamidine hydrochloride (1.97 g, 12.5 mmol) in CH2Cl2 (10 ml) was added trichloromethyl hypochlorothioite (1.45 ml, 13.3 mmol). The reaction mixture was cooled to 50C and a solution of sodium hydroxide (2.50 g, 62.5 mmol) in water (4 mL) was added by slow dropwise addition. The reaction mixture was stirred for 1.5 h at 5C. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (6 x 30 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated. Purification by chromatography on silica (eluted with 0% to 25% EtOAc in hexanes) gave tert- butyl 3-bromo-l,2,4-thiadiazol-5-ylcarbamate. Purification chromatography on silica (eluted with 0 -> 10% MeOHVCH2Cl2 + 0 -> 1% NH4OH) gave 2-(5-chloro-l ,2,4-thiadiazol-3- yl)pyridine.

Reference： [1]Patent: WO2009/9122,2009,A2 .Location in patent: Page/Page column 38

19
[ 51285-26-8 ]
[ 607-81-8 ]
[ 863766-13-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a suspension of 2-amidinopyridinehydrochloride (25g, O. lmol) and ethanol, 28% methanol solution of sodium methoxide (60g, 0. 31 mol) was added under ice cooling and, after stirring the mixture for 15 minutes under continuous ice cooling, diethyl benzylmalonate (100g, 0. 4mol) was added thereto. After stirring the mixture for 1.5 hours under ice cooling and for 1 hour at room temperature, it was refluxed for 4 hours. After finishing the reaction, the precipitation, formed by adding concentrated hydrochloric acid (32g) under ice cooling, was filtered, washed with ethanol and then with diethyl ether, and dried in a desiccator to obtain 5-benzyl-2-pyridin-2-yl-lH-pyrimidine-4, 6-dione hydrochloride (38.7g) which was used in the next reaction without purification.

Reference： [1]Patent: WO2005/79798,2005,A1 .Location in patent: Page/Page column 148

20
[ 51285-26-8 ]
[ 56893-25-5 ]
[ 1201802-45-0 ]

Yield	Reaction Conditions	Operation in experiment
		2-Pyridinecarboxirmdamide HCl salt (11.7 g, 74.3 mmol) and sodium bicarbonate(13.7 g, 163 mmol) were suspended in 100 mL of THF and 30 mL of water. The suspension was heated to reflux, to which was slowly added <strong>[56893-25-5]methyl 4-(bromoacetyl)benzoate</strong> (Intermediate 6, 21 g, 82 mmol) in 70 mL of THF over 4 h. The reflux was continued overnight. The reaction mixture was cooled to rt, partially concentrated, and cooled with an ice-water bath. The precipitate was collected by filtration, rinsed with two 50-mL portions of water, and air-dried to provide the desired product. LCMS: 280 [M+l].

Reference： [1]Patent: WO2009/152025,2009,A1 .Location in patent: Page/Page column 31

21
[ 51285-26-8 ]
[ 289-96-3 ]
[ 10198-83-1 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 2492 - 2494

22
[ 51285-26-8 ]
[ 87-13-8 ]
[ 56406-45-2 ]

Yield	Reaction Conditions	Operation in experiment
65%		Step B: 4-hvdroxy-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid (10-c)To picolinamidine hydrochloride (10-b) (1 12 g, 0.71mol) in MeOH (1.1L) was added sodium methoxide (39.4g, 0.7 lmol) and diethyl ethoxymethylenemalonate (2-b) (142g, 0.71 mol). The reaction was heated at reflux overnight and then cooled to room temperature. The resulting mixture was filtered and to the filtrate was added potassium hydroxide (71.4 g, 1.37 mol) in water (265 mL). The reaction was heated at reflux for 2h. The reaction mixture was cooled to room temperature before adding cone. HC1 (37 %, 180 mL, 2.35 mol) in portions. The reaction aged for 2 h. The solids were filtered and rinsed with EtOH, Et20 and then hexane to provide compound 10-c (1 lOg, 65%).
65%		Step B: 4-hvdroiY-2 Dvridiji-2-vnDvrimidine-5-carhoxvlic acid (10-c)To picolinamidine hydrochloride (10-b) (112 g, 0.71mol) in MeOH (1.1L) was added sodium methoxide (39.4g, 0.7 lmol) and diethyl ethoxymethylenemalonate (2-b) (142g, 0.71 mol). The reaction was heated at reflux overnight and then cooled to room temperature. The resulting mixture was filtered and to the filtrate was added potassium hydroxide (71.4 g, 1.37 mol) in water (265 mL). The reaction was heated at reflux for 2h. The reaction mixture was cooled to room temperature before adding cone. HC1 (37 %, 180 mL, 2.35 mol) in portions. The reaction aged for 2 h. The solids were filtered and rinsed with EtOH, Et20 and then hexane to provide compound 10-c (HOg, 65%).
65%	With sodium methylate; In methanol;Reflux;	To picolinamidine hydrochloride (1-1-g) (112 g, 0.71mol) in MeOH (1.1L) was added sodium methoxide (39.4g, 0.71mol) and diethyl ethoxymethylenemalonate (142g,0.7 lmol). The reaction mixture was heated at reflux overnight and then cooled to roomtemperature. The resulting mixture was filtered and to the filtrate was added potassium hydroxide (71.4 g, 1.37mol) in water (265 mL). The reaction was heated at reflux for 2h. The reaction was cooled to room temperature before adding concentrated HCl (180mL, 2.35mol) in portions. The reaction was aged for 2 h. The solids were filtered and rinsed with EtOH, Et20 and then hexane to provide the product, 1-1-h, (110g, 65%)

65%

Step E: 4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid (1-1-h) To picolinamidine hydrochloride (1-1-g) (1 12 g, 0.71mol) in MeOH (1.1L) was added sodium methoxide (39.4g, 0.71mol) and diethyl ethoxymethylenemalonate (142g, 0.71mol). The reaction mixture was heated at reflux overnight and then cooled to room temperature. The resulting mixture was filtered and to the filtrate was added potassium hydroxide (71.4 g, 1.37mol) in water (265 mL). The reaction was heated at reflux for 2h. The reaction was cooled to room temperature before adding concentrated HC1 (180mL, 2.35mol) in portions. The reaction was aged for 2 h. The solids were filtered and rinsed with EtOH, Et20 and then hexane to provide the product, 1-1-h, (1 lOg,

Reference： [1]Patent: WO2011/130908,2011,A1 .Location in patent: Page/Page column 53
[2]Patent: WO2011/133444,2011,A1 .Location in patent: Page/Page column 52
[3]Patent: WO2013/40790,2013,A1 .Location in patent: Page/Page column 33
[4]Patent: WO2013/43624,2013,A1 .Location in patent: Page/Page column 32; 33

23
C₁₂H₉Cl₂FO₃ [ No CAS ]
[ 51285-26-8 ]
[ 1078164-75-6 ]

Yield	Reaction Conditions	Operation in experiment
50%		To a solution of A (3.8 g, 13.2 mmol) in i-PrOH (30 mL) was added 2-amidinopyridinium chloride (2 g, 12.4 mmol) and sodium acetate (123 mg, 1.50 mmol). The mixture was heated at reflux for 12 h, and was then cooled, evaporated, and dissolved in a 1: 1 mixture of 0.5 M HCl (aq)/EtOAc (60 mL). The organic layer was extracted with 1 M HCl (20 mL). The combined aqueous layers were washed with ether, rendered basic with ammonia solution (36 wt%), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2S04, and evaporated. The product was purified by column chromatography (1:5 EtOAc/ hexane) to give B (2.6 g, 50%) as a yellow solid. MS (M+H+, m/z) 394.
50%	With sodium acetate; In isopropyl alcohol; for 12h;Reflux;	Compound B. To a solution of A (3.8 g, 13.2 mmol) in i-PrOH (30 mL) was added 2-amidinopyridinium chloride (2 g, 12.4 mmol) and sodium acetate (123 mg, 1.50 mmol). The mixture was heated at reflux for 12 h, and was then cooled, evaporated, and dissolved in a 1: 1 mixture of 0.5 M HCl (aq)/EtOAc (60 mL). The organic layer was extracted with 1 M HCl (20 mL). The combined aqueous layers were washed with ether, rendered basic with ammonia solution (36 wt%), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2S04, and evaporated. The product was purified by column chromatography (1:5 EtOAc/ hexane) to give B (2.6 g, 50%) as a yellow solid. MS (M+H+, m/z) 394.

Reference： [1]Patent: WO2013/19967,2013,A1 .Location in patent: Page/Page column 33; 34
[2]Patent: WO2014/74906,2014,A1 .Location in patent: Page/Page column 29

24
[ 226990-49-4 ]
[ 51285-26-8 ]
[ 1428527-76-7 ]

Yield	Reaction Conditions	Operation in experiment
39%	With triethylamine; In methanol; at 20℃;	A mixture of compound 37-b (15 g, 71 mmol), compound 37-h (12.2 g, 77.8 mmol), triethylamine (21.4 g, 212 mmol) in methanol (200 mL) was stirred overnight at room temperature. The residue obtained from removal of the solvent was purified by flashchromatography (DCM) to afford compound 37-i (7.5 g, 39%) as a yellow solid. 1H NMR (300 MHz, CDCI3) delta 8.668-8.649 (m, 1H), 8.428-8.395 (m, 1H), 8.257 (s, 1H), 7.937-7.880 (m, 1H), 7.517-7.471 (m, 1H), 0.285 (s, 9H). LC-MS (ESI): 270 [M+H]+
39%	With triethylamine; In methanol; at 20℃;	Step F: 2-(Pyridin-2-yl)-5-((trimethylsilyl)ethvnyl)pyrimidin-4-ol (37-i) A mixture of compound 37-b (15 g, 71 mmol), compound 37-h (12.2 g, 77.8 mmol), triethylamine (21.4 g, 212 mmol) in methanol (200 mL) was stirred overnight at room temperature. The residue obtained from removal of the solvent was purified by flash chromatography (DCM) to afford compound 37-i (7.5 g, 39%) as a yellow solid. 1H NMR (300 MHz, CDCI3) delta 8.668-8.649 (m, 1H), 8.428-8.395 (m, 1H), 8.257 (s, 1H), 7.937-7.880 (m, 1H), 7.517-7.471 (m, 1H), 0.285 (s, 9H). LC-MS (ESI): 270 [M+H]+

Reference： [1]Patent: WO2013/40790,2013,A1 .Location in patent: Page/Page column 104
[2]Patent: WO2013/43624,2013,A1 .Location in patent: Page/Page column 104

