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[ CAS No. 63603-09-8 ] {[proInfo.proName]}

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2D 3D

Chemical Structure| 63603-09-8

Chemical Structure| 63603-09-8

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Quality Control of [ 63603-09-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 63603-09-8 ]

CAS No. :	63603-09-8	MDL No. :	MFCD16140357
Formula :	C₉H₈ClNO₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QNYHMMOXMRPWTK-UHFFFAOYSA-N
M.W :	245.62	Pubchem ID :	49757533
Synonyms :

Calculated chemistry of [ 63603-09-8 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	4
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	58.05
TPSA :	81.35 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.24 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.93
Log Po/w (XLOGP3) :	2.2
Log Po/w (WLOGP) :	2.04
Log Po/w (MLOGP) :	1.18
Log Po/w (SILICOS-IT) :	0.27
Consensus Log Po/w :	1.52

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.76
Solubility :	0.425 mg/ml ; 0.00173 mol/l
Class :	Soluble
Log S (Ali) :	-3.54
Solubility :	0.0704 mg/ml ; 0.000287 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.6
Solubility :	0.611 mg/ml ; 0.00249 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.33

Safety of [ 63603-09-8 ]

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

Application In Synthesis of [ 63603-09-8 ]

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

Upstream synthesis route of [ 63603-09-8 ]
Downstream synthetic route of [ 63603-09-8 ]

[ 63603-09-8 ] Synthesis Path-Upstream 1~2

1
[ 42590-00-1 ]
[ 63603-09-8 ]

Yield	Reaction Conditions	Operation in experiment
65%	at 0 - 80℃;	Step (ii): Methyl 4-chloro-3-methoxy-5-nitrobenzoate (3)A solution of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2) (4.4 g, 19 mmol) in DMF (30 mL) at 0°C was treated with oxalyl chloride (5.09 mL, 58.1 mmol) dropwise. The mixture was then stirred at 80°C for 3 h under a CaCI₂ drying tube. The mixture was allowed to cool to RT, poured in to iced water (100 mL) and stirred for 15 min. The precipitate was collected by filtration and washed with water and MeOH to afford methyl 4-chloro-3-methoxy-5-nitrobenzoate (3) (3.2 g, 65percent yield) as a yellow solid: ¹H NMR (400 MHz, CDCI₃) δ: 8.04 (1 H, d), 7.77 (1 H, d), 4.04 (3H, s), 3.97 (3H, s).
65%	With oxalyl dichloride In N,N-dimethyl-formamide at 0 - 80℃; for 3 h;	A solution of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2) (4.4 g, 19 mmol) in DMF (30 mL) at 0° C. was treated with oxalyl chloride (5.09 mL, 58.1 mmol) dropwise. The mixture was then stirred at 80° C. for 3 h under a CaCl₂ drying tube. The mixture was allowed to cool to RT, poured in to iced water (100 mL) and stirred for 15 min. The precipitate was collected by filtration and washed with water and MeOH to afford methyl 4-chloro-3-methoxy-5-nitrobenzoate (3) (3.2 g, 65percent yield) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ: 8.04 (1H, d), 7.77 (1H, d), 4.04 (3H, s), 3.97 (3H, s).

Reference： [1] Organic Letters, 2009, vol. 11, # 8, p. 1809 - 1812
[2] Journal of the American Chemical Society, 1983, vol. 105, # 15, p. 5015 - 5024
[3] Patent: WO2011/27106, 2011, A1, . Location in patent: Page/Page column 152
[4] Patent: US2012/149737, 2012, A1, . Location in patent: Page/Page column 89

2
[ 3943-74-6 ]
[ 63603-09-8 ]

Reference： [1] Journal of the American Chemical Society, 1983, vol. 105, # 15, p. 5015 - 5024
[2] Patent: WO2011/27106, 2011, A1,
[3] Patent: US2012/149737, 2012, A1,

[ 63603-09-8 ] Synthesis Path-Downstream 1~10

1
[ 42590-00-1 ]
[ 63603-09-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With oxalyl dichloride In N,N-dimethyl-formamide at -20 - 80℃; for 3h;
90%	With oxalyl dichloride; N,N-dimethyl-formamide at 0 - 80℃; for 12h;	1.2 Step 2: Preparation of methyl 4-chlo -3-methoxy-5-nitrobenzoate (3) To a stirred solution of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2, 18 g, 79.29 mmol) in DMF (100 mL) was added oxalyl chloride (14.27 mL, 113.28 mmol) under 0°C slowly, then the reaction mixture was refluxed under 80°C for about 12 h (reaction condition b). To the reaction mixture ice cold water was added and the resulting solid was filtered. The solid was dried under high vacuum to obtain the product as brown solid (17.5 g, 90% yield). MS (ESI): mass calcd. for C9H8ClNO5, 245.01; m/z found, 246 [M+H]+.
88%	With oxalyl dichloride In N,N-dimethyl-formamide -20 deg C; 80 deg C, 3 h;

