[ CAS No. 2486-69-3 ]

Name: 2486-69-3|4-Amino-3-methoxybenzoic acid|97%
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Quality Control of [ 2486-69-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 2486-69-3 ]

CAS No. :	2486-69-3	MDL No. :	MFCD00016539
Formula :	C₈H₉NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JNFGLYJROFAOQP-UHFFFAOYSA-N
M.W :	167.16	Pubchem ID :	288057
Synonyms :

Calculated chemistry of [ 2486-69-3 ]

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) :	-6.54 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.1
Log Po/w (XLOGP3) :	1.1
Log Po/w (WLOGP) :	0.98
Log Po/w (MLOGP) :	-0.37
Log Po/w (SILICOS-IT) :	0.5
Consensus Log Po/w :	0.66

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-1.81
Solubility :	2.6 mg/ml ; 0.0156 mol/l
Class :	Very soluble
Log S (Ali) :	-2.22
Solubility :	1.02 mg/ml ; 0.00608 mol/l
Class :	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 :	1.35

Safety of [ 2486-69-3 ]

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 [ 2486-69-3 ]

* 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 [ 2486-69-3 ]
Downstream synthetic route of [ 2486-69-3 ]

[ 2486-69-3 ] Synthesis Path-Upstream 1~12

1
[ 2486-69-3 ]
[ 85740-98-3 ]

Reference： [1] Patent: EP279698, 1990, A3,

2
[ 121-34-6 ]
[ 2486-69-3 ]

Reference： [1] Patent: US2012/107886, 2012, A1, . Location in patent: Page/Page column 19
[2] Patent: WO2012/75053, 2012, A2, . Location in patent: Page/Page column 83-84

3
[ 5081-36-7 ]
[ 2486-69-3 ]

Reference： [1] Journal of the Chemical Society, 1921, vol. 119, p. 1431
[2] Journal of the Chemical Society, 1917, vol. 111, p. 232

4
[ 619-14-7 ]
[ 2486-69-3 ]

Reference： [1] Journal of the Chemical Society, 1917, vol. 111, p. 232

5
[ 586-38-9 ]
[ 2486-69-3 ]

Reference： [1] Journal of the Chemical Society, 1921, vol. 119, p. 1431

6
[ 67-56-1 ]
[ 2486-69-3 ]
[ 41608-64-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: at 70℃; for 24 h; Stage #2: With sodium hydroxide In water	A solution of 4-amino-3-methoxybenzoic acid (1.5 g, 8.97 mmole) in 15 ml methanol and 4.8 ml sulfuric acid 95-98percent was heated at 70° C. for 24 hrs. Upon completion, the mixture was concentrated down and basified with 2N NaOH solution to pH=8. A solid precipitated out. The suspension was filtered off, solid was washed with water, dried to afford 1.62 g tan solid (56), 100percent yield. ¹H-NMR (400 MHz, DMSO)
96%	at 80℃; for 3 h;	Take a 25ml jar, add 5ml of methanol and 0.5g in order4-amino-3-methoxybenzoic acid, stirring, slowly adding 1 ml of concentrated sulfuric acid,The reaction was refluxed at 80 °C for 3 h. After TLC monitored the reaction, the methanol was decontaminated under vacuum.Saturated sodium carbonate solution was added dropwise to adjust the pH to 9 and 5 ml of dichloromethane was added.The liquid was separated, the organic layer was washed 3 times with saturated sodium chloride, and the aqueous layers were combined.Dichloromethane was extracted twice, the organic layers were combined, and the organic phase was dried over anhydrous sodium sulfate for 1 hour. After the silica gel column, the petroleum ether is separated from the ethyl acetate by 4:1.In other words, 0.52-g methyl 4-amino-3-methoxybenzoate was obtained as an off-white solid.Yield 96percent.
92%	Stage #1: at 0 - 0.7℃; for 1 h; Stage #2: at 15 - 30℃; for 72 h;	This procedure was adopted from a procedure reported in J. Med. Chem., 54, 7815-7833 (2011). Thionyl chloride (1.78g, 0.015 mol) was added dropwise to methanol (8 mL) at 0 °C over a -25 mm. period keeping the temperature at or below 0.7 °C. The resulting mixture was stirred at 0 °C for 1 hr., then 4-amino-3- methoxybenzoic acid (0.5g, 0,003 mol) [ACROS Chemicals] was added in one portion. The reaction mixture was stirred at ambient temperature for 3 days after which the mixture was concentrated in vacuo. Water (5 mL) was added to the residue and sodium bicarbonate (0.3g, 3.6 mmol) was added in one portion and the mixture was stirred at ambient temperature for 30 min. The mixture was extracted several times with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give 0.5g (92percent) of methyl 4-amino-3-methoxybenzoate as a brown solid. MS: m/z 182.1 (MH⁺). 1H NMR (500 MHz, DMSO-d₆): 6 3.741 (s, 3H), 3.797 (s, 3H), 5.608 (s, 2H), 6.630 (d, 1H), 7.281 (d, 1H), 7.375 (dd, 1H).

Reference： [1] Patent: US2009/130076, 2009, A1, . Location in patent: Page/Page column 31; 32
[2] Synlett, 2008, # 11, p. 1698 - 1702
[3] Tetrahedron, 2007, vol. 63, # 2, p. 347 - 355
[4] Patent: CN107827776, 2018, A, . Location in patent: Paragraph 0031; 0032; 0033; 0034
[5] Tetrahedron, 2003, vol. 59, # 28, p. 5317 - 5322
[6] Patent: WO2014/165816, 2014, A1, . Location in patent: Page/Page column 79
[7] Journal of Organic Chemistry, 1996, vol. 61, # 17, p. 5804 - 5812
[8] Patent: WO2014/28669, 2014, A1, . Location in patent: Paragraph 00729
[9] Patent: EP2842939, 2015, A1, . Location in patent: Paragraph 1539; 1540

7
[ 2486-69-3 ]
[ 41608-64-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogenchloride In methanol; ethyl acetate	(a) Methyl 4-amino-3-methoxybenzoate. A stirred solution of 4-amino-3-methoxybenzoic acid (2.50 g, 14.97 mmol) in MeOH saturated with HCl gas was heated at reflux overnight. The volatiles were removed under reduced pressure and the residue dissolved in EtOAc, washed with saturated NaHCO₃ solution, dried over MgSO₄ and concentrated under reduced pressure. The title compound was isolated as a tan solid (97percent).¹H NMR (CDCl₃) δ: 3.87 (s, 3H), 3.91 (s, 3H), 4.5 (br s, 2H), 6.73 (d, 1H, J = 8.1Hz), 7.46 (s, 1H, with fine splitting). Anal. (C₁₂H₁₁NO₃) C, H, N.

Reference： [1] Patent: EP1109560, 2003, B1,

8
[ 2486-69-3 ]
[ 56256-14-5 ]

Reference： [1] Organic Letters, 2006, vol. 8, # 26, p. 5963 - 5966
[2] Beilstein Journal of Organic Chemistry, 2017, vol. 13, p. 1518 - 1523

9
[ 2486-69-3 ]
[ 102362-04-9 ]

Reference： [1] Archiv der Pharmazie, 1990, vol. 323, # 8, p. 507 - 512

10
[ 64-17-5 ]
[ 2486-69-3 ]
[ 73368-41-9 ]

Yield	Reaction Conditions	Operation in experiment
89.1%	Reflux; Inert atmosphere; Cooling; Large scale	A 22-L 3-necked RBF equipped with an electrical heating mantle, a thermocouple probe, overhead mechanical stirrer, water-cooled condenser, nitrogen bubbler and addition funnel was charged with 4-amino-3-methoxybenzoic acid (1.0 kg, 5.98 mol, 1.0 equiv.) and ethanol (200 proof) (10.0 L, 10 vol.) to produce a stirrable slurry. Without external cooling, sulfuric acid (1.17 kg, 0.64 L, 12.0 mol, 2.0 equiv.) was then added slowly over 1 h, the slurry initially goes thick, but breaks up and eventually all solids dissolve to form a dark solution. The exothermic addition increased the temperature to -45 °C; additional heating was then applied to bring the solution to reflux and was held at reflux overnight. An HPLC sample was taken and showed -5percent starting benzoic acid remaining. The reflux head was switched to full takeoff and 2.5 L was distilled off. The reaction was cooled to 6 °C in an ice bath and the pH slowly adjusted to 12 by the addition of a solution of sodium hydroxide (50 wt percent, 1.03 kg, 681 ml, 12.9 mol, 2.15 equiv.) in water (3.5 L) keeping the temperature below 20 °C. Following a 30 min. post-stir, an additional quantity of water (4.0 L) was added and stirred at ca. 10 °C for 30 min. The solid were filtered, washed thoroughly with water (4.0 L), and then vacuum dried at 65 °C overnight. The yield of ethyl 4- amino-3-methoxybenzoate was 1.04 kg (89.1percent) as a light brown solid. m.p.= 83-87 °C (DSC); 1H NMR (300 MHz, CDC1₃) δ 7.56 (1H, dd, J = 7.9, 1.5 Hz), 7.47 (1H, d J=1.5 Hz), 6.66 (1H, d, J= 7.9 Hz), 4.33 (2H, t, J= 7.2 Hz), 4.27 (1H, br s), 3.90 (3H), 1.37 (3H, t, J = 7.2 Hz).

Reference： [1] Journal of the American Chemical Society, 1998, vol. 120, # 14, p. 3332 - 3339
[2] Patent: WO2014/128094, 2014, A1, . Location in patent: Page/Page column 22
[3] European Journal of Medicinal Chemistry, 2007, vol. 42, # 5, p. 567 - 579
[4] Patent: US2009/259049, 2009, A1, . Location in patent: Page/Page column 12
[5] Patent: US2011/86882, 2011, A1, . Location in patent: Page/Page column 27

11
[ 2486-69-3 ]
[ 73368-41-9 ]

Reference： [1] Patent: US6024937, 2000, A,

12
[ 2486-69-3 ]
[ 180624-10-6 ]

Reference： [1] Tetrahedron, 2007, vol. 63, # 2, p. 347 - 355
[2] Journal of Organic Chemistry, 1996, vol. 61, # 17, p. 5804 - 5812

[ 2486-69-3 ] Synthesis Path-Downstream 1~57

1
[ 2486-69-3 ]
[ 544-92-3 ]
[ 102362-00-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium nitrite 1.) H₂O, 0-5 deg C, 1 h, 2.a) 50 deg C, 2.b) 2 h, reflux; Yield given. Multistep reaction;

Reference： [1]Barraclough; Black; Cambridge; Demaine; Gerskowitch; Giles; Hill; Hull; Lyer; King; Livingstone; Nobbs; Randall; Shah; Whiting [Archiv der Pharmazie, 1990, vol. 323, # 8, p. 507 - 512]

2
[ 64-17-5 ]
[ 2486-69-3 ]
[ 73368-41-9 ]

Yield	Reaction Conditions	Operation in experiment
89.1%	With sulfuric acid;Reflux; Inert atmosphere; Cooling; Large scale;	A 22-L 3-necked RBF equipped with an electrical heating mantle, a thermocouple probe, overhead mechanical stirrer, water-cooled condenser, nitrogen bubbler and addition funnel was charged with 4-amino-3-methoxybenzoic acid (1.0 kg, 5.98 mol, 1.0 equiv.) and ethanol (200 proof) (10.0 L, 10 vol.) to produce a stirrable slurry. Without external cooling, sulfuric acid (1.17 kg, 0.64 L, 12.0 mol, 2.0 equiv.) was then added slowly over 1 h, the slurry initially goes thick, but breaks up and eventually all solids dissolve to form a dark solution. The exothermic addition increased the temperature to -45 C; additional heating was then applied to bring the solution to reflux and was held at reflux overnight. An HPLC sample was taken and showed -5% starting benzoic acid remaining. The reflux head was switched to full takeoff and 2.5 L was distilled off. The reaction was cooled to 6 C in an ice bath and the pH slowly adjusted to 12 by the addition of a solution of sodium hydroxide (50 wt %, 1.03 kg, 681 ml, 12.9 mol, 2.15 equiv.) in water (3.5 L) keeping the temperature below 20 C. Following a 30 min. post-stir, an additional quantity of water (4.0 L) was added and stirred at ca. 10 C for 30 min. The solid were filtered, washed thoroughly with water (4.0 L), and then vacuum dried at 65 C overnight. The yield of ethyl 4- amino-3-methoxybenzoate was 1.04 kg (89.1%) as a light brown solid. m.p.= 83-87 C (DSC); 1H NMR (300 MHz, CDC13) delta 7.56 (1H, dd, J = 7.9, 1.5 Hz), 7.47 (1H, d J=1.5 Hz), 6.66 (1H, d, J= 7.9 Hz), 4.33 (2H, t, J= 7.2 Hz), 4.27 (1H, br s), 3.90 (3H), 1.37 (3H, t, J = 7.2 Hz).
		To a mixture of 4-amino-3-methoxybenzoic acid (15 g, 89.7 mmol) and ethanol (170 mL) was added concentrated sulfuric acid (5 mL), and the mixture was heated to reflux for 7 hours. The reaction mixture was then returned to room temperature. The solvent in the filtrate was distilled off under reduced pressure. Water, a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added to the residue After thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was then filtered, and the solvent in the filtrate was distilled off under reduced pressure to obtain the title compound (17.8 g, 91.2 mmol). 1H-NMR (CDCl3) delta: 1.37 (t, J=6.8 Hz, 3H), 3.90 (s, 3H), 4.32 (q, J=6.8 Hz, 2H) 6.66 (d, J=8.0 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.54 (dd, T=1.6, 8.0 Hz, 1H).
		Production Example 13-1Ethyl 4-amino-3-methoxybenzoate To a mixture of 4-amino-3-methoxybenzoic acid (15 g, 89.7 mmol) and ethanol (170 mL), was added concentrated sulfuric acid (5 mL), and the mixture was heated to reflux for seven hours. The reaction mixture was returned to mom temperature. The solvent in the mixture was distilled off under reduced pressure. To the residue, were added water, a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate.After thoroughly shaking the mixture, the organic layer was separated, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure to obtain the title compound (17.8 g, 91.2 mmol).1H-NMR (CDCl3) delta: 1.37 (t, J=6.8 Hz, 3H), 3.90 (s, 3H), 4.32 (q, J=6.8 Hz, 2H), 6.66 (d, J=8.0 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.54 (dd, J=1.6, 8.0 Hz, 1H).

