[ CAS No. 60547-92-4 ] {[proInfo.proName]}

Name: 60547-92-4|4-(Benzyloxy)-5-methoxy-2-nitrobenzoic acid|98%
Brand: Ambeed
SKU: A202613
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2D 3D

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Quality Control of [ 60547-92-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 60547-92-4 ]

SDS Specification

Alternatived Products of [ 60547-92-4 ]

Product Details of [ 60547-92-4 ]

CAS No. :	60547-92-4	MDL No. :	MFCD04114356
Formula :	C₁₅H₁₃NO₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VTHHRADLOLKTLD-UHFFFAOYSA-N
M.W :	303.27	Pubchem ID :	10859633
Synonyms :

Calculated chemistry of [ 60547-92-4 ]

Physicochemical Properties

Num. heavy atoms :	22
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.13
Num. rotatable bonds :	6
Num. H-bond acceptors :	6.0
Num. H-bond donors :	1.0
Molar Refractivity :	79.69
TPSA :	101.58 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.23 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.9
Log Po/w (XLOGP3) :	2.71
Log Po/w (WLOGP) :	2.73
Log Po/w (MLOGP) :	1.51
Log Po/w (SILICOS-IT) :	0.67
Consensus Log Po/w :	1.9

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.44
Solubility :	0.111 mg/ml ; 0.000367 mol/l
Class :	Soluble
Log S (Ali) :	-4.5
Solubility :	0.00967 mg/ml ; 0.0000319 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-3.93
Solubility :	0.0357 mg/ml ; 0.000118 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.71

Safety of [ 60547-92-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 60547-92-4 ]

* 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 [ 60547-92-4 ]
Downstream synthetic route of [ 60547-92-4 ]

[ 60547-92-4 ] Synthesis Path-Upstream 1~14

1
[ 2426-84-8 ]
[ 60547-92-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium permanganate In acetone at 30 - 50℃; for 2 h;	The compound (20g, 69.62 mmol) obtained in <Step 1> was dissolved in acetone (200 mL), and a hot 10percent potassium permanganate solution was slowly added thereto at 30°C. The mixture was stirred at 50°C for 2 hours, and cooled to room temperature. Subsequently, the mixture was filtered through a Celite pad, and washed with acetone and a small amount of hot water. The filtrate was concentrated under reduced pressure and cooled to 0°C. Then, the concentrate was acidified into pH 4 using hydrochloric acid, and the resulting mixture was stirred for 30 min and filtered to the title compound as a solid (18.5g, 88percent). NMR(300 MHz, DMSO-d₆):<5 13.58(brs, 1H), 7.70(s, 1H), 7.46-7.40(m, 6H), 7.39(s, 1H), 5.25(s, 2H), 3.92(s, 3H).MS(ESI⁺, m/z): 304 [M+H]⁺
79%	With potassium permanganate In water; acetone at 70℃; for 4 h;	A solution of 4-(benzyloxy)-5-methoxy-2-nitrobenzaldehyde (32) (8.0 g, 28 mmol) in acetone (300 mL) was quickly charged with a hot (70 °C) solution of potassium permanganate (16.5 g, 104 mmol) in water (150 ml). The mixture was then stirred at 70 °C for 4 h. The reaction mixture was then allowed to cool to room temperature and passed through a pad of celite, which was then washed with hot water (120 mL). A solution of sodium bisulfite in hydrochloric acid (1 M, 120 mL) was added to the filtrate, which was then extracted with dichloromethane (2 x 200 mL). The combined organic extracts were subsequently dried over sodium sulfate, filtered and concentrated to give the title compound (6.7 g, 79percent) as a yellow solid, which was used in the subsequent step without further purification. (1547) NMR (400 MHz, CDCI₃) £7-55 (s, lH), 7-49"7-37 (m, 6H), 5.17 (s, 2H), 4-99 (br s, lH), 3-93 (s, 3H); C NMR (100 MHz, MeOD) £168.6, 154.1, 151.0, 142.9, 137-3, 129-7, 129.4, 129.0, 123.2, 112.5, 110.0, 72.3, 57.1; MS (ES+): m/z = 302 (M+H)⁺, MS (ES-): m/z = 302 (M-l)-; LCMS (Method B): t_R = 3.62 min, LCMS (Method A): t_R= 7.02 min
50%	With potassium permanganate In ethyl acetate; acetone	PREPARATION 80 5-Methoxy-2-nitro-4-(phenylmethyloxy)benzoic acid A solution of 5-methoxy-2-nitro-4-(phenylmethyloxy) benzaldehyde (45.11 g, 0.157 mole) in 600 ml of acetone was prepared. To this solution was added 400 ml of 10percent potassium permanganate solution over 1 hr. The resultant mixture was stirred for 1 hr at room temperature. The reaction mixture was cooled to room temperature and filtered with Celite.(R)., acetone was removed. The resulting material was made acidic with concentrated hydrochloric acid. A yellow solid formed and was separated from aqueous solution, and air dried. The yellow solid was dissolved in ethyl acetate, and filtered through sodium sulfate to remove traces of manganese dioxide, after which 25.84 g of yellow solid was obtained. A 2 g sample was recrystallized from isopropyl alcohol. The yellow solid isolated was dried in vacuo overnight at 80° C., to give 1.85 g (50percent yield) of yellow solid, mp 188° C. (with decomposition). Analysis: Calculated for C₁₅ H₁₃ NO₆: C, 59.41; H, 4.32; N, 4.62. Found: C, 59.27; H, 4.40; N, 4.46.

Reference： [1] Patent: WO2012/30160, 2012, A2, . Location in patent: Page/Page column 50
[2] Patent: WO2017/194960, 2017, A1, . Location in patent: Page/Page column 187
[3] Patent: US4950674, 1990, A,
[4] Farmaco, Edizione Scientifica, 1977, vol. 32, # 8, p. 579 - 591
[5] Tetrahedron Letters, 1986, vol. 27, # 10, p. 1149 - 1152

2
[ 61032-41-5 ]
[ 60547-92-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With water; triethylamine; sodium hydroxide In tetrahydrofuran at 50℃; for 5 h;	To a solution of methyl 4-(benzyloxy)-5-methoxy-2- nitrobenzoate (Harve Chem, 15 g, 47.3 mmol) in tetrahydrofuran (THF, 350 mL) was added a solution of aq. NaOH (56.7 mL, 142 mmol, 2.5M). The reaction was stirred at 50 °C for 5 h. The reaction was cooled to room temperature (RT) and then concentrated in vacuo to remove the THF. The remaining aqueous layer was acidified with aq. HC1 (6 N) to pH 2. The resulting yellow precipitate was filtered, washed with water, and dried under vacuum to give 4- (benzyloxy)-5-methoxy-2-nitrobenzoic acid (14.32 g, 100percent yield). LCMS (M+H) = 304.08; NMR (400MHz, METHANOL-d₄) δ 7.60 (s, 1H), 7.53 - 7.45 (m, 2H), 7.45 - 7.31 (m, 3H), 7.29 (s, 1H), 5.23 (s, 2H), 3.98 (s, 3H).
100%	With water; sodium hydroxide In tetrahydrofuran at 50℃; for 5 h;	To a rt solution of methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (15 g, 47 mmol) inTHF (350 mL) was added 2.5 M aq. NaOH (56.7 mL, 142 mmol). The reaction was stirred at 50°C for 5 h. The reaction was cooled to rt and then concentrated in vacuo to remove the THF. Theremaining aqueous layer was acidified with 6 N aq. HCl to pH 2. The resulting yellow precipitatewas filtered, washed with water, and dried under vacuum to provide S1 (14.32 g, quant.).
92%	at 50℃; for 1 h;	4-Benzyloxy-5-methoxy-benzoic acid methyl ester (9.1 g, 29 mmol) was dissolved in methanol (145 mL) and sodium hydroxide (6 M solution, 24 mL) was added at once. Reaction mixture was stirred for 1 h at 50 degrees and methanol was evaporated. Concentrated hydrochloric acid (12 mL) was added slowly to the residue with stirring. Formed precipitate was filtered off, washed with water and dried to afford 8.1 g of 3 (92percent yield).¹H NMR (500 MHz, DMSO-d6) : 7.69 (s, 1H), 7.36-7.47 (m, 5H),7.31 (s, 1H), 5.24 (s, 2H), 3.91 (s, 3H).

92%	at 50℃; for 1 h;	4-benzyloxy-5-methoxy-2-nitro-benzoic acid methyl ester (9.1 g, 29 mmol) was dissolved in methanol (145 mL) and sodium hydroxide (6 M solution, 24 mL) was added at once. Reaction mixture was stirred for 1 h at 50 degrees and methanol was evaporated.Concentrated hydrochloric acid (12 mL) was added slowly to the residue with stirring.Formed precipitate was filtered off, washed with water and dried to afford 8.1 g of 3 (92percent yield). ¹H NMR (500 MHz, DMSO-d6) δ: 7,69 (s, 1H), 7,36-7,47 (m, 5H),7,31 (s, 1H), 5.24 (s, 21-1), 3.91 (s, 3H).
91%	With lithium hydroxide In methanol; water at 20℃; for 2 h;	A solution of 40 (2.3 g, 7.25 mmol) in MeOH (20 mL) was added a solution of LiOH (2.25 mL, 36.24 mmol) in water (5 mL). The reaction mixture was stirred at 20° C. for 2 h. The mixture was poured into water (50 mL), and washed with EtOAc (50 mL). The water phase was adjust pH to 3-4 with 2M HCl, and extracted with EtOAc (50 mL*3). It was washed with NaCl (25 mL), dried over Na₂SO₄ and concentrated in vacuo to give crude 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid 41 (2.0 g, 6.59 mmol, 91percent yield) as white solid.
1.5 kg	With lithium hydroxide monohydrate; water In tetrahydrofuran at 20℃; for 16 h; Large scale	To a solution of compound 3 (2.50 kg, 7.93 mol) in THF (20 L) and H₂0 (20 L) was added LiOH H₂0 (332.68 g, 7.93 mol) in one portion at 20 °C to give a suspension, the reaction was stirred at this temperature for 16 h. TLC (petroleum ether: ethyl acetate = 2: 1) showed that the reaction was completed. The solvent was evaporated under vacuum to remove THF. The residue was acidified with 2N HC1 until pH = 2 to give a yellow

Reference： [1] Patent: WO2016/209951, 2016, A1, . Location in patent: Paragraph 00146-00147
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 23, p. 5267 - 5271
[3] Patent: WO2018/53552, 2018, A2, . Location in patent: Paragraph 000473-000475
[4] Patent: WO2018/71455, 2018, A1, . Location in patent: Paragraph 0009; 00114; 00119-00121
[5] Patent: US2017/95570, 2017, A1, . Location in patent: Paragraph 0571; 0574
[6] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 20, p. 5427 - 5436
[7] Patent: WO2018/195245, 2018, A1, . Location in patent: Page/Page column 27

3
[ 1486-53-9 ]
[ 60547-92-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With nitric acid; acetic acid In dichloromethane for 6 h;	4-(Benzyloxy)-3-methoxybenzoic acid (63.5 g, 246.0 mmol) in the mixture of CH2CI2 (400 ml) and I lOAc (100 ml) was added HNO₃ (fuming, 25.0 ml, 528.5 mmol). The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried over the oven at 40 °C with vacuum to afford the title compound (63.3 g, 85percent yield). ESI MS m/z+ 326.1 (M + Na).
85%	With nitric acid; acetic acid In dichloromethane for 6 h;	Example 9. 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid 4-(Benzyloxy)-3-methoxybenzoic acid (63.5 g, 246.0 mmol) in the mixture of CH2C12(400 ml) and FIOAc (100 ml) was added HNO3 (fuming, 25.0 ml, 528.5 mmoi). The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried over the oven at 40 °Cwith vacuum to afford the title compound (63.3 g, 85percent yield). ESI MS mlz+ 326.1 (M +Na).
85%	With nitric acid; acetic acid In dichloromethane for 6 h;	To a solution of compound 238 (63.5 g, 246.0 mmol) in CH₂Cl₂ (400 ml) and HOAc (100 ml) was added HNO₃ (fuming, 25.0 ml, 528.5 mmol). The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried at 40 °C under vacuum to afford the title compound (63.3 g, 85percent yield). ESI MS m/z 326.1 ([M+Na]⁺).