85%	With oxalyl dichloride In N,N-dimethyl-formamide at -20 - 80℃; for 3h;	d (d) Preparation of methyl 3-nitro-4-chloro-5-methoxybenzoate Methyl 3-nitro-4-hydroxy-5-methoxybenzoate (22.7 g, 0.1 mol) was dissolved in 200 mL of anhydrous N,N-dimethylformamide.At minus 20 degrees, oxalyl chloride (38.1 g, 0.3 mol) was added, and the temperature was slowly raised to 80 °C, and the reaction was carried out for 3 hours, and then the reaction solution was slowly poured into 400 ml of crushed ice.After vigorously stirring to room temperature, the solid was filtered, and the filtrate was extracted with chloroform. The organic phase was washed sequentially with saturated sodium hydrogen carbonate and saturated sodium chloride.The organic phase was dried and concentrated, and the obtained solid was crystallised from ethyl acetate and petroleum ether.Methyl 3-nitro-4-chloro-5-methoxybenzoate, 20.8 g, was obtained in a yield of 85%
65%	With oxalyl dichloride at 0 - 80℃;	115.ii Step (ii): Methyl 4-chloro-3-methoxy-5-nitrobenzoate (3)A solution of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2) (4.4 g, 19 mmol) in DMF (30 mL) at 0°C was treated with oxalyl chloride (5.09 mL, 58.1 mmol) dropwise. The mixture was then stirred at 80°C for 3 h under a CaCI2 drying tube. The mixture was allowed to cool to RT, poured in to iced water (100 mL) and stirred for 15 min. The precipitate was collected by filtration and washed with water and MeOH to afford methyl 4-chloro-3-methoxy-5-nitrobenzoate (3) (3.2 g, 65% yield) as a yellow solid: 1H NMR (400 MHz, CDCI3) δ: 8.04 (1 H, d), 7.77 (1 H, d), 4.04 (3H, s), 3.97 (3H, s).
65%	With oxalyl dichloride In N,N-dimethyl-formamide at 0 - 80℃; for 3h;	115.ii A solution of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2) (4.4 g, 19 mmol) in DMF (30 mL) at 0° C. was treated with oxalyl chloride (5.09 mL, 58.1 mmol) dropwise. The mixture was then stirred at 80° C. for 3 h under a CaCl2 drying tube. The mixture was allowed to cool to RT, poured in to iced water (100 mL) and stirred for 15 min. The precipitate was collected by filtration and washed with water and MeOH to afford methyl 4-chloro-3-methoxy-5-nitrobenzoate (3) (3.2 g, 65% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ: 8.04 (1H, d), 7.77 (1H, d), 4.04 (3H, s), 3.97 (3H, s).
63.9%	With oxalyl dichloride; N,N-dimethyl-formamide at -20 - 80℃; for 3h;	1.2 Step 2: Synthesis of methyl 4-chloro-3-methoxy-5-nitrobenzoate Methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (21 g, 0.095 mol) was dissolved in DMF (200 mL), cooled to -20 ° C, and oxalyl chloride (23.7 mL) was slowly added dropwise.After the completion of the dropwise addition, the mixture was heated to 80 ° C and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into ice water and stirred overnight. Filtration, the filter cake was dissolved in methylene chloride, washed with EtOAc EtOAc EtOAc. The crude product was recrystallized from methanol to give the desired product (14.5 g, yield: 63.9%).
	With oxalyl dichloride In N,N-dimethyl-formamide	11 Example 11 4-chloro-3-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-ylamino)-7, 8dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methoxy-N-methylbe nzamide (I-11) Compound Ia-11 was synthesized according to the process described in the patent application . Compound Ib-11 was synthesized with reference to Example 1. In a glass sealed tube, Compound Ib-11 (9mmol) was dissolved in 30ml ethanol, and a methylamine alcohol solution (15ml) was added. The mixture was reacted at 50°C overnight to produce Compound Ib-11' (7.2mmol). With reference to the procedure of Example 10, methyl vanillate, N-BOC-4-piperidinone, N-ethylpiperazine and 2-chloro-5-nitropyridine were used as starting materials to synthesize and produce Compound Ik-11. Compound Ik-11 (1.0 mmol) was dissolved in 15ml dichloromethane, and a HCl gas was introduced for 30min. The mixture was concentrated to produce Compound Im-11 (1.0 mmol). Compound Im-11 (1.0 mmol) and Compound Ib-11' (1.05 mmol) were suspended in 10ml dioxane, and cesium carbonate (4.5 mmol) was added. The mixture was stirred evenly, Pd2(dba)3 (0.1 mmol) and BINAP (0.12 mmol) were added. The mixture was reacted under the nitrogen protection at 100°C for 48 hours, cooled to room temperature and filtered. The filtrate was concentrated to an oily substance, and an appropriate amount of methanol was added. A solid separated out. The mixture was filtered to remove the solid (BINAP), and the filtrate was separated by thin layer chromatography to produce Compound I-11 (0.2mmol) in a yield of 20%. H1-NMR (deuterated DMSO) : δ9.3(s, 1H), δ8.57(s, 1H), δ8.48(s, 1H), δ8.26(s, 1H), δ7.89(s, 1H), δ7.35(d, 2H), δ6.85(s, 1H), δ4.13(s, 2H), δ3.91(s, 3H), δ3.42(m, 2H), δ3.20(t, 4H), δ2.82(t, 2H), δ2.68(s, 3H), δ2.49(m, 4H)δ2.35(m, 2H), δ1.05(t, 3H). H1-NMR (deuterated DMSO) for intermediate Ib-11': δ8.65(s, 1H), δ7.92(s, 1H), δ7.6(s, 1H), δ3.91(s, 3H), δ2.78(d, 3H). ESI(+)m/z: 537