25
[ 1446678-39-2 ]
[ 51285-26-8 ]
[ 1446678-41-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In N,N-dimethyl-formamide; at 75℃; for 1h;Sealed tube;	Compound 44 Compound 43a (crude mixture, 3 g, 11.14 mmol), <strong>[51285-26-8]pyridine-2-carboximidamide hydrochloride</strong> (1.93 g, 12.25 mmol), Na2C03 (1.77 g, 16.7 mmol) and DMF (13.6 mL) were heated in a pressure tube in an oil bath at 75C for 1 hour. The resulting reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residu was taken up in water-CH2Cl2 (150 mL/150 mL) and the water layerwas extracted with CH2C12 (2 x 100 mL). The combined extracts were washed with brine, dried (MgS04), filtered and concentrated in vacuo. The obtained residue was chromatographed by silica gel column chromatography (isocratic CH2C12) The desired fractions were concentrated in vacuo yielding compound 44, which was used as such. Method A; Rt: 1.09 min. m/z : 345.4 (M+H)+ Exact mass: 344.2;

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 56

26
[ 1446680-56-3 ]
[ 51285-26-8 ]
[ 1446678-43-8 ]

Yield	Reaction Conditions	Operation in experiment
4.7 g	With potassium acetate; In N,N-dimethyl-formamide; at 110℃; for 1h;Sealed tube;	Compound 45 Procedure D: Compound 43b (9.4 g, 36.3 mmol), <strong>[51285-26-8]pyridine-2-carboximidamide hydrochloride</strong> (6.86 g, 43.5 mmol), KOAc (5.34 g, 54.4 mmol) and DMF (87 mL) were heated in a pressure tube to 110C for 1 hour. The resulting reaction mixture was cooled to room temperature and concentrated in vacuo. The residu was taken up in water-CH2Cl2 (150 mL-150 mL). The water layer was extracted twice (CH2C12, 2 x 100 mL) and the combined extracts were washed with brine, dried (MgS04), filtered and concentrated in vacuo yielding a brown oil. This oil was purified by silicagel column chromatography (gradient elution: EtO Ac-heptane 1 :9 to 3:7) yielding compound 45 (4.7 g) which was used as such. Method E; Rt: 0.95 min. m/z : 335.1 (M+H)+ Exact mass: 334.1;

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 56

27
[ 1023289-76-0 ]
[ 51285-26-8 ]
[ 1446678-89-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In N,N-dimethyl-formamide; at 70℃; for 1h;Sealed tube;	Compound 67 Starting from Compound 43e using procedure D, using Na2C03 instead of KOAc, heating at 70C for 1 hour instead of 110C for 1 hour. Purificiation was performed using silica gel column chromatography with CH2C12 as eluent.

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 65

28
[ 10425-82-8 ]
[ 51285-26-8 ]
[ 1446679-03-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In N,N-dimethyl-formamide; at 75℃; for 2h;Sealed tube;	Compound 75 Prepared starting from Compound 43f according to procedure D, using Na2C03 instead of KOAc, heating at 75C for 2 hours instead of 110C for 1 hour. Purification was performed using silica gel column chromatography with CH2C12 as eluent.

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 68

29
[ 51285-26-8 ]
[ 31541-55-6 ]
[ 1446679-10-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 70℃; for 3h;Sealed tube;	compound 82 Prepared according to procedure D, heating at 70C for 3 hours using sodium bicarbonate (6 equiv) instead of KOAc, starting from compound 43g, purification by silicagel column chromatography (gradient elution: CH2Cl2-MeOH 100:0- > 98:2). Method A; Rt: 0.86 min. m/z : 319.1 (M+H)+ Exact mass:318.1 ;

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 71

30
potassium (morpholin-4-yl)methyltrifluoroborate [ No CAS ]
[ 1446677-76-4 ]
[ 51285-26-8 ]
[ 1446677-78-6 ]

Yield	Reaction Conditions	Operation in experiment
59 mg		Compound 13 To <strong>[51285-26-8]pyridine-2-carboximidamide hydrochloride</strong> (0.813 g, 5.16 mmol), Dimethyl- formamide (22 mL, 281 mmol) and sodium carbonate (0.994 g, 9.38 mmol) under nitrogen atmosphere and the reaction mixture was stirred for 5 minutes. Then compound 12 (1.26 g, 4.69 mmol) was added and the reaction mixture was heated and stirred at 60C for 90 hours and sonicated and the suspension was brought over into a 50 mL round bottomed flask and stirred 18 hours at 68C and allowed to come to room temperature. The reaction mixture was poured onto ice water and stirred for 30 minutes. Extracted with diisopropyl ether (3 x 50 mL). The combined organic extracts were dried (Na2S04), and concentrated under reduced pressure to afford a sticky oil which was purified using silica gel column chromatography (gradient elution, 30-100%) dichloromethane in heptane)The desired fractions were collected and concentrated in vacuo resulting in a residue (356 mg). This residue (356 mg, 0.995 mmol) was dissolved in phosphorous oxychloride (1.61 mL, 22.4 mmol) and heated at 120C for 1 hour. The reaction mixture was concentrated to dryness using a nitrogen flow, overnight at 40C. The obtained residue was dissolved in dichloromethane and washed with aqueous saturated sodium bicarbonate, brine, dried (Na2S04) and evaporated to dryness resulting in a residue (219 mg) as a dark brown sticky oil which was used as such in the next step. A 10 mL microwave tube was loaded with a stirring bar, potassium (morpholin-4-yl) methyltrifluoroborate (254 mg, 1.16 mmol), the above obtained residue (219 mg), distilled water (315 mu, 17.5 mmol) and 1 ,2-dimethoxy- ethane (3 mL). Nitrogen gas was bubbled through during 10 minutes. Under nitrogen atmosphere cesium carbonate (1.14 g, 3.49 mmol), palladium (II) acetate (13.2 mg, 0.0582 mmol)and butyldi-l-adamantylphosphine (33.4 mg, 0.0931 mmol) were added and the reaction mixture was stirred at 140C for 10 minutes in microwave oven under nitrogen atmosphere. The product was extracted with dichloromethane and the organic layers were combined, dried (Na2S04) and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient elution, 5 to 100% ethyl acetate in heptane) resulting in compound 13 (59 mg) as a white powder . Method A; Rt: 1.17 min. m/z : 441.5 (M+H)+ Exact mass: 440.2

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 34-35

31
[ 1446678-77-8 ]
[ 51285-26-8 ]
[ 1446678-79-0 ]

Yield	Reaction Conditions	Operation in experiment
430 mg		Compound 63 Under a nitrogen atmosphere, a round bottom flak was charged with a magnetic stirring bar, <strong>[51285-26-8]pyridine-2-carboximidamide hydrochloride</strong> (9.50 g, 60.3 mmol), N,N-Dimethyl- formamide (120 mL) and sodium carbonate (12.8 g, 121 mmol). The reaction mixture was stirred for 10 minutes at room temperature. Compound 62 ( 8.81 g, 30.1 mmol) was added, the reaction mixture was sealed with a rubber septum and heated at 70C for 17 hours. After cooling to roomtemperature, the reaction mixture was poured into ice water (300 mL) and extracted with diisopropyl ether (3 x 200 mL). The combined organic extracts were dried (Na2S04) and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate in heptane in a gradient from 0 to 100 %. The desired fractions were concentrated in vacuo and the residue was purified using silica gel column chromatography with ethyl acetate in heptane 30 %. The desired fractions were concentrated in vacuo and the residue was purified using silica gel column chromatography with dichloromethane 100% resulting in compound 63 (430 mg)

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 63

32
[ 1268340-94-8 ]
[ 1446679-31-7 ]
[ 51285-26-8 ]
[ 1446679-52-2 ]

Yield	Reaction Conditions	Operation in experiment
35 mg		Compound 103 (245 mg; 0.761 mmol), 2-amidinopyridiniumchloride (240 mg; 1.52 mmol), sodium bicarbonate (340 mg, 4.05 mmol) in DMF was stirred and heated for 2 hours at 80C. The mixture was cooled to room temperature, diluted with Et20 and H20 and extracted with Et20. The combined organic phases where dried on Na2S04. After filtration and evaporation of the solvent, the obtained residue (239 mg) was stirred at 90C for 2.5 hours in POCl3 (5 mL). The volatiles were removed in vacuo, the obtained residue was dissolved in CH2C12 and stirred with saturated NaHC03 for 30 minutes. The mixture was extracted with CH2C12, dried on Na2S04, and after filtration the solvent was removed. The black residue was dissolved in CH2C12 and filtered on a path of silica. After rincing with CH2C12 the solvent was removed, resulting in a slightly yellow residue. This residue was stirred in a mixture of ethylene glycol dimethylether (5 mL), water (0.26 mL), morpholin-4-yl)methyltrifluoroborate internal salt (70 mg, 0.41 mmol) and K2CO3 (79 mg; 0.57 mmol). Nitrogen was bubbled through the mixture for 10 minutes and then bis(tri-t-Butylphosphine)palladium(0) (40.7 mg, 0.08 mmol) was added. The mixture was heated under microwave irradiation for 15 minutes at 140C. CH2CI2 was added, the mixture was washed with H20, and the water layer was extracted with CH2CI2. The organic layer was dried on Na2S04, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography with heptane to heptane/EtOAc 50/50, resulting in compound 124 (35 mg). Method E; Rt: 1.13 m/z : 457.2 (M+H)+ Exact mass:456.2

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 92-93

33
[ 1446680-59-6 ]
[ 51285-26-8 ]
[ 1446679-22-6 ]

Yield	Reaction Conditions	Operation in experiment
254 mg	With sodium carbonate; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;	compound 94 A mixture of dimethyl 2-(6-fluoro-2,3-dihydro-lH-inden-l-ylidene)malonate (2 g, 7.57 mmol; Prepared from 6-fluoro-l-indanone and dimethylmalonate similar as exemplified for compound 62), <strong>[51285-26-8]pyridine-2-carboxamidine hydrochloride</strong> (1.63 g, 10.3 mmol) and Na2C03 (2.17 g, 20.5 mmol) in DMF (20 mL) was stirred overnight at 60C under nitrogen atmosphere. The solvent was removed in vacuo. The residue was suspended in dichloromethane (100 mL) and the formed precipitate was filtered off. The filtrate, after concentration in vacuo, was purified using silica gel column chromatography twice. (Gradient: ethyl acetate in heptane from 0 to 40 %) and next methanol in CH2C12 from 0 to 2 %) to afford compound 94 (254 mg) which was used as such in the next step. Method A; Rt: 1.00 m/z : 354.1 (M+H)+ Exact mass: 353.1

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 77

34
[ 1446679-35-1 ]
[ 51285-26-8 ]
[ 1446679-36-2 ]

Yield	Reaction Conditions	Operation in experiment
3.83 g	With sodium hydrogencarbonate; In 1,4-dioxane; at 120℃; for 5h;	A mixture of compound 107 (6.8 g), 2-amidinopyridiniumchloride (3.35g; 21.3 mmol), and sodium bicarbonate (7.15g)) in dioxane (100 mL) were stirred and heated 5 hours at 120C. The reaction mixture was filtrated while still warm and the filtrate was concentrated in vacuo. The obtained residue was purified by column chromatography on silica using a gradient elution from 5 to 100% EtOAc in heptane. The product fractions were combined, concentrated and dried overnight in vacuo yielding compound 108 (diastereomeric mixture; 3.83 g) as a white powder. Method A; Rt: 1.00 and 1.03 m/z : 372.1 (M+H)+ Exact mass: 371.1.