Reference： [1]Journal of the American Chemical Society,1998,vol. 120,p. 3332 - 3339
[2]Patent: WO2014/128094,2014,A1 .Location in patent: Page/Page column 22
[3]European Journal of Medicinal Chemistry,2007,vol. 42,p. 567 - 579
[4]Patent: US2009/259049,2009,A1 .Location in patent: Page/Page column 12
[5]Patent: US2011/86882,2011,A1 .Location in patent: Page/Page column 27

3
[ 67-56-1 ]
[ 2486-69-3 ]
[ 41608-64-4 ]

Yield	Reaction Conditions	Operation in experiment
100%		A solution of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (1.5 g, 8.97 mmole) in 15 ml methanol and 4.8 ml sulfuric acid 95-98% was heated at 70 C. for 24 hrs. Upon completion, the mixture was concentrated down and basified with 2N NaOH solution to pH=8. A solid precipitated out. The suspension was filtered off, solid was washed with water, dried to afford 1.62 g tan solid (56), 100% yield. 1H-NMR (400 MHz, DMSO)
96%	With sulfuric acid; at 80℃; for 3h;	Take a 25ml jar, add 5ml of methanol and 0.5g in order<strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong>, stirring, slowly adding 1 ml of concentrated sulfuric acid,The reaction was refluxed at 80 C for 3 h. After TLC monitored the reaction, the methanol was decontaminated under vacuum.Saturated sodium carbonate solution was added dropwise to adjust the pH to 9 and 5 ml of dichloromethane was added.The liquid was separated, the organic layer was washed 3 times with saturated sodium chloride, and the aqueous layers were combined.Dichloromethane was extracted twice, the organic layers were combined, and the organic phase was dried over anhydrous sodium sulfate for 1 hour. After the silica gel column, the petroleum ether is separated from the ethyl acetate by 4:1.In other words, 0.52-g methyl 4-amino-3-methoxybenzoate was obtained as an off-white solid.Yield 96%.
92%		This procedure was adopted from a procedure reported in J. Med. Chem., 54, 7815-7833 (2011). Thionyl chloride (1.78g, 0.015 mol) was added dropwise to methanol (8 mL) at 0 C over a -25 mm. period keeping the temperature at or below 0.7 C. The resulting mixture was stirred at 0 C for 1 hr., then 4-amino-3- methoxybenzoic acid (0.5g, 0,003 mol) [ACROS Chemicals] was added in one portion. The reaction mixture was stirred at ambient temperature for 3 days after which the mixture was concentrated in vacuo. Water (5 mL) was added to the residue and sodium bicarbonate (0.3g, 3.6 mmol) was added in one portion and the mixture was stirred at ambient temperature for 30 min. The mixture was extracted several times with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give 0.5g (92%) of methyl 4-amino-3-methoxybenzoate as a brown solid. MS: m/z 182.1 (MH+). 1H NMR (500 MHz, DMSO-d6): 6 3.741 (s, 3H), 3.797 (s, 3H), 5.608 (s, 2H), 6.630 (d, 1H), 7.281 (d, 1H), 7.375 (dd, 1H).

	With thionyl chloride;Cooling with ice; Reflux;	Stepl: To a mixture of compound 38b-l (25.5 g, 153 mmol, 1.0 eq.) in dry MeOH (250 mL) was added dropwise SOCl2 (50 mL) under ice-water bath, and then the mixture was stirred at reflux overnight. TLC (PE/EA = 2/1) showed that the reaction was complete. Then the mixture was concentrated under reduced pressure. The mixture was diluted with water (500 mL), basified to pH = 9 with 1 N aq. NaOH, and extracted with EA (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2S04, filtered, and concentrated to give target compound 38b-2. 'HNMR: (400 MHz, DMSO) delta: 7.40 (dd, J = 8.4, 1.6 Etazeta,IotaEta), 7.29 (d, / = 1.6 Hz, 1H), 6.64 (d, / = 8.4 Hz, 1H), 5.65 (br, 2H), 3.81 (s, 3H), 3.76 (s, 3H).
	With sulfuric acid; at 65℃; for 13h;Reflux;	[Example 729] Compound q8 Methyl 4-amino-3-methoxybenzoate [1539] <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> under the same conditions as for Compound dd5. However, the reaction was performed at a temperature of 65C.

Reference： [1]Patent: US2009/130076,2009,A1 .Location in patent: Page/Page column 31; 32
[2]Synlett,2008,p. 1698 - 1702
[3]Tetrahedron,2007,vol. 63,p. 347 - 355
[4]Patent: CN107827776,2018,A .Location in patent: Paragraph 0031; 0032; 0033; 0034
[5]Tetrahedron,2003,vol. 59,p. 5317 - 5322
[6]Patent: WO2014/165816,2014,A1 .Location in patent: Page/Page column 79
[7]Journal of Organic Chemistry,1996,vol. 61,p. 5804 - 5812
[8]Patent: WO2014/28669,2014,A1 .Location in patent: Paragraph 00729
[9]Patent: EP2842939,2015,A1 .Location in patent: Paragraph 1539; 1540

4
[ 24424-99-5 ]
[ 2486-69-3 ]
[ 180976-98-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In 1,4-dioxane;	A. N-BOC-<strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (1 g, 5.98 mmol) was reacted with di-t-butyl dicarbonate (1.96 g, 6.58 mmol) in dioxane (12 ml) and 0.5 M NaOH (12 ml) according to the same procedure as N-BOC-4-aminobenzoic acid. 1.50 g (93.7%) of tan crystals were obtained after recrystallization from ethyl acetate and hexanes. mp 176-178 C.; 1 H NMR (CD3 OD) 1.52 (9H, s), 3.92 (3H, s), 7.56 (1H, s), 7.62 (1H, d, J=8.4 Hz), 7.96 (1H, s), 8.03 (1H, d, J=8.4 Hz); 13 C NMR (CD3 OD) 28.53, 56.35, 81.78, 112.01, 118.58, 124.20, 125.76, 133.84, 149.04, 154.20, 169.60; HRMS calc. for C13 H17 NO5, 267.1107; found, 267.1103.
	With sodium hydroxide; In 1,4-dioxane;	N-BOC-<strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (1 g, 5.98 mmol) was reacted with di-t-butyl dicarbonate (1.96 g, 6.58 mmol) in dioxane (12 ml) and 0.5M NaOH (12 ml) according to the same procedure as N-BOC-4-aminobenzoic acid. 1.50 g (93.7%) of tan crystals were obtained after recrystallization from ethyl acetate and hexanes. mp 176-178 C.; 1 H NMR (CD3 OD) 1.52 (9 H, s), 3.92 (3 H, s), 7.56 (1 H, s), 7.62 (1 H, d, J=8.4 Hz), 7.96 (1 H, s), 8.03 (1 H, d, J=8.4 Hz); 13 C NMR (CD3 OD) 28.53, 56.35, 81.78, 112.01, 118.58, 124.20, 125.76, 133.84, 149.04, 154.20, 169.60; HRMS calc. for C13 H17 NO5 267.1107; found, 267.1103.
	With sodium hydroxide; In 1,4-dioxane; water; at 20℃; for 24h;	General procedure: To a mixture of 4-aminobenzoic acid 1a (5.00g, 36.5mmol) in dioxane (70mL) and water (35mL) were added NaOH (1.46g, 36.5mmol) followed by di-tert-butyl dicarbonate (11.9g, 54.8mmol). The reaction mixture was stirred at room temperature for 24h. Solvent was removed by rotary evaporation, and 3N aqueous hydrochloric acid was added dropwise to the residue to adjust pH 3. A precipitate was obtained, collected, washed with water, and dried to provide 2a (8.28g, 96%) as a solid.

Reference： [1]Bioorganic and Medicinal Chemistry,1999,vol. 7,p. 3011 - 3024
[2]Patent: US5965539,1999,A
[3]Patent: US5834434,1998,A
[4]European Journal of Medicinal Chemistry,2015,vol. 95,p. 174 - 184

5
[ 134-47-4 ]
[ 2486-69-3 ]
C₃₇H₂₈N₆O₁₅S₂ [ No CAS ]

Reference： [1]Bioorganic Chemistry,2000,vol. 28,p. 140 - 155

6
[ 2486-69-3 ]
[ 56256-14-5 ]

Yield	Reaction Conditions	Operation in experiment
		In a 50-mL round-bottom flask, 4-aminoanisidic acid (14, 0.84 g, 5.0 mmol) wasdissolved in MeCN (10 mL). To the solution was added slowly 47% aqueous HBr (10mL) at 0 C, and then NaNO2 (0.38 g, 5.5 mmol) was added to give a brown suspension.After the suspension was stirred for 30 min, CuBr (0.86 g, 6.0 mmol) was added.Subsequently, the reaction mixture was warmed to 50 C and stirred for 1 h. Thereaction mixture was then cooled to 0 C, and cold H2O (20 mL) was poured into the flask to form white precipitates. The solid was filtrated, washed with cold H2O, and dried in vacuo. The reaction proceeded quantitatively to afford 9a, and the crude product was used without further purification.

Reference： [1]Organic Letters,2006,vol. 8,p. 5963 - 5966
[2]Beilstein Journal of Organic Chemistry,2017,vol. 13,p. 1518 - 1523

7
[ 946825-98-5 ]
[ 2486-69-3 ]
[ 946822-60-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	With hydrogenchloride; In ethanol; water; at 90℃; for 24h;	Method D: 4-(9-Cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxo-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-1); 2-Chloro-9-cyclopentyl-8,9-dihydro-5-methyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (150 mg, 0.536 mmol) in ethanol (2.25 ml) and water (9 ml) was treated with conc. HCl (0.088 ml) and <strong>[2486-69-3]4-amino-3-methoxy benzoic acid</strong> (134 mg, 0.804 mmol). The mixture was stirred at 90 C. 24 hours, concentrated and the residue triturated with methanol/ether, filtered and the solid washed with ethanol then ether to give 4-(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxo-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as a buff powder (185.5 mg, 84%). NMR DMSO D6 1.51-1.79 (6H, m), 1.82-1.93 (2H, m), 2.70-2.75 (2H m), 3.18 (3H, s), 3.72-3.78 (2H, m), 3.98 (3H, s), 4.81-4.93 (1H, m), 7.57-7.64 (2H, m), 8.15-8.22 (2H, m), 9.46 (1H, br s); HPLC rt(min): 6.57.
68%	In ethanol; water; for 36h;Heating / reflux;	To a solution of 110-Chloro-2-cyclopentyl-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1, 10.62 g, 36 mmol) and <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (Aldrich, 6.795 g, 40.7 mmol) in ethanol (150 mL) was added water (450 mL) and conc hydrochloric acid 96 mL, 72 mmol). The mixture was heated under reflux for 36 hours. The reaction was cooled and a brown solid precipitate formed which was filtered, triturated with cold acetonitrile and dried in vacuo to give the title compound (10.1 g, 68%).1H NMR (399.9 MHz, DMSO-d6) delta1.55-1.75 (6H, m), 1.87-1.95 (2H, m), 2.71-2.75 (2H, m), 3.18 (3H, s), 3.71-3.76 (2H, m), 3.95 (3H, s), 4.79-4.93 (1H, m), 7.58-7.62 (2H, m), 8.19 (1H, d), 8.19 (1H, s), 9.37 (1H, s); MS m/z 412 [M+H]+.
64%	With trifluoroacetic acid; In 2,2,2-trifluoroethanol; for 20h;Heating / reflux;Product distribution / selectivity;	Intermediate 8: 4-(9-Cyclopentyl~5-methyl-6-oxo-6, 7,8,9-tetrahydro-5H-pyrimido[4,5- bjfl, 4]diazepin-2-ylamino)-3-methoxybenzoic acid; 2-Chloro-9-cyclopentyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][l,4]diazepin-6(7H)- one (Intermediate 1) (0.70 g, 2.5 mmol, 1 eq), <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (1.25 g, 7.5 mmol, 3 eq) and TFA (0.93 mL, 12.5 mmol, 5 eq) were heated to reflux in TFE (25 mL) for 20 hours. Solvent was evaporated in vacuo and the resulting residue was triturated with MeOH to give 4-(9-cyclopentyl-5-methyl-6-oxo-6, 7,8,9-tetrahydro-5H- pyrimido[4,5-b][l,4]diazepin-2-ylamino)-3-methoxybenzoic acid (0.66 g, 64%).Rt = 1.88 min (AnalyticalJ); MS(+ve): 412.4, MS (-ve): 410.5.

