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[ CAS No. 2486-80-8 ]

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Chemical Structure| 2486-80-8

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COA NMR CNMR HPLC LC-MS

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Product Details of [ 2486-80-8 ]

CAS No. :	2486-80-8	MDL No. :	MFCD00114479
Formula :	C₈H₉NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	167.16 g/mol	Pubchem ID :	-
Synonyms :

Calculated chemistry of of [ 2486-80-8 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	44.3
TPSA :	72.55 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.0 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.98
Log Po/w (XLOGP3) :	0.45
Log Po/w (WLOGP) :	0.98
Log Po/w (MLOGP) :	-0.37
Log Po/w (SILICOS-IT) :	0.5
Consensus Log Po/w :	0.51

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.85

Water Solubility

Log S (ESOL) :	-1.4
Solubility :	6.69 mg/ml ; 0.04 mol/l
Class :	Very soluble
Log S (Ali) :	-1.54
Solubility :	4.8 mg/ml ; 0.0287 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.53
Solubility :	4.91 mg/ml ; 0.0294 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.3

Safety of [ 2486-80-8 ]

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

Application In Synthesis of [ 2486-80-8 ]

* 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 [ 2486-80-8 ]
Downstream synthetic route of [ 2486-80-8 ]

[ 2486-80-8 ] Synthesis Path-Upstream 1~4

1
[ 67-56-1 ]
[ 2486-80-8 ]
[ 27492-84-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	at 0℃; Heating / reflux	2.9 g of 4-amino-2-methoxy-benzoic acid (77.17 mmol) was dissolved in 200 mL MeOH. At 0° C., to this solution was added 2 eq SOCl2 (12.5 mL, 154.24 mmol) The reaction mixture was heated to reflux temperature overnight. After solvent and excess of SOCl2 were removed under reduced pressure, the residue was suspended in 10percent Na2CO3. The precipitate that formed was solution was filtered and filter cake was washed with cold water until the washing became neutral. The product was then dried under vacuum at 50° C. About 12.04 g product was obtained after drying (86percent). M+H+(182).

Reference： [1] Patent: US2004/142940, 2004, A1, . Location in patent: Page/Page column 70

2
[ 186581-53-3 ]
[ 2486-80-8 ]
[ 27492-84-8 ]

Reference： [1] Archiv der Pharmazie (Weinheim, Germany), 1951, vol. 284, p. 341,346

3
[ 773837-37-9 ]
[ 2486-80-8 ]
[ 89469-52-3 ]

Reference： [1] European Journal of Organic Chemistry, 2016, vol. 2016, # 32, p. 5365 - 5376

4
[ 2486-80-8 ]
[ 544-92-3 ]
[ 89469-52-3 ]

Reference： [1] Tetrahedron Letters, 1986, vol. 27, # 49, p. 5997 - 6000

[ 2486-80-8 ] Synthesis Path-Downstream 1~32

1
[ 27492-84-8 ]
[ 2486-80-8 ]

Yield	Reaction Conditions	Operation in experiment
67%	With sodium hydroxide In ethanol for 0.666667h; Heating;
	With potassium hydroxide
	With potassium hydroxide at 60℃; for 0.5h; Yield given;

	With lithium hydroxide In tetrahydrofuran; methanol
	Multi-step reaction with 2 steps 1: 89 percent / ethanol / 2 h / 50 °C 2: KOH / methanol; H₂O / 2 h / Heating
	With water; sodium hydroxide In methanol for 2.5h; Reflux; Inert atmosphere;

Reference： [1]Hewlett, William A.; De Paulis, Tomas; Mason, N. Scott; Schmidt, Dennis E.; Trivedi, Bakula L.; Zhang, Zhang-Jin; Ebert, Michael H. [Chemical and Pharmaceutical Bulletin, 1997, vol. 45, # 12, p. 2079 - 2084]
[2]Murakami et al. [Chemical and pharmaceutical bulletin, 1971, vol. 19, p. 1696,1698]
[3]Elz; Keller [Archiv der Pharmazie, 1995, vol. 328, # 7-8, p. 585 - 594]
[4]Chumpradit, S.; Choi, S. R.; Zhuang, Z.-P.; Kung, H. F. [Journal of labelled compounds and radiopharmaceuticals, 2001, vol. 44, p. S225 - S227]
[5]Pham, Tien Q.; Greguric, Ivan; Liu, Xiang; Berghofer, Paula; Ballantyne, Patrice; Chapman, Janette; Mattner, Filomena; Dikic, Branko; Jackson, Timothy; Loc'h, Christian; Katsifis, Andrew [Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3561 - 3572]
[6]Liu, Feng; Wu, Na; Cheng, Xu [Organic Letters, 2021, vol. 23, # 8, p. 3015 - 3020]