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 84-85

35
[ 1446679-63-5 ]
[ 51285-26-8 ]
[ 1446679-64-6 ]

Yield	Reaction Conditions	Operation in experiment
2.5 g	With sodium carbonate; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;	6 A mixture of compound 135 (6 g, 22.7 mmol), 2-amidinopyridiniumchloride (5.3 g, 33.6 mmol) and Na2C03 (7.2 g, 67.9 mmol) in DMF (60 mL) was stirred overnight at 60C under N2. The solvent was removed in vacuo. The residue was suspended in dichloromethane (100 mL). The precipitate was filtered off. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography. (Gradient eluent: petroleum ether: ethyl acetate: from 100:0 to 60:40), resulting in compound 136 (2.5 g) Method B; Rt: 1.04 m/z : 353.9 (M+H)+ Exact mass: 353.1.

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 100

36
[ 1446679-63-5 ]
[ 51285-26-8 ]
[ 1446680-61-0 ]

Yield	Reaction Conditions	Operation in experiment
0.4 g		Compound 145 A mixture of compound 135 (12.5 g, 47.3 mmol), NBS (9.3 g, 52.3 mmol) and Benzoyl Peroxide (12 mg, 0.05 mmol) in CC14 (120 mL) was stirred overnight at 80C under N2. The solvent was removed in vacuo. The residue was purified by silica gel chromatography, (gradient eluent: petroleum ether: ethyl acetate: from 200: 1 to 100: 1) resulting in a monobrominated derivative of compound 135 (7.2 g). A mixture of above obtained monobrominated derivative of compound 135 (3.6 g, 10.5 mmol), pyridine-2- carboximidamide hydrochloride (2.5 g, 16.0 mmol) and Na2C03 (3.38 g, 31.9 mmol) in DMF (60 mL) was stirred for 4 hours at 90C under N2. The solvent was removed in vacuo. The residue was suspended in dichloromethane (100 mL). The precipitate was filtered and the obtained filtrate concentrated in vacuo. The resulting residue was purified by silica gel column chromatography. (Gradient eluent: petroleum ether: ethyl acetate: from 50: 1 to 1 :5) resulting in methyl 5-fiuoro-6'-oxo-2'-(pyridin-2-yl)-5',6'- dihydro- H-spiro[indene-l,4'-pyrimidine]-5'-carboxylate (0.4 g). methyl 5-fluoro-6'- oxo-2'-(pyridin-2-yl)-56'-dihydro-lH-spiro[indene-l,4'-pyrimidine]-5'-carboxylate (0.6 g, 1.71 mmol) in POCl3 (10 mL, 105.7 mmol) was stirred for 2 hours at 120C. The reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane (10 mL). The organic layer was washed with saturated aqueous NaHC03 (3 x 30 mL) and brine and dried over Na2S04. The solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (gradient eluent: petroleum ether: ethyl acetate: from 100:0 to 70:30) resulting in methyl 6'-chloro-5-fluoro-2'-(pyridin-2-yl)- 1 'H-spiro[indene- 1 ,4'-pyrimidine]-5'- carboxylate (0.07 g). A mixture of methyl 6'-chloro-5-fluoro-2'-(pyridin-2-yl)- H- spiro[indene-l,4'-pyrimidine]-5'-carboxylate (75 mg, 0.2 mmol), potassium (morpholin-4-yl)methyltrifluoroborate (84 mg, 0.41 mmol), Pd(OAc)2 (45 mg, 0.2 mmol), butyldi-l-adamantyl-phosphine (11 mg, 0.033 mmol) and Cs2C03 (390 mg, 1.20 mmol) in DME (1.4 mL) and H20 (0.14 mL) was heated by microwave irradiation for 20 minutes at 140C under N2 atmosphere. Water (5 mL) and dichloromethane (5 mL) were added. The organic layer was separated and washed with water (2 x 5 mL). The organic layer was exctraced with IN HC1 (5 mL). The aqueous layer was washed with dichloromethane (2 x 5 mL) and basified with NaHC03 to pH=7~8. The mixture was extracted with dichloromethane (15 mL). The organic layer was washed with brine and dried over Na2S04. The solvent was removed in vacuo, resulting in compound 145 (12 mg). Method H; Rt: 3.29 m/z; 435.2 (M+H)+ Exact mass: 434.2. 1H NMR (400 MHz, CHLOROFORM- ) delta ppm 10.22 (1 H, br. s), 8.61 (1 H, d, J=4.5 Hz), 8.14 (1 H, d, J=8.0 Hz), 7.71 (1 H, td, J=7.5, 1.5 Hz), 7.36 (1 H, ddd, J=7.5, 5.0, 1.5 Hz), 7.19 (1 H, dd, J=8.0, 5.5 Hz), 6.97 (1 H, dd, J=8.8, 2.5 Hz), 6.81 (1 H, ddd, J=10.0, 8.0, 2.0 Hz), 6.65 (1 H, d, J=5.5 Hz), 6.54 (1 H, d, J=5.5 Hz), 3.82 - 3.89 (4 H, m), 3.81 (1 H, d, J=16.5 Hz), 3.73 (1 H, d, J=16.5 Hz), 3.33 (3 H, s), 2.57 - 2.71 (4 H, m).

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 104-105

37
[ 1446680-63-2 ]
[ 51285-26-8 ]
[ 1446680-64-3 ]

Yield	Reaction Conditions	Operation in experiment
1.5 g	With sodium carbonate; In 1,2-dichloro-ethane; at 80℃; for 12h;Molecular sieve; Inert atmosphere;	Compound 146 To the solution of 5-fluoro-3-methyl-2,3-dihydro-lH-inden-l-one (24 g, 146 mmol), and dimethyl malonate (57.9 g, 439 mmol) in CH2C12 (500 mL) and THF (500 mL) TiCLt (54.7 g, 292 mmol) was added dropwise at -40 C. The reaction mixture was stirred for 30 minutes at -40 C. Pyridine (57 g, 731 mmol) was added dropwise at -40 C. The reaction mixture was stirred for 12 hours at room temperature. The solid was filtered off and the filtrate was concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate=5: l), resulting in dimethyl 2-(5-fluoro-3-methyl-2,3-dihydro-lH-inden-l-ylidene)malonate (9.5 g). The mixture of dimethyl 2-(5-fluoro-3-methyl-2,3-dihydro-lH-inden-l-ylidene)malonate (9.2 g, 33.09 mmol), pyridine-2-carboximidamide (12 g, 99.2 mmol), Na2C03 (10.5 g, 99.2 mmol) and 4A molecular sieves (10 g) in CICH2CH2CI (50 mL) was stirred for 12 hours at 80 C under nitrogen atmosphere. The solvent was removed in vacuo and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate=l :1) resulting in methyl 5-fluoro-3-methyl-6'-oxo-2'-(pyridin-2-yl)-2,3,5',6'- tetrahydro- H-spiro[indene-l,4'-pyrimidine]-5'-carboxylate (1.5 g). The mixture of methyl 5-fluoro-3-methyl-6'-oxo-2'-(pyridin-2-yl)-2,3,5',6'-tetrahydro- H- spiro[indene-l,4'-pyrimidine]-5'-carboxylate (1 g, 2.74 mmol) and POCI3 (10 mL) was stirred for 5 hour under reflux. When the reaction was completed, the mixture was poured onto ice-water (20mL) and extracted with ethyl acetate (3 x 10 mL). The combined layers were dried and concentrated to dryness. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate=l : 1), resulting in methyl 6'-chloro-5-fluoro-3-methyl-2'-(pyridin-2-yl)-2,3-dihydro- 1 'H-spiro[indene- 1 ,4'- pyrimidine]-5'-carboxylate (0.42 g). The mixture of methyl 6'-chloro-5-fluoro-3- methyl-2'-(pyridin-2-yl)-2,3-dihydro-lH-spiro[indene-l,4'-pyrimidine]-5'-carboxylate (400 mg, 1.03 mmol), Pd(OAc)2 (22 mg, 0.10 mmol), butyldi-l-adamanty-lphosphine (35.8 mg, 0.103 mmol), potassium (morpholin-4-yl)methyltrifluoroborate (256 mg, 1.23 mmol), Cs2C03 (669 mg, 2.06 mmol), DME (10 mL) and H20 (1 mL) was stirred for 50 minutes under microwave irradiation at 140 C. The reaction mixture was concentrated in vacuo and the obtained residue was dissolved in ethyl acetate and washed with brine (2 x 10 mL). The organic layer was concentrated to dryness. The crude product was purified by preparative high-performance chromatography (eluent: CH3CN/ H20= 30/70 to 80/ 20, 0.1% CF3COOH). The desired fraction was collected and the pH value of the solution was adjusted to about 8 with K2C03. Then, the organic solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined and dried over Na2S04. The solution was evaporated and the pure product was dried in vacuo resulting in compound 146 (60 mg, 7/3 diastereomeric mixture). Method J; Rt: 6.44 m/z; 451.2 (M+H)+ Exact mass: 450.2.

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 105-107

38
[ 1446679-94-2 ]
[ 51285-26-8 ]
[ 1446680-82-5 ]

Yield	Reaction Conditions	Operation in experiment
6.1 g	With sodium hydrogencarbonate; In 1,4-dioxane; at 40 - 60℃;	Compound 167 Separated diastereoisomers of diastereoisomeric mixture 167: 167A and 167B Compound 165 (10.2 g, 23.1 mmol), <strong>[51285-26-8]pyridine-2-carboximidamide hydrochloride</strong>(6.37g, 40.4 mmol), sodium bicarbonate (7.76 g , 92.4 mmol) and dioxane (200 mL) were heated and stirred at 60C during 6 hours and stirred further overnight at 40C. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane. The product fractions were combined and concentrated yielding methyl 2,2,3,5-tetrafluoro-6'-oxo-2'-(pyridin-2-yl)-2,3,5',6'-tetrahydro- H-spiro[indene-l,4'- pyrimidine] -5 '-carboxylate (6. lg) as a light yellow amorphous powder. A solution of methyl 2',2',3',5'-tetrafiuoro-6-oxo-2-(2-pyridyl)spiro[ 1 ,5-dihydropyrimidine-4, 1 '- indane] -5 -carboxylate in phosphorus oxychloride (50 g) equiped with a CaCl2 drying tube was heated at 110C during 210 minutes. The reaction mixture was concentrated, the residue dissolved in CH2C12 (200 mL), poured in saturated NaHC03 (200 mL) solution and stirred 30 minutes. The organic layer was dried over sodium sulphate, filtered and concentrated.The residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane, methyl 6'-chloro-2,2,3,5- tetrafluoro-2'-(pyridin-2-yl)-2,3-dihydro- 1 'H-spiro[indene- 1 ,4'-pyrimidine]-5'- carboxylate was isolated as two separate diastereoisomers: and compound 167A (1046 mg after second purification) and compound 167B (1705 mg). Compound 167A: Method L; Rt: 1.94 m/z; 425.9 (M+H)+ Exact mass: 425.1. Compound 167B: Method L; Rt: 2.06 m/z; 425.9 (M+H)+ Exact mass: 425.1.