14%	With hydrogenchloride; In ethanol; water; for 4h;Heating / reflux;Product distribution / selectivity;	Step 6: (Compound [I]) 4-(9-Cyclopentyl-5-methyl-6-oxo-6, 7,8,9-tetrahydro-5H- pyrimido[4, 5-bJ[l, 4]diazepin-2-ylamino)-benzoic acid.; Coupling Method A; 2-Chloro-9-cyclopentyl-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-o] [1 ,4]diazepin- 6-one (248 mg, 0.0009 mol) and <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (221 mg, 0.0013 mol, 1.5 eq), cone. HCl (152 mul) and H2OZEtOH (8:2 ml) were added to a RBF and the resulting RM heated to reflux for 4h. Progress of the reaction was monitored by HPLC and when no starting material remained (4h reaction time), the RM was concentrated under reduced pressure and the product extracted using DCM/H2O. The organic extracts were combined, washed with sat NaCl, dried using MgSO4, filtered and the filtrate evaporated under reduced pressure and further dried in vacuo to give a brown oily residue. A few drops of MeOH were added to the residue and the solid ppt formed was collected by suction filtration, washed with MeOH and further dried in vacuo to give the product as a purple solid (51 mg, 14%); Rt = 11.2 min (0_60_20 min, purity 100%); 1H NMR (DMSO-betafe): delta 1.61 (bs, 4H, cyclopent-H), 1.72 (bs, 2eta, cyclopent-H), 1.94 (bs, 2H, cyclopent-H), 2.59 (dd, J= 4.5 Hz, 2H, CH2), 3.18 (s, 3eta, CH3), 3.63 (dd, J = 4.5 Hz, 2H, CH2), 3.95 (s, 3eta, CH3), 7.51 (s, 1eta), 7.56 (d, J= 8 Hz, IH3 phe-H), 7.82 (s, IH5 8.10 (s, IH, 8.47 (d, J= 8.5 Hz, IH, phe-H), 12.64 (bs, 1eta, NH); MS+ve: 412.2.
	With hydrogenchloride; In ethanol; water; at 100℃;	Step d A mixture of 0.135 g (0.00048 mole) of 2-chloro-9-cyclopentyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-10), 0.096 g (0.00058 mole) of <strong>[2486-69-3]4-amino-3-methoxy-benzoic acid</strong>, 1 mL of ethanol, 3 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.14 g of 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-10) as an off-white solid.
	With hydrogenchloride; In ethanol; water; at 100℃; for 24h;	A mixture of Compound 7, l-(4-amino-3-methoxyphenyl)-2-hydroxyethanone (Compound 8), ethanol (4.7 ml), water (18.3 ml) and concentrated hydrochloric acid (0.18 ml) was stirred at 1000C for 24 hours. The mixture was concentrated in vacuo. The residue was crystallized from ethanol - diethyl ether to give Compound 9 as a white powder. 1H NMR (300 MHz, DMSO-J6) delta 1.50 - 1.76 (6 H, m), 1.82 - 2.01 (2 H, m), 2.66 - 2.81 (2 H, m), 3.17 (3 H, s), 3.69 - 3.79 (2 H, m), 3.94 (3 H, s), 4.88 (1 H, quintet, J=8.1 <n="161"/>Hz), 7.53 - 7.70 (2 H, m), 8.15 (1 H, d, J=8.3 Hz), 8.19 (1 H, s), 9.50 (1 H, s), 12.94 (1 H, br. s.). [M+H] calc'd for C2iH25N5O4, 412; found, 412.

Reference： [1]Patent: US2008/167289,2008,A1 .Location in patent: Page/Page column 60
[2]Patent: US2008/9482,2008,A1 .Location in patent: Page/Page column 42
[3]Patent: WO2009/40556,2009,A1 .Location in patent: Page/Page column 83
[4]Patent: WO2009/40556,2009,A1 .Location in patent: Page/Page column 46
[5]Patent: US2008/234255,2008,A1 .Location in patent: Page/Page column 16
[6]Patent: WO2009/67547,2009,A1 .Location in patent: Page/Page column 158; 159-160
[7]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1247 - 1250

8
[ 2486-69-3 ]
[ 108-91-8 ]
[ 959785-39-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 18 - 25℃; for 18h;	EDAC (7.46 g, 3.90 mmol) was added to a stirred solution of 4-amino-3-methoxy acid(Aldrich; 5 g, 2.9 mmol), cyclohexylamine (Aldrich; 5.13 mL, 4.49 mmol) and DMAP (11 g, 9 mmol) in DCM (200 mL) and the reaction mixture was stirred for a 18 hrs. under an atmosphere of nitrogen. The mixture was washed with 1M citric acid solution (×3), saturated sodium bicarbonate solution and dried. The solvent was evaporated off and the residue triturated with diethylether to give the title compound as a pink solid (5.3 g, 71%)MS m/z 293 [M+H]+.

Reference： [1]Patent: US2008/9482,2008,A1 .Location in patent: Page/Page column 123-124

9
[ 946826-05-7 ]
[ 2486-69-3 ]
[ 946823-71-8 ]

Yield	Reaction Conditions	Operation in experiment
76%	With trifluoroacetic acid; In 2,2,2-trifluoroethanol; for 36h;Heating / reflux;	Intermediate 6: 4-(9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7,8,9-tetrahydroSH- pyrimido[4, 5-b][l, 4]diazepin-2-ylamino)-3-methoxybenzoic acid; 2-CWoro-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][l;,4]diazepin- 6(7H)-one (Intermediate 3) (0.35 g, 1.14 mmol, 1 eq), <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (0.57 g, 3.42 mmol, 3 eq) and TFA (0.42 mL, 5.7 mmol, 5 eq) were heated to reflux in TFE (10 mL) for 36 hours. Solvent was evaporated in vacuo and the resulting residue was triturated with EtOAc to give 4-(9-cyclopentyl-5) 7, 7-trimethyl-6-oxo-6, 7,8,9- tetrahydro-5H-pyrimido[4>5-b][l,4]diazepin-2-ylamino)-3-methoxybenzoic acid (0.38 g, 76%).MS(+ve): 440.3, MS(-ve): 438.5.
70%	With hydrogenchloride; In water; isopropyl alcohol; at 100℃; for 20h;	4-(9-Cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido[4,5-b] [l,4]diazepin-2-ylamino)-3-methoxybenzoic acid; A mixture of 2- chloro-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5b][l,4]diazepin-6(7H)- <n="211"/>one (2 g, 6.48 mmol), <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (1 g, 6.5 mmol), isopropanol (30 ml), and concentrated hydrochloric acid (20 drops) was stirred at 1000C for 20 h. Solid was filtered to give 1.92 g 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido[4,5-b][l,4]diazepin-2-ylamino)-3-methoxybenzoic acid as white solid (70%). 1H NMR (400 MHz, DMSO-J6) delta ppm 1.14 (s, 6 H) 1.53 - 1.70 (m, 4 H) 1.73 (d, J=5.3 Hz, 2 H) 1.79 - 1.91 (m, 1 H) 1.85 (d, J=5.8 Hz, 1 H) 3.17 (s, 4 H) 3.94 (s, 3 H) 5.12 (qd, J=8.4, 8.2 Hz, 1 H) 7.60 (d, J=I.5 Hz, 1 H) 7.58 (s, 1 H) 8.08 (s, 1 H) 8.15 (d, J=8.3 Hz, 1 H) 9.33 (br. s., 1 H) 12.96 (br. s., 1 H). [M+H] calc'd for C23H29N5O4, 440; found, 440.
48%	With hydrogenchloride; In ethanol; water; for 36h;Heating / reflux;	To a solution of 10-chloro-2-cyclopentyl-4,4,6-trimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 126; 616 mg, 2.0 mmol) and <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (378 mg, 2.2 mmol) in ethanol (5 mL) was added water (15 mL) and conc hydrochloric acid (0.335 mL). The mixture was heated under reflux for 36 hours. The reaction was cooled and a brown solid precipitated. This was filtered, dried and triturated under cold acetonitrile and then dried in vacuo to give the product as a pale brown solid (420 mg), 48%)1H NMR (400.13 MHz, DMSO-d6) delta1.15 (6H, s), 1.55-1.90 (8H, m), 3.19 (3H, s), 3.53 (2H, s), 3.95 (3H, s), 5.07-5.16 (1H, m), 7.59-7.61 (2H, m), 8.11 (1H, s), 8.13 (1H, d), 9.53 (1H, s); MS m/z 440 [M+H]+.

With hydrogenchloride; In ethanol; water; for 17h;Heating / reflux;

Step e A mixture of 25.26 g (0.0818 mole) 2-chloro-9-cyclopentyl-5,7,7-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-38), 15.35 g (0.0900 mole) of <strong>[2486-69-3]4-amino-3-methoxy-benzoic acid</strong>, 300 mL of ethanol and 1200 mL of 1M hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the precipitate which formed was collected by filtration to give 18.7 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-38) as white solid.

Reference： [1]Patent: WO2009/40556,2009,A1 .Location in patent: Page/Page column 82
[2]Patent: WO2009/67547,2009,A1 .Location in patent: Page/Page column 207; 209-210
[3]Patent: US2008/9482,2008,A1 .Location in patent: Page/Page column 65
[4]Patent: US2008/234255,2008,A1 .Location in patent: Page/Page column 28
[5]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1247 - 1250

10
[ 4774-14-5 ]
[ 2486-69-3 ]
[ 1000068-09-6 ]

Yield	Reaction Conditions	Operation in experiment
77%	With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 135℃;Heating / reflux;Product distribution / selectivity;	Intermediate 21 4-[(6-chloropyrazin-2-yl)amino]-3-methoxybenzoic acid A mixture of 2,6-dichloropyrazine (200 mg, 1.35 mmol), 4-amino 3-methoxy benzoic acid (251 mg, 1.5 mmol), Pd2(dba)3 ( 10 mg), Xantphos (20 mg) and NaOtBu (288 mg, 3 mmol) was suspended in dioxane ( 10 ml) and stirred un- der nitrogen atl35C in a sealed tube for 3h. The resulting suspension was partitioned between ethyl acetate and water. The aqueous phase was neutralised with a few drops of cone, hydrochloric acid to produce a precipitate. Back extraction of the mixture with ethyl acetate followed by drying and concentration of the organic phase gave the title product a brown solid (289 mg, 77%, >90% purity).; Example 153 <n="128"/>N-(4-.[3-(dimethylaniino)pyrrolidin-l-yl1carbonyl.-2-niethoxyphenyl)-6-(lH- indol-2-yl)pyrazin-2-amine1.6 g (1 1.0 mmol) of 2,6-dichloropyrazine was dissolved in 150 mL dioxane and to the solution were 2.0 g (12.0 mmol) of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong>, 2.1 g (22.0 mmol) of NaOtBu, 160 mg Xantphos and 80 mg Pd2dba3 added. The mixture was heated at 1350C overnight and then partioned between water and EtOAc, and the aques phase was treated with a few drops of cone HCl and then extracted with EtOAc several times. The collected organic phases after acidification were combined, filtrated and concentrated to give 4-[(6- chloropyrazin-2-yl)amino]-3-methoxybenzoic acid as a yellow solid, amount 2.5 g.; Example 1744-[6-(5-chloro-lH-indol-2-yl)pyrazin-2-yl1anino)-3-nethoxy-N-nethyl-N- ( l-methylpyrrolidin-3-yl)benzamide trifluoroacetateA mixture of 2,6-dichloropyrazine (3.30 g, 22.2 mmol), 4-amino-3- methoxybenzoic acid (4.07 g, 24.4 mmol), NaOtBu (4.47 g, 46.5 mmol), Xant- phos (390 mg, 0.7 mmol) and Pd2(dba)3 (203 mg, 0.2 mmol) was stirred in dry dioxane (200 mL). The reaction mixture was refluxed at 135 0C for 4 hours, then allowed to attain rt and stored over night. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in a 125 mL EtOAc and 150 mL 1 M aq HCl. The phases were separated, and the aqueous layer was extracted with EtOAc (2x125 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated to give a redbrown solid (5.24 g) of 4-[(6-chloropyrazin-2-yl)amino]-3-methoxybenzoic acid. The material was used without further purification. MS (ESI+) for C12H10CIN3O3 m/z 280 (M+H)+. To a solution of 4-[(6-chloropyrazin-2-yl)amino]-3-methoxybenzoic acid (1.4Og, 5.00 mmol) in dry MeCN (50 mL) were added NEt3 (1.39 mL, 10.0 mmol), 2,4,6-tripropyl- l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50% in EtOAc, 5.96 mL, 10.0 mmol) and N, l-dimethylpyrrolidin-3-amine (857 mg, 7.51 mmol). The mixture was heated at 60 0C for 100 min. The mixture was concentrated in vacuo and residue was dissolved in EtOAc ( 100 mL) and 1 M aq NaOH (150 mL). The phases were separated, and the aqueous layer was extracted with EtOAc (2x100 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated to give 1.8 g of a dark brown gum. Purification was performed by flash chromatography (DCM/NEt3/MeOH, 98: 1 : 1). This gave 4-[(6-chloropyrazin-2-yl)amino]-3-methoxy-N-methyl-N-(l- <n="154"/>methylpyrrolidin-3-yl)benzamide as a light brown solid (930 mg). MS (ESI+) for Ci8H22ClN5O2 m/z 376 (M+H)+. 4-[(6-A mixture of chloropyrazin-2-yl)amino]-3- methoxy-N-methyl-N-(l-methylpyrrolidin-3-yl)benzamide (20 mg, 0.05 mmol), [l-(tert-butoxycarbonyl)-5-chloro- lH-indol-2-yl]boronic acid (17 mg, 0.06 mmol), NaHCO3 (16 mg, 0.19 mmol) and Pd(PPh3J4 (3 mg, 0.003 mmol) inDME/water (3.5: 1, 1 mL) were irradiated in a microwave oven at 120 0C for 10 min. Additional [l-(tert-butoxycarbonyl)-5-chloro- lH-indol-2-yl]boronic acid (1 eq), NaHCO3 (3 eq) and Pd(PPh3)4 (5 mg) were added and reacted at 120 0C for 10 min. The reaction mixture was extracted with EtOAc (2x3 mL) and washed with IM aqueous NaOH (3 mL). The organic layers were combined and concentrated in vacuo. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA, MeCN) to give the title compound as a brown gum (2 mg). HPLC 99% (System A), 99% (System B). MS (ESI+) calcd for C26H27ClN6O2 490.1884, found 490.1880.; Intermediate 456-chloro-N-(4-[(3R)-3-(dimethylamino)pyrrolidin-l-yl]carbonyl}-2- methoxyphenyl)pyrazin-2-amine2,6-Dichloropyrazine (2.00 g, 13.4 mmol), <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (2.47 g, 14.8 mmol), NaOtBu (2.71 g, 28.2 mmol), Xantphos (233 mg, 0.40 mmol) and Pd2(dba)3 (123 mg, 0.13 mmol) were stirred in dry dioxane (100 mL). The reaction mixture was refluxed at 135 0C over night. The mixture was extracted with EtOAc (3x 100 mL) and IM aq HCl (125 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated under reduced pressure to give 3.22 g of a brown solid. The material was used in the next step without further purification. Half of the material was suspended in dry MeCN (50 mL) and NEt3 (1.58 mL, 1 1.4 mmol), 2,4,6-tripropyl- 1,3, 5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide (...