2
[ 2597-56-0 ]
[ 2486-80-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen In methanol	49.A 15.2 g of 2-methoxy-4-nitro-benzoic acid (75.6 mmol) was dissolved in 200 mL MeOH. To this solution was added Pd/C (10%, 20 mg/per mmol) under N2 protection. The solution was degassed for 5 min. Hydrogenation under 30 psi H2 was carried out overnight. Palladium catalyst was removed by filtration through Celite. The combined organic solvent was concentrated to dryness and 13 g of product was obtained (100%). M+H+(168).
80%	With water; iron; acetic acid In propan-1-ol for 3h; Heating; Inert atmosphere;	4-Amino-2-methoxybenzoic acid (18) Compound 17, 5 g (25.38 mmol), was dissolved under stirring and heating in a mixture of 60 mL of propanol, 30 mL of water, and 1.25 mL of AcOH. Carbonyl iron, 5.4 g(96.43 mg-at) was then added to the resulting solution under argon. The mixture was stirred for 3 h and filtered to remove iron sludge. The filtrate was evaporated to dryness under argon, and the residue was recrystallized from water. Yield 80%, mp 103-105°.1 NMR spectrum (DMSO-d6), δ, ppm: 3.72 s (3,3), 5.89 s (2, NH2), 6.12 d (1, 5, J 7.2 Hz),6.20 s (1, 3), 7.50 d (1, 6, J 7.2 Hz), 11.43 br.s(1, COOH). 13 NMR spectrum (DMSO-d6), δ, ppm:56.6 (3), 96.7 (3), 106.0 (5), 106.2 (1), 134.3(6), 155.0 (4), 161.7 (2), 166.8 (COOH). Found, %: 57.41; 5.45; N 8.30. C8H9NO3. Calculated, %: C57.48; 5.43; N 8.38.
	With ethanol; nickel at 20℃; Hydrogenation;

	With ethanol; nickel at 70℃; Hydrogenation;
	With hydrogenchloride; iron
	With tin(ll) chloride
	With ethyl acetate; platinum Hydrogenation;
	With hydrogen In ethanol at 20℃;	9 Example 9 2-Methoxy-4- [3- (4-phenoxy-phenyl)-ureido]-benzoic acid To a solution of 4-nitro-2-methoxybenzoic acid (5. 0g, mmol) in ethanol (100 pL) was added Pd/C (200 mg, 20% w/w). The reaction mixture was stirred at room temperature under a hydrogen atmosphere over night. The catalyst was filtered off through a pad of celite and the filtrate was concentrated in vacuo giving 4-amino-2-methoxybenzoic acid. To a solution of 4-amino-2-methoxybenzoic acid (0.50 g, 3.0 mmol) in dichloromethane (10 jj. L) was added 4-phenoxyphenylisocyanate (0.65 µL, 3.6 mmol) under inert atmosphere. The reaction mixture was stirred for three days at room temperature and a precipitate was formed. Filtration gave 1.1 g (97%) of the title compound.'H NMR (300 MHz, CDCI3) : 6 3.79 (s, 3H), 6.92-7. 02 (m, 5H), 7.09 (t, 1 H), 7.32-7. 42 (m, 3H), 7.48 (d, 2H), 7.66 (d, 1 H), 8.79 (s, 1 H), and 9.03 (s, 1 H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2004/142940, 2004, A1 Location in patent: Page/Page column 69-70
[2]Lomov [Russian Journal of Organic Chemistry, 2019, vol. 55, # 8, p. 1093 - 1098][Zh. Org. Khim., 2019, vol. 55, # 8, p. 1182 - 1187,6]
[3]Bhate et al. [Proceedings - Indian Academy of Sciences, Section A, 1950, vol. <A> 32, p. 357,362]
[4]Nodzu et al. [Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan, 1959, vol. 79, p. 1378,1379][Chem.Abstr., 1960, p. 10936]
[5]Clinton et al. [Journal of the American Chemical Society, 1952, vol. 74, p. 592,595]
[6]Froelicher; Cohen [Journal of the Chemical Society, 1922, vol. 121, p. 1656]
[7]Vanderhaeghe; Derudder [Bulletin des Societes Chimiques Belges, 1952, vol. 61, p. 310,319, 320]
[8]Current Patent Assignee: 7TM PHARMA AS - WO2003/87045, 2003, A1 Location in patent: Page/Page column 50

3
[ 2486-80-8 ]
[ 544-92-3 ]
[ 89469-52-3 ]

Reference： [1]Tetrahedron Letters,1986,vol. 27,p. 5997 - 6000

4
[ 2486-80-8 ]
4-Carboxy-3-methoxy-benzenediazonium; chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 0.5h;

Reference： [1]Barraclough, P.; Beams, R. M.; Black, J. W.; Cambridge, D.; Collard, D.; et al. [European Journal of Medicinal Chemistry, 1990, vol. 25, # 6, p. 467 - 477]

5
[ 4093-29-2 ]
[ 2486-80-8 ]

Reference： [1]European Journal of Medicinal Chemistry,1990,vol. 25,p. 467 - 477
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 3561 - 3572

6
[ 2486-80-8 ]
[ 88915-26-8 ]
4-amino-N-[(1-benzyl-4-piperidinyl)methyl]-2-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-amino-2-methoxybenzoic acid; 4-aminomethyl-1-benzylpiperidine With benzotriazol-1-ol In N,N-dimethyl-formamide at 0℃; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;
	Stage #1: 4-amino-2-methoxybenzoic acid; 4-aminomethyl-1-benzylpiperidine With benzotriazol-1-ol In N,N-dimethyl-formamide cooling; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;

Reference： [1]Itoh, Katsuhiko; Kanzaki, Koji; Ikebe, Tsuguo; Kuroita, Takanobu; Tomozane, Hideo; Sonda, Shuji; Sato, Noriko; Haga, Keiichiro; Kawakita, Takeshi [European Journal of Medicinal Chemistry, 1999, vol. 34, # 4, p. 329 - 341]
[2]Itoh, Katsuhiko; Kanzaki, Koji; Ikebe, Tsuguo; Kuroita, Takanobu; Tomozane, Hideo; Sonda, Shuji; Sato, Noriko; Haga, Keiichiro; Kawakita, Takeshi [European Journal of Medicinal Chemistry, 1999, vol. 34, # 11, p. 977 - 989]