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 124

39
[ 1233506-04-1 ]
[ 51285-26-8 ]
[ 108-59-8 ]
[ 1446678-08-5 ]

Yield	Reaction Conditions	Operation in experiment
1.14 g		Compound 28 A 10 mL microwave tube was charged with dimethyl malonate (1.21 g, 9.17 mmol), 3-chloro-5-fluorophenylacetylene (1.70 g, 11.0 mmol), indium(III) trichloride (243 mg, 1.10 mmol), xylene (6 mL) and flushed with nitrogen and closed. The reaction mixture was stirred at 135C for 40 hours, allowed to cool to room temperature and used as such in next step. A 50 mL round bottomed flask was charged with pyridine-2- carboximidamide hydrochloride (1.52 g, 9.62 mmol), dimethylformamide (8.98 mL), and sodium carbonate (2.91 g, 27.5 mmol) under a nitrogen atmosphere and the reaction mixture was stirred for 10 minutes zy room temperature. Then the reaction mixture in xylene obtained above (9.17 mmol) was added and the obtained mixture was heated and stirred at 60C overnight. The mixture was poured into ice water and stirred for 30 minutes and extracted with diisopropyl ether (3 x 50 mL). The combined organic extracts were dried (Na2S04), concentrated under reduced pressure and the residue was purified using silica gel column chromatography (gradient elution 30 to 100% dichloromethane: in heptane) The desired fractions were concentrated in vacuo resulting in compound 28 (1.14 g) as a brown oil.

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 43

40
[ 766-98-3 ]
[ 51285-26-8 ]
[ 105-53-3 ]
[ 1446677-52-6 ]

Yield	Reaction Conditions	Operation in experiment
21.3 g		Compound 1 A pressure tube was charged with xylene (30 mL), diethyl malonate (13.3 g, 83.3 mmol), indium chloride (368.2 mg, 1.66 mmol) and 4-fiuorophenylacetylene (15 g, 125 mmol). The tube was flushed with nitrogen, closed and stirred in an oil bath at 135C for 17 hours. The reaction mixture was cooled to room temperature and the solution was used as such below. A pressure tube was charged with Pyridine-2- carboximidamide hydrochloride (14.2 g, 90.3 mmol) and l-Methyl-2-pyrrolidinone (NuMuRho,IotaOmicronOmicron mL). Potassium tert-butoxide (18.42g, 164 mmol) was added under nitrogen and the reaction mixture was stirred for 30 minutes. Then the above obtained solution in xylene was added, the pressure tube was heated and stirred in an oil bath at 80C for 5 hours. The reaction mixture was cooled in an ice bath and concentrated in vacuo until only NMP remained. The mixture was poured into ice- water and was stirred for 30 minutes. After extraction with diisopropylether (3 x 100 mL). The combined extracts were washed with brine, dried (MgS04), filtered and concentrated in vacuo yielding a brown oil. This oil was purified by silica gel column chromatography (gradient CH2CI2- heptane 50:50 to 100:0). The desired fractions were collected and concentrated in vacuo, yielding compound 1 as a yellow oil which solidified upon standing (21.3g) Method A; Rt: 1.03 and 1.07 min. m/z : 356.3 (M+H)+ Exact mass: 355.1

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 26-27

41
[ 1446677-80-0 ]
[ 51285-26-8 ]
[ 1446677-82-2 ]

Yield	Reaction Conditions	Operation in experiment
681 mg	With potassium tert-butylate; In N,N-dimethyl-formamide; at 60℃; for 45h;Sealed tube; Inert atmosphere;	Compound 15 In a sealed pressure tube was loaded under nitrogen atmosphere a stirring bar compound 14 (939 mg, 2.98 mmol), <strong>[51285-26-8]pyridine-2-carboximidamide hydrochloride</strong> (470 mg, 2.98 mmol), dry N,N-Dimethylformamide (23.1 mL, 298 mmol) and Potassium tert-butoxide (670 mg, 5.97 mmol). The reaction mixture was stirred at 60C for 45 hours, allowed to reach room temperature and poured into ice water. The emulsion was neutralized (pH= 7) using aqueous hydrochloric acid (1M) (pH paper check) and extracted with dichloromethane. The combined organic layers were dried (Na2S04) and concentrated to dryness. Nu,Nu-Dimethylformamide was azeotropically removed using toluene to afford a pale yellow oil, which was purified using silica gel column chromatography (10 to 40% ethyl acetate in heptane) resulting in compound 15 (681 mg) which was used as such in the next reaction. Method E; Rt: 1.15 and 1.17 min. m/z : 390.1 (M+H)+ Exact mass: 389.1

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 35-36

42
[ 1446680-49-4 ]
[ 51285-26-8 ]
[ 1446678-17-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate; In N,N-dimethyl-formamide; at 110℃; for 2h;	Compound 32 THF (300 mL) was slowly added to T1CI4 (1 M in dichloromethane; 20.3 mL 184.0 mmol) in an icebath. CCI4 (4 mL) was added.Then a mixture of 2,2,2,4'-tetrafluoro- acetophenone (18.9 g, 98.1 mmol) and diethylmalonate (15.7 g, 98.1 mmol) was added at a temperature between 0-5C. The recipient was rinsed with CC14 (1 mL).The reaction mixture was stirred 90 minutes at roomtemperature.Then pyridine (30.7 mL) was added dropwise during 5 minutes. The reaction mixture was stirred 90 minutes at room temperature. Water was added until the white precipitate dissolved completely. The mixture was extracted twice with diethylether (250 mL). The organic layer was separated, dried over sodium sulphate, filtered and concentrated.The residue was purified by silica gel column chromatography using a gradient elution from 0 till 10% EtOAc in heptane. The pure fractions were combined and concentrated resulting in diethyl 2-(2,2,2-trifluoro-l-(4-fluorophenyl)ethylidene)malonate as a clear liquid (5.35g). 1H NMR (400 MHz, DMSO-d6) ppm 0.88 (t, J=1.0 Hz, 3 H), 1.27 (t, J=7.0 Hz, 3 H), 3.99 (q, J=7.2 Hz, 2 H), 4.33 (q, J=7.1 Hz, 2 H), 7.28 - 7.37 (m, 2 H), 7.37 - 7.45 (m, 2 H). Diethyl 2-(2,2,2-trifluoro-l-(4-fluorophenyl)ethylidene)malonate (15.4 mmol), (2.43g, 15.4 mmol), <strong>[51285-26-8]pyridine-2-carboximidamide hydrochloride</strong>, potassium acetate (2.27 g; 23.1mmol) in DMF (23 mL) was stirred and heated at 110C in during 2 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in water (50 mL) and dichloromethane (50 mL). The organic layer was dried over an HM-N isolute cartridge and concentrated. The residue was purified by silica gel column chromato- graphy using a gradient from 1 till 10% methanol. The product fractions were collected and concentrated. Impure fractions were crystallized from 90/10 heptane/ethylacetate mixtures. The white powders were filtered off and dried in vacuum overnight at 50C resulting in compound 32 (2.33 g). The filtrates were combined and concentrated resulting in an oily residue (2.06g) which was further purified by Prep HPLC on (RP Vydac Denali CI 8 - IotaOmicronmuiotaeta, 200g, 5cm). Mobile phase (0.25% NH4HCO3 solution in water, CH3CN), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again, resulting in more compound 32 (1.48g) as a white powder. 1H NMR (400 MHz, DMSO-d6) ppm 0.74 (t, J=7.0 Hz, 2 H), 1.14 (t, J=7.2 Hz, 1 H), 3.68 - 3.83 (m, 1 H), 4.07 - 4.19 (m, 1 H), 4.57 - 4.65 (m, 1 H), 7.20 - 7.37 (m, 2 H), 7.61 - 7.81 (m, 2 H), 8.00 (dd, J=8.8, 5.5 Hz, 1 H), 8.05 - 8.14 (m, 1 H), 8.37 (dt, J=8.0, 1.0 Hz, 1 H), 8.47 (dt, J=7.8, 1.0 Hz, 1 H), 8.68 - 8.78 (m, 1 H), 11.25 (s, 1 H), 11.42 (s, 1 H)

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 46

43
[ 1446678-26-7 ]
[ 51285-26-8 ]
[ 1446678-27-8 ]

Yield	Reaction Conditions	Operation in experiment
1.78 g	With sodium carbonate; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;	Compound 37 A mixture of compound 36 (7 g, 23.9 mmol), <strong>[51285-26-8]pyridine-2-carboximidamide hydrochloride</strong> (5.7 g) and Na2C03 (7.6 g, 71.8 mmol) in DMF (70 mL) was stirred overnight at 60C under N2. The solvent was removed in vacuo. The obtained residue was suspended in dichloro methane (100 mL) and the precipitate was filtered off. The filtrate was concentrated and purified by silica gel column chromatography. (Gradient eluent: petroleum ether: ethyl acetate: from 100:0 to 60:40) resulting in compound 37 (1.78 g). Method B; Rt: 1.12 min. m/z : 368.1 (M+H)+ Exact mass: 367.1

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 49

44
[ 1446680-50-7 ]
[ 51285-26-8 ]
[ 1446680-51-8 ]