Reference： [1]Patent: WO2007/147874,2007,A1 .Location in patent: Page/Page column 120-121; 126-127; 152-153; 164-165

11
[ 2486-69-3 ]
[ 180624-10-6 ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 347 - 355
[2]Journal of Organic Chemistry,1996,vol. 61,p. 5804 - 5812

12
[ 2486-69-3 ]
[ 102362-04-9 ]

Reference： [1]Archiv der Pharmazie,1990,vol. 323,p. 507 - 512

13
[ 755039-55-5 ]
[ 2486-69-3 ]
[ 755039-56-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ethanol; water; for 48.0h;Heating / reflux;	6.0 g of the compound Z3e and 5.1 g (31 mmol) 4-amino-3-methoxybenzoic acid are suspended in 90 mL ethanol and 350 mL water, combined with 3.5 mL concentrated hydrochloric acid and refluxed for 48 h. The reaction mixture is evaporated down, the residue stirred with methanol/diethyl ether and the precipitate formed is suction filtered. Yield: 6.3 g of a compound Z3 (light beige crystals)
	With hydrogenchloride; In ethanol; water; for 48.0h;Heating / reflux;	6.0 g of the compound Z3e and 5.1 g (31 mmol) of 4-amino-3-methoxybenzoic acid are suspended in 90 mL ethanol and 350 mL water, combined with 3.5 mL conc. hydrochloric acid and refluxed for 48 h. The reaction mixture is evaporated down, the residue is stirred with methanol/diethyl ether and the precipitate formed is suction filtered. Yield: 6.3 g of a compound Z3 (light beige crystals)
	With hydrogenchloride; In ethanol; water; for 48.0h;Heating / reflux;	6.0 g of the compound Z3e and 5.1 g (31 mmol) 4-amino-3-methoxybenzoic acid were suspended in 90 mL ethanol and 350 mL water, combined with 3.5 mL conc. hydrochloric acid and refluxed for 48 h. The reaction mixture was evaporated down, the residue stirred with methanol/diethyl ether and the precipitate formed was suction filtered. Yield: 6.3 g of a compound Z3 (light beige crystals)

Reference： [1]ChemBioChem,2016,vol. 17,p. 759 - 767
[2]Angewandte Chemie - International Edition,2011,vol. 50,p. 9378 - 9381
[3]Patent: WO2006/18182,2006,A1 .Location in patent: Page/Page column 47; 59
[4]Patent: US2006/35903,2006,A1 .Location in patent: Page/Page column 15
[5]Patent: US2004/176380,2004,A1 .Location in patent: Page/Page column 10
[6]Patent: WO2004/76454,2004,A1 .Location in patent: Page/Page column 28; 29
[7]Journal of Medicinal Chemistry,2018,vol. 61,p. 7785 - 7795

14
[ 755039-65-7 ]
[ 2486-69-3 ]
[ 755039-66-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; water; for 40h;Heating / reflux;	14.0 g of the compound Z5d and 10.0 g (0.06 mol) <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> are suspended in 200 mL dioxane and 80 mL water, combined with 10 mL concentrated hydrochloric acid and refluxed for 40 h. The precipitate formed on cooling is suction filtered and washed with water, dioxane and diethyl ether. Yield: 13.9 g of a compound Z5 (colourless crystals)
	With hydrogenchloride; In 1,4-dioxane; water; for 40h;Heating / reflux;	14.0 g of the compound Z5d and 10.0 g (0.06 mol) <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> are suspended in 200 mL dioxane and 80 mL water, combined with 10 mL conc. hydrochloric acid and refluxed for 40 h. The precipitate formed on cooling is suction filtered and washed with water, dioxane and diethyl ether. Yield: 13.9 g of a compound Z5 (colourless crystals)
	With hydrogenchloride; In 1,4-dioxane; water; for 40h;Heating / reflux;	14.0 g of the compound Z5d and 10.0 g (0.06 mol) <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> were suspended in 200 mL dioxane and 80 mL water, combined with 10 mL conc. hydrochloric acid and refluxed for 40 h. The precipitate formed on cooling was suction filtered and washed with water, dioxane and diethyl ether. Yield: 13.9 g of a compound Z5 (colourless crystals)

Reference： [1]Patent: WO2006/18182,2006,A1 .Location in patent: Page/Page column 63
[2]Patent: US2006/35903,2006,A1 .Location in patent: Page/Page column 16
[3]Patent: US2004/176380,2004,A1 .Location in patent: Page/Page column 11
[4]Patent: WO2004/76454,2004,A1 .Location in patent: Page/Page column 33

15
[ 2486-69-3 ]
[ 18107-18-1 ]
[ 24812-90-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	In methanol; ethyl acetate;	Step 1: Methyl-3-amino-4-methoxy benzoate. To a cooled (about 0 C.), stirred solution of 4-amino-3methoxybenzoic acid (5.0 g, 30 mmol) in dry methanol (150 mL) was added trimethylsilyldiazomethane (60 mL of 2solution in hexanes, 120 mmol) slowly over 1 hour. After stirring for 4 hours, the reaction was concentrated at reduced pressure, dissolved in ethyl acetate (200 mL), washed with 10% aqueous sodium carbonate and brine, then dried (MgSO4), filtered, and concentrated in vacuo to provide the desired ester as an off-white solid (94% yield).

Reference： [1]Patent: US2003/69284,2003,A1

16
[ 2486-69-3 ]
[ 73368-41-9 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water;	STR25 Ethyl-4-amino-3 -methoxybenzoate To a solution of 3.343 g (20 mmole) of 4-amino-3-methoxybenzoic acid in 200 mL EtOH is bubbled a stream of HCl gas for three minutes. The HCl saturated solution is stirred at room temperature for two days. Solvent is evaporated under vacuum and the resulting residue is dissolved in 100 mL water. The water layer is basified with K2 CO3 and extracted with CH2 Cl2 (3*200 mL). The combined CH2 Cl2 layer is washed with saturated NaHCO3 (200 mL), brine and then dried over MgSO4, filtered and evaporated under reduced pressure to give the desired product.

Reference： [1]Patent: US6024937,2000,A

17
[ 2486-69-3 ]
[ 41608-64-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogenchloride; In methanol; ethyl acetate;	(a) Methyl 4-amino-3-methoxybenzoate. A stirred solution of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (2.50 g, 14.97 mmol) in MeOH saturated with HCl gas was heated at reflux overnight. The volatiles were removed under reduced pressure and the residue dissolved in EtOAc, washed with saturated NaHCO3 solution, dried over MgSO4 and concentrated under reduced pressure. The title compound was isolated as a tan solid (97%).1H NMR (CDCl3) delta: 3.87 (s, 3H), 3.91 (s, 3H), 4.5 (br s, 2H), 6.73 (d, 1H, J = 8.1Hz), 7.46 (s, 1H, with fine splitting). Anal. (C12H11NO3) C, H, N.

Reference： [1]Patent: EP1109560,2003,B1

18
[ 2486-69-3 ]
[ 85740-98-3 ]

Yield	Reaction Conditions	Operation in experiment
	In (CD3)2CO;	Synthesis of 4-chloro-3-methoxybenzoic acid (used in the synthesis of Compound 17) 4-Chloro-3-methoxybenzoic acid was prepared from 4-amino-3-methoxybenzoic acid (supplied by Biochemical Laboratories Inc) using the methodology used in the preparation of 3,4,5-trichlorobenzoic acid. Nuclear magnetic resonance spectrum (NMR) was as follows: 'H (ppm from TMS in (CD3)2CO, integral, number of peaks): 3.95, 3H, s; 7.50, 1H, d; 7.60, 1H, dd; 7.65, 1H, d.

Reference： [1]Patent: EP279698,1990,A3

19
[ 946826-28-4 ]
[ 2486-69-3 ]
[ 1062242-18-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	With trifluoroacetic acid; In 2,2,2-trifluoroethanol; for 18h;Heating / reflux;	Intermediate 5: 4-(9'~cyclopentyl-5'-methyl-6'-oxo-5'. 6',8',9'- tetrhydrospiro[cyclopropane-l, 7'-pyrimido[4, 5-bJfJ, 4]diazepine]-2 '-ylamino)-3- methoxybenzoic acid; 2'-Chloro-9'-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclopropane- 1 ,7'-pyrimido[4,5- b][l,4]diazepin]-6'(5'H)-one (Intermediate 2) (0.70 g, 2.5 mmol, 1 eq), 4-amino-3- methoxybenzoic acid (1.25 g, 7.5 mmol, 3 eq) and TFA (1.43 g, 12.5 mmol, 5 eq) were heated to reflux in TFE (25 mL) for 18 hours. Solvent was evaporated in vacuo and the resulting residue was triturated with MeOH to give 4-(9'-cyclopentyl-5'-methyl-6'-oxo- 5',6',8', 9'-tetrahydrospiro[cyclopropane-l, 7'-pyrimido[4, 5-b][l, 4]diazepine]-2 - ylamino)-3-methoxybenzoic acid (0.81 g, 74%). <n="83"/>Rt = 1.88 min (AnalyticalJ) MS(+ve): 438.4, MS (-ve): 436.5.
	With hydrogenchloride; In ethanol; water; for 17h;Heating / reflux;	Step e A mixture of 0.406 g (0.00133 mole) of 2-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1'-cyclopropan]-6(7H)-one (VII-53), 0.237 g (0.00142 mole) of 4-amino-3-methoxylbenzoic acid, 7 mL of ethanol, 28 mL of water and 1.2 mL of hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the precipitate which formed was collected by filtration to give 0.250 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1'-cyclopropan]-2-yl)amino]-3-methoxybenzoic acid (I-53) as a white solid.
	With hydrogenchloride; In water; isopropyl alcohol; at 100℃; for 20h;	4-(91-Cyclopentyl-51-methyl-61-oxo-51,61,81,91- tetrahydr ospiro [cyclopropane- 1 ,7'-pyrimido [5,4-b] [ 1 ,4] diazepine] -2 '-ylamino)-3- methoxybenzoic acid; A mixture of 2'-chloro-9'-cyclopentyl-5'-methyl-8',9'- dihydrospiro[cyclopropane-l,7'-pyrimido[5,4-b][l,4]diazepin]-6'(5'H)-one, 4-amino-3- methoxybenzoic acid (1 equivalent), isopropanol (30 ml), and concentrated hydrochloric acid (20 drops) was stirred at 1000C for 20 h. Solid was filtered to give 4-(9'-cyclopentyl-5'-methyl-6'-oxo-56^8^9'-tetrahydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][ 1,4] diazepine] -2'-ylamino)-3-methoxybenzoic acid as white solid. 1H NMR (400 MHz,DMSO-J6) delta ppm 0.71 - 0.85 (m, 2 H) 0.97 - 1.09 (m, 2 H) 1.43 - 1.62 (m, 4 H) 1.62 -1.77 (m, 2 H) 1.77 - 1.93 (m, 2 H) 3.16 (s, 3 H) 3.65 (br. s., 2 H) 3.80 (s, 1 H) 3.95 (s, 3 H)4.78 - 4.97 (m, 1 H) 7.57 - 7.62 (m, 2 H) 8.06 (s, 1 H) 8.14 (d, J=8.84 Hz, 1 H) 9.44 (br. s., 1 H). [M+H] calc'd for C23H27ClN5O4, 438; found, 438.