7
[ 1000068-47-2 ]
[ 2486-80-8 ]
[ 1000068-01-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In 1,4-dioxane; water at 130℃;	General procedure 1: Synthesis of intermediates 4-[6-(4- hydroxyphenyl)pyrazin-2-yl]amino\|-2-benzoic acids and 3-j[6-(4- hydroxyphenyl)pyrazin-2-yl]amino\|-2-benzoic acidsA typical experimental procedure: A mixture of 4-(6-chloropyrazin-2-yl)phenol (100 mg, 0.84 mmol), the amino benzoic acid (1 mmol), Pd2(dba)3 (10 mg), Xantphos (15 mg), NaO £Bu (200 mg, 2.03 mmol) and dioxane (10 ml) was heated in a sealed tube under a nitrogen atmosphere at 13O0C. The reaction mixture was allowed to cool and then diluted with dioxane (5 ml) and water (5 ml). The solution was adjusted to pH=7 to produce a precipitate which was isolated by centrifuging the suspension in a Whatman filter vial, subsequently washing the residue with methanol and drying to give the product in >90% purity. Materials subsequently used without further purification.; Intermediate 12 4-[6-(4-Hydroxyphenyl)pyrazin-2-yl]amino}-2-methoxybenzoic acidThe title compound was synthesised using general procedure 1 starting from 4-(6-chloropyrazin-2-yl)phenol (300 mg, 1.45 mmol), 4-amino 2-methoxy benzoic acid (267 mg, 1.60 mmol), Pd2(dba)3 (30 mg, 0.0363 mmol), Xantphos (40 mg, 0.0725 mmol), NaBuO (200 mg, 2.03 mmol) and dioxane (20 ml). Crude material subsequently used without further purification.

Reference： [1]Current Patent Assignee: SWEDISH ORPHAN BIOVITRUM AB - WO2007/147874, 2007, A1 Location in patent: Page/Page column 90-91

8
[ 2486-80-8 ]
[ 102362-24-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: 1.) aq. H₂SO₄, NaNO₂, 2.) NaN₃ / 1.) H₂O, 0-5 deg C, 45 min, 2.) H₂O, 0 deg C, 45 min 2: SOCl₂ / 1 h / Heating 3: 1.) n-BuLi / 1.) ether, hexane, -60 deg C, 2.) ether, hexane, THF, a) 0-5 deg C, 1 h, b) RT, 2 h 4: dioxane / 0.5 h / Heating 5: 71 percent / 2-pyrrolidone hydrotribromide, 2-pyrrolidone / tetrahydrofuran / 0.33 h / Heating 6: 36 percent / ethanol / 5 h / 80 °C 7: 67 percent / H₂, Et₃N / 5percent Pd/C / ethanol / 2 h / 760 Torr

Reference： [1]Barraclough; Black; Cambridge; Capon; Cox; Firmin; Gerskowitch; Giles; Glen; Hill; Hull; Iyer; Kettle; King; Nobbs; Randall; Skone; Smith; Vine; et al. [European Journal of Medicinal Chemistry, 1992, vol. 27, # 3, p. 207 - 217]

9
[ 2486-80-8 ]
[ 102361-86-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: 1.) aq. H₂SO₄, NaNO₂, 2.) NaN₃ / 1.) H₂O, 0-5 deg C, 45 min, 2.) H₂O, 0 deg C, 45 min 2: SOCl₂ / 1 h / Heating 3: 1.) n-BuLi / 1.) ether, hexane, -60 deg C, 2.) ether, hexane, THF, a) 0-5 deg C, 1 h, b) RT, 2 h 4: dioxane / 0.5 h / Heating 5: 71 percent / 2-pyrrolidone hydrotribromide, 2-pyrrolidone / tetrahydrofuran / 0.33 h / Heating 6: 36 percent / ethanol / 5 h / 80 °C 7: 67 percent / H₂, Et₃N / 5percent Pd/C / ethanol / 2 h / 760 Torr 8: pyridine / 17 h / 0 - 5 °C

Reference： [1]Barraclough; Black; Cambridge; Capon; Cox; Firmin; Gerskowitch; Giles; Glen; Hill; Hull; Iyer; Kettle; King; Nobbs; Randall; Skone; Smith; Vine; et al. [European Journal of Medicinal Chemistry, 1992, vol. 27, # 3, p. 207 - 217]

10
[ 2486-80-8 ]
[ 1548-13-6 ]
[ 617244-73-2 ]

Yield	Reaction Conditions	Operation in experiment
79%	In dichloromethane at 20℃;	7 Example 7; 2-METHOXY-4- [3- (4-TRIFLUOROMETHYL-PHENYL)-UREIDO]-BENZOIC acid To a solution of 4-amino-2-methoxybenzoic acid (3.4 g, 20.3 MMOL) in dry DICHLOROMETHANE (300 mL) under inert atmosphere was 4-trifluoromethylphenyl isocyanate (5.0 g, 26.7 MMOL) added drop wise. The reaction was stirred over night at room temperature and a precipitate was formed during the reaction. The precipitate was filtered and washed with DICHLOROMETHANE and gave 5.7 g (79 %) of the title product NMR (300 MHz, DMSO-D6) : 8 3.8 (s, 3H), 6.9 (dd, 1H), 7.4 (d, 1H), 7.4-7. 7 (m, 5H), 9.2 (d, 2H), 12.2 (s, 1H). LCMS (AN20N15) ; RT = 8.306 min, 352.9 m/z