Yield	Reaction Conditions	Operation in experiment
		Compound 41 POPd (126 mg, 0.250 mmol) and potassium carbonate (2.08 g, 15.0 mmol) were added to a nitrogen purged stirring mixture of diethyl 2-(l-chloroethylidene)malonate (1.10 g, 5.00 mmol), 2-chloro-4-fluorophenylboronic acid (1.57 g, 9.00 mmol), tetrahydro- furane (10.0 mL) and water (1.0 mL) in a microwave tube. The reaction mixture was sealed with a silicon septum and subjected to microwave irradiation for 60 minutes at 100 C. The reaction was repeated in total 5 times, the seperated reaction vessels were allowed to cool to room temperature, the reaction mixtures were combined, diluted with heptane (600 mL) and washed with sodium carbonate (2 x 100 mL), water (1 x 50 mL) and Brine (50 mL). After drying (MgS04) the solvents were removed in vacuo. The residue was purified using silica gel column chromatography by gradient elution with 0 to 6% ethyl acetate in heptane resulting in diethyl 2-(l-(2-chloro-4-fluoro- phenyl)ethylidene)malonate as a liquid (860 mg). A pressure tube with a magnetic stirring bar, <strong>[51285-26-8]pyridine-2-carboximidamide hydrochloride</strong> (0.594 g, 3.77 mmol) and N-Methyl-2-Pyrrolidone (10 mL) under a nitrogen atmosphere was cooled to 0C. Potassium tert-butoxide (0.564 g, 5.03 mmol) was added under a nitrogen atmosphere and the reaction mixture was stirred for 15 minutes at room temperature. Diethyl 2-(l-(2-chloro-4-fluorophenyl)ethylidene)malonate (860 mg, 2.51 mmol) in N-Methyl- 2-Pyrrolidone (5 mL) was added and the pressure tube was heated and stirred in an oil bath at 88C for 44 hours. After cooling to room temperature; the reaction mixture was poured into water (200 mL) and hydrochloric acid (IN, 4 mL) was added. The mixture was stirred for 5 minutes and extracted with diisopropyl ether (3 x 100 mL). The combined organic extracts were dried (Na2S04) and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography by gradient elution with 30 to 100%. dichloromethane in heptanes. The desired fractions were concentrated in vacuo, resulting in ethyl 4-(2-chloro-4-fluorophenyl)-4-methyl-6- oxo-2-(pyridin-2-yl)-l,4,5,6-tetrahydropyrimidine-5-carboxylate (311 mg). Under a nitrogen atmosphere, ethyl 4-(2-chloro-4-fluorophenyl)-4-methyl-6-oxo-2-(pyridin-2- yl)-l,4,5,6-tetrahydropyrimidine-5-carboxylate (311 mg, 0.798 mmol) and phosphorous oxychloride (1.48 mL, 16.0 mmol) where stirred and heated at 110C for 30 minutes. After cooling, the reaction mixture was concentrated to dryness in vacuo. The obtained residue was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (2 x 20 mL) and brine (20 mL). After drying (Na2S04) the volatiles were removed in vacuo resulting in a residue (260 mg) which was used as such in the next step. A microwave (10 mL) tube was loaded with a stirring bar, potassium (morpholin-4-yl) methyltrifluoroborate (128 mg, 0.588 mmol), the above obtained residue (260 mg, 0.452 mmol), water (245 mu, 13.6 mmol) and 1, 2-dimethoxyethane (2.35 mL) and purged with nitrogen for 10 minutes. Under nitrogen atmosphere Bis(tri- tert-butylphosphine) palladium (0) (23.1 mg, 0.0452 mmol) and potassium carbonate (281 mg, 2.04 mmol) were added and the reaction mixture was stirred under microwave irradiation at 140C for 10 minutes. After cooling, nitrogen gas was bubbled through the reaction mixture and more butyldi-l-adamantylphosphine (24.3 mg, 0.0678 mmol) and palladium (II) acetate (10.2 mg, 0.0452 mmol) were added. The reaction mixture was stirred under microwave irradiation at 140C for 10 minutes under a nitrogen atmosphere. The water layer was extracted with dichloromethane, the organic layers were combined and washed with sodium carbonate, dried (Na2S04) and evaporated to dryness. The residue was purified using silica gel column chromatography by gradient elution with 5% to 50% ethyl acetate in heptane resulting in compound 41 (73 mg). Method D; Rt: 1.22 min. m/z : 473.1 (M+H)+ Exact mass: 472.2 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.92 (t, J=7.0 Hz, 3 H), 1.92 (s, 3 H), 2.53 - 2.67 (m, 4 H), 3.67 (d, J=16.8 Hz, 1 H), 3.77 - 3.90 (m, 7 H), 6.97 (td, J=8.4, 2.8 Hz, 1 H), 7.04 (dd, J=8.8, 2.8 Hz, 1 H), 7.36 (ddd, J=7.5, 5.0, 1.1 Hz, 1 H), 7.61 (dd, J=9.0, 6.3 Hz, 1 H), 7.72 (td, J=7.8, 1.8 Hz, 1 H), 8.13 (br. d, J=7.8 Hz, 1 H), 8.61 (br. d, J=4.5 Hz, 1 H), 10.19 (s, l H)

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 51-52

45
[ 1446680-53-0 ]
[ 51285-26-8 ]
[ 1446680-54-1 ]

Yield	Reaction Conditions	Operation in experiment
203 mg	With potassium tert-butylate; In N,N-dimethyl-formamide; at 60℃; for 45h;Inert atmosphere; Sealed tube;	Compound 42 POPd (582 mg, 1.16 mmol) was added to a nitrogen purged stirred mixture of diethyl 2-(l-chloroethylidene)malonate (3.00 g, 13.6 mmol), 2,4-difluorophenylboronic acid (3.22 g, 20.4 mmol), potassium carbonate (5.64 g, 40.8 mmol), tetrahydrofuran (16.0 mL) and water (3.00 mL) in a microwave tube. The reaction mixture was sealed and subjected to microwave irradiation for 1 hour at 100 C. After cooling to room temperature the reaction mixture was diluted with dichloromethane (150 mL), washed with water, saturated aqueous sodium carbonate and water (3 x 40 mL), dried (Na2S04) and evaporated to dryness. The residue was purified using silica gel column chromato- graphy by gradient elution with 0 to 15% ethyl acetate in heptane resulting in diethyl 2-(l-(2,4-difluorophenyl)ethylidene)malonate as an oil (1.06 g). Under a nitrogen atmosphere, a pressure tube was charged with a magnetic stirring bar, <strong>[51285-26-8]pyridine-2-carboximidamide hydrochloride</strong> (268 mg, 1.70 mmol), N,N-Dimethyl- formamide (13.2 mL), potassium tert-butoxide (382 mg, 3.41 mmol) and diethyl 2-(l-(2,4-difluorophenyl)ethylidene)malonate (508 mg, 1.70 mmol). The reaction mixture was sealed and stirred at 60C for 45 hours. After cooling to room temperature, the reaction mixture was poured into ice water (200 mL) and the resulting emulsion was neutralized (pH= 7) using hydrochloric acid (IN). The mixture was extracted with dichloromethane. The combined organic extracts were dried (Na2S04) and concentrated under reduced pressure. Nu,Nu-Dimethylformamide was co evaporated using toluene and the resulting yellow oil was purified using silica gel column chromatography with ethyl acetate in heptane in a gradient from 10 to 40%. The desired fractions were concentrated in vacuo yielding ethyl 4-(2,4-difluorophenyl)-4-methyl-6-oxo-2-(pyridin- 2-yl)-l,4,5,6-tetrahydropyrimidine-5-carboxylate (203 mg). Under a nitrogen atmosphere, a tube was charged with a stirring bar, ethyl 4-(2,4-difluorophenyl)-4- methyl-6-oxo-2-(pyridin-2-yl)-l,4,5,6-tetrahydropyrimidine-5-carboxylate (137 mg, 0.367 mmol) and phosphorous oxychloride (0.509 mL, 5.48 mmol). The mixture was stirred and heated at reflux for 30 minutes. After cooling to room temperature, the reaction mixture was concentrated to dryness. The obtained residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate (3 x 10 mL), dried (isolute HM-N) and evaporated to resulting in ethyl 6-chloro-4-(2,4-difluoro- phenyl)-4-methyl-2-(pyridin-2-yl)-l,4-dihydropyrimidine-5-carboxylate (154 mg) as a yellow powder which was used as such in the next step. A 10 mL microwave tube was loaded with a stirring bar, potassium (morpholin-4-yl)- methyltrifluoroborate (381 mg, 1.84 mmol), ethyl 6-chloro-4-(2,4-difluorophenyl)-4- methyl-2-(pyridin-2-yl)-l,4-dihydropyrimidine-5-carboxylate (154 mg, 0.354 mmol), cesium carbonate (1.38 g, 4.25 mmol) , distilled water (300 mu) and toluene (3mL). Nitrogen gas was bubbled through for 5 minute and under a nitrogen atmosphere palladium(II) acetate (16.0 mg, 0.0708 mmol) and butyldi-l-adamantylphosphine (40.6 mg, 0.113 mmol) were added. The reaction mixture was stirred at 120C for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with dichloromethane (50 mL). The mixture was washed with saturated aqueous sodium carbonate (2 x 5 mL) and water (5 mL). The organic layer was dried over an HM-N cartridge and concentrated to dryness to afford a brown sticky residue. This residue was purified using silica gel column chromatography by gradient elution with 0 to 2% methanol (7 N ammonia) in dichloromethane and again by gradient elution with 0 to 2% methanol in dichloromethane resulting in compound 42 (81 mg) after drying overnight in vacuum oven at 50C. Method A; Rt: 1.23 min. m/z : 457.4 (M+H)+ Exact mass:456.2; 1H NMR (400 MHz, CHLOROFORM-d): ppm 1.00 (t, J=7.2 Hz, 3 H), 1.91 (s, 3 H), 2.54 - 2.65 (m, 4 H), 3.65 (d, J=16.8 Hz, 1 H), 3.77 - 3.85 (m, 5 H), 3.92 (m, 2 H), 6.69 (ddd, J=11.7, 9.0, 2.6 Hz, 1 H), 6.78-6.86 (m, 1 H), 7.36 (ddd, J=7.5, 4.8, 1.3 Hz, 1 H), 7.44 (td, J=9.0, 6.5 Hz, 1 H), 7.72 (td, J=7.7, 1.6 Hz, 1 H), 8.14 (dt, J=7.8, 1.1 Hz, 1 H), 8.60 (ddd, J=4.8, 1.5, 0.8 Hz, 1 H), 10.10 (br. s, 1 H)

Reference： [1]Patent: WO2013/102655,2013,A1 .Location in patent: Page/Page column 52-54

46
[ 1538-08-5 ]
[ 51285-26-8 ]
[ 219508-27-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; for 12h;Reflux;	Ethyl trifluoroacetate and hydrazine hydrate (1:1.2) were added in anhydrous THF (30ml) and the mixture was stirred at room temperature for 12h. The equiv of NaOH with 2-iminazole pyridine hydrochloride (1:1) were added in above-mentioned solution and heated to reflux for 12h. Sodium carbonate was used to adjust pH value. The solution was extracted into ethyl acetate, which was combined, dried over MgSO4. The residue was subjected to silica gel column chromatography using a 1:3 mixture of ethyl acetate and hexane as the eluent and crystallized in ethyl acetate. The white crystals were obtained. Yield: 80%. 1H NMR (600MHz, CDCl3): delta 14.05(1H, dr), 8.84(1H, d), 8.35(1H, d), 7.99(1H, dt), 7.55(1H, ddd); FT-IR (KBr) cm-1: 3137 1606, 1494, 1461, 1428, 1217, 1189, 1009, 765, 714
	With sodium hydroxide; In tetrahydrofuran; for 12h;Inert atmosphere; Reflux;	b. A mixture solution of ethyl trifluoroacetate (2.0 g, 14 mmol), hydrazine hydrate (1.0 g, 21 mmol), and THF (20 mL) was stirred for 12 h at room temperature under nitrogen atmosphere. Then after NaOH (0.5 g, 14 mmol) and pyridine-2-carboximidamide hydrochloride (2.0 g, 15 mmol) were added into the mixture and heated to reflux for 12 h. After cooling to room temperature, the saturated NaHCO3 solution was added and then extracted with ethyl acetate. The organic extract was with water and dried over anhydrous MgSO4. The crude product was subjected to silica gel column chromatography using a 3:1 mixture of petroleum ether and ethyl acetate as the eluent. The white crystals of 2-(3-(trifluoromethyl)-1H-1,2,4 -triazol-5-yl)pyridine were obtained. Yield: 82 %. 1H NMR (600 MHz, CDCl3, delta): 13.40 (s, 1H), 8.82 - 8.77 (m, 1H), 8.32 (d, 1H, J = 7.9 Hz), 7.97 (t, 1H, J = 7.8 Hz), 7.53 (d, J = 7.7 Hz, 1H). FT-IR (KBr, cm-1): 3137, 1606, 1494, 1461, 1428, 1217, 1189, 1009, 765, 714. Anal. Calcd for C8H16N5F3: C, 40.17; N, 29.29; H, 6.69. Found: C, 40.55; N, 28.87; H, 7.13.