Reference： [1]Wang, Lin; Gong, Jianxian; Deng, Lujiang; Xiang, Zheng; Chen, Zhixing; Wang, Yuefan; Chen, Jiahua; Yang, Zhen [Organic Letters, 2009, vol. 11, # 8, p. 1809 - 1812]
[2]Current Patent Assignee: JUBILANT PHARMOVA LTD - WO2019/58393, 2019, A1 Location in patent: Paragraph 000145
[3]Meyers; Babiak; Campbell; et al. [Journal of the American Chemical Society, 1983, vol. 105, # 15, p. 5015 - 5024]
[4]Current Patent Assignee: SHAOXING UNIVERSITY - CN110016016, 2019, A Location in patent: Paragraph 0028; 0037; 0038
[5]Current Patent Assignee: UNIVERSITY OF LONDON - WO2011/27106, 2011, A1 Location in patent: Page/Page column 152
[6]Current Patent Assignee: UNIVERSITY OF LONDON - US2012/149737, 2012, A1 Location in patent: Page/Page column 89
[7]Current Patent Assignee: NANJING TRANSTHERA BIOSCIENCES - CN110194770, 2019, A Location in patent: Paragraph 0398; 0399; 0403; 0404; 0405
[8]Current Patent Assignee: ALLIST PHARMACEUTICALS INC - EP3466948, 2019, A1 Location in patent: Paragraph 0092-0096

2
[ 63603-09-8 ]
[ 63603-10-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride In ethanol; water at 70℃; for 3h; Inert atmosphere;	115.iii Step (Hi): Methyl 3-amino-4-chloro-5-methoxybenzoate (4)A suspension of methyl 4-chloro-3-methoxy-5-nitrobenzoate (3) (900 mg, 3.66 mmol) and iron powder (614 mg, 1 1.0 mmol) in a mixture of EtOH (15 mL) and water (15 mL) was heated to 70°C and degassed with nitrogen for 20 min. Cone. HCI (44.5 pL, 1.47 mmol) was added and the reaction mixture was stirred at 70°C for 3 h. Celite (1 g) was added and the suspension stirred for 10 min then filtered through a celite pad. The solvent was removed in vacuo and the residue was partitioned between EtOAc (15 mL) and water (15 mL). The phases were separated and the organic solution was washed with brine (2 x 15 mL). The solvent was removed in vacuo to afford methyl 3-amino-4-chloro-5- methoxybenzoate (0.82 g, 100 % yield) as a yellow solid: 1H NMR (400 MHz, DMSO-cf6) δ: 7.10 (1 H, d), 6.78 (1 H, d), 5.68 (2H, s), 3.81 (6H, m).
100%	With iron In ethanol; water at 70℃; for 0.333333h; Inert atmosphere;	115.iii A suspension of methyl 4-chloro-3-methoxy-5-nitrobenzoate (3) (900 mg, 3.66 mmol) and iron powder (614 mg, 11.0 mmol) in a mixture of EtOH (15 mL) and water (15 mL) was heated to 70° C. and degassed with nitrogen for 20 min. Conc. HCl (44.5 μL, 1.47 mmol) was added and the reaction mixture was stirred at 70° C. for 3 h. Celite (1 g) was added and the suspension stirred for 10 min then filtered through a celite pad. The solvent was removed in vacuo and the residue was partitioned between EtOAc (15 mL) and water (15 mL). The phases were separated and the organic solution was washed with brine (2*15 mL). The solvent was removed in vacuo to afford methyl 3-amino-4-chloro-5-methoxybenzoate (0.82 g, 100% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ: 7.10 (1H, d), 6.78 (1H, d), 5.68 (2H, s), 3.81 (6H, m).
90%	With 5%-palladium/activated carbon; hydrogen In ethanol at 25℃; Inert atmosphere;