Reference： [1]Current Patent Assignee: 7TM PHARMA AS - WO2004/48319, 2004, A1 Location in patent: Page 34

11
[ 67-56-1 ]
[ 2486-80-8 ]
[ 27492-84-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With thionyl chloride at 0℃; Heating / reflux;	49.B 2.9 g of 4-amino-2-methoxy-benzoic acid (77.17 mmol) was dissolved in 200 mL MeOH. At 0° C., to this solution was added 2 eq SOCl2 (12.5 mL, 154.24 mmol) The reaction mixture was heated to reflux temperature overnight. After solvent and excess of SOCl2 were removed under reduced pressure, the residue was suspended in 10% Na2CO3. The precipitate that formed was solution was filtered and filter cake was washed with cold water until the washing became neutral. The product was then dried under vacuum at 50° C. About 12.04 g product was obtained after drying (86%). M+H+(182).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2004/142940, 2004, A1 Location in patent: Page/Page column 70

12
[ 2486-80-8 ]
[ 49845-33-2 ]
C₁₈H₁₄FN₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: meta-fluoroaniline; 2,4-Dichloro-5-nitropyrimidine In DMF (N,N-dimethyl-formamide) at -60 - -40℃; for 2h; Stage #2: 4-amino-2-methoxybenzoic acid In DMF (N,N-dimethyl-formamide) at -50℃;	A.A6a A solution of 2, 4-dichloro-5-nitropyrimidine (0. 005 mol) in DMF (25 ml) was cooled TO-60°C, then a mixture of 3-fluorobenzenamine (0. 005 mol) in DMF (12. 5 ML) was slowly added dropwise and the mixture was stirred for 2 hours AT-40° A-60°C. A mixture of 4-AMINO-2-METHOXYBENZOIC acid (0. 005 mol) in DMF (12. 5 ml) was slowly added dropwise at-50°C and the reaction mixture was stirred overnight. H20 and CH3CN were added, then the resulting precipitate was filtered off, washed and dried (vacuum), yielding INTERMEDIATE 24.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2005/12307, 2005, A1 Location in patent: Page/Page column 54

13
[ 2486-80-8 ]
[ 59377-19-4 ]
[ 617244-40-3 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane at 20℃; for 72h;	9 Example 9 2-Methoxy-4- [3- (4-phenoxy-phenyl)-ureido]-benzoic acid To a solution of 4-nitro-2-methoxybenzoic acid (5. 0g, mmol) in ethanol (100 pL) was added Pd/C (200 mg, 20% w/w). The reaction mixture was stirred at room temperature under a hydrogen atmosphere over night. The catalyst was filtered off through a pad of celite and the filtrate was concentrated in vacuo giving 4-amino-2-methoxybenzoic acid. To a solution of 4-amino-2-methoxybenzoic acid (0.50 g, 3.0 mmol) in dichloromethane (10 jj. L) was added 4-phenoxyphenylisocyanate (0.65 µL, 3.6 mmol) under inert atmosphere. The reaction mixture was stirred for three days at room temperature and a precipitate was formed. Filtration gave 1.1 g (97%) of the title compound.'H NMR (300 MHz, CDCI3) : 6 3.79 (s, 3H), 6.92-7. 02 (m, 5H), 7.09 (t, 1 H), 7.32-7. 42 (m, 3H), 7.48 (d, 2H), 7.66 (d, 1 H), 8.79 (s, 1 H), and 9.03 (s, 1 H).

Reference： [1]Current Patent Assignee: 7TM PHARMA AS - WO2003/87045, 2003, A1 Location in patent: Page/Page column 50

14
[ 2486-80-8 ]
[ 35037-73-1 ]
[ 617244-73-2 ]

Yield	Reaction Conditions	Operation in experiment
79%	In dichloromethane at 20℃;	45 Example 45 2-Methoxy-4- [3- (4-trifluoromethyl-phenyl)-ureido]-benzoic acid To a solution of 4-amino-2-methoxybenzoic acid (3.4 g, 20.3 mmol) in dry dichloromethane (300 mL) under inert atmosphere was 4-trifluoromethylphenyl isocyanate (5.0 g, 26.7 mmol) added drop wise. The reaction was stirred over night at room temperature and a precipitate was formed during the reaction. The precipitate was filtered and washed with dichloromethane and gave 5.7 g (79 %) of the title product.'H NMR (300 MHz, dmso-d6) : 8 3.8 (s, 3H), 6.9 (dd, 1H), 7.4 (d, 1H), 7.4-7. 7 (m, 5H), 9.2 (d, 2H), 12.2 (s, 1H). LCMS(an20n15) ; RT = 8.306 min, 352.9 m/z

Reference： [1]Current Patent Assignee: 7TM PHARMA AS - WO2003/87045, 2003, A1 Location in patent: Page/Page column 63

15
[ 2486-80-8 ]
[ 28682-73-7 ]
2-(2-methoxy-4-amino-phenyl)-5H-imidazo[4,5-d]pyridazin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 45 2-(2-Methoxy-4-amino-phenyl)-5H-imidazo[4,5-d]pyridazin-4-one Prepared analogously to Example 1 from <strong>[28682-73-7]4,5-diamino-2H-pyridazin-3-one</strong> and 2-methoxy-4-amino-benzoic acid. M.p.: 295-300 C. (decomp.).