59%

With nitric acid In dichloromethane; acetic acid at 0 - 20℃; for 3 h;

Compound 33a (20 g, 77 mmol) was added as a thick suspension in anhydrous dichloromethane (100 mL) and was cooled to 0° C. Acetic acid (191 mL) was added, resulting in a clear solution which stirred at 0° C. until cool. Nitric acid (26 mL, 581 mmol) was added slowly dropwise through an addition funnel. The ice bath was removed and the solution continued to stir at room temperature. After 3 hours, the reaction was diluted with deionized water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the filtrate concentrated in vacuo. The crude residue was recrystallized using ethyl acetate and hexanes. The solid was filtered and washed with hexanes to give compound 33b as a yellow fluffy solid (13.8 g, y=59percent). ¹H NMR (400 Hz, CDCl₃): δ 7.48-7.43 (m, 6H), 7.25 (s, 1H), 5.25 (s, 2H), 4.02 (s, 3H), MS (m/z): 326.1 (M+Na)⁺. See FIG. 45.

Reference： [1] Patent: WO2015/28850, 2015, A1, . Location in patent: Page/Page column 84
[2] Patent: WO2015/155753, 2015, A2, . Location in patent: Page/Page column 87
[3] Patent: WO2016/59622, 2016, A2, . Location in patent: Page/Page column 126
[4] Patent: WO2018/86139, 2018, A1, . Location in patent: Page/Page column 182; 183
[5] Synthesis, 1990, # 1, p. 81 - 84
[6] Patent: US9169272, 2015, B2, . Location in patent: Page/Page column 247
[7] Heterocycles, 1984, vol. 22, # 2, p. 253 - 256
[8] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 15, p. 1933 - 1935
[9] Patent: US6562806, 2003, B1,

4
[ 56441-97-5 ]
[ 60547-92-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 20, p. 5427 - 5436
[2] Patent: WO2018/71455, 2018, A1,
[3] Patent: US2017/95570, 2017, A1,
[4] Patent: WO2018/53552, 2018, A2,
[5] Patent: WO2018/195245, 2018, A1,

5
[ 121-34-6 ]
[ 60547-92-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 15, p. 1933 - 1935
[2] Synthesis, 1990, # 1, p. 81 - 84
[3] Patent: WO2015/28850, 2015, A1,
[4] Patent: WO2015/155753, 2015, A2,
[5] Patent: WO2016/59622, 2016, A2,
[6] Patent: WO2018/86139, 2018, A1,

6
[ 100-39-0 ]
[ 60547-92-4 ]

Reference： [1] Patent: WO2015/28850, 2015, A1,
[2] Patent: WO2015/155753, 2015, A2,
[3] Patent: WO2016/59622, 2016, A2,
[4] Patent: WO2017/194960, 2017, A1,
[5] Patent: US2017/95570, 2017, A1,
[6] Patent: WO2018/86139, 2018, A1,
[7] Patent: WO2018/195245, 2018, A1,

7
[ 3943-74-6 ]
[ 60547-92-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 20, p. 5427 - 5436
[2] Patent: US2017/95570, 2017, A1,
[3] Patent: WO2018/195245, 2018, A1,

8
[ 2426-87-1 ]
[ 60547-92-4 ]

Reference： [1] Heterocycles, 1984, vol. 22, # 2, p. 253 - 256
[2] Patent: WO2012/30160, 2012, A2,
[3] Patent: WO2017/194960, 2017, A1,

9
[ 100-44-7 ]
[ 60547-92-4 ]

Reference： [1] Synthesis, 1990, # 1, p. 81 - 84

10
[ 121-33-5 ]
[ 60547-92-4 ]

Reference： [1] Patent: WO2017/194960, 2017, A1,

11
[ 60547-92-4 ]
[ 155666-33-4 ]

Reference： [1] Journal of Organic Chemistry, 2001, vol. 66, # 8, p. 2881 - 2883
[2] Tetrahedron, 1995, vol. 51, # 19, p. 5617 - 5630
[3] Journal of Organic Chemistry, 1995, vol. 60, # 13, p. 4006 - 4012
[4] Heterocycles, 1994, vol. 37, # 1, p. 387 - 400

12
[ 60547-92-4 ]
[ 155666-33-4 ]

Reference： [1] Patent: US2003/187253, 2003, A1,

13
[ 60547-92-4 ]
[ 196603-96-0 ]

Reference： [1] Patent: WO2012/30160, 2012, A2,

14
[ 60547-92-4 ]
[ 768350-54-5 ]

Reference： [1] Patent: WO2012/30160, 2012, A2,

[ 60547-92-4 ] Synthesis Path-Downstream 1~34

1
[ 60547-92-4 ]
[ 64154-78-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; dichloromethane; at 20℃;	To a stirred solution of <strong>[60547-92-4]4-benzyloxy-5-methoxy-2-nitrobenzoic acid</strong> 3 (7.01 g, 23.1 mmol) in anhydrous dichloromethane (100 rnL) and THF (10 rnL) was added oxalyl chloride (4.1 mL, 46.2 mmol) and DMF (30 muL, 0.38 mmol) at room temperature. Large amounts of bubbles formed after the addition of the DMF. The mixture was stirred overnight (the reaction usual]y finished within 3 hours) and then the solvents were removed by rotary evaporation in vacuo. The residue was co-evaporated one more time by addition of anhydrous dichloromethane and high vacuumed to give the acetyl chloride 4 as a yel]ow solid, which was directly used for the next step.
100%	With oxalyl dichloride; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 3h;Inert atmosphere;	Oxalyl chloride (3.61 mL, 41.2 mmol) was added dropwise to a stirred solution of compound 11(5.0 g, 16.49 mmol) in dichloromethane (42.8 mL), tetrahydrofuran (4.28 mL) anddimethylformamide (0.020 mL, 0.264 mmol) at 0 C under Ar. The reaction mixture was warmedto room temperature and was stirred for 3 h. The reaction mixture was concentrated and placedunder high vacuum to obtain compound 62 as a pale yellow solid and was taken onto the next stepwithout purification (5.3 g, 16.49 mmol, 100% yield).
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃;	Example 11 : 8,8'-[1,5-pentanediylbis(oxy)]-bis[(S)-2-methylene-7-methoxy-1,2,3,11 a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] ; [Show Image] To a solution of <strong>[60547-92-4]4-benzyloxy-5-methoxy-2-nitrobenzoic acid</strong> (4.8 g, 16 mmol) in anhydrous dichloromethane (80 mL) and THF (5 mL) was added oxalyl chloride (2.8 mL, 32 mmol) and DMF (30 muL, 0.38 mmol) at room temperature. Large amounts of bubble formed after the addition of DMF. The mixture was stirred overnight then the solvents were removed by rotary evaporation in vacuo. The residue was co-evaporated one more time by addition of anhydrous dichloromethane to give the acetyl chloride as a yellow solid.