	With hydrogenchloride; iron	11 Example 11 4-chloro-3-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-ylamino)-7, 8dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methoxy-N-methylbe nzamide (I-11) Compound Ia-11 was synthesized according to the process described in the patent application . Compound Ib-11 was synthesized with reference to Example 1. In a glass sealed tube, Compound Ib-11 (9mmol) was dissolved in 30ml ethanol, and a methylamine alcohol solution (15ml) was added. The mixture was reacted at 50°C overnight to produce Compound Ib-11' (7.2mmol). With reference to the procedure of Example 10, methyl vanillate, N-BOC-4-piperidinone, N-ethylpiperazine and 2-chloro-5-nitropyridine were used as starting materials to synthesize and produce Compound Ik-11. Compound Ik-11 (1.0 mmol) was dissolved in 15ml dichloromethane, and a HCl gas was introduced for 30min. The mixture was concentrated to produce Compound Im-11 (1.0 mmol). Compound Im-11 (1.0 mmol) and Compound Ib-11' (1.05 mmol) were suspended in 10ml dioxane, and cesium carbonate (4.5 mmol) was added. The mixture was stirred evenly, Pd2(dba)3 (0.1 mmol) and BINAP (0.12 mmol) were added. The mixture was reacted under the nitrogen protection at 100°C for 48 hours, cooled to room temperature and filtered. The filtrate was concentrated to an oily substance, and an appropriate amount of methanol was added. A solid separated out. The mixture was filtered to remove the solid (BINAP), and the filtrate was separated by thin layer chromatography to produce Compound I-11 (0.2mmol) in a yield of 20%. H1-NMR (deuterated DMSO) : δ9.3(s, 1H), δ8.57(s, 1H), δ8.48(s, 1H), δ8.26(s, 1H), δ7.89(s, 1H), δ7.35(d, 2H), δ6.85(s, 1H), δ4.13(s, 2H), δ3.91(s, 3H), δ3.42(m, 2H), δ3.20(t, 4H), δ2.82(t, 2H), δ2.68(s, 3H), δ2.49(m, 4H)δ2.35(m, 2H), δ1.05(t, 3H). H1-NMR (deuterated DMSO) for intermediate Ib-11': δ8.65(s, 1H), δ7.92(s, 1H), δ7.6(s, 1H), δ3.91(s, 3H), δ2.78(d, 3H). ESI(+)m/z: 537
	With iron; ammonium chloride In ethanol; water at 70℃; for 2h;	I.1 Intermediate compound 72: A solution of methyl 4-chloro-3-methoxy-5-nitrobenzoate (15 g, 61.07 mmol, 1 eq), iron (13.64 g, 244.28 mmol, 4 eq) and NH4C1 (26.13 g, 488.57 mmol, 8 eq) in EtOH (225 mL) and H20 (75 mL) was stirred at 70 °C for 2 hrs. After cooled to the ambient temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with H20 (300 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2S04 and filtered. The filtrate was concentrated under reduced pressure to give the crude intermediate compound 72 (14.38 g) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) d 7.11 (s, 1 H), 6.86 - 6.71 (m, 1 H), 5.74 - 5.60 (m, 2 H), 3.82 (s, 6 H).

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - WO2011/27106, 2011, A1 Location in patent: Page/Page column 152
[2]Current Patent Assignee: UNIVERSITY OF LONDON - US2012/149737, 2012, A1 Location in patent: Page/Page column 89
[3]Wang, Lin; Gong, Jianxian; Deng, Lujiang; Xiang, Zheng; Chen, Zhixing; Wang, Yuefan; Chen, Jiahua; Yang, Zhen [Organic Letters, 2009, vol. 11, # 8, p. 1809 - 1812]
[4]Current Patent Assignee: ALLIST PHARMACEUTICALS INC - EP3466948, 2019, A1 Location in patent: Paragraph 0092-0096
[5]Current Patent Assignee: ITEOS THERAPEUTICS SA - WO2021/204896, 2021, A1 Location in patent: Paragraph 0486; 0554