Reference： [1]Patent: US4722929,1988,A

16
[ 2486-80-8 ]
[ 59338-90-8 ]

Yield	Reaction Conditions	Operation in experiment
64.9%		III Stage 1: 2-Methoxy 4-amino 5-nitro benzoic acid EXAMPLE III Stage 1: 2-Methoxy 4-amino 5-nitro benzoic acid As above described 16.7 g (0.1 mol) of 2-methoxy 4-amino benzoic acid were nitrated. 13.8 g (yield 64.9%) of 2-methoxy 4-amino 5-nitro benzoic acid having a melting point of 254° C. were obtained.

Reference： [1]Current Patent Assignee: ILE DE FRANCE - US4039672, 1977, A

17
[ 2486-80-8 ]
[ 24424-99-5 ]
[ 162046-57-3 ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine In methanol at 20℃; for 7.5h;
37%	With triethylamine In methanol at 20℃; for 6h;
1.1 g	With sodium hydroxide In 1,4-dioxane; water at 20℃; for 24h; Inert atmosphere;

Reference： [1]Location in patent: experimental part Muehlhausen, Ute; Ermert, Johannes; Coenen, Heinz H. [Journal of labelled compounds and radiopharmaceuticals, 2009, vol. 52, # 1, p. 13 - 22]
[2]Willmann, Michael; Hegger, Julian; Neumaier, Bernd; Ermert, Johannes [ACS Medicinal Chemistry Letters, 2021, vol. 12, # 5, p. 738 - 744]
[3]Liu, Feng; Wu, Na; Cheng, Xu [Organic Letters, 2021, vol. 23, # 8, p. 3015 - 3020]

18
[ 2486-80-8 ]
[ 1124212-41-4 ]
[ 1124213-84-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane at 20℃;	18.A A: 3-((4-(4-Amino-2-methoxybenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide 1-Propanephosphonic acid cyclic anhydride (12.91 g, 20.2 mmol, 12.91 mL) was added dropwise to a solution of 4-amino-2-methoxybenzoic acid (1.70 g, 10.1 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (3.07 g, 11.2 mmol) and triethylamine (3.08 g. 30.3 mmol, 4.23 mL) in dichloromethane. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was taken up with ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (1.39 g). MS (ESI) m/z 425.4 [M+H]+
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane at 20℃; for 1h;	18.A 1-Propanephosphonic acid cyclic anhydride (12.91g, 20.2mmol, 12.91 mL) was added dropwise to a solution of 4-amino-2-methoxybenzoic acid (1.7Og, 10.1 mmol), N-tert- butyl-3-(piperazin-1-ylmethyl)benzamide (3.07g, 11.2mmol) and triethylamine (3.08g, 30.3mmol, 4.23mL) in dichloromethane. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was taken up with ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (1.39g). MS (ESI) m/z 425.4 [M+H]+

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2009/264416, 2009, A1 Location in patent: Page/Page column 24
[2]Current Patent Assignee: ORGANON & CO; MERCK & CO INC; LIGAND PHARMACEUTICALS INC - WO2009/24550, 2009, A1 Location in patent: Page/Page column 42-43

19
[ 2486-80-8 ]
[ 1338815-21-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-amino-2-methoxybenzoic acid With hydrogenchloride; sodium nitrite In water at 0℃; for 5.08333h; Stage #2: With hydrogenchloride; tin(ll) chloride In water at 0 - 20℃; for 64h;	A23 To a suspension of 4-amino-2-methoxybenzoic acid (3.00 g, 18.0 mmol) in hydrochoric acid (1.0 M, 30 mL) at 0°C was added a solution of sodium nitrite (1 .28 g, 18.5 mmol) in water (5.0 mL) over 5 min. The reaction mixture was maintained at 0°C for 5 hr and was then treated with tin(ll) chloride (9.53 g, 50.3 mmol) in hydrochloric acid (1 M, 60 mL) and warmed to RT for 64 hr. A thick precipitate formed which was isolated by filtration, washed with water (50 mL) and ether (15 mL) and dried in vacuo to afford 2-methoxy-4-hydrazinylbenzoic acid hydrochloride as a beige solid (1.05 g, 90% purity, 24%); R' 0.17 min (Method 2); m/z 181 (M+H)+, (ES+). This material was used in the subsequent step without further purification.
	Stage #1: 4-amino-2-methoxybenzoic acid With hydrogenchloride; sodium nitrite In water at 0℃; for 5.08333h; Stage #2: With hydrogenchloride; tin(ll) chloride In water at 0 - 20℃; for 64h;	Intermediate A16: 3-ferf-Butyl-1 -(3-methoxy-4-((triisopropylsilyloxy)methyl)phenyl)-1 H- pyrazol-5-amine.; To a suspension of 4-amino-2-methoxybenzoic acid (3.00 g, 18.0 mmol) in hydrochoric acid (1 .0 M, 30 mL) at 0°C was added a solution of sodium nitrite (1 .28 g, 18.5 mmol) in water (5.0 mL) over 5 min. The reaction mixture was maintained at 0°C for 5 hr and was then treated with tin(ll) chloride (9.53 g, 50.3 mmol) in hydrochloric acid (1 M, 60 mL) and warmed to RT for 64 hr. A thick precipitate formed which was isolated by filtration, washed with water (50 mL) and ether (15 mL) and dried in vacuo to afford 2-methoxy-4-hydrazinylbenzoic acid hydrochloride as a beige solid (1 .05 g, 90% purity, 24%); R' 0.17 min (Method 2); m/z 181 (M+H)+, (ES+). This material was used in the subsequent step without further purification.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2011/124930, 2011, A1 Location in patent: Page/Page column 50
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2011/158044, 2011, A2 Location in patent: Page/Page column 40