	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;	A catalytic amount of DMF (30 ul) was added to a solution of 4-(benzyloxy)-5- methoxy-2-nitrobenzoic acid (2.70 g, 8.91 mmol) and oxalyl chloride (2.0 mL, 22.50 mmol) in anhydrous CH2CI2 (70 mL) and the resulting mixture was stirred at room temperature (RT) for 2 h. Excess CH2CI2 and oxalyl chloride was removed with rotavap. The actyl chloride was resuspended in fresh ( LCL (70 ml . ) and was added dropwise to a solution of 4-methylene-L- proline methyl ester HC1 salt (1.58 g, 8.91 mmol), Et3N (6 mL) at 0C under argon atmosphere. The reaction mixture was allowed to warm to RT and stirring was continued for 8 h. After removal of ( LCI : and E N, the residue was partitioned between I LO and EtOAc (70/70 mL). The aqueous layer was further extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with brine (40 mL), dried ( MgSO.t ) and concentrated. Purification of the residue with flash chromatography (silica gel, 2:8 hexanes/EtOAc) yielded (S)-methyl l~(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)~4~methylenepyrrolidine~2~cai-boxylate (2.88 g, 76.1 % yield); EIMS ml/, 449.1 ([M]++Na).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;	A catalytic amount of DMF (30 mul) was added to a solution of compound 239 (2.70 g, 8.91 mmol) and oxalyl chloride (2.0 mL, 22.50 mmol) in anhydrous CH2Cl2 (70 mL) and the resulting mixture was stirred at room temperature for 2 h. Excess CH2Cl2 and oxalyl chloride was removed with rotavap. The acetyl chloride was re-suspended in fresh CH2Cl2 (70 mL) and was added slowly to a pre-mixed solution of 236 (1.58 g, 8.91 mmol) and Et3N (6 mL) in CH2Cl2 at 0 C under N2 atmosphere. The reaction mixture was allowed to warm to r.t. and stirring was continued for 8 h. After removal of CH2Cl2 and Et3N, the residue was partitioned between H2O and EtOAc (70/70 mL). The aqueous layer was further extracted with EtOAc (2 × 60 mL). The combined organic layers were washed with brine (40 mL), dried (MgSO4) and concentrated. Purification of the residue with flash chromatography (silica gel, 2:8 hexanes/EtOAc) yielded compound 240 (2.88 g, 76% yield). EI MS m/z 449.1 ([M+Na]+).
	With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; at 22℃;Inert atmosphere;	Referring to FIG. 3, to an argon-purged solution of <strong>[60547-92-4]4-benzyloxy-5-methoxy-2-nitro-benzoic acid</strong> (8) (4.00 g, 13.2 mmol) in tetrahydrofuran (THF) (16 mL) at 22 00 oxalyl chloride (1.68 mL, 19.8 mmol) was added, followed by dimethyl formamide (DMF) (0.2 mL). The reaction was stirred at 22 00 overnight, under an atmosphere of Ar. The mixture was then concentrated in vacuo, re-dissolved in THF and concentrated again to provide the crude acid chloride
	With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; at 20℃; for 35h;	To a solution of the above nitrobenzoic acid (1.2 g, 3.96 mmol) in THF (30 mL) was added dropwise oxalyl chloride (0.416 mL, 4.75 mmol), followed by N,N-dimethyl- formamide (DMF, 20 uL). The resulting solution was stirred at RT for 35 h before it was concentrated in vacuo to give acid chloride 1 as a yellow solid.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2h;	A solution of <strong>[60547-92-4]4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid</strong> (33) (1.00 g, 3.30 mmol) and oxalyl chloride (0.84 mL, 9.90 mmol) in anhydrous dichloromethane (10 mL) was charged with ,Lambda^-dimethylformamide (drops) at o C. The resulting mixture was stirred for 2 h at room temperature, and then concentrated in vacuo. Anhydrous toluene was then charged to the resulting residue and the mixture concentrated again. After re-solubilising in anhydrous dichloromethane (10 mL), the resulting solution was then added dropwise to a solution of (S,)-piperidin-2-ylmethanol (494 mg, 4.30 mmol) and triethylamine (1.4 mL, 9.9 mmol) in anhydrous dichloromethane (10 mL). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched with hydrochloric acid (1 M, 20 mL), the phases were separated and the organic extract was washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification was carried out by column chromatography (silica), eluting with ethyl acetate/hexane (from 0% to 50%), to give the title compound (974 mg, 74%) as an amber oil. (1550) NMR (400 MHz, CDCI3) 7-76 (s, iotaEta), 7·44"7·38 (m, 5H), 6.83 (s, lH), 5.20 (s, 2H), 4-37 (br s, lH), 3.98 (s, 3H), 3-94-3-78 (m, 4H), 3.16 (m, 2H), 2.19-1.83 (m, 5H); MS (ES+): m/z = 401 (M+H)+; LCMS (Method B ): tR = 3.60 min.
	With thionyl chloride; N,N-dimethyl-formamide; In benzene; for 6h;Product distribution / selectivity;	Example 1 [4-(Benzyloxy)-5-methoxy-2-nitrophenyi][4-(2-methoxyphenyl) piperazino] methanone (7a)DMF was added to a stirred suspension of 4- benzoyloxy-5-methoxy -2-nitro benzoic acid (6) (0.500mg, 1.65mmol) and thionyl chloride (3 ml) in dry benzene (30 ml) and Jhe stirring was continued for 6h. The benzene was evaporated in vacuum and the resultant oil dissolved in dry THF (50 ml) and added drop wise over a period of 1h to a stirred suspension of 1-(2-methoxyphenyl) piperazine (316mg 15.6mmol) triethyl amine (5ml,). After the completion of addition, the reaction mixture was brought to ambient temperature and stirred for an additional hour. The THF was evaporated in vacuum and the aqueous layer was washed with ethyl acetate. The aqueous phase was then adjusted to pH 3 using 6 N HCI and extracted with ethyl acetate and washed with brine, dried over Na2SO4 and evaporated in vacuum to afford the crude product of 2-amino-4- benzyloxy)-5-methoxyphenyl][4-(2-methoxyphenyl) piperazino] methanone (7a) in 93% yield (670 mg, 85 % yield). 1H NMR (CDCl3) delta 3.20- 3.30 (m, 4H), 3.40-3.55 (m, 4H), 3.85 (S, 3H), 3.95 (s, 3H), 5.20 (s, 2H), 6.80-7.00 (m, 5H), 7.30-7.50 (m, 5H), 7.70 (s, IH); FABMS: 477 (M+H). Example 3 [4-(Benzyloxy)-5-methoxy-2-nitrophenyl][4-(2-pyridyl)piperazino]methanone (7b)DMF was added to a stirred suspension of 4- benzoyloxy-5-methoxy -2-nitro benzoic acid (6) (0.500mg, 1.65 mmol) and thionyl chloride (3 ml) in dry benzene (30 ml) and the stirring was continued for 6h. The benzene was evaporated in vacuum and the resultant oil dissolved in dry THF (50 ml) and added dropwise over a period of 1 h to a stirred suspension of (2-pyridyl) piperazine (268mg 1.65 mmol) triethyl amine (5ml). After the completion of addition, the reaction mixture was brought to ambient temperature and stirred for an additional hour. The THF was evaporated in vacuum and the aqueous layer was washed with ethyl acetate. The aqueous phase was then adjusted to pH 3 using 6 N HCI and extracted with ethyl acetate and washed with brine, dried over Na2SO4 and evaporated in vacuum to afford the crude product [4-(benzyloxy)-5-methoxy-2- nitrophenyl][4-(2-pyridyl) piperazino] methanone (7b) (610 mg, in 82% yield). 1H NMR (CDCl3) delta 3.10- 3.25 (m, 4H), 3.65-3.80 (m, 4H), 3.95 (s, 3H), 5.20 (s, 2H), 7.00-7.50 (m, 5H), 7.70 (s, IH), 8.25-8.35 (d, J=9.05,2H); FABMS: 448 (M+H). Example 5[4~(Benzyloxy)-5-methoxy-2-nitrophenyl][4-(2-pyrimidinyl)piperazino]methanone (7c) DMF was added to a stirred suspension of 4- benzoyloxy-5-methoxy -2-nitro benzoic acid (6) (0.500mg, 1.65 mmol) and thionyl chloride (3 ml) in dry benzene (30 ml) and the stirring was continued for 6h. The benzene was evaporated in vacuum and the resultant oil dissolved in dry THF (50 ml) and added dropwise over a period of 1h to a stirred suspension of 1-(2-pyrimidinylpyperazine) piperazine (270mg 1.65 mmol) triethyl amine (5ml,). After the completion of addition, the reaction mixture was brought to ambient temperature and stirred for an additional hour. The THF was evaporated in vacuum and the aqueous layer was washed with ethyl acetate. The aqueous phase was then adjusted to pH 3 using 6 N HCI and extracted with ethyl acetate and washed with brine, dried over Na2SO4 and evaporated in vacuum to afford the crude product of (7c), (635 mg, in 85% yield).1H NMR (CDCl3) delta 3.10- 3.25 (m, 4H), 3.60-3.80 (m, 4H), 3.95 (s, 3H), 5.20 (s, 2H), 6.55-6.55, (t, IH) 6.75 (s, IH), 7.30-7.60 (m, 5H), 7.80 (s, IH); FABMS: 449 (M+H). Example 7[4-(Benzyloxy)-5-methoxy-2-nitrophenyl][4-(4-quinazolinyl) piperazinoj methanone (Td) DMF was added to a stirred suspension of 4- benzoyloxy-5-methoxy -2-nitro benzoic acid (6)(0.500mg, 1.65 mmol) and thionyl chloride (3 ml) in dry benzene (30 ml) and the stirring was continued for 6h. The benzene was evaporated in vacuum and the resultant oil dissolved in dry THF (50 ml) and added dropwise over a period of 1h to a stirred suspension of (4-quinazolinyl) piperazine (350mg, 1.65 mmol) triethyl amine (5ml,). After the completion of addition, the reaction mixture was brought to ambient temperature and stirred for an additional hour. The THF was evaporated in vacuum and the aqueous layer was washed with ethyl acetate. The aqueous phase was then adjusted to pH 3 using 6 N HCI and extracted with ethyl acetate and washed with brine, dried over Na2SO4 and evaporated in vacuum to afford the crude product of (7d), (700mg in 84% yield).1H NMR (CDCl3) delta 3.15- 3.30 (m, 4H), 3.65-3.75 (m, 4H), 3.95 (s, 3H), 5.20 (s, 2H), 6.45-6.55 (t, IH) 6.70 (s, IH), 7.30-7.50 (m, 5H), 7.55-7.65 (t, IH), 7.65 (s, IH), 7.70- 7.90(m, 2H), 7.85-7.95 (m, 2H); FABMS: 500 (M+H). Example 9N1-(9H-9-FluorBnyl)-4-(benzyloxy)-5-methoxy-2-nitrobenzamide { 7e) [DMF was added to a stirred suspension of 4- benzoyloxy-5-methoxy -2-nitro benzoic acid (6)(0:500mg, 1.65 mmol) and thionyl chloride (3 ml) in dry benzene(30 ml) and the stirring was continued for 6h. The benzene was evaporated ...
	With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 16h;	To a solution of compound 4 (500 g, 1.65 mol) in CH2C12 (2.0 L) and THF (500 mL) was added DMF (6.03 g, 82.50 mmol), cooled with ice-water bath to 0-10 C. (COCl)2 (418.54 g, 3.30 mol, 288.65 mL) was drop wise added to the mixture maintaining the temperature between 0-10 C. The mixture was then warmed to 20 C and stirred at this temperature for 16 h. TLC (petroleum ether: ethyl acetate = 2: 1) showed that the reaction was completed. The solvent was removed under vacuum to give compound 5 (550 g, crude) as a yellow solid.
	With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere;	Oxalyl chloride (3.61 mL, 41.2 mmol) was added dropwise to a stirred solutionof compound 1 (5.0 g, 16.49 mmol) in DCM (42.8 mL), THF (4.28 mL) and DMF (0.020 mL, 0.264 mmol) at 0 oc under Ar. The reaction mixture was warmed to rt andwas stirred for 3 h. The reaction mixture was concentrated and placed under high vacuum to obtain compound 2 as a pale yellow solid and was taken onto the next stepwithout purification (5.3 g, 16.49 mmol, 100% yield).
	With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; dichloromethane; at 0 - 25℃; for 3h;Inert atmosphere;	Step 1: Oxalyl chloride (3.61 mL, 41.2 mmol) was added dropwise to a stirred solution of compound Al (5.0 g, 16.49 mmol) in DCM (42.8 mL), THF (4.28 mL) and DMF (0.020 mL, 0.264 mmol) at 0 C under Ar. The reaction mixture was warmed to rt and was stirred for 3 h. The reaction mixture was concentrated and placed under high vacuum to obtain compound A2 as a pale yellow solid and was taken onto the next step without purification (5.3 g, 16.49 mmol, 100% yield)
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;	A catalytic amount of DMF (30 mul) was added to a solution of 4- (benzyloxy) -5-methoxy-2-nitrobenzoic acid (2.70 g, 8.91 mmol) and oxalyl chloride (2.0 mL, 22.50 mmol) in anhydrous CH 2Cl 2 (70 mL) and the resulting mixture was stirred at room temperature for 2 h. Excess CH 2Cl 2 and oxalyl chloride was removed with rotavap. The acetyl chloride was re-suspended in fresh CH 2Cl 2 (70 mL) and was added slowly to a pre-mixed solution of (S) - (4-methylenepyrrolidin-2-yl) methanol, hydrochloride salt (1.32 g, 8.91 mmol) and Et 3N (6 mL) in CH 2Cl 2 at 0 under N 2 atmosphere. The reaction mixture was allowed to warm to r.t. and stirring was continued for 8 h. After removal of CH 2Cl 2 and Et 3N, the residue was partitioned between H 2O and EtOAc (70/70 mL) . The aqueous layer was further extracted with EtOAc (2 × 60 mL) . The combined organic layers were washed with brine (40 mL) , dried (MgSO 4) and concentrated. Purification of the residue with flash chromatography (silica gel, 2: 8 hexanes/EtOAc) yielded the title compound (2.80 g, 79%yield) . EI MS m/z 421.2 ( [M+Na] +) .
100 mg	With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; dichloromethane; at 0℃; for 0.5h;Inert atmosphere;	[0515] To a solution of compound Int-1-4 (100 mg, 0.33 mmol) in anhydrous THF (500 muL) and anhydrous DCM (1.5 mL) were slowly added dropwise oxalyl chloride (42.4 muL) and added 1 drop of DMF at 0C. under N2 atmosphere. After stirring for 30 min, the reaction mixture was concentrated under reduced pressure. The compound Int-1 was used directly in the next step without further purification.
	With oxalyl dichloride; N,N-dimethyl-formamide; In acetonitrile; at 20℃;	The <strong>[60547-92-4]4-benzyloxy-5-methoxy-2-nitro-benzoic acid</strong> S4 (5 g, 16.5 mmol) was dissolvedin 30 mL of anhydrous acetonitrile. To this solution, oxalyl chloride (2.4 mL, 18.15mmol, 1.1 equiv.) and a catalytic amount of DMF were added. The reaction was stirredat room temperature overnight to prepare the acid chloride derivative. The acidchloride solution was added dropwise over one hour to a solution of Spyrrolidinemethanol(2 mL, 20 mmol, 1.2 equiv.) and TEA (3.65 mL, 36.47 mmol, 2.21equiv.) in anhydrous acetonitrile under a nitrogen atmosphere at a temperature of -30C throughout using a liquid nitrogen and chloroform slush. The reaction was allowedto reach room temperature and stir overnight. The solution was then extracted withCHCl3 (4 × 100 mL) and the combined organic fractions were washed with 1 M HCl (2× 50 mL), H2O (2 × 75 mL), brine (2 × 50 mL) and H2O (2 × 50 mL), dried using MgSO4and the solvent evaporated in vacuo to afford a yellow oil. The oil was purified by flashchromatography (CHCl3 then gradient to 5% MeOH-CHCl3) to afford S5 (3.19 g, 50%)as a pale-yellow oil, which slowly crystallised on standing.