3
[ 63603-09-8 ]
[ 74-89-5 ]
[ 1549812-20-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium carbonate In tetrahydrofuran at 60℃; for 24h;	1 Methyl 3-methoxy-4-(methylamino)-5-nitrobenzoate (EV-AX9482-002)- Step 1 Methyl 3-methoxy-4-(methylamino)-5-nitrobenzoate (EV-AX9482-002)- Step 1 Potassium carbonate (11.3 g, 81.4 mmol) and 2 M MeNH2 in THF (61 ml) were added at room temperature to a stirred solution of methyl 4-chloro-3-methoxy-5-nitrobenzoate (CAS 63603-09-8, 10.0 g, and 40.71 mmol) in THF (180 ml). The resulting mixture was stirred at 60°C for 24 h and concentrated in vacuo. The residue was re-dissolved in ethyl acetate (500 ml), washed with water (2 × 250 ml) and saturated aqueous sodium chloride (200 ml). The organic extracts were dried over sodium sulfate and concentrated in vacuo to afford 9.38 g (96%) of methyl 3-methoxy-4-(methylamino)-5-nitrobenzoate (EV-AX9482-001) as an orange powder. LCMS (method D): retention time 1.30min, M/z = 241 (M + 1).
81%	In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 80℃; for 3h;	1.3 Step 3: Synthesis of methyl 3-methoxy-4-(methylamino)-5-nitrobenzoate Methyl 4-chloro-3-methoxy-5-nitrobenzoate (14 g, 0.057 mol) was dissolved in DMF (140 mL).The methylamine solution (2mol/L tetrahydrofuran solution, 114mL) was added dropwise. After the addition, the reaction mixture was heated to 80 ° C and stirred for 3 hours, cooled to room temperature, diluted with water and filtered to give an orange solid product (11.1 g, yield 81%) ).
	In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 80℃; for 3h;	methyl 3-methoxy-4-(methylamino)-5-nitrobenzoate Methyl 4-ch loro-3-methoxy-5-nitrobenzoate (available from, for example, Apollo Scientific Ltd) (14 g, 57.0 mmol) was dissolved in N,N-dimethylformamide (DMF) (140 mL) and cooled to -0°C in an ice/water bath. Methanamine (2M in THF) (114 mL, 228 mmol) was added dropwise with vigorous stirring using a dropping funnel and the mixture was flushed withnitrogen and heated at 80 °C for 3hr. The mixture was allowed to cool to room temperature over the weekend. The reaction mixture was diluted with water (500 mL), and filtered under vacuum to give the title compound as an orange solid (13.69 g).LCMS (Method A): Rt = 1.04 mi MH+ = 241.05

13.69 g	In tetrahydrofuran; N,N-dimethyl-formamide at 80℃; for 3h; Inert atmosphere;	Intermediate 23: Methyl 3-methoxy-4-(methylamino)-5-nitrobenzoate Intermediate 23: Methyl 3-methoxy-4-(methylamino)-5-nitrobenzoate Methyl 4-chloro-3-methoxy-5-nitrobenzoate (available from, for example, Apollo Scientific Ltd) (14 g, 57.0 mmol) was dissolved in N,N-dimethylformamide (DMF) (140 mL) and cooled to ˜0° C. in an ice/water bath. Methanamine (2M in THF) (114 mL, 228 mmol) was added dropwise with vigorous stirring using a dropping funnel and the mixture was flushed with nitrogen and heated at 80° C. for 3 hr. The mixture was allowed to cool to room temperature over the weekend. The reaction mixture was diluted with water (500 mL), and filtered under vacuum to give the title compound as an orange solid (13.69 g).LCMS (Method A): Rt=1.04 min, MH+=241.05
13.69 g	In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 80℃; for 3h;	104 Methyl 3-metho -4-(methylamino)-5-nitrobenzoate Methyl 4-chloro-3-methoxy-5-nitrobenzoate (available from, for example, Apollo Scientific Ltd) (14 g, 57.0 mmol) was dissolved in Ν,Ν-dimethylformamide (DMF) (140 mL) and cooled to ~0 °C in an ice/water bath. Methanamine (2M in THF) (114 mL, 228 mmol) was added dropwise with vigorous stirring using a dropping funnel and the mixture was flushed with nitrogen and heated at 80 °C for 3 h. The mixture was allowed to cool to rt over the weekend. The reaction mixture was diluted with water (500 mL), and filtered under vacuum to give the title compound as an orange solid (13.69 g).LCMS (Method A): Rt = 1.04 min, MH+ = 241.05
	In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 80℃; for 4h;	Methyl 3-methoxy-4-(methylamino)-5-nitrobenzoate: To a stirred solution of methyl 4- chloro-3-methoxy-5-nitrobenzoate (2456 mg, 30 mmol) in DMF (20 mL) was added 2.0 M methylamine in THF (4057 mg, 90 mmol) at 0oC dropwise. The reaction mixture was stirred at ambient temperature for 1 hour and then heated at 80oC for 3h. After completion of reaction as indicated by TLC, the reaction mixture was cooled to room temperature then water (100 mL) was added and stirred for 30 min. The obtained orange solid was filtered, washed with water, and dried to give the title compound (2135 mg, 88.88 % yield) which was used for the next step without purification. MS (ESI): m/z 241 [M+1]+.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/147102, 2017, A1 Location in patent: Paragraph 00350-00351
[2]Current Patent Assignee: NANJING TRANSTHERA BIOSCIENCES - CN110194770, 2019, A Location in patent: Paragraph 0398; 0399; 0406; 0407; 0408; 0409
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2014/15905, 2014, A1 Location in patent: Page/Page column 52
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2015/175600, 2015, A1 Location in patent: Paragraph 0404; 0405; 0406
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2016/185279, 2016, A1 Location in patent: Page/Page column 118; 119
[6]Current Patent Assignee: WISTAR INSTITUTE - WO2020/252407, 2020, A1 Location in patent: Page/Page column 72-73