20
[ 2486-80-8 ]
[ 260046-05-7 ]
[ 1395886-03-9 ]

Yield	Reaction Conditions	Operation in experiment
57%	In ethanol at 150℃; for 0.333333h; Microwave irradiation;	9g 7V4-(2-Chlorophenyl)-iV2-(4-carboxyl-3-methoxyphenyl)pyrimidine-2,4-diamine hydrochloride (9g, method s in Fig. 7): A mixture of chloropyrimidine 21 (0.100 g, 0.416 mmol) and 4-amino-2-methoxybenzoic acid (0.070 g, 0.418 mmol) in EtOH (0.5 mL) was heated with a microwave reactor at 150 °C for 20 min. The solvent was evaporated from the resulting thick mass under reduced pressure. The residue was suspended in ethyl acetate (8 mL) and sonicated for 10 min. The mixture was filtered and the solid was washed with ethyl acetate (8 mL) and ethyl acetate:methanol (1 : 1, 1 mL) to provide the title compound 9g (0.068 g, 57%) as a gray solid, m.p. 160-162 °C. HPLC 95% [Rt = 4.5 min, 50% MeOH, 50% water (with 0.1% TFA) 20 min.]; 'H NMR (400 MHz, DMSO-i¾), δ 12.69 (s, IH), 10.42 (s, IH), 10.24 (s, IH), 7.95 (d, J= 6.2 Hz, IH), 7.64-7.51 (m, 3H), 7.48 (d, J= 8.4 Hz, IH), 7.36 (t, J= 7.7 Hz, IH), 7.29 (t, J= 7.4 Hz, IH), 6.98 (d, J= 8.8 Hz, IH), 6.45 (s, IH), 3.76 (s, 3H); 13C NMR (100 MHz, DMSO-i¾), δ 167.37, 162.97, 155.67, 152.95, 144.61, 134.39, 130.51, 129.61, 129.00, 128.35, 127.11, 124.90, 122.22, 113.36, 99.26, 56.70; LC-MS (ESI+) m/z 371.09 (M-C1)+; HRMS (ESI+) m/z calculated for Ci8H16ClN403 (M-C1)+ 371.0905, found 371.0909.

Reference： [1]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2012/135641, 2012, A2 Location in patent: Page/Page column 90

21
[ 2486-80-8 ]
2-methoxy-4-hydrazinylbenzoic acid hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-amino-2-methoxybenzoic acid With hydrogenchloride; sodium nitrite In water at 0℃; for 5h; Stage #2: With hydrogenchloride; tin(ll) chloride at 0 - 20℃; for 64h;	Intermediate A16: 3-tert-Butyl-1-(3-methoxy-4-((triisopropylsilyloxy)methyl)phenyl)-1H-pyrazol-5-amine Intermediate A16: 3-tert-Butyl-1-(3-methoxy-4-((triisopropylsilyloxy)methyl)phenyl)-1H-pyrazol-5-amine To a suspension of 4-amino-2-methoxybenzoic acid (3.00 g, 18.0 mmol) in hydrochoric acid (1.0 M, 30 mL) at 0° C. was added a solution of sodium nitrite (1.28 g, 18.5 mmol) in water (5.0 mL) over 5 min. The reaction mixture was maintained at 0° C. for 5 hr and was then treated with tin(II) chloride (9.53 g, 50.3 mmol) in hydrochloric acid (1M, 60 mL) and warmed to RT for 64 hr. A thick precipitate formed which was isolated by filtration, washed with water (50 mL) and ether (15 mL) and dried in vacuo to afford 2-methoxy-4-hydrazinylbenzoic acid hydrochloride as a beige solid (1.05 g, 90% purity, 24%); Rt 0.17 min (Method 2); m/z 181 (M+H)+, (ES+).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2013/156826, 2013, A1 Location in patent: Paragraph 0261; 0262

22
[ 2486-80-8 ]
[ 392691-05-3 ]
4-amino-2-methoxy-N-[(1-propyl-4-piperidyl)methyl]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere;	Representative procedure (l) for the synthesis of 17a-d General procedure: To a stirred solution of acid derivative (1.0 eq.) in DMF (5mL/mmol) were added Et3N (1.0 eq.), EDC (1.0 eq.), HOBt (1.0 eq.) and amine derivatives (1.0 eq.) under nitrogen atmosphere and the resulting mixture was stirred at room temperature for 18-72h. After evaporation in vacuo to remove DMF, the residue was purified by chromatography on silica gel column and concentrated under reduced pressure to afford expected amide derivative (25-44% isolated yields).

Reference： [1]Lalut, Julien; Tournier, Benjamin B.; Cailly, Thomas; Lecoutey, Cédric; Corvaisier, Sophie; Davis, Audrey; Ballandonne, Céline; Since, Marc; Millet, Philippe; Fabis, Frédéric; Dallemagne, Patrick; Rochais, Christophe [European Journal of Medicinal Chemistry, 2016, vol. 116, p. 90 - 101]

23
[ 2486-80-8 ]
(1-(cyclohexylmethyl)piperidin-4-yl)methanamine [ No CAS ]
4-amino-N-[1-(cyclohexylmethyl)piperidin-4-yl]methyl}-2-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 48h; Inert atmosphere;	Representative procedure (l) for the synthesis of 17a-d General procedure: To a stirred solution of acid derivative (1.0 eq.) in DMF (5mL/mmol) were added Et3N (1.0 eq.), EDC (1.0 eq.), HOBt (1.0 eq.) and amine derivatives (1.0 eq.) under nitrogen atmosphere and the resulting mixture was stirred at room temperature for 18-72h. After evaporation in vacuo to remove DMF, the residue was purified by chromatography on silica gel column and concentrated under reduced pressure to afford expected amide derivative (25-44% isolated yields).