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[2]Patent: WO2010/91150,2010,A1 .Location in patent: Page/Page column 101
[3]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2455 - 2458
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[35]Molecules,2020,vol. 25
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2
[ 60547-92-4 ]
[ 155666-33-4 ]

Reference： [1]Journal of Organic Chemistry,2001,vol. 66,p. 2881 - 2883
[2]Tetrahedron,1995,vol. 51,p. 5617 - 5630
[3]Journal of Organic Chemistry,1995,vol. 60,p. 4006 - 4012
[4]Heterocycles,1994,vol. 37,p. 387 - 400

3
[ 2426-84-8 ]
[ 60547-92-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium permanganate; In acetone; at 30 - 50℃; for 2h;	The compound (20g, 69.62 mmol) obtained in <Step 1> was dissolved in acetone (200 mL), and a hot 10% potassium permanganate solution was slowly added thereto at 30C. The mixture was stirred at 50C for 2 hours, and cooled to room temperature. Subsequently, the mixture was filtered through a Celite pad, and washed with acetone and a small amount of hot water. The filtrate was concentrated under reduced pressure and cooled to 0C. Then, the concentrate was acidified into pH 4 using hydrochloric acid, and the resulting mixture was stirred for 30 min and filtered to the title compound as a solid (18.5g, 88%). NMR(300 MHz, DMSO-d6):<5 13.58(brs, 1H), 7.70(s, 1H), 7.46-7.40(m, 6H), 7.39(s, 1H), 5.25(s, 2H), 3.92(s, 3H).MS(ESI+, m/z): 304 [M+H]+
79%	With potassium permanganate; In water; acetone; at 70℃; for 4h;	A solution of 4-(benzyloxy)-5-methoxy-2-nitrobenzaldehyde (32) (8.0 g, 28 mmol) in acetone (300 mL) was quickly charged with a hot (70 C) solution of potassium permanganate (16.5 g, 104 mmol) in water (150 ml). The mixture was then stirred at 70 C for 4 h. The reaction mixture was then allowed to cool to room temperature and passed through a pad of celite, which was then washed with hot water (120 mL). A solution of sodium bisulfite in hydrochloric acid (1 M, 120 mL) was added to the filtrate, which was then extracted with dichloromethane (2 x 200 mL). The combined organic extracts were subsequently dried over sodium sulfate, filtered and concentrated to give the title compound (6.7 g, 79%) as a yellow solid, which was used in the subsequent step without further purification. (1547) NMR (400 MHz, CDCI3) £7-55 (s, lH), 7-49"7-37 (m, 6H), 5.17 (s, 2H), 4-99 (br s, lH), 3-93 (s, 3H); C NMR (100 MHz, MeOD) £168.6, 154.1, 151.0, 142.9, 137-3, 129-7, 129.4, 129.0, 123.2, 112.5, 110.0, 72.3, 57.1; MS (ES+): m/z = 302 (M+H)+, MS (ES-): m/z = 302 (M-l)-; LCMS (Method B): tR = 3.62 min, LCMS (Method A): tR= 7.02 min
66%	With sodium chlorite; sodium dihydrogenphosphate; dihydrogen peroxide; In water; acetonitrile; at 0 - 20℃; for 6h;	A solution of NaClO2 (8 g, 87 mmol, 5 equiv.) in H2O (75 mL) was slowly added at 0C to a solution of 4-(benzyloxy)-5-methoxy-2-nitrobenzaldehyde S3 (5 g, 17.4 mmol),NaH2PO4 (5 g, 34.8 mmol, 2.5 equiv.) and H2O2 (4.65 mL) in acetonitrile:H2O 3:2 (100mL). The reaction mixture was stirred at room temperature for 6 h until no more oxygenevolved from the reaction. After acidification with 10% HCl to pH = 3, the solution wasextracted with EtOAc (3 × 30 mL), dried over MgSO4 and evaporated under reducedpressure to yield S4 (5.6 g, 66%) of product.

63%	With potassium permanganate; water; In acetone; at 70℃; for 2h;	A solution of 4-(benzyloxy)-5-methoxy-2-nitrobenzalclehycle (2) (36.00 g, 125.3 mmol)in acetone (500 mL) was charged with a hot solution of potassium permanganate (10%w/v in water) (19.80 g, 125.3 mmol) and then stirred at 70 C for 2 h, before cooling toroom temperature. The mixture was acidified to pH = 4 using hydrochloric acid (2 N),and then extracted with ethyl acetate. The combined organic extracts were washed with cold water and dried over anhycirous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica) and eluteci with clichloromethane/methanol (20:1) to afford the title compound (24.0 g, 63%) as ayellow solid. 1H NMR (400 MHz, DMSO-c16) 6 7.64 (s, 1H), 7.47-7.37 (m, H), 7.26 (s,1H), 5.22 (s, 2H), 3.90 (s, 3H).
50%	With potassium permanganate; In ethyl acetate; acetone;	PREPARATION 80 5-Methoxy-2-nitro-4-(phenylmethyloxy)benzoic acid A solution of 5-methoxy-2-nitro-4-(phenylmethyloxy) benzaldehyde (45.11 g, 0.157 mole) in 600 ml of acetone was prepared. To this solution was added 400 ml of 10% potassium permanganate solution over 1 hr. The resultant mixture was stirred for 1 hr at room temperature. The reaction mixture was cooled to room temperature and filtered with Celite, acetone was removed. The resulting material was made acidic with concentrated hydrochloric acid. A yellow solid formed and was separated from aqueous solution, and air dried. The yellow solid was dissolved in ethyl acetate, and filtered through sodium sulfate to remove traces of manganese dioxide, after which 25.84 g of yellow solid was obtained. A 2 g sample was recrystallized from isopropyl alcohol. The yellow solid isolated was dried in vacuo overnight at 80 C., to give 1.85 g (50% yield) of yellow solid, mp 188 C. (with decomposition). Analysis: Calculated for C15 H13 NO6: C, 59.41; H, 4.32; N, 4.62. Found: C, 59.27; H, 4.40; N, 4.46.

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[2]Patent: WO2017/194960,2017,A1 .Location in patent: Page/Page column 187
[3]Molecules,2020,vol. 25
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[6]Farmaco, Edizione Scientifica,1977,vol. 32,p. 579 - 591
[7]Tetrahedron Letters,1986,vol. 27,p. 1149 - 1152

4
[ 1486-53-9 ]
[ 60547-92-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With nitric acid; acetic acid; In dichloromethane; for 6h;	4-(Benzyloxy)-3-methoxybenzoic acid (63.5 g, 246.0 mmol) in the mixture of CH2CI2 (400 ml) and I lOAc (100 ml) was added HNO3 (fuming, 25.0 ml, 528.5 mmol). The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried over the oven at 40 C with vacuum to afford the title compound (63.3 g, 85% yield). ESI MS m/z+ 326.1 (M + Na).
85%	With nitric acid; acetic acid; In dichloromethane; for 6h;	Example 9. 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid 4-(Benzyloxy)-3-methoxybenzoic acid (63.5 g, 246.0 mmol) in the mixture of CH2C12(400 ml) and FIOAc (100 ml) was added HNO3 (fuming, 25.0 ml, 528.5 mmoi). The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried over the oven at 40 Cwith vacuum to afford the title compound (63.3 g, 85% yield). ESI MS mlz+ 326.1 (M +Na).
85%	With nitric acid; acetic acid; In dichloromethane; for 6h;	To a solution of compound 238 (63.5 g, 246.0 mmol) in CH2Cl2 (400 ml) and HOAc (100 ml) was added HNO3 (fuming, 25.0 ml, 528.5 mmol). The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried at 40 C under vacuum to afford the title compound (63.3 g, 85% yield). ESI MS m/z 326.1 ([M+Na]+).