Reference： [1]Dyes and Pigments,2013,vol. 99,p. 67 - 73
[2]Tetrahedron,2016,vol. 72,p. 8335 - 8341

47
1-(4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one [ No CAS ]
[ 51285-26-8 ]
[ 1613046-32-4 ]

Yield	Reaction Conditions	Operation in experiment
35%	With sodium hydride; In N,N-dimethyl-formamide; at 135 - 140℃;	General procedure: In a 50 mL R.B. flask, chalcone (3, 2 mmol) and amidine ( 5, 2 mmol) in the presence of base NaH (3 mmol) were stirred in DMF (10 ml) at 135-140 oC. After the completion of reaction, reaction mixture was poured in cold water with vigorous stirring and neutralized it with N/5 HCl solution. The precipitate was filtered and dried. The crude was purified by column chromatography with a mixture of chloroform-methanol to give the desired product 6.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 2892 - 2896

48
[ 51285-26-8 ]
[ 103-72-0 ]
N-(phenylcarbamothioyl)pyridine-2-carboximidamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With triethylamine; In methanol; acetonitrile; at 50℃; for 2h;	To a solution of 2-amidinopyridine hydrochloride (1.58 mmol) in solvent (acetonitrile/MeOH, v/v=1:1) were added phenyl isothiocyanate(1.58 mmol) and triethylamine (3.48 mmol), and stirred for 2 h at 50 C. The reaction mixture was concentrated under reduced pressure. Water was added to the crude mixture, and extracted with ethyl acetate. The combined organic layer was dried over MgSO4 and filtered. After removal of the solvent in vacuum, diethyl ether was added to the residue. The oily compound becomes solid. The resulting solid was collected and washed with the solvent (140 mg, 35%).

Reference： [1]Tetrahedron,2014,vol. 70,p. 8737 - 8743

49
[ 51285-26-8 ]
[ 88284-48-4 ]
[ 71635-88-6 ]

Yield	Reaction Conditions	Operation in experiment
61%	With caesium carbonate; cesium fluoride; In acetonitrile; at 50℃; for 5h;	General procedure: To a suspension of free-base amidine or HCl salt ofamidine (0.2 mmol) in MeCN (4.0 ml) were added o-silyl aryl triflate (1.5 eq.), Cs2CO3 (1.5eq. if used) and CsF (2.0 eq.). The reaction mixture was stirred at 50 C forthe time indicated. The reaction was diluted with DCM (5 mL), filtered andconcentrated. The product was purified by chromatography.

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 4623 - 4626

50
[ 57611-47-9 ]
[ 51285-26-8 ]
6-benzyl-2-pyridin-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 9697 - 9711

51
[ 3128-32-3 ]
[ 51285-26-8 ]
2-(3-vinyl-1H-1,2-4-triazol-5-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In tetrahydrofuran; at 80℃; for 1h;	Ligand Synthesis Example 7 Synthesis of 2-(3-vinyl-1H-1,2-4-triazol-3-yl)pyridine Acrylohydrazide (7-2) was prepared by dissolving ethyl acrylate (7-1) and hydrazine in tetrahydrofuran (THF) and reacting the resulting solution at 80 C. for 1 hour. After the temperature of the resulting solution containing the acrylohydrazide (7-2) was lowered to room temperature, 2-amidino pyridine hydrochloride (7-3) and sodium hydroxide (NaOH) were added thereto and reacted at 80 C. for 1 hour, thereby preparing 2-(3-vinyl-1H-1,2-4-triazol-3-yl)pyridine (7-4). After the temperature was lowered to room temperature again, the reaction was terminated with sodium hydrogen carbonate (NaHCO3) and then extracted with ethyl acetate. Then, purification was performed by column chromatography using hexane and ethyl acetate (1:1) as a solvent.

Reference： [1]Patent: US9150601,2015,B2 .Location in patent: Page/Page column 18

52
[ 300-57-2 ]
[ 51285-26-8 ]
4-phenyl-2-(pyridin-2-yl)pyrimidine [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 5538 - 5546

53
[ 51285-26-8 ]
ethyl 2-[(3,4-dichlorophenyl)methyl]-4,4,4-trifluoro-3-oxobutanoate [ No CAS ]
5-(3,4-dichlorobenzyl)-2-(pyridin-2-yl)-6-(trifluoromethyl)pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate; In 1,4-dioxane; for 8h;Reflux;	A mixture of 966 mg (7.0 mmol) of potassium carbonate, 826 mg (5.2 mmol) of 2-amidinopyridine hydrochloride and 600 mg (1.7 mmol) of ethyl 2-(3,4-dichlorobenzyl)-4,4,4-trifluoro-3-oxobutanoate (purity 68.3%; CAS 179110-12-4; WO 2012/041817, Intermediate 56) in 4 ml of dioxane was heated under reflux for 8 h. The solution was then filtered, the residue was washed with DMSO and the filtrate was purified by preparative HPLC (mobile phase: acetonitrile/water gradient with 0.1% of formic acid). This gave 412 mg (59% of theory) of the title compound.
412 mg	With potassium carbonate; In 1,4-dioxane; for 8h;Reflux;	5-(3,4-dichlorobenzyl)-2-(pyridin-2-yl)-6-(trifluoromethyl)pyrimidin-4(3H)-one A mixture of 966 mg (7.0 mmol) of potassium carbonate, 826 mg (5.2 mmol) of 2-amidinopyridine hydrochloride and 600 mg (1.7 mmol) of ethyl 2-(3,4-dichlorobenzyl)-4,4,4-trifluoro-3-oxobutanoate (purity 68.3%; CAS 179110-12-4; WO 2012/041817, Intermediate 56) in 4 ml of dioxane was heated under reflux for 8 h. The solution was then filtered, the residue was washed with DMSO and the filtrate was purified by preparative HPLC (mobile phase: acetonitrile/water gradient with 0.1% of formic acid). This gave 412 mg (59% of theory) of the title compound. LC-MS (Method 1): Rt=1.31 min; MS (ESpos): m/z=400.1 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=4.00 (s, 2H), 7.20 (dd, 1H), 7.46-7.58 (m, 2H), 7.69 (dd, 1H), 8.09 (td, 1H), 8.33 (d, 1H), 8.78 (d, 1H), 13.07 (br. s, 1H).

Reference： [1]Patent: TW2016/5831,2016,A .Location in patent: Paragraph 0214
[2]Patent: US2016/237059,2016,A1 .Location in patent: Paragraph 0527-0529

54
[ 51285-26-8 ]
[ 3282-30-2 ]
[ 741252-33-5 ]

Yield	Reaction Conditions	Operation in experiment
53.8%	With sodium carbonate; In dichloromethane; water; at 20℃; for 2h;	A solution of pivalic acid chloride (3.54 g, 29.3 mmol) in 10 mL CH2Cl2 is added drop wise to <strong>[51285-26-8]2-pyridinecarboximidamide hydrochloride</strong> (4 g, 29.3 mmol) and Na2CO3(3.1 g, 29.3 mmol) in 100 mL H2O. The reaction mixture is stirred at RT for 2 h, yielding a white precipitate. The precipitate is filtered, and the solid washed with water and ethanol. The solid then is suspended in 5 mL of ethylene glycol and heated to 200C for 2 h, yielding a pale yellow solution. Upon cooling to room temperature, a white solid is formed, filtered of and washed with de-ionized water. The solid is dried under vacuum and used without further purification (3.2 g, 15.8 mmol, 53.8%).

Reference： [1]Patent: KR2015/13888,2015,A .Location in patent: Paragraph 0245; 0246; 0247; 0248; 0249

55
C₁₅H₂₀N₂O₃S [ No CAS ]
[ 51285-26-8 ]
6-(4-methylsulfonylphenyl)-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1 g	With potassium carbonate; In ethanol; at 80℃;	Step 3: Preparation of 6-(4-methylsulfonylphenyl)-2-(2-pyridyl)-7,8-dihydro-5H- pyrido[4,3-d]pyrimidine Crude 1-(4-methylsulfonylphenyl)piperidin-4-one (1.64 g, 6.75 mmol) was stirred with DMFDMA (10 mL) at 90 oC for 3 hrs. The resulting mixture was concentrated in vacuo. The residue was dissolved in EtOH (20mL). To the solution was added <strong>[51285-26-8]pyridine-2-carboxamidine hydrochloride</strong> (1.06 g, 6.75 mmol) and K2CO3 (1.86 g, 13.5 mmol) successively. After being heated at 80 oC with stirring overnight, the resulting mixture was cooled down to rt and purified by prep-HPLC to give 6-(4-methylsulfonylphenyl)-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3- d]pyrimidine (1.0 g) as light yellow solid.

Reference： [1]Patent: WO2016/177655,2016,A1 .Location in patent: Page/Page column 65

56
C₁₅H₁₈F₂N₂O₂ [ No CAS ]
[ 51285-26-8 ]
6-(3,4-difluoro-5-methoxy-phenyl)-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5 g	With potassium carbonate; In ethanol; at 80℃;	Step 3: Preparation of 6-(3,4-difluoro-5-methoxy-phenyl)-2-(2-pyridyl)-7,8-dihydro- 5H-pyrido[4,3-d]pyrimidine Crude 1-(3,4-difluoro-5-hydroxy-phenyl)piperidin-4-one (8.1 g, 33.75 mmol) was stirred in DMFDMA (30 mL) at 90 oC for 3 hrs. The resulting mixture was concentrated in vacuo and the residue was dissolved in EtOH (50mL). To the solution was added <strong>[51285-26-8]pyridine-2-carboxamidine hydrochloride</strong> (5.3 g, 33.75 mmol) and K2CO3 (9.3 g, 67.5 mmol) successively. The resulting mixture was heated at 80 oC with stirring overnight, then cooled down to rt and purified by prep- HPLC to give 6-(3,4-difluoro-5-methoxy-phenyl)-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3- d]pyrimidine (5.0 g).