Reference： [1]Lalut, Julien; Tournier, Benjamin B.; Cailly, Thomas; Lecoutey, Cédric; Corvaisier, Sophie; Davis, Audrey; Ballandonne, Céline; Since, Marc; Millet, Philippe; Fabis, Frédéric; Dallemagne, Patrick; Rochais, Christophe [European Journal of Medicinal Chemistry, 2016, vol. 116, p. 90 - 101]

24
[ 2486-80-8 ]
[ 90-60-8 ]
4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-methoxybenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: 4-amino-2-methoxybenzoic acid; 3,5-dichlorosalicyclaldehyde In ethanol for 0.5h; Reflux; Stage #2: With sodium tetrahydroborate In ethanol at 20℃;	4.2. 4-((3,5-Dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoicacid (1). General procedure: A solution of3,5-dichloro-2-hydroxybenzaldehyde (8)(2.0 g, 10.5 mmol) in ethanol (25 mL) was added 4-amino-2-hydroxybenzoic acid (9) (1.6 g, 10.5 mmol), stirred andrefluxed for 30 min, and then cooled to room temperature (22-25 °C). Theprecipitated solid was isolated by filtering the reaction mixture and driedunder infrared light. The intermediate was dissolved in ethanol (25 mL), andNaBH4(0.8 g, 21.2mmol) was added into the mixture at 0-5 °C. Then the reaction mixture wasstirred at room temperature. After disappearance of the reactant (monitored byTLC), water (25 mL) was added to the mixture to remove residual NaBH4.The reaction mixture was adjusted to pH 3-4 with concentrated hydrochloricacid, and concentrated to 25 mL under reduced pressure. The precipitate wasisolated by filtration and dried at 50 oC to give 1 (2.7g) as a white solid in 78% yield.

Reference： [1]Chen, Dongyin; Zhao, Ting; Ni, Kaidong; Dai, Peng; Yang, Lei; Xu, Yi; Li, Fei [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 9, p. 2152 - 2155]

25
[ 22065-57-2 ]
[ 2486-80-8 ]
4-((2-ethoxy-2-oxo-1-phenylethyl)amino)-2-methoxybenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With C₄₃H₃₇Br₂CuN₃P₂⁽¹⁺⁾*ClO₄^(1-) In methanol at 0 - 20℃; for 3h; Schlenk technique; Inert atmosphere; chemoselective reaction;

Reference： [1]Ramakrishna, Kankanala; Sivasankar, Chinnappan [Journal of Organic Chemistry, 2016, vol. 81, # 15, p. 6609 - 6616]

26
[ 2486-80-8 ]
[ 218792-82-6 ]
4-((2-(benzyloxy)-2-oxo-1-phenylethyl)amino)-2-methoxybenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With C₄₃H₃₇Br₂CuN₃P₂⁽¹⁺⁾*ClO₄^(1-) In methanol at 0 - 20℃; for 4h; Schlenk technique; Inert atmosphere; chemoselective reaction;

Reference： [1]Ramakrishna, Kankanala; Sivasankar, Chinnappan [Journal of Organic Chemistry, 2016, vol. 81, # 15, p. 6609 - 6616]

27
[ 2486-80-8 ]
[ 6148-64-7 ]
C₁₂H₁₅NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With 1,1'-carbonyldiimidazole; magnesium chloride In tetrahydrofuran at 20℃; for 48h;	25 3 - (2-methoxy-4-methyl phenyl) - 3-oxo-ethyl ester The 320mgCDI (1.98mmol) carefully added to the containing 300mg4-amino-2-methoxybenzoic acid (1.78mmol) is distilled of a suspension of 15mlTHF in. Stirring the mixture at room temperature for 4 hours. Next, each adding 366 mg of 3-ethyl-3-oxo-b ester sylvite (2.16mmol) and 205 mg of MgCl2(2.16mmol). The reaction mixture is stirred at room temperature 2 days. Using 30mlEt2O expansion solution, water for sequentially, NaHCO3saturated solution of NaCl saturated solution and washing. Using MgSO4after drying, evaporating the organic phase, the purification of a crude product on silica gel (gradient elution: DCM/AcOEt95/5 than the DCM), the obtained 195 mg of 3 - (4-amino-2-methoxyphenyl) - 3-oxo-ethyl ester in the yield of 46%.