85%	With nitric acid; In dichloromethane; acetic acid; for 6h;	To a solution of 4- (benzyloxy) -3-methoxybenzoic acid (63.5 g, 246.0 mmol) in CH 2Cl 2 (400 ml) and HOAc (100 ml) was added HNO 3 (fuming, 25.0 ml, 528.5 mmol) . The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried at 40 under vacuum to afford the title compound (63.3 g, 85%yield) . ESI MS m/z 326.1 ( [M+Na] +) .
85%	With nitric acid; acetic acid; In dichloromethane; for 6h;	To a solution of 4- (benzyloxy) -3-methoxybenzoic acid (63.5 g, 246.0 mmol) in dichloromethane (400 mL) and acetic acid (100 mL) was added fuming nitric acid (25.0 mL, 528.5 mmol). The mixture was stirred for 6 hours, concentrated, crystallized from ethanol,Drying under vacuum at 40 C gave the title compound (63.3 g, 85% yield).
59%	With nitric acid; In dichloromethane; acetic acid; at 0 - 20℃; for 3h;	Compound 33a (20 g, 77 mmol) was added as a thick suspension in anhydrous dichloromethane (100 mL) and was cooled to 0 C. Acetic acid (191 mL) was added, resulting in a clear solution which stirred at 0 C. until cool. Nitric acid (26 mL, 581 mmol) was added slowly dropwise through an addition funnel. The ice bath was removed and the solution continued to stir at room temperature. After 3 hours, the reaction was diluted with deionized water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the filtrate concentrated in vacuo. The crude residue was recrystallized using ethyl acetate and hexanes. The solid was filtered and washed with hexanes to give compound 33b as a yellow fluffy solid (13.8 g, y=59%). 1H NMR (400 Hz, CDCl3): delta 7.48-7.43 (m, 6H), 7.25 (s, 1H), 5.25 (s, 2H), 4.02 (s, 3H), MS (m/z): 326.1 (M+Na)+. See FIG. 45.
	With nitric acid; tin(IV) chloride; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;	Synthesis of 4-Benzyloxy-5-methoxy-2-nitrobenzoic acid (3) Method A: A freshly prepared mixture of SnCl4 (5 g, 19.5 mmol) and fuming nitric acid (1.67 g, 26.5 mmol) was added dropwise over 5 minutes to a mechanically stirred solution of 2 (4.35 g, 17 rmmol) in DCM at -25 C. (dry ice/carbon tetrachloride). The mixture was maintained at the same temperature for a further 15 min, quenched with water (150 ml), and allowed to warm to room temperature After the organic layer was separated, the aqueous layer was extracted with EtOAc (2*75 ml). The combined organic phase was dried (MgSO4) and evaporated in vacuo to afford a light brown gum which was recrystallized to form 3 as pale yellow needles. Yield=4.16 g (82%) Method B: 4-benzyloxy-3-methoxybenzoic acid (8.5 g, 32.9 mmol) was added in small portions over 30 minutes to stirred solution of 70% nitric acid (100 ml). When addition was complete the reaction mixture was allowed to warm to 15 C. and maintained at that temperature for a further 30 min. The reaction mixture was then poured onto ice and the resultant precipitate was collected by filtration, washed with ice-cold water and dried to afford the nitrated product 3 as a yellow powder. Yield (after recrystallisation from EtOAc/hexane) 7.8 g (78%); mp 182>=185 C.; IR (cm-1) 3400-3200, 2820-2930, 1670, 1600, 1580, 1550, 1510, 1450, 1410, 1400, 1370, 1350, 1330, 1265, 1210, 1160, 1160, 1055, 1005; 1H-NMR (CDCl3+DMSO-d6) delta 7.36-7.45 (m, 6H), 7.16 (s, 1H), 5.19 (s, 2H), 3.95 (s, 3H); 13C-NMR (CDCl3+DMSO-d6) delta 167.3, 152.7, 149.0, 140.9, 135.2, 128.4, 127.6, 127.3, 111.1, 71.2, 56.5; MS (EI) (m/z, relative intensity) 303 (M+, 64), 286 (36), 273 (5), 259 (5), 181 (7), 123 (8), 105 (13), 91 (100), 77 (8), 65 (63), 51 (23); EI-HRMS m/z 303.0824 (calc'd for C15H13NO6 m/z 303.0743).

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[2]Patent: WO2015/155753,2015,A2 .Location in patent: Page/Page column 87
[3]Patent: WO2016/59622,2016,A2 .Location in patent: Page/Page column 126
[4]Patent: WO2018/86139,2018,A1 .Location in patent: Page/Page column 182; 183
[5]Patent: WO2020/6722,2020,A1 .Location in patent: Page/Page column 145-146
[6]Patent: CN110621673,2019,A .Location in patent: Paragraph 1092-1094
[7]Patent: WO2020/73345,2020,A1 .Location in patent: Page/Page column 291-292
[8]Synthesis,1990,p. 81 - 84
[9]Patent: US9169272,2015,B2 .Location in patent: Page/Page column 247
[10]Heterocycles,1984,vol. 22,p. 253 - 256
[11]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 1933 - 1935
[12]Patent: US6562806,2003,B1

5
[ 60547-92-4 ]
[ 23356-96-9 ]
[ 260391-49-9 ]

Yield	Reaction Conditions	Operation in experiment
89%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	4- (benzyloxy) -5-methoxy-2-nitrobenzoic acid (10.20 g, 33.65 mmol) and (S) -pyrrolidin-2-ylmethanol (3.85 g, 38.09 mmol) in dry DMF (150 ml) was added EDC (19.50 g, 101.56 mmol) . The mixture was stirred at RT for overnight, concentrated and purified on SiO 2 column eluted with EtOAc/CH 2Cl 2 (1: 4) to afford the title compound (11.56 g, 89%yield) . MS ESI m/z calcd for C 20H 23N 2O 6 [M+H] + 387.15, found 387.65.

Reference： [1]Patent: WO2020/6722,2020,A1 .Location in patent: Page/Page column 169
[2]Patent: WO2020/73345,2020,A1 .Location in patent: Page/Page column 314
[3]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 2083 - 2086

6
[ 60547-92-4 ]
[ 40216-83-9 ]
[ 382137-65-7 ]

Reference： [1]Tetrahedron,2010,vol. 66,p. 5498 - 5506
[2]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3955 - 3958

7
[ 60547-92-4 ]
[ 2133-40-6 ]
[ 140646-99-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide;	<strong>[60547-92-4]4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid</strong> (2.00 g, 6.60 mmol), L-proline methyl ester HC1 salt (1.09 g, 6.60 mmol), EDC (3.50 g, 18.22 mmol) and DIPEA (1.0 ml, 5.75 mmol) was stirred in 25 ml of DMA over night. The mixture was evaporated, diluted with IX M. washed with washed 1M NaH2P04/NaCl (cone) and 0.1 M NaHC03/NaCl (cone) separately. The organic was dried over MgSQ4, filtered, concentrated and purified on Si02 chromatography eluted with EtOAc/DCM (1:15) to afford 1.96 g (72%) of the title product. EIMS m/ 437.1 (M + Na).
72%		To a rt solution of S1 (1.2 g, 4.0 mmol) in THF (30 mL) was added dropwise oxalylchloride (0.416 mL, 4.75 mmol), followed by DMF (20 muL). The resulting solution was stirred atrt for 35 h, and then it was concentrated in vacuo.The crude material was dissolved in THF (20 mL) and added dropwise to a 0 C solutionof L-proline methyl ester hydrochloride (0.768 g, 4.75 mmol) and triethylamine (1.65 mL, 11.87mmol) in THF ( 10 mL). The reaction mixture was warmed to rt and stirred for 1 h, then it wasquenched with aq. LiCl. The mixture was concentrated to remove the THF, and then it wasextracted with EtOAc (3x). The combined organic layers were washed with sat. aq. NaHCO3 andbrine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by flashchromatography (80 g silica gel; linear gradient 0-100% EtOAc-CH2Cl2) to provide S2 (1.18mg, 72%).

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5427 - 5436
[2]Patent: WO2015/28850,2015,A1 .Location in patent: Page/Page column 90
[3]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 5267 - 5271

8
[ 61032-41-5 ]
[ 60547-92-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With water; triethylamine; sodium hydroxide; In tetrahydrofuran; at 50℃; for 5h;	To a solution of methyl 4-(benzyloxy)-5-methoxy-2- nitrobenzoate (Harve Chem, 15 g, 47.3 mmol) in tetrahydrofuran (THF, 350 mL) was added a solution of aq. NaOH (56.7 mL, 142 mmol, 2.5M). The reaction was stirred at 50 C for 5 h. The reaction was cooled to room temperature (RT) and then concentrated in vacuo to remove the THF. The remaining aqueous layer was acidified with aq. HC1 (6 N) to pH 2. The resulting yellow precipitate was filtered, washed with water, and dried under vacuum to give 4- (benzyloxy)-5-methoxy-2-nitrobenzoic acid (14.32 g, 100% yield). LCMS (M+H) = 304.08; NMR (400MHz, METHANOL-d4) delta 7.60 (s, 1H), 7.53 - 7.45 (m, 2H), 7.45 - 7.31 (m, 3H), 7.29 (s, 1H), 5.23 (s, 2H), 3.98 (s, 3H).
100%	With water; sodium hydroxide; In tetrahydrofuran; at 50℃; for 5h;	To a rt solution of methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (15 g, 47 mmol) inTHF (350 mL) was added 2.5 M aq. NaOH (56.7 mL, 142 mmol). The reaction was stirred at 50C for 5 h. The reaction was cooled to rt and then concentrated in vacuo to remove the THF. Theremaining aqueous layer was acidified with 6 N aq. HCl to pH 2. The resulting yellow precipitatewas filtered, washed with water, and dried under vacuum to provide S1 (14.32 g, quant.).
97%	With sodium hydroxide; In tetrahydrofuran; methanol; at 20 - 65℃; for 5h;	[0512] To a solution of compound Int-1-3 (85.5 g, 0.27 mol) in THF (800 mL) and MeOH (300 mL) was added 2N NaOH (404 mL, 0.81 mol). After stirring for 5 hr at 65C., the reaction was cooled to room temperature and adjusted to pH 2 by addition of 2N HCl solution, and then extracted with distilled water (100 mL) and EA (300 mL2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue solid was collected and washed with hexane to obtain compound Int-1-4 (79.2 g, 97%). [0513] 1H NMR (400 MHz, DMSO-d6) delta 7.69 (s, 1H), 7.47-7.35 (m, 5H), 7.03 (s, 1H), 5.24 (s, 2H), 3.91 (s, 3H).