4
[ 63603-09-8 ]
[ 593-51-1 ]
[ 1549812-20-5 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; Inert atmosphere; Sealed tube;	1.1; 3.1 Methyl 3-methoxy-4-(methylamino)-5-nitrobenzoate EV-AR0065-002 - step 1 To a stirred solution of methyl 4-chloro-3-methoxy-5-nitrobenzoate (CAS 63603- 09-8, 2.0 g, 8.14 mmol) in DMF (10 ml) was added K2C03 (99%, 1.37 g, 9.81 mmol). To this solution was added methanamine hydrochloride (1 : 1) (0.62 g, 9.18 mmol) and the mixture was stirred in a sealed tube under nitrogen at 80°C for 16h. The reaction crude was concentrated in vacuo and partitioned between DCM (100ml) and water (10ml). The organic layer was washed further with water (2 x 10ml) and saturated aqueous sodium chloride (10ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford an orange powder which was purified by flash column chromatography (15-40% EtO Ac/heptane) to obtain 1.49 g (76%) of methyl 3-methoxy-4-(methylamino)-5- nitrobenzoate EV-AR0065-002 as an orange powder. LCMS (method D): retention time 1.13min, M/z = 241 (M + 1).
76%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; Sealed tube; Inert atmosphere;	5.1 Methyl 3-methoxy-4-(methylamino)-5-nitrobenzoate EV-AR0065-002 - step 1 To a stirred solution of methyl 4-chloro-3-methoxy-5-nitrobenzoate (CAS 63603-09-8, 2.00 g, 8.i4 mmol) in DMF (iO ml) was added K2C03 (99%, i.37 g, 9.8i mmol). To this solution was added methanamine hydrochloride (i:i) (0.62 g, 9.i8 mmol) and the mixture was stirred in a sealed tube under nitrogen at 80°C for i6h. The reaction cmde was concentrated in vacuo and partitioned between DCM (iOO ml) and water (iO ml). The organic layer was washed further with water (2 x i0ml) and saturated aqueous sodium chloride (iOml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford an orange powder which was purified by flash column chromatography (i5-40% EtOAc/heptane) to obtain i .49 g (76%) of methyl 3-methoxy-4-(methylamino)-5- nitrobenzoate EV-AR0065-002 as an orange powder. LCMS (method D): retention time i.i3min, M/z = 24i (M + i).
	With triethylamine In N,N-dimethyl-formamide at 75℃; for 16h; Sealed tube;	1.1 Preparation of methyl 2-(6-bromo-1H-indol-2-yl)-7-methoxy-1-methyl-1H- benzo[d]imidazole-5-carboxylate (I-7a) Step 1. A 250 mL round bottom flask was charged with methyl 4-chloro-3-methoxy-5- nitrobenzoate (14.0 g, 57 mmol) and methylamine hydrochloride salt (4.65 g, 69 mmol). The solids were taken in DMF (100 mL) and triethylamine (14.1 g, 143 mmol) was added. The flask was sealed and the reaction mixture was stirred at 75 °C for 16 h. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM and the combined organics were washed with water then brine. The combined organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was dissolved in hot EtOAc (80 mL) and hexanes (220 mL) were added. The mixture was allowed to cool to room temperature and the crystallization was aged overnight before collecting solids by filtration to afford methyl 2-(6-bromo-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylate. ES/MS: m/z 241.0 [M+H]+.