Reference： [1]Patent: WO2009/40556,2009,A1 .Location in patent: Page/Page column 81-82
[2]Patent: US2008/234255,2008,A1 .Location in patent: Page/Page column 38
[3]Patent: WO2009/67547,2009,A1 .Location in patent: Page/Page column 268; 270
[4]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1247 - 1250

20
[ 946826-63-7 ]
[ 2486-69-3 ]
[ 1062241-02-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ethanol; water; at 100℃;	Step d A mixture of 0.058 g (0.00019 mole) of (rac)-2-chloro-9-cyclopentyl-7-ethyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-12), 0.038 g (0.00023 mole) of <strong>[2486-69-3]4-amino-3-methoxy-benzoic acid</strong>, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.046 g of (rac)-4-(9-cyclopentyl-7-ethyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-12) as an off-white solid.

Reference： [1]Patent: US2008/234255,2008,A1 .Location in patent: Page/Page column 17
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1247 - 1250

21
[ 2486-69-3 ]
[ 76272-41-8 ]
[ 1001346-73-1 ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 25℃; for 18h;	A mixture of 4-Amino-3-Methoxybenzoic Acid (Aldrich; 5.015 g, 30 mmol) and Endo-9- methyl-9-azabicyclo[3,3,l]nonane-3-one (Chempacific; 5.095 g, 33 mol) were dissolved in DMF (150 mL), and to the solution was added DIPEA (10.4 mL, 60 mmol). The reaction was cooled on an ice-bath, and to the reaction was added, portionwise, HATU (12.55 g, 33 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was removed by evaporation, and the residue was partitioned between Ethyl Acetate (200 mL), and saturated aqueous sodium carbonate solution (3 x 50 mL)., washed with brine (3 x 50 <n="141"/>mL), dried over anhydrous magnesium sulphate, filtered, and the solvent removed by evaporation to give the crude product as an an oil (14g), which was purified on SCX-2 columns (4 x 50 g), developing and eluting with : 1) water; 2) MeOH ; and 3) 3.5M NH3- MeOH. The solvent was removed by evaporation to give the product as a semi-solid, which 5 was triturated with diethylether and filtered to yield the title compound as a tan coloured solid (4.84 g, 53percent).1HNMR (400.1MHz ; DMSO-d6) delta 0.88-0.96 (IH, d), 1.38-1.50 (3H, m), 1.86-1.96 (2H, m), 2.00-2.10 (IH, m), 2.10-2.20 (2H, m), 2.42 (3H, s), 2.92-3.00 (2H, d), 3.82 (3H, s), 4.22-4.38 (IH, m), 5.17 (2H, s), 6.58-6.62 (IH, d), 7.28 (IH, s), 7.30 (IH, s), 7.60-7.64 (IH, d). MS m/z 10 292 [M+H]+.

Reference： [1]Patent: WO2008/40951,2008,A1 .Location in patent: Page/Page column 139-140

22
[ 2486-69-3 ]
[ 87120-72-7 ]
[ 1001347-33-6 ]

Yield	Reaction Conditions	Operation in experiment
57%		To a solution of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (Aldrich; 2.4 g, 14.36 mmol) in DMF (100 niL) was added 4-amino-l-bocpiperidine (Aldrich; 3.15 g, 15.72 mmol) and DIPEA (7.5 mL, 43.06 mmol). The resultant solution was carefully treated portionwise (2-3 portions) with HATU (6.88 g, 18.09 mmol) and the resultant mixture was stirred, under nitrogen, at ambient temperature overnight.The solvent was removed in vacuo and the residue partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The organic phase was separated and washed with water (150 mL) and brine (150 mL), dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on a silica cartridge eluting with a rising gradient of 0-10% Methanol in DCM. Product containing fractions were combined and evaporated to yield the title compound as a peach coloured foam (2.88 g, 57%) 1H NMR (400.132 MHz, DMSO) delta 1.35 - 1.47 (HH, m), 1.72 - 1.80 (2H, m), 2.76 - 2.90 (2H, m), 3.81 (3H, s), 3.91 - 4.00 (3H, m), 5.20 (2H, s), 6.61 (IH, d), 7.28 - 7.30 (2H, m), 7.80 (IH, d); MS m/z 348 [M-H]+.

Reference： [1]Patent: WO2008/40951,2008,A1 .Location in patent: Page/Page column 152-153

23
[ 2486-69-3 ]
[ 2516-47-4 ]
[ 1018318-08-5 ]

Yield	Reaction Conditions	Operation in experiment
46%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 18 - 25℃;	To a solution of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (Aldrich; 1.1 g, 6.58 mmol) in DMF (25 mL) was added cyclopropylmethylamine (Aldrich; 504 mg, 7.07 mmol). And DIPEA (3.4 mL, 19.52 mmol) . HATU (3.18 g, 8.36 mmol) was added to the resultant solution giving a mild exotherm. .The resultant mixture was stirred, under nitrogen, at ambient temperature over the weekend.The solvent was removed in vacuo and the resultant residue partitioned between DCM (100 mL) and a saturated aqueous solution of sodium hydrogen carbonate (100 mL). The organic phase was separated, washed with brine, dried over magnesium sulphate and evaporated to give a dark amber oil which was purified by flash column chromatography on silica (12O g cartridge), eluting with 50-100% ethyl acetate in isohexane. Product containing fractions were combined and evaporated to afford a the title compound as a viscous amber gum (665 mg, 46%) 1H NMR (400.132 MHz, DMSO) delta 0.23 (m, 2H), 0.43 (m, 2H), 1.03 (m, IH), 3.12 (t, 2H), 3.83 (s, 3H), 5.20 (s, 2H), 6.63 (d, IH), 7.32 (m, 2H), 8.12 (t, IH); MS m/z 292 [M+H]+.

Reference： [1]Patent: WO2008/40951,2008,A1 .Location in patent: Page/Page column 153-154

24
[ 2486-69-3 ]
[ 552-70-5 ]
4-amino-3-methoxy-N-[(3-endo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 25℃; for 18h;	HATU (12.55 g) was added in portions to a cooled (ice-bath) mixture of 4-amino-3- methoxybenzoic acid (5.02 g), enJo-9-methyl-9-azabicyclo[3.3.1]nonane-3-one (5.1 g) and DIPEA (10.4 mL) in DMF (150 mL). The reaction mixture was stirred at r.t. for 18h then the solvent was removed by evaporation. The residue was partitioned between EtOAc (200 mL) and sat. aq. Na2CO3 (3 x 50 mL) then the phases were separated. The organic portion was washed with brine (3 x 50 mL), dried (MgSO4) and concentrated in vacuo to afford an oil (14 g). The oil was purified by SCX-2, washing with water then MeOH then eluting with 3.5M NH3-MeOH to give the a semi-solid material. Trituration with diethyl ether afforded the title compound (4.84 g, 53%) as a brown solid; 1H NMR: 0.88-0.96 (IH, d), 1.38-1.50 (3H, m), 1.86-1.96 (2H, m), 2.00-2.10 (IH, m), 2.10-2.20 (2H, m), 2.42 (3H, s), 2.92-3.00 (2H, d), 3.82 (3H, s), 4.22-4.38 (IH, m), 5.17 (2H, s), 6.58-6.62 (IH, d), 7.28 (IH, s), 7.30 (IH, s), 7.60-7.64 (IH, d); m/z: MH+ 304.

Reference： [1]Patent: WO2009/24824,2009,A1 .Location in patent: Page/Page column 85

25
[ 41838-46-4 ]
[ 2486-69-3 ]
[ 876126-60-2 ]

Yield	Reaction Conditions	Operation in experiment
62%		4~Amino-3-methoxy-N-(l-methyl-piperidin-4-yl)-benzamide; <n="64"/>To <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (1.064 g mg, 6.37 mmol) in dichloromethane (50 ml) was added DIPEA (2.22 ul, 12.74 mmol) and TBTU (2.25 g, 7.0 mmol) and the mixture stirred for 10 minutes. 4-amino-l-methylpiperidine (0.872 g, 7.65 mmol) was added and stirring continued for 16 hours. The resulting soild was filtered and dried under vacuum (1.04 g, 3.95 mmol, 62%).1H NMR (DMSO): 1.54 (2H, m, CH)5 1.68 (2H5 m5 CH), 1.90 (2H, m, CH), 2.15 (3H, s, N-CH3), 2.76 (2H5 d, J 11.5Hz, CH)5 3.66 (IH, m, CH), 3.77 (3H5 S5 OCH3), 6.56 (IH, m5 Ar-H)5 7.26 (IH5 m, Ar-H)5 7.75 (IH5 d, J 7.5Hz); MS (+ve) 264.4; tR = 7.45 min (Vydac 2).
59%		General procedure: Method c: To a mixture of benzoic acid (1.0 equiv.), TBTU (1.1 equiv.), and DCM was added DIPEA (2.0 equiv.). The solution was stirred at room temperature for 30 min followed by the addition of l-methylpiperidin-4-amine (1.2 equiv.). The reaction mixture was further stirred at room temperature overnight. Work-up and product isolation procedure are described below.
59%		General procedure: To a mixture of benzoic acid (1.0 equiv.), TBTU (1.1 equiv.), and DCM was added DIPEA (2.0 equiv.). The solution was stirred at room temperature for 30 min followed by the addition of 1- methylpiperidin-4-amine (1.2 equiv.). The reaction mixture was further stirred at room temperature overnight. Work-up and product isolation procedure are described below.

With benzotriazol-1-ol; triethylamine; In dichloromethane; N,N-dimethyl-formamide; for 20h;

Step 6: 4-amino-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide A mixture of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (0.334 g), resin supported N-[3-(benzyloxy) propyl]-N'-cyclohexylcarbodiimide (loading 1.2 mmol/g, 2.16 g), HOBT (88%, 0.399 g), triethylamine (0.280 ml) and 1-methylpiperidin-4-amine (0.250 g) in a mixture of dichloromethane (20 ml) and dimethylformamide (4 ml) was shaken for 20 hours. The polymer was filtered off, washed with dichloromethane, acetonitrile and again dichloro-methane. The solution was concentrated and the residue was dissolved in a mixture of ethyl acetate, 1M K2CO3 and a saturated solution of NaCl. The organic phase was separated, dried over Na2SO4 and concentrated to give the title compound as orange solid. 1H NMR (DMSO-d6) delta ppm): 7.75 (d, 1 H); 7.25 - 7.32 (m, 2 H); 6.59 (d, 1 H); 5.17 (s, 2 H); 3.80 (s, 3 H); 3.62 - 3.77 (m, 1 H); 2.76 (d, 2 H); 2.16 (s, 3 H); 1.92 (td, 2 H); 1.66 - 1.81 (m, 2 H); 1.55 (ddd, 2 H). MS (ESI Pos, 3.2 kV, 20 V, 400C): m/z 264,24 (MH+).

Reference： [1]Patent: WO2009/40556,2009,A1 .Location in patent: Page/Page column 62-63
[2]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 128-129
[3]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 240
[4]Patent: EP2100894,2009,A1 .Location in patent: Page/Page column 21
[5]Bulletin of the Korean Chemical Society,2014,vol. 35,p. 1929 - 1930

26
[ 946826-25-1 ]
[ 2486-69-3 ]
[ 1137213-43-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	With trifluoroacetic acid; In 2,2,2-trifluoroethanol; for 24h;Heating / reflux;	Intermediate 7: 4-(9 '-cyclopentyl-5 '-methyl-6'-oxo-5 ',6',8',9 '- tetrahydrospiro[cyclobutane-l, 7'-pyrimido[4, 5-bJ[l, 4]diazepine]-2 '-ylamino)-3- methoxybenzoic acid; 2'-Chloro-9'-eyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclobutane-l,7f-pyrimido[4,5- b][l,4]diazepin]-6'(5'H)-one (Intermediate 4) (1.02 g, 3.18 mmol, 1 eq), 4-amino-3- methoxybenzoic acid (1.6 g, 9.5 mmol, 3 eq) and TFA (1.2 mL, 15.9 mmol, 5 eq) were heated to reflux in TFE (40 mL) for 24 hours. Solvent was evaporated in vacuo and the resulting residue was triturated with EtOAc to give 4- (9' -cyclopentyl-5 '-methyl-6'-oxo- 5' 689'-tetrhydrospiro[cyclobutane-l, 7'-pyrimido[4, 5-b][l, 4]diazepine]-2 '- ylamino)-3-methoxybenzoic acid (1.08 g, 75%). <n="84"/>Rt = 2.10 min (Analytical); MS(+ve): 452.3, MS (-ve): 450.4.
	With hydrogenchloride; In water; isopropyl alcohol; at 100℃; for 20h;	4-(9 '-cyclopentyl-5 '-methyl-6 '-oxo-5 ',6 ',8 ',9 '-tetrahydrospiro [cyclobutane- l,7'-pyrimido[4,5-b] [l,4]diazepine]-2'-ylamino)-3-methoxybenzoic acid; A mixture of 2'-chloro-9'-cyclopentyl-8',9'-dihydrospiro[cyclobutane-l,7'-pyrimido[4,5- b][l,4]diazepin]-6'(5'H)-one, <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (1 equivalent), isopropanol (30 ml), and concentrated hydrochloric acid (20 drops) was stirred at 1000C for 20 h. Solid was filtered to give 4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'- tetrahydrospiro[cyclobutane-l,7'-pyrimido[4,5-b][l,4]diazepine]-2'-ylamino)-3- methoxybenzoic acid as white solid. [M+H] calc'd for C24H29ClNsO4, 452; found, 452.