92%	With methanol; sodium hydroxide; at 50℃; for 1h;	4-Benzyloxy-5-methoxy-benzoic acid methyl ester (9.1 g, 29 mmol) was dissolved in methanol (145 mL) and sodium hydroxide (6 M solution, 24 mL) was added at once. Reaction mixture was stirred for 1 h at 50 degrees and methanol was evaporated. Concentrated hydrochloric acid (12 mL) was added slowly to the residue with stirring. Formed precipitate was filtered off, washed with water and dried to afford 8.1 g of 3 (92% yield).1H NMR (500 MHz, DMSO-d6) : 7.69 (s, 1H), 7.36-7.47 (m, 5H),7.31 (s, 1H), 5.24 (s, 2H), 3.91 (s, 3H).
92%	With methanol; sodium hydroxide; at 50℃; for 1h;	4-benzyloxy-5-methoxy-2-nitro-benzoic acid methyl ester (9.1 g, 29 mmol) was dissolved in methanol (145 mL) and sodium hydroxide (6 M solution, 24 mL) was added at once. Reaction mixture was stirred for 1 h at 50 degrees and methanol was evaporated.Concentrated hydrochloric acid (12 mL) was added slowly to the residue with stirring.Formed precipitate was filtered off, washed with water and dried to afford 8.1 g of 3 (92% yield). 1H NMR (500 MHz, DMSO-d6) delta: 7,69 (s, 1H), 7,36-7,47 (m, 5H),7,31 (s, 1H), 5.24 (s, 21-1), 3.91 (s, 3H).
91%	With lithium hydroxide; In methanol; water; at 20℃; for 2h;	A solution of 40 (2.3 g, 7.25 mmol) in MeOH (20 mL) was added a solution of LiOH (2.25 mL, 36.24 mmol) in water (5 mL). The reaction mixture was stirred at 20 C. for 2 h. The mixture was poured into water (50 mL), and washed with EtOAc (50 mL). The water phase was adjust pH to 3-4 with 2M HCl, and extracted with EtOAc (50 mL*3). It was washed with NaCl (25 mL), dried over Na2SO4 and concentrated in vacuo to give crude 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid 41 (2.0 g, 6.59 mmol, 91% yield) as white solid.
1.5 kg	With lithium hydroxide monohydrate; water; In tetrahydrofuran; at 20℃; for 16h;Large scale;	To a solution of compound 3 (2.50 kg, 7.93 mol) in THF (20 L) and H20 (20 L) was added LiOH H20 (332.68 g, 7.93 mol) in one portion at 20 C to give a suspension, the reaction was stirred at this temperature for 16 h. TLC (petroleum ether: ethyl acetate = 2: 1) showed that the reaction was completed. The solvent was evaporated under vacuum to remove THF. The residue was acidified with 2N HC1 until pH = 2 to give a yellow

Reference： [1]Patent: WO2016/209951,2016,A1 .Location in patent: Paragraph 00146-00147
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 5267 - 5271
[3]Patent: US2019/367488,2019,A1 .Location in patent: Paragraph 0511-0513
[4]Patent: WO2020/89687,2020,A2 .Location in patent: Page/Page column 85-86
[5]Patent: WO2018/53552,2018,A2 .Location in patent: Paragraph 000473-000475
[6]Patent: WO2018/71455,2018,A1 .Location in patent: Paragraph 0009; 00114; 00119-00121
[7]Patent: US2017/95570,2017,A1 .Location in patent: Paragraph 0571; 0574
[8]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5427 - 5436
[9]Patent: WO2018/195245,2018,A1 .Location in patent: Page/Page column 27

9
[ 56441-97-5 ]
[ 60547-92-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5427 - 5436
[2]Patent: WO2018/71455,2018,A1
[3]Patent: US2017/95570,2017,A1
[4]Patent: WO2018/53552,2018,A2
[5]Patent: WO2018/195245,2018,A1
[6]Patent: US2019/367488,2019,A1

10
[ 60547-92-4 ]
[ 81307-24-6 ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 2132 - 2151
[2]Tetrahedron,1992,vol. 48,p. 751 - 758
[3]Synthesis,1990,p. 81 - 84
[4]Patent: WO2015/28850,2015,A1
[5]Molecules,2020,vol. 25

11
[ 60547-92-4 ]
[ 807639-53-8 ]

Yield	Reaction Conditions	Operation in experiment
65%		KOH (75 g) was added to H20 (175 ml), stirred at RT. 4-benzyloxy-5-methoxy-2- nitro-benzoic acid (0.031 mol;) was added portionwise and the suspension was heated for 12 hours at 75 C. The reaction mixture was filtered and the filtrate was acidified with HC1 (CONE.). The resulting precipitate was filtered off, stirred in DIPE, filtered off and dried, yielding 5.75 g (65%) of intermediate 38.

Reference： [1]Patent: WO2004/105765,2004,A1 .Location in patent: Page 78

12
SnCl_2.2H₂O [ No CAS ]
[ 60547-92-4 ]
[ 155666-33-4 ]

Yield	Reaction Conditions	Operation in experiment
15.1 g (92%)	In methanol; ethyl acetate;	EXAMPLE 1 Synthesis of 2-Amino-4-benzyloxy-5-methoxybenzoic acid A solution of 4-benzyloxy-5-methoxy 2-nitrobenzoic acid (18.18 g, 60 mmol)(D. E. Thurston et al., Synthesis (1990), 81) and SnCl2.2H2O (137 g, 0.6 mol) (Showa Chemical Company, Japan) in MeOH (800 mL) was stirred at 70 C. for 5 h. The mixture was concentrated under vacuum to a thick syrup. Ethyl acetate (300 mL) was then added. The organic phase was washed with water until it turned to a clear solution, then washed with brine, and dried over MgSO4. After removal of solvent, the crude was recrystallized from ethyl acetate to obtain the title compound in the form of a yellow solid with a yield of 15.1 g (92%).

Reference： [1]Patent: US2003/187253,2003,A1

13
thionyl chloride(200 ml)was [ No CAS ]
[ 60547-92-4 ]
[ 60547-94-6 ]

Yield	Reaction Conditions	Operation in experiment
77.5%	With ammonia; In ethanol; dichloromethane;	PREPARATION 97 5-Methoxy-2-nitro-4-(phenylmethoxy)benzamide A solution of 5-methoxy-2-nitro-4-(phenylmethoxy)benzoic acid(25.84 g, 0.085 mole)and thionyl chloride(200 ml)was heated overnight at gentle reflux in 100 ml of methylene chloride. The reaction mixture was concentrated to dryness and dried in vacuo. To this residue was added 200 ml of dioxane(dried over molecular sieves). Ammonia was slowly added to the solution with constant agitation. A brown solid was formed and the mixture was filtered. The brown solid was washed with dioxane, water, and 2-propanol. The gray solid thus obtained was dried in vacuo at room temperature(23.2 g). A 2 g portion was triturated in refluxing ethanol and then cooled to room temperature. A white solid was collected by filtration and dried in vacuo at 80 C. overnight. This furnished 1.72 g (77.5% yield) of white, crystalline solid, m.p. 222-223.5 C. with decomposition. Analysis: Calculated for C15 H14 N2 O5: C, 59.60; H, 4.67; N, 9.27. Found: C, 59.48; H, 4.68; N, 9.19.

Reference： [1]Patent: US4950674,1990,A

14
[ 60547-92-4 ]
[ 63407-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; under 262.526 Torr; for 24h;	W1) 2-Amino-4-hydroxy-5-methoxy-benzoic acid:; A solution of 4-benzyl-5-methoxy-2-nitro-benzoic acid (5.0 g, 16.48 mmol) in MeOH (100 ml) containing 10% palladium on carbon (0.5 g) is subjected to catalytic hydrogenation (0.35 bar) at room temperature for 24 h. The reaction mixture is filtered through Celite (filter agent), washing with MeOH. The filtrate is concentrated to dryness in vacuo to yield the title compound. [M+H]+ 184.

Reference： [1]Patent: WO2007/65662,2007,A2 .Location in patent: Page/Page column 61

15
[ 60547-92-4 ]
[ 18650-38-9 ]
(R)-methyl 1-(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)piperidine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE;	(R)-Methyl 1 -(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)piperidine-2-carboxylate (239)[283] 4-(benzoyloxy)-5-methoxy-2-nitrobenzoic acid (1.70 g, 5.61 mmol), (R)-methyl piperidine-2-carboxylate (1.05 g, 5.84 mmol), EDC (3.90 g, 20.31 mmo) and DIPEA (1.0 ml, 5.75 mmol) was stirred in 20 ml of DMA over night. The mixture was evaporated, diluted with DCM, washed with washed IM NaH2PO4/NaCl (cone) and 0.1 M NaHCO3/NaCl (cone) separately. The organic solvent layer was separated and dried over MgSO4, filtered, concentrated and purified on SiO2 chromatography eluted with EtAc/DCM (1 :15) to afford 1.772 g (74%) of the title product. 1R NMR (CDCl3) 7.69 (s, IH), 7.40 - 7.38 (m, 2H), 7.35 -7.27 (m, 3H), 6.76 (d, IH), 5.15 (s, 2H), 3.91 (s, 3H), 3.83 (s, IH), 3.73 (s, 3H), 3.18 (m, 2H), 1.70 (m 2H), 1.47 (m, 4H); 13C NMR 171.89, 171.33, 155.10, 154.78, 148.32, 135.59, 129.05, 128.74, 127.80, 109.66, 109.58, 109.41, 71.63, 56.92, 52.70, 52.19, 45.70, 39.92, 27.29, 26.35, 21.63; MS nVz+ 451.2 (M + Na).

Reference： [1]Patent: WO2010/91150,2010,A1 .Location in patent: Page/Page column 163-164

16
[ 60547-92-4 ]
[ 60547-94-6 ]

Yield	Reaction Conditions	Operation in experiment
99%		The compound (18.5g, 61.00 mmol) obtained in <Step 2> was dissolved in toluene (200 mL), oxalyl chloride (8 mL, 91.50 mmol) was added thereto, and the mixture was heated under reflux for 2 hours. After removing the solvent under reduced pressure, the resultant was dissolved in 1,4-dioxane (300 mL), and the mixture was stirred under ammonia gas for 2 hours. The resulting solid was dissolved in hexane, filtered, and washed with hexane to obtain the title compound (18.22g, 99%). NMR(300 MHz, CDC13):«5 8.05(s, 1H), 7.68-7.35(m, 5H), 6.97(s, 1H), 5.80(brs, 2H), 5.22(s, 2H), 3.99(s, 2H).MS(ESI+, m/z): 303 [M+H]+

Reference： [1]Patent: WO2012/30160,2012,A2 .Location in patent: Page/Page column 50-51

17
[ 60547-92-4 ]
[ 196603-96-0 ]

Reference： [1]Patent: WO2012/30160,2012,A2

18
[ 60547-92-4 ]
[ 768350-54-5 ]

Reference： [1]Patent: WO2012/30160,2012,A2

19
[ 349495-48-3 ]
[ 60547-92-4 ]
4-(benzyloxy)-N-(2-cyclohexyl-2-oxoethyl)-5-methoxy-2-nitrobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; 1-hydroxybenzotriazol-hydrate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; for 0.25h; Inert atmosphere; Stage #2: 2-amino-1-cyclohexyl-1-ethanone hydrogen chloride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere;

Reference： [1]Viviano, Monica; Milite, Ciro; Rescigno, Donatella; Castellano, Sabrina; Sbardella, Gianluca [RSC Advances, 2015, vol. 5, # 2, p. 1268 - 1273]

20
[ 60547-92-4 ]
(S)-methyl 4-methylenepyrrolidine-2-carboxylate hydrochloride [ No CAS ]
[ 945490-07-3 ]

Yield	Reaction Conditions	Operation in experiment
76.1%		Example 15. (S)-methyl 1 -(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)-4- methylenepyrrolidine-2-carboxylate A catalytic amount of DMF (30 tl) was added to a solution of 4-(benzyloxy)-5- methoxy-2-nitrobenzoic acid (2.70 g, 8.91 mmol) and oxalyl chloride (2.0 mL, 22.50 mmol) in anhydrous CH2C12 (70 mL) and the resulting mixture was stirred at room temperature (RT) for 2 h. Excess CH2C12 and oxalyl chloride was removed with rotavap. Theactyl chloride was resuspended in fresh CH2C12 (70 mL) and was added dropwise to a solution of 4-methylene-L-proline methyl ester HC1 salt (1.58 g, 8.91 mmol), Et3N (6 mL) at 0C under argon atmosphere. The reaction mixture was allowed to warm to RT and stirring was continued for 8 h. After removal of CH2C12 and Et3N, the residue was partitioned between H20 and EtOAc (70/70 mL). The aqueous layer was further extracted withEtOAc (2 x 60 mL). The combined organic layers were washed with brine (40 mL), dried (MgSO4) and concentrated. Purification of the residue with flash chromatography (silica gel, 2:8 hexanes/EtOAc) yielded (S )-methyl 1 -(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)- 4-methylenepyrrolidine-2-carboxylate (2.88 g, 76.1% yield); ElMS mlz 449.1 ([Mj+Na).