With triethylamine In N,N-dimethyl-formamide at 75℃; for 16h; Sealed tube;

1.1 Preparation of methyl 2-(6-bromo-1H-indol-2-yl)-7-methoxy-1-methyl-1H- benzo[d]imidazole-5-carboxylate (I-7a) Step 1. A 250 mL round bottom flask was charged with methyl 4-chloro-3-methoxy-5- nitrobenzoate (14.0 g, 57 mmol) and methylamine hydrochloride salt (4.65 g, 69 mmol). The solids were taken in DMF (100 mL) and triethylamine (14.1 g, 143 mmol) was added. The flask was sealed and the reaction mixture was stirred at 75 °C for 16 h. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM and the combined organics were washed with water then brine. The combined organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was dissolved in hot EtOAc (80 mL) and hexanes (220 mL) were added. The mixture was allowed to cool to room temperature and the crystallization was aged overnight before collecting solids by filtration to afford methyl 2-(6-bromo-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylate. ES/MS: m/z 241.0 [M+H]+.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/100594, 2017, A1 Location in patent: Paragraph 00105; 00181
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2018/22897, 2018, A1 Location in patent: Paragraph 00158; 00159; 00160
[3]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/222353, 2021, A1 Location in patent: Page/Page column 135; 143
[4]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/222353, 2021, A1 Location in patent: Page/Page column 135; 143

5
[ 612511-81-6 ]
[ 63603-09-8 ]
methyl 3-methoxy-4-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-5-nitrobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
740 mg	With potassium carbonate; In dimethyl sulfoxide; at 50℃; for 48h;	To methyl 4-chloro-3-methoxy-5-nitrobenzoate (1 g, 4.07 mmol) in DMSO (8 mL) were added (1 -methyl-1 H-pyrazol-3-yl)methanamine (0.498 g, 4.48 mmol) and K2C03 (0.731 g, 5.29 mmol), and the reaction mixture was stirred at 50 °C for 48 hours. The reaction was quenched with water (25 mL), and the resulting precipitate was collected by filtration and dried in vacuum over to afford crude methyl 3-methoxy-4-(((1 -methyl-1 H-pyrazol-3- yl)methyl)amino)-5-nitrobenzoate (740 mg) as an orange solid. LC-MS (ES) m/z = 321 [M+H]+. NMR (400 MHz, DMSO-c/6): delta 3.78 (s, 3H), 3.84 (s, 3H), 3.91 (s, 3H), 4.73 (s, 2H), 6.10 (d, J = 2.0 Hz, 1 H), 7.46 (d, J = 1 .8 Hz, 1 H), 7.61 (d, J = 2.0 Hz, 1 H), 8.19 (d, J = 2.0 Hz, 1 H), 8.36 (br. s., 1 H).

Reference： [1]Patent: WO2019/49061,2019,A1 .Location in patent: Page/Page column 485

6
[ 46460-73-5 ]
[ 63603-09-8 ]
methyl 4-((3-(((benzyloxy)carbonyl)amino)propyl)amino)-3-methoxy-5-nitrobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.9%	With potassium carbonate In 1-methyl-pyrrolidin-2-one at 120℃; for 9h;

Reference： [1]Xi, Qiumu; Wang, Mingjin; Jia, Wenqiang; Yang, Mingjian; Hu, Jinping; Jin, Jing; Chen, Xiaoguang; Yin, Dali; Wang, Xiaojian [Journal of Medicinal Chemistry, 2020, vol. 63, # 1, p. 260 - 282]

7
[ 63603-09-8 ]
[ 144222-22-0 ]
tert-butyl 4-(((2-methoxy-4-(methoxycarbonyl)-6-nitrophenyl)amino)methyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 18h;	194 Intermediate 194A: Tert-butyl 4-(((2-methoxy-4-(methoxycarbonyl)-6- nitrophenyl)amino)methyl)piperidine-1-carboxylate A mixture of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (2.0 g, 9.33 mmol), methyl 4-chloro-3-methoxy-5-nitrobenzoate (2.292 g, 9.33 mmol) and potassium carbonate (3.87 g, 28.0 mmol) in DMF (30 mL) was stirred at 80 °C for 18 hour. The mixture was diluted with EtOAc (15 mL) and was washed with a solution of aqueous saturated sodium bicarbonate (2 x 15 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient) to yield tert-butyl 4-(((2-methoxy-4- (methoxycarbonyl)-6-nitrophenyl)amino)methyl)piperidine-1-carboxylate (3.42 g, 7.67 mmol, 82 % yield) as orange gum. LC/MS (2M+Na): 869; LC retention time: 1.08 min (analytical HPLC Method 3).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2020/33514, 2020, A1 Location in patent: Paragraph 00254