Reference： [1]Patent: WO2009/40556,2009,A1 .Location in patent: Page/Page column 82-83
[2]Patent: WO2009/67547,2009,A1 .Location in patent: Page/Page column 281; 283

27
[ 1137869-79-4 ]
[ 2486-69-3 ]
[ 1137868-27-9 ]

Yield	Reaction Conditions	Operation in experiment
83%	In water; isopropyl alcohol; at 100℃; for 20h;	4-(9-Cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido[4,5-b][l,4]diazepin-2-ylamino)-3-methoxybenzoic acid: A mixture of 2-chloro- 9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b] [ 1 ,4]diazepin- 6(7H)-one (630 mg, 1.93 mmol), <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (484 mg, 2.9 mmol), isopropanol (20 ml), and concentrated hydrochloric acid (10 drops) was stirred at 1000C for 20 h. Solid was filtered to give 730 mg product as white solid (83%). 1H NMR (400 MHz, DMSO-J6) delta ppm 0.92 (t, J=7.3 Hz, 3 H) 1.56 (br. s., 3 H) 1.67 - 1.96 (m, 6 H) 3.28 (s, 3 H) 3.74 - 3.92 (m, 3 H) 3.94 (s, 3 H) 4.91 (t, J=7.8 Hz, 1 H) 7.21 - 7.43 (m, 1 H) 7.47 - 7.69 (m, 2 H) 8.13 (d, J=8.1 Hz, 1 H) 8.24 (s, 1 H) 9.32 (br. s., 1 H). [M+H] calc'd for C23H28FN5O4, 458; found 458.

Reference： [1]Patent: WO2009/42711,2009,A1 .Location in patent: Page/Page column 330; 333

28
[ 1157849-31-4 ]
[ 2486-69-3 ]
[ 1157847-54-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	hydrogenchloride; In water; isopropyl alcohol; at 100℃; for 20h;	4-(9-Cyclohexyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5- b][l,4]diazepin-2-ylamino)-3-methoxybenzoic acid; A mixture of 2-chloro-9- cyclohexyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][l,4]diazepin-6(7H)-one (0.47 g, 1.45 mmol), <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (0.36 g, 2.18 mmol), isopropanol (10 ml), and concentrated hydrochloric acid (4 drops) was stirred at 1000C for 20 h. Solid was filtered to give 0.43 g product 4-(9-cyclohexyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro- 5H-pyrimido[4,5-b][l,4]diazepin-2-ylamino)-3-methoxybenzoic acid as white solid (65%). 1H NMR (400 MHz, DMSO-J6) delta ppm 1.14 (s, 6 H) 1.58-1.90 (m, 10 H) 3.17 (s, 4 H) 3.94 (s, 3 H) 5.12 (qd, J=8.4, 8.2 Hz, 1 H) 7.60 (d, J=1.5 Hz, 1 H) 7.58 (s, 1 H) 8.08 (s, 1 H) 8.15 (d, J=8.3 Hz, 1 H) 9.33 (br. s., 1 H) 12.96 (br. s., 1 H). [M+H] calculated for C24H32N5O4, 454; found 454.

Reference： [1]Patent: WO2009/67547,2009,A1 .Location in patent: Page/Page column 223; 225

29
[ 1192166-72-5 ]
[ 2486-69-3 ]
[ 1192166-73-6 ]

Yield	Reaction Conditions	Operation in experiment
56%	With hydrogenchloride; In water; acetonitrile; at 20℃;Heating; Reflux;	To a white suspension of 2-chloro-8-dimethylamino-7-ethyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (1460 mg, 5.41 mmol) in acetonitrile (25 ml) was added <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (905 mg, 5.41 mmol) at RT followed by 2M aq. HCl (5.4 ml, 10.8 mmol). The mixture was heated under reflux (oil bath temp 90C) for 35 h. The mixture was cooled to RT. The precipitate was collected by filtration, washed with MeOH (5 ml) and Et2O (5 ml) to give 885 mg of the title compound. The filtrate was heated under reflux for another 3 d and treated as above to give another 335 mg of the title compound. Total yield: 1220 mg (3.05 mmol, 56%). TLC (EtOH: Toluene: NH3conc = 4:5:1): Rf = 0.32. MH+ = 401.
56%	With hydrogenchloride; In water; acetonitrile; for 35h;Reflux;	4-(8-Dimethylamino-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-3-methoxy-benzoic acid To a white suspension of 2-chloro-8-dimethylamino-7-ethyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (1460 mg, 5.41 mmol) in acetonitrile (25 ml) was added <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (905 mg, 5.41 mmol) at RT followed by 2M aq. HCl (5.4 ml, 10.8 mmol). The mixture was heated under reflux (oil bath temp 90C) for 35 h. The mixture was cooled to RT. The precipitate was collected by filtration, washed with MeOH (5 ml) and Et2O (5 ml) to give 885 mg of the title compound. The filtrate was heated under reflux for another 3 d and treated as above to give another 335 mg of the title compound. Total yield: 1220 mg (3.05 mmol, 56%). TLC (EtOH : Toluene : NH3conc = 4:5: 1): Rf = 0.32. MH+ = 401.

Reference： [1]Patent: EP2112152,2009,A1 .Location in patent: Page/Page column 29
[2]Patent: EP2325185,2011,A1 .Location in patent: Page/Page column 22

30
[ 1192166-74-7 ]
[ 2486-69-3 ]
[ 1192166-75-8 ]

Yield	Reaction Conditions	Operation in experiment
48%	With hydrogenchloride; In water; acetonitrile; at 20℃; for 20h;Reflux;	To a white suspension of 2-chloro-8-((cyclopentylmethyl)(methyl)amino)-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (312 mg, 0.923 mmol) in acetonitrile (4.5 ml) was added <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (154 mg, 0.923 mmol) at RT followed by 2 M aq. HCl (0.923 ml, 1.847 mmol). The mixture was stirred at reflux (oil bath temp 90C) for 20 h, when TLC (EtOAc/c-hexane 1:1) showed starting material left and the formation of one major product. The mixture was evaporated to dryness, the residue was suspended in iPrOH (3 ml), the mixture was heated to reflux and sonicated. The precipitate was collected by filtration, washed with iPrOH (2 x 1ml) and dried in vacuo to give 208 mg (0.443 mmol; 48%) of the title compound. MH+ = 469

Reference： [1]Patent: EP2112152,2009,A1 .Location in patent: Page/Page column 31

31
[ 2486-69-3 ]
[ 282087-44-9 ]

Yield	Reaction Conditions	Operation in experiment
46%		To a solution of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (5 mg, 29.9 mmol) in H2O (30 mL) and HCI 37% (30 mL) at 0 0C, a solution of NaNO2 (2.27 g, 32.9 mmol) in H2O (10 mL) was slowly added. The solution obtained was then stirred for 20 minutes and then added at 0 0C to a solutionn of Kl (34.75 g, 7 mmol) in H2O (1OmL). The mixture was stirred for 3 hours. After cooling in an ice-water bath, the solid was filtered off. The filtrate was diluted with ethyl acetate, washed with 10% sodium methabisulphite, dried over anhydrous Na2SU4and concentrated to give 3.7 g of the title compound (46% yield).1H NMR (400 MHz, DMSO-d6) delta ppm: 3.90 (s, 3 H) 7.31 (dd, J 1.71 Hz and J 8.05 Hz, 1 H), 7.43 (d, J 1.71 Hz, 1 H), 7.92 (d, J 8.05 Hz, 1 H), 13.15 (b.s., 1H).
46%		Preparation 9; 4-lodo-3-methoxybenzoic acid; To a solution of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (5 mg, 29.9 mmol) in H2O (30 mL) and HCI 37% (30 mL) at 00C, was slowly added a solution of NaNO2 (2.27 g, 32.9 mmol) in H2O (10 mL). The solution obtained was then stirred for 20 minutes and then added at 00C to a solutionn of Kl (34.75 g, 7 mmol) in H2O (1 OmL). The mixture was stirred for 3 hours. After cooling in an ice-water bath, the solid was filtered off. The filtrate was diluted with ethyla actetae, washed with 10% sodium methabisulphite, dried over anhydrous Na2SU4and concentrated to give 3.7 g of the title compound (46% yield).1H NMR (400 MHz, DMSO-d6) delta ppm: 3.90 (s, 3 H) 7.31 (dd, J 1.71 Hz and J 8.05 Hz, 1 H), 7.43 (d, J 1.71 Hz, 1H), 7.92 (d, J 8.05 Hz, 1 H), 13.15 (b.s., 1H).
		General procedure: To a solution of 42 (200 mg, 0.9 mmol) in H2O (2 mL) and HCl 37% (2 mL) at 0C, was slowly added a solution of NaNO2 (70 mg, 1.0 mmol) in H2O (2 mL). The solution obtained was then stirred for 20 minutes and then added at 0C to a solution of KI (520 mg, 3.15 mmol) in H2O (2 mL). The mixture was stirred for 3 hours. After cooling in an ice-water bath, the solid was filtered off. The filtrate was diluted with EtOAc, washed with 10% sodium methabisulphite, dried over anhydrous Na2SO4 and concentrated to give 225 mg of 44 (75% yield) as a white solid.

Reference： [1]Patent: WO2010/108921,2010,A1 .Location in patent: Page/Page column 44
[2]Patent: WO2009/156315,2009,A1 .Location in patent: Page/Page column 62
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4507 - 4511

32
[ 1265228-20-3 ]
[ 2486-69-3 ]
3-methoxy-4-[4-(4-nitro-phenoxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-benzoic acid hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With hydrogenchloride; In water; isopropyl alcohol; at 20℃; for 4h;Reflux;	b-4.); 3.50 g of 2-chloro-4-(4-nitrophenyloxy)-5-trifluoromethylpyrimidine and 2.03 g of 4- amino-3-methoxy-benzoic acid are suspended in 90 ml. 2-propanol. 0.18 ml. of concentrated hydrochloric acid are added. The reaction mixture is heated to reflux for 3.5 hours. The suspension is cooled to 20 0C and stirred at this temperature for 30 minutes. The precipitate is filtered and washed with 18 ml. 2-propanol and 10 ml. methanol. After drying in a vacuum drying oven at 50 0C 4.69 g (88 % of theory) of the corresponding 2- amino pyrimidine derivative product, i.e. 3-methoxy-4-[4-(4-nitro-phenoxy)-5- trifluoromethyl-pyrimidin-2-ylamino]-benzoic acid is obtained as hydrochloride salt. 3- HPLC: Rt = 14.1 min[Column: lnertsil ODS-3, 5 mum; dimension: 150 x 4.0 mm; temperature: 30 0C; mobile phase: A: water/0.3 % KH2PO4 pH = 3, B: acetonitrile; gradient: A / B (85:15) 1 min, from A / B (85:15 ) to A / B (60:40) in 5 min, from A / B (60:40) to A / B (40:60) in 5 min, from A / B (40:60) to A / B (30:70) in 3 min, hold for 3 min at A / B (30:70); flow rate: 2.0 mL/min; detection UV 210 nm]
88%	With hydrogenchloride; In water; isopropyl alcohol; at 20℃; for 4h;Reflux;	b-4.) 3.50 g of 2-chloro-4-(4-nitrophenyloxy)-5-trifluoromethylpyrimidine and 2.03 g of <strong>[2486-69-3]4-amino-3-methoxy-benzoic acid</strong> are suspended in 90 mL 2-propanol. 0.18 mL of concentrated hydrochloric acid are added. The reaction mixture is heated to reflux for 3.5 hours. The suspension is cooled to 20 C. and stirred at this temperature for 30 minutes. The precipitate is filtered and washed with 18 mL 2-propanol and 10 mL methanol. After drying in a vacuum drying oven at 50 C. 4.69 g (88% of theory) of the corresponding 2-amino pyrimidine derivative product, i.e. 3-methoxy-4-[4-(4-nitro-phenoxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-benzoic acid is obtained as hydrochloride salt. 3 HPLC: Rt=14.1 min [Column: Inertsil ODS-3, 5 mum; dimension: 150*4.0 mm; temperature: 30 C.; mobile phase: A: water/0.3% KH2PO4 pH=3, B: acetonitrile; gradient: A/B (85:15) 1 min, from A/B (85:15) to A/B (60:40) in 5 min, from A/B (60:40) to A/B (40:60) in 5 min, from A/B (40:60) to A/B (30:70) in 3 min, hold for 3 min at A/B (30:70); flow rate: 2.0 mL/min; detection UV 210 nm]