Reference： [1]Patent: WO2015/155753,2015,A2 .Location in patent: Page/Page column 89

21
[ 741288-31-3 ]
[ 60547-92-4 ]
methyl (S)-4-(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)morpholine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.7%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 8h;	A mixture of 41 (460.0 mg, 1.52 mmol) and <strong>[741288-31-3]methyl (S)-morpholine-3-carboxylate</strong> 42, CAS Reg. No. 741288-31-3, Hicks, F. et al, (2013) Organic Process Research & Development, 17(5):829-837, (330 mg, 2.28 mmol) and diisopropylethylamine, DIEA (392 mg, 3.03 mmol) in DCM (30 mL) was added HATU (865 mg, 2.28 mmol). The reaction solution was stirred at 20 C. for 8 h. The solution was concentrated in vacuo and purified by chromatography on silica (0-50% EtOAC in petroleum ether) to give methyl (S)-4-(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)morpholine-3-carboxylate 43 (520 mg, 1.21 mmol, 79.7% yield) as a yellow oil. LCMS (5-95AB/1.5 min): RT=0.731 min, [M+Na]+ 453.0

Reference： [1]Patent: US2017/95570,2017,A1 .Location in patent: Paragraph 0571; 0575

22
[ 18881-17-9 ]
[ 60547-92-4 ]
[ 762245-27-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 4-benzyloxy-5-methoxy-2-nitrobenzoic acid (9) (10.0 g, 33.0 mmol) in DCM (100 mL) added HATU (16.3 g, 42.9 mmol) and DIEA (8.61 mL, 49.5 mmol). The mixture was stirred at 22 C for 15 min, then added (S)-(1,2,3,4- tetrahydroisoquinolin-3-y])methanol (6.46 g, 39.6 mmol). The resulting mixture was stirred at 22 C for 2 hr, under Ar, then MeOH (50 mL) was added and the resulting precipitate was filtered and washed with DCM (100 mL). The resulting filtrate was concentrated and purified via column chromatography (25?85% EtOAc in hexane) to afford impure 10 (15.3 g 34.1 mmol) as a yellow foam. 1H NMR (500 MHz, CDCl3) (contains rotamers and impurities) delta: 8.67 (d, J= 4.6 Hz, 0.3H), 8,43 (d, J= 8.5 Hz, 0.3H), 7,85-7.82 (m, 2H), 7.79 (s, 0.3H ), 7,50 (t, J= 5.4 Hz, 5H), 7.46-7.43 (m, 4H), 7.40-7.38 (m, 2H), 7.26-7.22 (m, 2H), 7.19-7.16 (m, IH), 7.11-7.06 (m, 0.3H), 6.87 (d, ./ 7.0 Hz, IH), 6.75 (d l. ./ 1.8, 0.5 Hz, 0.3H), 6.67 (s, 1H). 5.62-5.52 (m, 1H), 5 ,26 (s, 21 1). 5.25-5 ,25 (m, H), 5.11 (s, 0.3H), 4,98-4.96 (m, 1H). 4.46-4.41 (m, IH), 4.34 (d, J= 15.4 Hz, 1H), 4.28-4.23 (m, IH), 4.03 (s, 2H), 3.97 (s, 3H), 3.93-3.91 (m, 3H), 3.80-3.75 (m, IH), 3.68-3.62 (m, 1H), 3.49-3.48 (m, IH), 3.28-3.22 (m, 0.3H), 3.19- 3.10 (m, IH), 3 ,08-3,03 (m, 1H), 2.82 (s, 14H). LC/MS: retention time = 3.15 min. (ESI) C25H25N2O6: [M+H]+ 449; found 449.

Reference： [1]Patent: WO2018/71455,2018,A1 .Location in patent: Paragraph 0021; 00392; 00397-00400

23
[ 60547-92-4 ]
[ 79815-19-3 ]
[ 762245-26-1 ]

Yield	Reaction Conditions	Operation in experiment
79%		A mixture of <strong>[60547-92-4]4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid</strong> (2.0 g, 6.6 mmol), oxalyl chloride (1.70 mL, 19.8 mmol) and anhydrous /V,/V- dimethyl formamide (2 drops) in anhydrous dichloromethane (40 mL) was stirred at room temperature for 3 h. Anhydrous toluene (8 mL) was added to the reaction mixture which was then concentrated in vacuo. A solution of the resulting residue in anhydrous dichloromethane (10 mL) was added dropwise to a solution of methyl (S)- 1, 2,3,4- tetrahydroisoquinoline-3-carboxylate (1.65 g, 7.26 mmol) and triethylamine (2.0 mL, 14.5 mmol) in anhydrous dichloromethane (30 mL) at - 10 C. The reaction mixture was stirred at room temperature for 2 h and then washed with a saturated aqueous solution of hydrochloric acid (1 M, 20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography (silica), eluting with acetone/di chloro methane (from 0% to 30%), to give the title compound (2.5 g, 79%) as a yellow oil. NMR (400 MHz, CDCl3) d 7.49- 7.42 (m, 6H), 7-24-7-19 (m, 5H), 5-25 (s, 2H), 4-64-4-60 (m, lH), 4.38-4.26 (m, 2H), 3-93 (s, 3H), 3-58 (s, 3H), 3-33-3-23 (m, 2H); C NMR (100 MHz, CDCl3) d 170.8, 170.3, 154-6, 148.4, 135-3, 133-5, 130-5, 130-1, 128.9, 128.8, 128.6, 128.4, 127-7, 127-4, 126.7, 109-3, 109-1, 71-4, 56.8, 52.6, 31.8, 31.0, 30.5; MS (ES+): m/z = 477 (M+H)+; LCMS (Method B): £R = 4.10 min.
57%		Acid 3 (3.03 g, 10 mmol) was dissolved in dichloromethane (33 mL), and DIEA (2.6 mL, 15 rnmol) was added followed by HATU (4.93 g, 13 mmol). Mixture was stirred for 30 minutes and amine 5 (2.29g, 12 mmol) was added at once. Reaction mixture was allowed to stir overnight, then washed with 0.5 M HCl, saturated NaHCO3 and concentrated to dryness. The residue was purified on a 110 g silica Teledyne Isco column (0-?35% EtOAc in hexane). Evaporation of product containing fractions afforded 2.73 g of 6 (57% yield). LC/MS: retention time 3.31 min. (ESI) C26H25N2O7 calculated for [M+H]+477; found 477.

Reference： [1]Patent: WO2019/43417,2019,A1 .Location in patent: Page/Page column 236-237
[2]Patent: WO2020/49286,2020,A1 .Location in patent: Page/Page column 233-234
[3]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 56 - 60
[4]Patent: WO2018/71455,2018,A1 .Location in patent: Paragraph 0009; 00114; 00125-00127

24
[ 60547-92-4 ]
C₁₁H₁₃NO [ No CAS ]
[ 762245-26-1 ]

Yield	Reaction Conditions	Operation in experiment
57%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; for 0.5h;	Acid 3 (3.03 g, 10 mmol) was dissolved in dichloromethane (33 mL), and DIEA (2.6 mL, 15 mmol) was added followed by HATU (4.93 g, 13 mmol). Mixture was stirred for 30 minutes and amine 5-(S) (2.29g, 12 mmol) was added at once. Reaction mixture was allowed to stir overnight, then washed with 0.5 M HCl, saturated NaHCO3 and concentrated to dryness. The residue was purified on 110 g silica Teledyne Isco column (035% EtOAc in hexane). Evaporation of product containing fractions afforded 2.73 g of 6-(S) (57% yield). LC/MS: retention time 3.31 min. (ESI) C26H24N2O7 calculated for [M+H] + 477; found 477.

Reference： [1]Patent: WO2018/53552,2018,A2 .Location in patent: Paragraph 000479-000481

25
[ 79-37-8 ]
[ 60547-92-4 ]
[ 64154-78-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N,N-dimethyl-formamide; In tetrahydrofuran; at 22℃;Inert atmosphere;	Referring to FIG. 3. to an argon-purged solution of 4-benzyioxy-5-rnethoxy-2-nitro-benzoic acid (8) (4.00 g, 13.2 mniol) in tetrahydrofuran (THF) (16 mU) at 22 C oxalyl chloride (1.68 mL, 19.8 mrnoi) was added, followed by dirnethyl formarnide (DMF) (0.2 mL). The reaction was stirred at 22 C overnight, under an atmosphere of Ar. The mixture was then concentrated in vacuo. re-dissolved in YE-IF and concentrated again toprovide the crude acid chloride.

Reference： [1]Patent: WO2018/53552,2018,A2 .Location in patent: Paragraph 000371

26
[ 60547-92-4 ]
methyl (2S)-6-methoxy-2,3-dihydro-1H-indole-2-carboxylate [ No CAS ]
methyl (2S)-1-(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)-6-methoxy-2,3-dihydro-1H-indole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.9%		The <strong>[60547-92-4]4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid</strong> 110 mg dissolved in 3 ml dichloromethane in, 0 C adding 62 mul oxalyl, reaction temperature to room temperature 3 hours, the reaction solution is concentrated to get yellow solid. The (S)-6 - methoxy indoline -2 - methyl formate 50 mg is dissolved in 5 ml dichloromethane in, 0 C adding 0.1 ml triethylamine, slowly dropping the the resulting solid of the dichloromethane solution, for 0 C reaction 2 h. Reaction solution diluted hydrochloric acid to adjust the PH to 4 - 5, extracted with ethyl acetate to 2 times, the combined organic layer, saturated salt water after washing, drying and concentrating. The resulting solid after column chromatography purification (petroleum ether: ethyl acetate=20:1), shall be 107 mg yellow solid, yield 89.9%.