Reference： [1]Patent: WO2016/177655,2016,A1 .Location in patent: Page/Page column 67

57
[ 1383776-68-8 ]
[ 51285-26-8 ]
tert-butyl 5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In ethanol; at 100℃;	Step 1: Preparation of tert-butyl 5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3- d]pyrimidine-6-carboxylate To a solution of tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate (3.00 g, 14.1 mmol) in DMF (20 mL) was added DMFDMA (1.84 g, 15.47 mmol). The resulting mixture was heated at 90 oC with stirring overnight. After being cooled to rt, the resulting reaction mixture was concentrated in vacuo and the residue was dissolved in EtOH (50 mL). To the solution was added <strong>[51285-26-8]pyridine-2-carboxamidine hydrochloride</strong> (2.2 g, 14.1 mmol) and sodium methoxide (1.05 g, 19.4 mmol). After being heated at 100 oC with stirring overnight, the resulting mixture was cooled down to rt and concentrated in vacuo. The residue was diluted with water (15 mL) and then extracted with EA (30 mL) for three times. The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give crude tert-butyl 5-methyl-2-(2-pyridyl)- 7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate (2.5 g) which was used in the next step directly without further purification.

Reference： [1]Patent: WO2016/177655,2016,A1 .Location in patent: Page/Page column 61; 62

58
C₁₇H₂₂F₂N₂O₃ [ No CAS ]
[ 51285-26-8 ]
6-[3,4-difluoro-5-(2-methoxyethoxy)phenyl]-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.3 g	With potassium carbonate; In methanol; at 60℃; for 16h;	Step 4: Preparation of 6-[3,4-difluoro-5-(2-methoxyethoxy)phenyl]-2-(2-pyridyl)-7,8- dihydro-5H-pyrido[4,3-d]pyrimidine A mixture of 1-[3,4-difluoro-5-(2-methoxyethoxy)phenyl]piperidin-4-one(4.82 g, 16.9 mmol) and DMFDMF (50 mL) was heated at 120 oC with stirring for 4 hrs. The mixture was concentrated in vacuo and the residue was dissolved in MeOH (50 mL). To the solution was added <strong>[51285-26-8]pyridine-2-carboximidamide hydrochloride</strong> (2.35 g, 15 mmol), and K2CO3 (4.75 g, 33 mmol). After being heated at 60 oC with stirring for 16 hrs, the resulting mixture was cooled down to rt, diluted with saturated aqueous solution of NH4Cl and extracted with EA (100 mL) for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column to give 6-[3,4- difluoro-5-(2-methoxyethoxy)phenyl]-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine (2.3 g) as a pale yellow solid.

Reference： [1]Patent: WO2016/177655,2016,A1 .Location in patent: Page/Page column 78

59
C₂₁H₂₂F₂N₂O₂ [ No CAS ]
[ 51285-26-8 ]
6-(3-benzyloxy-4,5-difluoro-phenyl)-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15 g	With potassium carbonate; In methanol; at 70℃; for 12h;	Step 4: Preparation of 6-(3-benzyloxy-4,5-difluoro-phenyl)-2-(2-pyridyl)-7,8-dihydro- 5H-pyrido[4,3-d]pyrimidine A mixture of 1-(3-benzyloxy-4,5-difluoro-phenyl)piperidin-4-one (25.0 g, 78.8 mmol) in DMFDMA (250 mL) was heated at 120 oC with stirring for 4 hrs. The reaction mixture was cooled down to rt and concentrated in vacuo. The residue was dissolved in MeOH (300 mL) and to the solution was added <strong>[51285-26-8]pyridine-2-carboxamidine hydrochloride</strong> (12.4 g, 78.8 mmol) and K2CO3 (27.2 g, 197 mmol). The resulting mixture was heated at 70 oC for 12 hrs. The mixture was cooled down to rt and concentrated in vacuo. The residue was purified on silica gel column to give 6-(3-benzyloxy-4,5-difluoro-phenyl)-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3- d]pyrimidine (15 g) as yellow solid.

Reference： [1]Patent: WO2016/177655,2016,A1 .Location in patent: Page/Page column 85

60
[ 26510-52-1 ]
[ 51285-26-8 ]
[ 10239-68-6 ]

Reference： [1]Inorganic Chemistry,2017,vol. 56,p. 1418 - 1432

61
(2S,3aR,5aR,5bS,9S,13S,14R,16aR,16bS)-4-bromo-13-[(2R,5S,6R)-5-(dimethylamino)-6-methyloxan-2-yl]oxy}-9-ethyl-14-methyl-2-[(2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyloxan-2-yl]oxy}-1H,2H,3H,3aH,4H,5H,5aH,5bH,6H,7H,9H,10H,11H,12H,13H,14H,15H,16aH,16bH-as-indaceno[3,2-d]oxacyclododecane-5,7,15-trione [ No CAS ]
[ 51285-26-8 ]
(1S,2R,8R,10S,12S,13R,17R,18S,22S)-18-[(2R,5S,6R)-5-(dimethylamino)-6-methyloxan-2-yl]oxy}-22-ethyl-17-methyl-5-(pyridin-2-yl)-10-[(2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyloxan-2-yl]oxy}-23-oxa-4,6-diazapentacyclo[13.10.0.0²'¹³.0³'⁷.0^8,12]pentacosa-3⁽⁷⁾,4,14-triene-16,24-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.7%	With potassium carbonate; In acetonitrile; at 85℃;	To a solution of Intermediate 1 (1.0 g, 1.21 mmol) and Pyridine-2-carboxamidine hydrochloride (381 mg, 2.42 mmol) in acetonitrile (15 mL) was added potassium carbonate (501 mg, 3.63 mmol). The mixture was then heated to 85 C overnight. The mixture was concentrated under reduced pressure to give an oil, which was purified by column chromatography on silica gel (dichloromethane/methanol = 30/1 to 15/1) to give the crude product. The crude product was further purified by prep-HPLC to afford the title compound (28 mg, yield 2.7%) as a white solid. Partial 1H MR (400 MHz, CDC13): delta 8.48-8.45 (m, 1H), 8.16-8.10 (m, 1H), 7.74-7.70 (m, 1H), 7.21-7.16 (m, 1H), 6.85 (s, 1H), 4.95 (s, 1H), 4.77-4.70 (m, 1H), 4.48-4.42 (m, 2H), 4.18-4.09 (m, 1H), 3.41-3.36 (m, 1H), 3.32-3.22 (m, 3H), 3.16-3.05 (m, 2H), 2.82-2.74 (m, 1H), 2.23 (s, 6H). LCMS: m/z 849.1 [M+H]+.

Reference： [1]Patent: WO2017/40882,2017,A1 .Location in patent: Page/Page column 80

62
[ 51285-26-8 ]
[ 377082-44-5 ]
C₁₂H₁₂N₄O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		Na (12.7 g, 550 mmol) was dissolved in EtOH (200 mL). Compound 3 (37.5 g, 238 mmol) was added to the solution and the resulting mixture was stirred at room temperature for 0.5 h. Then compound 2 (45.6 g, 247 mmol) was added, the reaction was refluxed for 4 h, and then evaporated under reduced pressure. The residue was dissolved in water and neutralized with 10% HCl. The precipitated solid was filtered and re-crystallized from i-PrOH to yield 40.8 g (179 mmol, 75%) of compound 4 as white solid.

Reference： [1]Patent: US2017/174699,2017,A1 .Location in patent: Paragraph 1520; 1525

63
[ 157327-41-8 ]
[ 51285-26-8 ]
tert-butyl 2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With triethylamine; In tert-butyl alcohol; at 85℃; for 12h;	S2. A 100 ml flask was charged with 3 - ((N, N-dimethylamino) -methylene) -N-tert-butoxycarbonyl-4-piperidine(2.54 g, 10 mmol), 2-amidinopyridine hydrochloride (3) (1.73 g, 11 mmol), tert-butanol 50 ml, triethylamine(4.2 mL, 30 mmol) and the reaction was stirred at 85 C for 12 h. TLC showed the reaction was complete. Concentrated to give the crude product, and then separated by column chromatography,The conditions were petroleum ether: ethyl acetate = 1: 1 to give the compound 2- (2-pyridyl) -N-tert-butoxycarbonyl-5,7,8-trihydropyrido[4,3-d] pyrimidine (4) (light yellow solid, 1.56 g) in 50% yield.
	With sodium methylate; In ethanol; at 100℃;	A mixture of <strong>[157327-41-8]tert-butyl 3-(dimethylaminomethylene)-4-oxo-piperidine-1-carboxylate</strong> (10 g,39.37 mmol), pyridine-2-carboxamidine hydrochloride (6.2 g, 39.37 mmol) and CH3ONa (4.25 g,78.74 mmol) in ethanol (100 mL) was heated at 100 C with stirring overnight. The resultingmixture was concentrated in vacuo and the residue was dissolved in EA. The resulting solutionwas washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude tert-butyl 2- (2-pyridyl)-7 ,8 -dihydro-5H-pyrido [4,3-d]pyrimidine-6-carboxylate as an orange oil (12 g) as yellow solid, which was used in the next step directly without any further purification.

Reference： [1]Patent: CN106397433,2017,A .Location in patent: Paragraph 0026; 0030
[2]Patent: WO2018/83106,2018,A1 .Location in patent: Page/Page column 21; 22

64
C₁₈H₁₄FeNO [ No CAS ]
[ 51285-26-8 ]
C₂₅H₁₉FeN₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium hydroxide; In ethanol;Reflux;	(3) Synthesis of Ferrocenylpyrimidine Polydentate Ligand 6h: Unsaturated ketone (10 mmol) was dissolved in ethanol (35 mL), 1.74 g of 2-hydrazinopyridine hydrochloride (11 mmol) was added, and the mixture was stirred well. , 0.672g KOH (12mmol) was added and the reaction was warmed to reflux. The TLC spotter tracked the complete conversion of the unsaturated ketone, cooled, suction filtered, and the cake was washed three times and dried to give a 3.10 g reddish brown solid with a yield of 88%.