Reference： [1]Patent: WO2011/18518,2011,A1 .Location in patent: Page/Page column 26
[2]Patent: US2011/190499,2011,A1 .Location in patent: Page/Page column 10

33
[ 124-13-0 ]
[ 2486-69-3 ]
[ 1344028-81-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	With alpha-picoline-borane; In methanol; at 20℃;	General procedure: <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (4b) (~3 mmol) was dissolved in 15 mL methanol with alpha-picoline-borane (1.1 mol eq) and butanal (1.1 mol eq). The reaction was stoppered with a vent needle and stirred overnight at room temperature. After 16-24 h, solvent was removed in vacuo, 10 mL 1 M HCl was added to the flask, and stirred at room temperature for an additional 30 min. The pH was adjusted to neutral using NaHCO3 and the intermediate product was extracted with ethyl acetate (2 60 mL). The organic layer was washed with brine (1x 45 mL), dried with magnesium sulfate, filtered, removed in vacuo, and subsequently purified via column chromatography with 30% ethyl acetate in hexane to yield 3 (84%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6417 - 6419

34
[ 2486-69-3 ]
[ 123-72-8 ]
[ 1344028-59-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	With alpha-picoline-borane; In methanol; at 20℃;	General procedure: <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (4b) (~3 mmol) was dissolved in 15 mL methanol with alpha-picoline-borane (1.1 mol eq) and butanal (1.1 mol eq). The reaction was stoppered with a vent needle and stirred overnight at room temperature. After 16-24 h, solvent was removed in vacuo, 10 mL 1 M HCl was added to the flask, and stirred at room temperature for an additional 30 min. The pH was adjusted to neutral using NaHCO3 and the intermediate product was extracted with ethyl acetate (2 60 mL). The organic layer was washed with brine (1x 45 mL), dried with magnesium sulfate, filtered, removed in vacuo, and subsequently purified via column chromatography with 30% ethyl acetate in hexane to yield 3 (84%).
84%	With 2-picoline borane complex; In methanol; at 20℃;	<strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (4b) ( FontWeight="Bold" FontSize="10" 3 mmol) was dissolved in 15 mL methanol with alpha-picoline-borane (1.1 mol eq) and butanal (1.1 mol eq). The reaction was stoppered with a vent needle and stirred overnight at room temperature. After 16-24 h, solvent was removed in vacuo, 10 mL. A volume of 1 M HCl was added to the flask, and stirred at room temperature for an additional 30 min. The pH was adjusted to neutral using NaHCO3 and the intermediate product was extracted with ethyl acetate (2×60 mL). The organic layer was washed with brine (1×45 mL), dried with magnesium sulfate, filtered, removed in vacuo, and subsequently purified via column chromatography with 30% ethyl acetate in hexane to yield 3 (84%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6417 - 6419
[2]Patent: US2014/18422,2014,A1 .Location in patent: Paragraph 0114

35
[ 2486-69-3 ]
[ 67316-43-2 ]
[ 1351762-14-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In 1,4-dioxane; butan-1-ol at 120℃; for 0.666667h; snap-top microwave vial;	3 A mixture of 50 mg 2-chloro-5-fluoro-N-methylpyrimidin-4-amine, 57 mg 4-Amino-3-methoxybenzoic acid, 0.1 mL 4N HCl in 1,4-dioxane and 1 mL N-butanol was placed in a 10 mL snap-top microwave vial (CEM Corp.) and heated to 120° C. microwave for 40 min. The reaction was monitored by LC/MS. The precipitated solid was filtered to yield 80 mg of 4-(5-fluoro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxybenzoic acid.
80 mg	With hydrogenchloride In 1,4-dioxane; butan-1-ol at 120℃; for 0.666667h; Microwave irradiation;	3 Preparation 3: 4-(5-fluoro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxybenzoic acid A mixture of 50 mg 2-chloro-5-fluoro-N-methylpyrimidin-4-amine, 57 mg 4-Amino-3-methoxybenzoic acid, O.lmL 4N HCl in 1,4-dioxane and 1 mL N- butanol was placed in a lOmL snap-top microwave vial (CEM Corp.) and heated to 120°C microwave for 40 min. The reaction was monitored by LC/MS. The precipitated solid was filtered to yield 80 mg of 4-(5-fluoro-4- (methylamino)pyrimidin-2-ylamino)-3-methoxybenzoic acid.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2011/301141, 2011, A1 Location in patent: Page/Page column 23
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2013/79494, 2013, A1 Location in patent: Page/Page column 58-59

36
[ 18704-37-5 ]
[ 2486-69-3 ]
[ 1260082-06-1 ]

Yield	Reaction Conditions	Operation in experiment
74%	With pyridine; In dichloromethane; at 20℃; for 16h;Inert atmosphere;	Synthesis of intermediate LXXIX. To a stirred solution of appropriately substituted amine LXXVIII (30.3 mmol) under nitrogen atmosphere was added pyridine (50 ml) at 0 C. and stirred for 10 min Quinoline-8-sulfonyl chloride VI (8.94 gm, 39.4 mmol) was then added to the reaction mixture at the same temperature. The resulting mixture was stirred for 16 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. The traces of pyridine were removed by co-distillation with toluene. Diethyl ether was added to the resulting residue, and the solid product was filtered out and air-dried. The resulting crude product LXXIX (74%) was taken to the next step without further purification.
		To a stirred solution of appropriately substituted amine LXXVIII (30.3 mmol) under nitrogen atmosphere was added pyridine (50 ml) at 0 C. and stirred for 10 min. Quinoline-8-sulfonyl chloride VI (8.94 gm, 39.4 mmol) was then added to the reaction mixture at the same temperature. The resulting mixture was stirred for 16 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. The traces of pyridine were removed by co-distillation with toluene. Diethyl ether was added to the resulting residue, and the solid product was filtered out and air-dried. The resulting crude product LXXIX (74%) was taken to the next step without further purification.

Reference： [1]Patent: US2012/172349,2012,A1 .Location in patent: Page/Page column 67
[2]Patent: US9404081,2016,B2 .Location in patent: Page/Page column 198

37
[ 2486-69-3 ]
[ 124-40-3 ]
[ 1061358-40-4 ]

Yield	Reaction Conditions	Operation in experiment
59%	With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran;	4-Amino-3-methoxy-A/,A/-dimethylbenzamide (29); [00216] HATU (0.296 g, 0.778 mmol) was added to a solution of 4-amino-3- methoxybenzoic acid (0.1 g, 0.598 mmol), DIPEA (0.156 ml_, 0.897 mmol) and dimethylamine (2M in THF, 0.598 ml_, 1 .196 mmol) in THF (1 .617 ml). The reaction mixture was stirred overnight. It was then partitioned between EtOAc and water. The separated organic phase was washed with water, dried over Na2S04 and evaporated in vacuum. The crude was purified via Biotage (DCM/EtOAc 60/40 to 40/60; 25 g column) and was then filtered on SCX-2 column to afford the title compound as a colourless oil (69 mg, 59%). 1 H NMR (500 MHz, CDCI3) 3.06 (s, 6H), 3.87 (s, 1 H), 3.99 (br s, 2H), 6.65 (d, J = 7.9 Hz, 1 H), 6.89 (dd, J = 7.9, 1 .7 Hz, 1 H), 6.96 (d, J = 1 .7 Hz).
59%	With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran;	4-Amino-3-methoxy-N,N-dimethylbenzamide (29) HATU (0.296 g, 0.778 mmol) was added to a solution of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (0.1 g, 0.598 mmol), DIPEA (0.156 mL, 0.897 mmol) and dimethylamine (2M in THF, 0.598 mL, 1.196 mmol) in THF (1.617 ml). The reaction mixture was stirred overnight. It was then partitioned between EtOAc and water. The separated organic phase was washed with water, dried over Na2SO4 and evaporated in vacuum. The crude was purified via Biotage (DCM/EtOAc 60/40 to 40/60; 25 g column) and was then filtered on SCX-2 column to afford the title compound as a colourless oil (69 mg, 59%). 1H NMR (500 MHz, CDCl3) 3.06 (s, 6H), 3.87 (s, 1H), 3.99 (br s, 2H), 6.65 (d, J=7.9 Hz, 1H), 6.89 (dd, J=7.9, 1.7 Hz, 1H), 6.96 (d, J=1.7 Hz).
59%	With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; for 18h;	General procedure: Preparation 24: 4-amino-3-met oxy-A/,A/-dimet ylbenzamide HATU (0.296 g, 0.778 mmol) was added to a solution of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (0.1 g, 0.598 mmol), DIPEA (0.1 56 mL, 0.897 mmol) and dimethylamine (2M in THF, 0.598 mL, 1 .196 mmol) in THF (1 .61 7 ml). The reaction mixture was stirred for 18 hours. The reaction was partitioned between EtOAc and water, the organic layers were washed with water, dried over Na2S04 and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with DCM/EtOAc 60/40 to 40/60 followed by filtration through an SCX-2 column eluting with 2M NH3/MeOH to afford the title compound as a colourless oil (69 mg, 59%). 1 H NMR (500 MHz, MeOD): delta 6.95 (d, J = 1 .8 Hz, 1 H), 6.89 (dd, J = 8.0, 1 .8 Hz, 1 H), 6.74 (d, J = 8.0 Hz, 1 H), 3.88 (s, 3H), 3.08 (s, 6H). LCMS (ESI) Rt = 0.96 minutes MS m/z 1 95 [M+H]+

Reference： [1]Patent: WO2012/123745,2012,A1 .Location in patent: Page/Page column 75
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 10045 - 10065
[3]Patent: US2013/345181,2013,A1 .Location in patent: Paragraph 0650
[4]Patent: WO2014/37750,2014,A1 .Location in patent: Paragraph 0020-0022

38
[ 2486-69-3 ]
[ 57054-92-9 ]
[ 1351762-22-5 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 9416 - 9433

39
[ 2486-69-3 ]
[ 57054-92-9 ]
[ 1351759-25-5 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 9416 - 9433

40
3-methoxyazetidine hydrochloride [ No CAS ]
[ 2486-69-3 ]
[ 1400287-07-1 ]

Yield	Reaction Conditions	Operation in experiment
59%	With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran;	General procedure: Preparation 92: (4-amino-3-methoxyphenyl)(3-methoxyazetidin-1 -yl)methanone Method G HATU (2.70 g, 7.10 mmol) was added to a solution of 4-amino-3- methoxybenzoic acid (880 mg, 5.26 mmol), 3-methoxyazetidine hydrochloride (0.971 g, 7.86 mmol) and DIPEA (2.85 mL, 16.32 mmol) in THF (15 mL) at room temperature. THF was removed under reduced pressure, and the residue partitioned between EtOAc and saturated aqueous NaHC03. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 100% EtOAc in cyclohexane followed by a second chromatography eluting with 0 to 4% MeOH in DCM to afford the title compound (728 mg, 59%). 1 H NMR (500 MHz, CDCI3): delta 7.24 (d, J = 1 .7 Hz, 1 H), 7.06 (dd, J = 8.1 , 1.8 Hz, 1 H), 6.66 (d, J = 8.0 Hz, 1 H), 4.42 (br s, 2H), 4.31 - 3.99 (m, 5H), 3.91 (s, 3H), 3.34 (s, 3H).
59%	With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; at 20℃;	Preparation 28: (4-amino-3-methoxyphenyl)(3-methoxyazetidin-1 -yl)methanone HATU (2.70 g, 7.10 mmol) was added to a solution of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (880 mg, 5.26 mmol), 3-methoxyazetidine hydrochloride (0.971 g, 7.86 mmol) and DIPEA (2.85 mL, 16.32 mmol) in THF (15 mL) at room temperature. THF was removed under reduced pressure, and the residue partitioned between EtOAc and saturated aqueous NaHC03. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 1 00% EtOAc in cyclohexane followed by a second chromatography eluting with 0 to 4% MeOH in DCM to afford the title compound (728 mg, 59%). 1 H NMR (500 MHz, CDCI3): delta 7.24 (d, J = 1 .7 Hz, 1 H), 7.06 (dd, J = 8.1 , 1 .8 Hz, 1 H), 6.66 (d, J = 8.0 Hz, 1 H), 4.42 (br s, 2H), 4.31 - 3.99 (m, 5H), 3.91 (s, 3H), 3.34 (s, 3H).