Reference： [1]Patent: CN109180681,2019,A .Location in patent: Paragraph 0126-0128

27
[ 60547-92-4 ]
methyl (2S)-6-methoxy-2,3-dihydro-1H-indole-2-carboxylate [ No CAS ]
[ 1239587-81-5 ]

Yield	Reaction Conditions	Operation in experiment
95.4%		In 150 ml single-port bottle by adding <strong>[60547-92-4]4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid</strong> (5.73 g, 18 . 88 mmol) and 50 ml dichloromethane, added under mixing 0.1 ml DMF, in ice bath cooling [...] (3.2 ml, 37.8 mmol), canada finishes, the reaction the wet to react at room temperature for 4 h, TLC display raw material the reaction is complete. For the 45 C lower concentrated under reduced pressure, to remove the methylene chloride, the residue is dissolved in 30 ml THF in, spare.Take another 150 ml [...], adding (S)-6 - nitro - indoline -2 - carboxylic acid methyl ester (2.8 g, 12.6 mmol) and 30 ml THF, stirring add triethylamine (5.3 ml, 38.2 mmol), then the ice cooling next adds by drops of the above prepared solution of the acyl chloride THF, canada finishes, raising the temperature to react at room temperature overnight, TLC display raw material the reaction is complete. For the 45 C lower concentrated under reduced pressure, the residue is dissolved in 150 ml dichloromethane in, for sequentially 1 N HCl, water, saturated salt water of a washing, separating the organic layer, anhydrous sodium sulfate drying, filtering, for 40 C lower concentrated under reduced pressure, to obtain brown solid 9.5 g, crude product by 11.0 g silica gel coils, column chromatography, developing agent (PE: EA=5:1 - 1:1), to obtain a yellow solid 6.1 g, yield 95.4%.

Reference： [1]Patent: CN109180681,2019,A .Location in patent: Paragraph 0168-0170

28
[ 1103929-08-3 ]
[ 60547-92-4 ]
methyl (2S,4S)-1-(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)-4-hydroxypiperidine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		<strong>[60547-92-4]4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid</strong> (5.0 g, 16.5 mmol), was dissolved in N,Ndimethylformamide (50 mL). To this solution, HATU (9.4g, 24.75 mmol) and trimethylamine (9.67 ml 69.3 mmol) was added. The solution was allowed to stir for 30 minutes. The solution was then cooled to 0 C and methyl (2S,4S)-4- hydroxypiperidine-2-carboxylate (2.6 g, 16.5 mmol) was then added to the mixture.After four hours, the reaction was judged to have completed by LC-MS analysis. Water (soo ml) was then added to the solution, causing the formation of a suspension. The crude product was extracted using ethyl acetate (3x 500 ml) and the combined organic extract was washed sequentially with bicarbonate solution (soo ml) and brine (soo ml) and dried with magnesium sulphate. The crude product was purified using flashcolumn chromatography (acetone/dichloromethane, from 5% to 40% acetone),resolving a white solid in 82% yield. 1H NMR (400 MHz, CD3OD), rotameric mixture, 67.77 and 7.72 (2x s, 1H), 7.40-7.33 (m, 2H), 7.31-7.20 (m, 3H), 6.94 and 6.73 (2x s, 1H),5.14 and 5.12 (2 x 5, 2H), 4.05-3.99 (m, 1H), 3.91 and 3.89 (2x 5, 3H), 3.67 and 3.63 (2x5, 3H) 3.60-3.58 (m, 1H), 3.40-3.30 (m, iH) 2.52 and 2.24 (2x d, 1H, J= 14.4, 14.1 Hz),1.99-1.90 (m, 1H) 1.89-1.80 (m, 1H) 1.73-1.60 (m, 1H), 1.57-1.48 (m, 1H); MS (ES+):m/z = 445.0 (M+H) LC Retention Time (Method B): tR = 3.25 mm.

Reference： [1]Patent: WO2019/43417,2019,A1 .Location in patent: Page/Page column 257

29
[ 60547-92-4 ]
(2S,4S)-4-hydroxypiperidine-2-carboxylate hydrochloride [ No CAS ]
methyl (2S,4S)-1-(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)-4-hydroxypiperidine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		A solution of <strong>[60547-92-4]4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid</strong> () (20.00 g, 66.0 mmol) inN,N-climethylformamicle (100 mL) was charged with HATU (37.61 g, 98.9 mmol) andN,N-cliisopropylethylamine (21.31 g, 164.9 mmol) and stirred for 30 mm. The reaction mixture was then cooled to o C and methyl (2S,4S)-4-hydroxypiperidine-2-carboxylate hydrochloride (12.90 g, 66.0 mmol) was added. After the reaction was judged to have completed by TLC, it was diluted with water (300 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic extracts were washed with water and dried oversolid anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica), eluting with acetone/dichloromethane, from 5% to 40% acetone, to afford the title compound (22.00 g, 75%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) mixture of rotamers, 67.77 and 7.72 (2 x s, 1H), 7.40-7.33 (m, 2H), 7.31-7.20 (m, 3H), 6.94 and 6.73 (2 x s, 1H), 5.14 and5.12 (2 x 5, 2H), 4.05-3.99 (m, 1H), 3.91 and 3.89 (2 x 5, 3H), 3.67 and 3.63 (2 x 5, 3H)3.60-3.58 (m, 1H), 3.40-3.30 (m, 1H) 2.52 and 2.24 (2 x d, 1H, J=14.4 and 14.1 Hz),1.99-1.90 (m, 1H) 1.89-1.80 (m, 1H) 1.73-1.60 (m, 1H), 1.57-1.48 (m, 1H); MS (ES+):m/z = 445 (M+H) LCMS (Method B): tR = 3.25 mm.

Reference： [1]Patent: WO2019/43417,2019,A1 .Location in patent: Page/Page column 175-176

30
[ 60547-92-4 ]
C₇H₁₁NO₂*ClH [ No CAS ]
1-(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)-4-methylenepyrrolidine-2-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A catalytic amount of DMF (30 muL) was added to anhydrous 4- (benzyloxy) -5-methoxy-2-nitrobenzoic acid (2.70 g, 8.91 mmol) and oxalyl chloride (2.0 mL, 22.50 mmol). In a dichloromethane solution, the resulting mixture was stirred at room temperature for 2 hours. Excess dichloromethane and oxalyl chloride were removed using a rotary concentrator. Under N2, acetyl chloride was resuspended in fresh dichloromethane (70mL) at 0 C and slowly added to the premixed(S) -4-Methylenepyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.58 g, 8.91 mmol) and Et3N (6 mL) in dichloromethane. The reaction mixture was warmed to room temperature and stirring was continued for 8 hours.After dichloromethane and Et3N were removed, the residue was partitioned between water and ethyl acetate (70/70 mL).The aqueous layer was further extracted with ethyl acetate (2 × 60 mL). The combined organic layers were washed with brine (40 mL), dried (magnesium sulfate) and concentrated.The residue was purified by flash silica gel column chromatography (2: 8 n-hexane / ethyl acetate) to give the title compound (2.88 g, 76% yield).

Reference： [1]Patent: CN110621673,2019,A .Location in patent: Paragraph 1120-1122

31
[ 60547-92-4 ]
(2S)-(4-methylene-pyrrolidin-2-yl)-methanol hydrochloride [ No CAS ]
(4-(benzyloxy)-5-methoxy-2-nitrophenyl)(2-(hydroxymethyl)-4-methylenepyrrolidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		Add a catalytic amount of DMF (30 muL) toIn a solution of 4- (benzyloxy) -5-methoxy-2-nitrobenzoic acid (2.70 g, 8.91 mmol) and oxalyl chloride (2.0 mL, 22.50 mmol) in anhydrous dichloromethane, the resulting mixture was placed Stir at room temperature for 2 hours. Excess dichloromethane and oxalyl chloride were removed using a rotary concentrator. Under N2, acetyl chloride was resuspended in fresh dichloromethane (70 mL) at 0 C and slowly added to the pre-mixed ((S)-(4-methylenepyrrolidin-2-yl) methoxide Acid solution (1.32 g, 8.91 mmol) and Et3N (6 mL) in dichloromethane. The reaction mixture was warmed to room temperature and stirring was continued for 8 hours. After dichloromethane and Et3N were removed, the residue was taken up in water and ethyl acetate. (70/70 mL). The aqueous layer was further extracted with ethyl acetate (2 x 60 mL). The combined organic layers were washed with brine (40 mL), dried (magnesium sulfate) and concentrated. 2: 8 n-hexane / ethyl acetate) to purify the residue to give the title compound (2.88 g, 76% yield).

Reference： [1]Patent: CN110621673,2019,A .Location in patent: Paragraph 1095-1097

32
[ 60547-92-4 ]
[ 84348-41-4 ]
[ 945490-07-3 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: (S)-methyl 4-methylenepyrrolidine-2-carboxylate hydrochloride With triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 8h; Inert atmosphere;
76.1%	Stage #1: 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: (S)-methyl 4-methylenepyrrolidine-2-carboxylate hydrochloride With triethylamine In dichloromethane at 0 - 20℃; for 8h;	15 Example 15: (S)-methyl 1-(4- (benzyloxy)-5-methoxy-2-nitrobenzoyl)-4-methylenepyrrolidine-2-carboxylate Catalytic amounts of DMF (30 μl) were added to 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid (2.70 g, 8.91 mmol) and oxalyl chloride (2.70 g, 8.91 mmol) in anhydrous CH2Cl2.2.0 mL (22.50 mmol) was added and the resulting mixture was stirred at room temperature (RT) for 2 hours.Excess CH2Cl2 and oxalyl chloride were removed with a rotary evaporator.Acyl chloride was resuspended in fresh CH2Cl2 (70 mL) under an argon atmosphere.A solution of 4-methylene-L-proline methyl ester HCl salt (1.58 g, 8.91 mmol) and Et3N (6 mL) was added dropwise at 0 ° C.The reaction mixture was warmed to room temperature and stirring was continued for 8 hours.After removing CH2Cl2 and Et3N, the residue was partitioned between H2O and EtOAc (70/70 mL).The aqueous layer was further extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with brine (40 mL), dried (00544) and concentrated. By purifying the residue by flash chromatography (silica gel, 2: 8 hexane / EtOAc) (S)-methyl 1-(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)-4-methylenepyrrolidine-2-carboxylate was obtained (2.88 g, yield 76.1%).

Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1 Location in patent: Page/Page column 296-297
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - JP2021/73185, 2021, A Location in patent: Paragraph 0217-0218

33
[ 121-34-6 ]
[ 100-39-0 ]
[ 60547-92-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium hydroxide In ethanol at 65℃; for 8h;	8 Example 8: 4-(benzyloxy)-3-methoxybenzoic acid In a mixed solution of 4-hydroxy-3-methoxybenzoic acid (50.0 g, 297.5 mmol) in ethanol (350 mL) and a NaOH solution (2.0 M, 350 mL),BnBr (140.0 g, 823.5 mmol) was added.The mixture is stirred at 65 ° C. for 8 hours, concentrated, co-evaporated to about 400 mL with water (2 x 400 mL), acidified to pH 3.0 with 6M HCl and the solid filtered.Crystallized with EtOH and dried under vacuum at 45 ° C. to give the title compound (63.6 g, 83% yield).

Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - JP2021/73185, 2021, A Location in patent: Paragraph 0203-0204

34
[ 60547-92-4 ]
[ 27883-60-9 ]

Reference： [1]Patent: WO2021/74392,2021,A1
[2]Patent: WO2021/74392,2021,A1

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H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 60547-92-4 ] {[proInfo.proName]}

Quality Control of [ 60547-92-4 ]

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[ 60547-92-4 ] Synthesis Path-Upstream 1~14

[ 60547-92-4 ] Synthesis Path-Downstream 1~34

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Aryls

Ethers

Carboxylic Acids

Nitroes

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[ 60547-92-4 ]