Reference： [1]Patent: CN107383112,2017,A .Location in patent: Paragraph 0013-0014; 0033-0034; 0037

65
2-(4-(tert-butyl)phenyl)-4-methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)thiazole [ No CAS ]
[ 51285-26-8 ]
N-(4-(2-(4-(tert-butyl)phenyl)-4-methylthiazol-5-yl)pyrimidin-2-yl)picolinimidamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	In N,N-dimethyl-formamide; at 80℃;	General procedure: To a solution of 11 (0.1 g, 0.26 mmol) in dry DMF (5 mL), a properamine, hydrazine, guanidine or caboximidate (0.4 mmol); namely:ethylamine, cyclopentylamine, cyclohexylamine, dimethylamine,azetidine hydrochloride, morpholine, azetidin-3-ol hydrochloride,ethylenediamine, hydrazine hydrate, guanidine hydrochloride,methylguanidine hydrochloride, 1,1-dimethylguanidine hydrochloride,N,N-tetramethyl guanidine, pyrrolidine-1-carboximidamide hydroiodide, morpholine-4-carboximidamidehydroiodide, 4-methylpiperazine-1-carboximidamide hydroiodide,picolinmidamide hydrochloride, nicotinimidamide hydrochloride,was added. The reaction mixture was heated at 80 C for0.5e8 h, and then poured over ice water (50 mL). The formed solidwas filtered and washed with 50% ethanol and recrystallized fromabsolute ethanol. For 18, the crude solid was washed with boilingwater to remove the residual hydrazine. Physical properties andspectral analysis of isolated products are listed below:

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 151,p. 110 - 120

66
benzyl 3-(dimethylaminomethylene)-2-ethyl-4-oxopiperidine-1-carboxylate [ No CAS ]
[ 51285-26-8 ]
benzyl 5-ethyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15 g	With potassium carbonate; In methanol; at 50℃; for 12h;	To a solution of crude benzyl 3-(dimethylaminomethylene)-2-ethyl-4-oxo-piperidine-1- carboxylate (30 g, crude) in MeOH (300 mL) was added <strong>[51285-26-8]pyridine-2-carboxamidine hydrochloride</strong> (15 g, 95 mmol) and K2C03 (29 g, 163 mmol). The resulting mixture was stuffed50 C for 12 hrs and concentrated in vacuo. The residue was dissolved in DCM (500 mL) andthe solution was washed with brine, dried over with Na2SO4 and concentrated in vacuo. The residue was purified by column (eluting with DCM/MeOH=40/1, v:v) to give benzyl 5-ethyl-2- (2-pyridyl)-7 , 8-dihydro-5H-pyrido [4,3-d]pyrimidine-6-carboxylate (15 g) as a green oil.

Reference： [1]Patent: WO2018/83106,2018,A1 .Location in patent: Page/Page column 45

67
[ 51285-26-8 ]
[ 79099-07-3 ]
[ 4637-24-5 ]
tert-butyl 5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.5 g		To a solution of tert-butyl 2-methyl-4-oxo-piperidine- 1-carboxylate (3.00 g, 14.1 mmol) in DMF (20 mL) was added DMFDMA (1.84 g, 15.47 mmol). The resulting mixture was heated at 90 C with stirring overnight. After being cooled to rt, the resulting reaction mixture was concentrated in vacuo and the residue was dissolved in EtOH (50 mL). To the solution was added <strong>[51285-26-8]pyridine-2-carboxamidine hydrochloride</strong> (2.2 g, 14.1 mmol) and sodium methoxide (1.0519.4 mmol). After being heated at 100C with stirring overnight, the resulting mixture was cooled down to rt and concentrated in vacuo. The residue was diluted with water (15 mL) and then extracted with EA (30 mL) for three times. The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give crude tert-butyl 5-methyl-2-(2-pyridyl)- 7,8-dthydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate (2.5 g) which was used in the next stepdirectly without further purification.

Reference： [1]Patent: WO2018/83106,2018,A1 .Location in patent: Page/Page column 41; 42

68
[ 1877-72-1 ]
[ 51285-26-8 ]
C₁₄H₁₀N₄O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;	General procedure: A mixture of a carboxylic acid (2 mmol), the corresponding amidine salt (2 mmol), HBTU (834 mg, 2.2 mmol) and DIPEA (1.03 g,8 mmol) in DMF (8 mL) was stirred at room temperature for 3 h. Itwas then quenched with H2O (30 mL) and extracted with EtOAc(3 10 mL). The combined organic layer was washed with H2O(10 mL) and brine (10 mL) successively, dried over anhydrous Na2SO4, concentrated, and purified through silica gel column chromatography to give the substrate 2.

Reference： [1]Tetrahedron,2018,vol. 74,p. 4613 - 4618

69
[ 88-67-5 ]
[ 51285-26-8 ]
[ 28594-60-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With 8-quinolinol; sodium hydroxide; copper dichloride; In water; at 20℃; for 0.333333h;Sealed tube; Microwave irradiation;	General procedure: In a 10 mL glass tube 2-iodobenzoic acid (1.0 mmol), acetamidine hydrochloride (1.2 mmol), CuCl2 (0.1 mmol), L2 (0.1 mmol), and NaOH (4.0 equiv.) and 3.0 mL water were placed. The vessel was then sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 120 W by using a CEM Discover microwave synthesizer was used at the room temperature for 20 min. The reaction mixture was stirred continuously during the reaction. After completion of the reaction, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to afford the corresponding product. All the products were confirmed by NMR and MS spectroscopic analysis.

Reference： [1]Synthetic Communications,2018,vol. 48,p. 3089 - 3098

70
[ 51285-26-8 ]
[ 88-65-3 ]
[ 28594-60-7 ]

Yield	Reaction Conditions	Operation in experiment
83%	With 8-quinolinol; sodium hydroxide; copper dichloride; In water; at 20℃; for 0.333333h;Sealed tube; Microwave irradiation;	General procedure: In a 10 mL glass tube 2-iodobenzoic acid (1.0 mmol), acetamidine hydrochloride (1.2 mmol), CuCl2 (0.1 mmol), L2 (0.1 mmol), and NaOH (4.0 equiv.) and 3.0 mL water were placed. The vessel was then sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 120 W by using a CEM Discover microwave synthesizer was used at the room temperature for 20 min. The reaction mixture was stirred continuously during the reaction. After completion of the reaction, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to afford the corresponding product. All the products were confirmed by NMR and MS spectroscopic analysis.

Reference： [1]Synthetic Communications,2018,vol. 48,p. 3089 - 3098

71
[ 60838-50-8 ]
[ 51285-26-8 ]
[ 61310-37-0 ]

Yield	Reaction Conditions	Operation in experiment
73%		A mixture of 157.8 g. (1.0 mol) of 2-pyridinecarboxamidine hydrochloride 23, 54.2 g (1.0 mol) of sodium methoxide in 400 ml of dry methanol was stirred for 30 minutes. The sodium chloride was filtered and the filtrate was concentrated to dryness. The residue and 83 g (1.0 mole) of 3-methoxyacrylonitrile 24 were heated (100-160°) together for 3 hours, at this point the evolution of ethanol had stopped and the melt had started to crystallize. The product 25 was cooled to room temperature, suspended in methanol, filtered and dried to obtain 25 125.6 g, (73percent yield).

Reference： [1]Patent: WO2018/237084,2018,A1 .Location in patent: Paragraph 002089

72
[ 51285-26-8 ]
[ 10472-24-9 ]
2-pyridin-2-yl-1,5,6,7-tetrahydro-cyclopenta[e]pyrimidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With potassium carbonate; In ethanol; for 5h;Reflux;	2-amidinopyridine hydrochloride (7.88 g, 50 mmol) and K2CO3 (6.91 g,50 mmol) were added to methyl 2-oxocyclopentanecarboxylate (commercially sourced) (6.21mL, 50mmol) in ethanol (100mL). The mixture was heated to reflux for 5 hours. While themixture was still hot, it was acidified by the addition of 2MaqueousHCl (20mL) and water (30mL). The mixture was allowed to cool to room temperature overnight and wasthen partially concentrated in vacuo. The resulting precipitate was collected by filtration, washed with water and diethyl ether, and dried invacuo to give the desired product. Additional product was obtained by concentrating the filtrate in vacuo and purifying the resulting residueby recrystallization fromethanol/water.The two batches were combined to afford the title compound (3.63 g, 34%) (1HNMRd6-DMSO): 2.04 (2H,quintet), 2.71 (2H, t), 2.88 (2H, t), 7.63 (1H, dd), 8.04 (1H, t), 8.30 (1H, d),8.73 (1H, d), NH missing; m/z MH1 214):

Reference： [1]Molecular Pharmacology,2019,vol. 95,p. 222 - 234

73
O₁-benzyl O₃-ethyl 2-methyl-4-oxo-piperidine-1,3-dicarboxylate [ No CAS ]
[ 51285-26-8 ]
benzyl 4-hydroxy-5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60 g	With potassium carbonate; In 2,2,2-trifluoroethanol; at 80℃; for 12h;	To a solution of O1-benzyl O3-ethyl 2-methyl-4-oxopiperidine-1,3-dicarboxylate (75.0 g, 235 mmol) in 2,2,2-trifluoroethanol (750 mL) was added 2-amidinopyridine hydrochloride (38.9 g, 247 mmol) and K2CO3(97.4 g, 705 mmol). The mixture was heated at 80 C with stirring for 12 hrs. After being cooled to rt, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified column chromatography (eluting with DCM/MeOH=20/l, v:v) to give benzyl 4-hydroxy-5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6- carboxylate (60.0 g) as a yellow solid.

Reference： [1]Patent: WO2018/1952,2018,A1 .Location in patent: Page/Page column 79; 80

74
3-(dimethylamino)-2-(ethylsulfonyl)-1-(1-methyl-5-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)prop-2-en-1-one [ No CAS ]
[ 51285-26-8 ]
5-(ethylsulfonyl)-4-(1-methyl-5-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)-2,2'-bipyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.53 g	With triethylamine; In ethanol; at 20℃; for 1h;Reflux;	The aforementioned 3-(dimethylamino)-2-(ethylsulfonyl)-1-(1-methyl-5-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)prop-2-en-1-one obtained in Step 91 5 was dissolved in 29 ethanol (5 ml), and then stirred at room temperature. 94 Triethylamine (0.453 g, 4.47 mmol, 4.5 eq) and 95 2-amidinopyridine hydrochloride (0.36 g, 1.49 mmol, 1.5 eq) were added thereto, and then stirred for 1 hour under heating and refluxing. The resultant liquid was naturally cooled, and the solvent was removed by distillation under reduced pressure. 33 Water was added to the obtained residue, and extraction with chloroform was carried out. The obtained organic layer was dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography with silica gel. Thereby, the objective 96 product was obtained in an amount of 0.53 g (yield 92%, 2 steps).1H-NMR of the obtained objective product is shown below.1H-NMR (400 MHz, CDCl3): delta 9.65 (s, 1H), 9.09 (d, 2H), 7.54 (m, 3H), 7.36 (m, 2H), 7.31 (s, 1H), 4.23 (q, 2H), 3.93 (s, 3H), 1.46 (t, 3H).

Reference： [1]Patent: US2019/185459,2019,A1 .Location in patent: Paragraph 0572; 0573; 0574; 05752

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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. 51285-26-8 ] {[proInfo.proName]}

Quality Control of [ 51285-26-8 ]

Related Doc. of [ 51285-26-8 ]

Product Details of [ 51285-26-8 ]

Calculated chemistry of [ 51285-26-8 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 51285-26-8 ]

Application In Synthesis of [ 51285-26-8 ]

[ 51285-26-8 ] Synthesis Path-Upstream 1~6

[ 51285-26-8 ] Synthesis Path-Downstream 1~74

Related Functional Groups of [ 51285-26-8 ]

Amidines

Amines

Related Parent Nucleus of [ 51285-26-8 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 51285-26-8 ]

Related Parent Nucleus of
[ 51285-26-8 ]