8
[ 199174-29-3 ]
[ 63603-09-8 ]
tert-butyl (R)-3-(((2-methoxy-4-(methoxycarbonyl)-6-nitrophenyl)amino)methyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 18h;	A mixture of <strong>[199174-29-3]tert-butyl (R)-3-(aminomethyl)pyrrolidine-1-carboxylate</strong> (0.815 g, 4.07 mmol), methyl 4-chloro-3-methoxy-5-nitrobenzoate (1.00 g, 4.07 mmol) and potassium carbonate (1.688 g, 12.21 mmol) in DMF (20 mL) was stirred at 80 C for 18 hr. The mixture was diluted with EtOAc (35 mL) and was washed with a solution of aqueous saturated sodium bicarbonate (2 x 35 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient) to yield tert-butyl (R)-3-(((2-methoxy-4- (methoxycarbonyl)-6-nitrophenyl)amino)methyl)pyrrolidine-1-carboxylate (1.0 g, 2.442 mmol, 60.0 % yield). LC/MS (M+H): 410; LC retention time: 1.07 min (analytical HPLC Method 3).

Reference： [1]Patent: WO2020/33514,2020,A1 .Location in patent: Paragraph 00265

9
[ 63603-09-8 ]
[ 1016731-24-0 ]
[ 2410576-23-5 ]

Yield	Reaction Conditions	Operation in experiment
73.2%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 18h;	1 Intermediate 1A: Benzyl 3-(((2-methoxy-4-(methoxycarbonyl)-6- nitrophenyl)amino)methyl)azetidine-1-carboxylate A mixture of methyl 4-chloro-3-methoxy-5-nitrobenzoate (2.79 g, 11.35 mmol), benzyl 3-(aminomethyl)azetidine-1-carboxylate (2.5 g, 11.35 mmol) and potassium carbonate (4.71 g, 34.0 mmol) in DMF (20 mL) was stirred at 60 °C for 18 hours. The mixture was diluted with EtOAc (35 mL) and was washed with a solution of sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient) to yield benzyl 3-(((2- methoxy-4-(methoxycarbonyl)-6-nitrophenyl)amino)methyl)azetidine-1-carboxylate (3.755 g, 8.31 mmol, 73.2 % yield) as red gum. LC/MS (M+H): 430; LC retention time: 1.07 min (analytical HPLC Method 3). 1H NMR (499 MHz, CHLOROFORM-d) d 8.51 (d, J=1.9 Hz, 1H), 8.21 - 8.13 (m, 1H), 7.57 - 7.51 (m, 1H), 7.41 - 7.31 (m, 5H), 5.15 - 5.05 (m, 2H), 4.22 - 4.11 (m, 2H), 3.99 - 3.86 (m, 8H), 3.82 - 3.73 (m, 2H), 2.94 - 2.79 (m, 1H)

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2020/33514, 2020, A1 Location in patent: Paragraph 00188

10
[ 10269-01-9 ]
[ 63603-09-8 ]
methyl 4-((3-bromobenzyl)amino)-3-methoxy-5-nitrobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 50℃;	21.3; 41.3 Step 3: methyl 4-((3-bromobenzyl)amino)-3-methoxy-5-nitrobenzoate: To a 40 mL vial was added methyl 4-chloro-3-methoxy-5-nitrobenzoate (2 g, 8.14 mmol), hunig'sbase (2.84 mL, 16.29 mmol) and (3-bromophenyl)methanamine (3.03 g, 16.29 mmol) in DMF (15 mL). The mixture was heated to 50 °C overnight. The mixture was diluted in ethyl acetate, and washed twice with LiCl 10%, once water and once with brine. The mixture was purified via MPLC using a 20% to 30% ethyl acetate to hexanes gradient. Fractions containing the desired product were collected and concentrated in vacuo to yield the title compound (2.783 g, 86% yield). LCMS Tr = 1.04 m, MS ESI m/z = 395.2 (M+H) (Method 3).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2021/158840, 2021, A1 Location in patent: Page/Page column 83; 85; 107; 109

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Ghs Precautionary Statements

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Prevention
Code	Phrase
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H200	Unstable explosive
H201	Explosive; mass explosion hazard
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Code	Phrase
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H411	Toxic to aquatic life with long-lasting effects
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