Reference： [1]Patent: WO2014/37751,2014,A1 .Location in patent: Paragraph 00358; 00359
[2]Patent: WO2014/37750,2014,A1 .Location in patent: Paragraph 0038-0041

41
[ 2486-69-3 ]
[ 141-43-5 ]
[ 1323981-23-2 ]

Yield	Reaction Conditions	Operation in experiment
17%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	To a solution of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (1 equiv) in anhydrous DCM (0.6 M) was added triethylamine (4 equiv), N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (1.2 equiv) and 2-amino-ethanol (2 equiv) portionwise. The mixture was stirred at room temperature overnight. After the reaction was complete, as monitored by LCMS, the mixture was diluted with a mixture of isopropanol in chloroform (30%), washed with water and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica column to give the title compound as a white solid (17% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.05-8.02 (t, J=5.6 Hz, 1H), 7.32-7.27 (m, 1H), 6.60 (d, J=8.0 Hz, 1H), 5.21 (brs, 2H), 4.69 (t, J=5.6 Hz, 1H), 3.80 (s, 3H), 3.50-3.46 (m, 2H), 2.34-3.27 (m, 2H). MS (ESI) m/z 211.1 [M+1]+.
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide;	General procedure: 93 4-Amino-A/-(2-hydroxyethyl)- 1H NMR (500 MHz, CDCI3): delta 7.37 (d, J = 3-methoxybenzamide 1.92 Hz, 1H), 7.18 (dd, J= 1.92, 8.10 Hz, NH2 1H), 6.67 (d, J = 8.10 Hz, 1H), 3.91 (s, 3H), 3.86 - 3.80 (m, 2H), 3.64 - 3.60 (m, 2H). LCMS (ESI) Rt = 0.71 minutes MS m/z 211 [M+H]+ Using 2-aminoethanol in DMF and purification method A.

Reference： [1]Patent: US2014/200206,2014,A1 .Location in patent: Paragraph 0255
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 8989 - 9002
[3]Patent: WO2014/37751,2014,A1 .Location in patent: Paragraph 00360

42
[ 2486-69-3 ]
[ 5460-09-3 ]
[ 1608997-39-2 ]

Yield	Reaction Conditions	Operation in experiment
69%		General procedure: Aniline derivative (1 eq) was mixed with iced water and/or absolute EtOH (2 mL by mmol of reagent) and stirred at 0 C then hydrochloric acid 37% (4 eq) was added dropwise rapidly. Sodium nitrite (1.1 eq or 1.3 eq aniline substituent depending) was added solid or in solution (H2O/EtOH 1 M) and the reaction mixture was stirred at 0-2 C for 30 min. The solvent was removed carefully under reduced pressure without heating and can be used without further purification. 5-Amino-4-hydroxynaphtalene-2,7-disulfonic acid sodium salt (0.9 eq) was dissolved in iced water (5 mL by mmol of reagent) then pH was adjusted to 9 by adding 30% NaOH solution. The diazonium salt was added to the naphthalene moiety and pH maintained at 9 by addition of 10% NaOH solution. After complete addition of the diazonium salt to the 5-amino-4-hydroxynaphthalene-2,7-disulfonic acid monosodium salt, stirring was maintained at 0 C for 2 h. Degraded diazonium was removed after extraction with EtOAc and water soluble diazo compounds were recrystallized three times from EtOH/(H2O; pH 2) (1/1). All organic impurities were then extracted by washing with small portions of Et2O. The precipitated compounds were dried under vacuum.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 78,p. 236 - 247

43
[ 1609530-95-1 ]
[ 2486-69-3 ]
[ 1609531-03-4 ]

Yield	Reaction Conditions	Operation in experiment
53%	With sodium hexamethyldisilazane; In tetrahydrofuran; N,N-dimethyl acetamide; for 2h;	Stepl[00169j To a stirred solution of Intermediate 1(1.00 g, 4.88 mmol) in DMA (30 mL) was added <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (1.22 g, 7.32 mmol) followed by NaHMDS (1M in THF, 36.6 mL, 36.6 mmol). The reaction was stirred for 2 hours at which point the THF was removed in vacuo and HC1 (1M aqueous) was added to adjust to pH to 5,the resulting heterogeneous slurry was filtered off yielding Intermediate 10. The filtrate was extracted with DCM and washed with water (3x), dried, concentrated and purified by automated silica gel chromatography (0-100% MeOH/DCM) to yield additional material. Total yield = 0.87 g, 53%. ?H NMR (400MHz, DMSO-d6) oe 12.86 (br. s., 1H), 10.64 (s, 1H), 8.81 (d, J=4.4 Hz, 1H), 8.52 (s, 1H), 7.65 - 7.50 (m, 3H), 7.14 (s, 1H), 3.91 (s, 3H),2.80 (d, J=4.4 Hz, 3H). LC retention time 0.70 [J]. MS(Ej m/z: 336 (MHj.

Reference： [1]Patent: WO2014/74660,2014,A1 .Location in patent: Paragraph 00169
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 8973 - 8995

44
[ 2486-69-3 ]
[ 21635-88-1 ]
[ 1618663-53-8 ]

Yield	Reaction Conditions	Operation in experiment
53%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	To a solution of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (1 equiv) in DCM (0.1 M) was added HOBt (1.2 equiv), EDC (1.2 equiv) and DIEA (4 equiv). Oxetan-3-amine (1.2 equiv) was added and the reaction mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate. The solids were filtered off, the filtrate was concentrated and the product was purified by silica gel chromatography to afford the title compound (53% yield) as a yellow solid. MS (ESI) m/z 223.1 [M+1]+.

Reference： [1]Patent: US2014/200206,2014,A1 .Location in patent: Paragraph 0304; 0315
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 8989 - 9002

45
[ 2486-69-3 ]
[ 593-51-1 ]
[ 866329-57-9 ]

Yield	Reaction Conditions	Operation in experiment
63%	With sodium hydrogencarbonate; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	To a solution of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (1 equiv) in N-N-dimethylformamide (0.6 M) was added sodium bicarbonate (9.7 equiv), HATU (2 equiv) and methyl amine hydrochloride (10 equiv). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured on water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh, 0-10% MeOH in DCM as eluent) to give the title compound. (Yield: 63%). MS (ESI) m/z 181 [M+1]1.

Reference： [1]Patent: US2014/200206,2014,A1 .Location in patent: Paragraph 0230

46
[ 2486-69-3 ]
2-chloro-4-ethoxy-7-tosyl-7H-pyrrolo-[2,3-d]-pyrimidine [ No CAS ]
4-((4-ethoxy-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxybenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; water; at 90℃;	To a solution of 2-chloro-4-ethoxy-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (which may be prepared according to D2) (2.0 g, 5.68 mmol) and <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (1.140 g, 6.82 mmol) in 1 ,4-dioxane (1.5 mL) and water (0.2 mL) was added xantphos (0.493 g, 0.853mmol), K2C03 (2.357 g, 17.05 mmcl) and PdCl2(dppf)-CH2CI2 adduct (0.464 g, 0.568 mmcl). The mixture was stirred overnight at 90 C. The reaction was quenched with water and extracted with DCM (20 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The crude was purified by column chromatography on silica gel (DCM: CH3OH=20:1) to give the title compound D124 (2.60 g, 5.39 mmol, 95%yield) as a yellow solid.LCMS: 483[M+H]. tR=l.l3. (LCMS condition 2)?H NMR(400MHz, DMSO-d6): oe12.74(s, 1H), 8.64(d, J 10.0 Hz, 1H), 8.11 (s, 1H), 7.69(m, 2H), 7.69 (d, J = 12.0 Hz, 1 H ), 7.53 (m, 31-fl, 7.38 (m, 2H), 6.66 (d, J = 5.0 Hz, 1 H), 4.49(dd, J = 9.0 Hz, 2H), 3.95 (s, 3H), 2.31 (s, 3H), 1.35 (t, J = 9.0 Hz, 3H).

Reference： [1]Patent: WO2015/113451,2015,A1 .Location in patent: Page/Page column 76; 77

47
[ 2486-69-3 ]
C₁₆H₁₇ClN₄O [ No CAS ]
C₂₄H₂₅N₅O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With hydrogenchloride; In methanol; water; for 48h;Reflux;	General procedure: Intermediate 5 (2.13 mg, 7.2 mmol)And <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (1.88 mg, 11.2 mmol)Add 3 mL of methanol to 12 mL of water and 1.50 mL of concentrated hydrochloric acid,Reflux 48h. Under reduced pressure evaporated solvent,Methanol and ether to give intermediate 6.

Reference： [1]Patent: CN106543185,2017,A .Location in patent: Paragraph 0063; 0064

48
[ 1280667-23-3 ]
[ 2486-69-3 ]
C₂₂H₂₇N₅O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With hydrogenchloride; In ethanol; water;	A mixture of compound 8 (235 mg, 0.8 mmol) and <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (208 mg, 1.24 mmol) was added to a mixed solvent of 0.6 ml of ethanol, 2.4 ml of water and 260 mul of concentrated hydrochloric acid. 48h. Distillation under reduced pressure, column chromatography gave compound 9 (170 mg, yield 50%)

Reference： [1]Patent: CN107033147,2017,A .Location in patent: Paragraph 0077-0079
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 7785 - 7795

49
[ 877676-50-1 ]
[ 2486-69-3 ]
BI₂₅₃₆ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 7785 - 7795

50
[ 2486-69-3 ]
[ 76272-41-8 ]
[ 1018317-67-3 ]

Reference： [1]Patent: WO2008/40951,2008,A1

51
[ 21900-54-9 ]
[ 2486-69-3 ]
4-(2-chloro-4-fluorobenzamido)-3-methoxybenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.4 g	In N,N-dimethyl acetamide at 10 - 35℃; for 1h;	19 Reference Example 19 To a solution of 2-chloro-4-fluorobenzoyl chloride (1.0 mL) in DMA (10 mL) was added 4-amino-3-methoxybenzoic acid (1.253 g), and the mixture was stirred at room temperature for 1 hour. Then, water was added thereto, and the mixture was stirred. The precipitated powder was filtered, washed with water, and then dried to give 4-(2-chloro-4-fluorobenzamido)-3-methoxybenzoic acid (2.4 g).

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2019/4421, 2019, A1 Location in patent: Paragraph 0081; 0100

52
[ 6342-60-5 ]
[ 2486-69-3 ]
3-methoxy-4-(2-chloro-5-methylbenzamido)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.4 g		To a solution of <strong>[6342-60-5]2-chloro-5-methylbenzoic acid</strong> (0.83 g) in DMA (6.0 mL) was added dropwise SOC12 (0.36 mL) at room temperature under nitrogen atmosphere, and the mixture was stirred for 2 hours. To the reaction solution was added 4-amino-3-methoxybenzoic acid (1.0 g), and the mixture was stirred at room temperature for 1 day. Water was added thereto, and the precipitate was filtered and washed with water to give 3-methoxy-4-(2-chloro-5-methylbenzamido)benzoic acid (1.4g).

Reference： [1]Patent: WO2019/4421,2019,A1 .Location in patent: Paragraph 0081; 0107

53
[ 321-21-1 ]
[ 2486-69-3 ]
4-(4-fluoro-2-methylbenzamido)-3-methoxybenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.2 g		To a solution of <strong>[321-21-1]4-fluoro-2-methylbenzoic acid</strong> (2.77 g) in DMA (SO mL) was added SOC12 (1.379 mL) under nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. Then, 4-amino-3-methoxybenzoic acid (3 g) was added thereto. The mixture was stirred at room temperature for 3 hours, and then water was added thereto. A precipitated crystal was filtered and washed with water to give 4-(4-fluoro-2-methylbenzamido)-3-methoxybenzoic acid (5.20 g).

Reference： [1]Patent: WO2019/4421,2019,A1 .Location in patent: Paragraph 0081; 0114

54
[ 7149-42-0 ]
[ 2486-69-3 ]
[ 1187094-61-6 ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1443 - 1449

55
[ 7149-42-0 ]
[ 2486-69-3 ]
(R)-4-((4-cyclopentyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl)amino)-3-methoxy-N-((1-methylpiperidin-4-yl)methyl)benzamide [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1443 - 1449

56
[ 515824-43-8 ]
[ 2486-69-3 ]
3-methoxy-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid In iso-butanol at 100℃;

Reference： [1]Current Patent Assignee: DANA-FARBER CANCER INSTITUTE - WO2020/81682, 2020, A1 Location in patent: Paragraph 0170; 0179

57
[ 41608-64-4 ]
[ 2486-69-3 ]

Yield	Reaction Conditions	Operation in experiment
96.35%	With water; lithium hydroxide; In tetrahydrofuran; methanol; at 25℃; for 12h;Inert atmosphere;	To a solution of methyl 4-amino-3- methoxybenzoate (4.5 g, 23.59 mmol, 1 eq.) in MeOH (45 mL), water (15 mL), and THF (15 mL) was added LiOH (4.95 g, 117.97 mmol, 5 eq.) in one portion at 25 C under N2. The mixture was stirred at 25 C for 12 h. TLC analysis (PE:EtOAc = 3:1, Rf = 0) showed that the reaction was complete. The mixture was concentrated under reduced pressure at 40 C. The residue was poured into water (50 mL) and stirred for 1 min. The aqueous phase was extracted with EtOAc (30 mL x 3).2 N HCl was added to the aqueous phase to adjust the pH of the solution to 2. The aqueous phase was filtered and concentrated in vacuo to afford the desired product (4 g, 22.73 mmol, 96.35% yield) as a light yellow solid.

Reference： [1]Patent: WO2021/61643,2021,A1 .Location in patent: Paragraph 0289

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P378
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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
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H281	Contains refrigerated gas; may cause cryogenic burns or injury
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Health hazards
Code	Phrase
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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
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H316	Causes mild skin irritation
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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. 2486-69-3 ]

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[ 2486-69-3 ] Synthesis Path-Upstream 1~12

[ 2486-69-3 ] Synthesis Path-Downstream 1~57

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Aryls

Ethers

Amines

Carboxylic Acids

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