Reference： [1]Current Patent Assignee: UNIVERSITE DE CAEN BASSE NORMANDIE; UNIVERSITE DE CAEN - CN105705488, 2016, A Location in patent: Paragraph 0410; 0411; 0412; 0413; 0414; 0415; 0416

28
[ 773837-37-9 ]
[ 2486-80-8 ]
copper(l) cyanide [ No CAS ]
[ 89469-52-3 ]

Reference： [1]European Journal of Organic Chemistry,2016,vol. 2016,p. 5365 - 5376

29
[ 2486-80-8 ]
tetramethylammonium trifluoromethanethiolate [ No CAS ]
4-isothiocyanato-2-methoxybenzoyl fluoride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	In dichloromethane at 20℃; for 1h;

Reference： [1]Scattolin, Thomas; Deckers, Kristina; Schoenebeck, Franziska [Organic Letters, 2017, vol. 19, # 21, p. 5740 - 5743]

30
[ 2486-80-8 ]
[ 123-72-8 ]
4-(butylamino)-2-methoxybenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	VI.1 Synthesis of 4-(butylamino)-2-methoxybenzoic acid, (246). 4-amino-2-methoxybenzoic acid, 244 (4.8 g, 28.7 mmols) and butyraldehyde (2.07 g, 28.7 mmols) were dissolved in 96 ml of anhydrous 1,2-dichloroethane under Ar atm. Sodium triacetoxyborohydride (9.13 g, 43.1 mmols) was added in one portion followed by the addition of acetic acid (1.725 g, 28.7 mmols). The mixture was stirred at room temperature overnight. The solution was diluted with 300 ml of EtOAc; 300 ml of saturated NaHCCT were added and the mixture stirred 15 min at room temperature. Phases were separated, the organic phase was washed with saturated solution of NaHCCT (2 x 300 ml). The organic phase was dried over Na2S04, filtered and the solvent evaporated under vacuum. The precipitate obtained was triturated with hexanes (300 ml), EtOAc:Hex 5:95 (100 ml); EtOAc:Hex 10:90 (100 ml), and then dried under vacuum. Yield 3.64 g (57 %). 1 H NMR (400 MHz, CDCl3) d 7.93 (d, J = 8.7 Hz, 1H), 6.27 (dd, J = 8.7, 2.1Hz, 1H), 6.09 (d, J = 2.1Hz, 1H), 4.00 (d, J = 2.5 Hz, 3H), 3.17 (t, J = 7.1Hz, 2H), 1.62 (ddd, J = 12.4, 8.4, 6.5 Hz, 2H), 1.43 (dq, J = 14.4, 7.3 Hz, 2H), 0.96 (dd, J = 8.2, 6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 166.57, 160.59, 154.75, 135.82, 106.66, 105.93, 94.51, 56.78, 43.60, 31.81, 20.73, 14.36.

Reference： [1]Current Patent Assignee: ELEX BIOTECH - WO2019/191502, 2019, A1 Location in patent: Page/Page column 58-59

31
[ 2486-80-8 ]
[ 140-89-6 ]
[ 95420-72-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 4-amino-2-methoxybenzoic acid With hydrogenchloride; sodium nitrite In water at 0℃; Stage #2: potassium ethyl xanthogenate In water at 0 - 20℃; for 1h; Stage #3: With sodium hydroxide In ethanol for 7h; Reflux;	2-Methoxy-4-sulfanylbenzoic acid (15) b. A solution of 3.0 g (17.96 mmol) of amine 18 in7 mL of conc. HCl, cooled to 0°, was treated with a solution of 1.31 g (19.0 mmol) of NaNO2 in 5 mL of water. Potassium ethyl xanthate, 2.8 g (20 mmol), was then added to the resulting diazonium salt solution.The mixture was stirred at 20° for 1 h, and the crude xanthate that precipitated was filtered off. The precipitate was dissolved in 25 mL of ethanol, and 1.4 g(35.0 mmol) of NaOH was added. The mixture was heated under reflux for 7 h, after which the alcohol was removed by distillation, and the dry residue was acidified with 10% AcOH and filtered off. The product was extracted with heptane. Yield 78%, mp 96-97°.1 NMR spectrum (CDCl3), δ, ppm: 3.73 s (1, SH),4.06 s (3, 3), 6.90 s (1, 3), 6.98 d (1, 5, J8.0 Hz), 8.00 d (1, 6, J 8.0 Hz), 10.64 br.s (1,COOH). 13 NMR spectrum (CDCl3), δ, ppm: 56.9(3), 111.0 (5), 114.5 (1), 121.9 (3), 134.1 (6),141.3 (4), 158.2 (2), 165.6 (COOH). Found, %: 52.05; 4.40. C8H8O3S. Calculated, %: C 52.16; 4.38.

Reference： [1]Lomov [Russian Journal of Organic Chemistry, 2019, vol. 55, # 8, p. 1093 - 1098][Zh. Org. Khim., 2019, vol. 55, # 8, p. 1182 - 1187,6]

32
[ 2486-80-8 ]
(R)-N-(pyrrolidin-3-yl)quinazolin-2-amine hydrochloride [ No CAS ]
(R)-(4-amino-2-methoxyphenyl)(3-(quinazolin-2-ylamino)pyrrolidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃;	73.1 Step 1: (R)-(4-amino-2-methoxyphenyl)(3-(quinazolin-2-ylamino)pyrrolidin-l-yl)methanone A mixture of 4-amino-2-methoxybenzoic acid (500 mg, 2.99 mmol), (R)-N-(pyrrolidin-3- yl)quinazolin-2-amine hydrochloride (824 mg, 3.29 mmol), HATU (1.36 g, 3.58 mmol) and DIEA (2.46 mL, 14.95 mmol) in DMF (20 mL) was stirred at rt overnight. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL*3). The combined organic layer was washed with brine (30 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by by silica gel chromatography (DCM/MeOH = 20/1) to afford (R)-(4-amino-2-methoxyphenyl)(3- (quinazolin-2-ylamino)pyrrolidin-l-yl)methanone (750 mg, 69%) as a yellow solid. [M+H] Calc’d for C20H21N5O2, 364.1; Found, 364.1

Reference： [1]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2019/213403, 2019, A1 Location in patent: Paragraph 00360

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

Ghs Hazard Statements

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