[ CAS No. 22474-47-1 ] {[proInfo.proName]}

Name: 22474-47-1|(2-Methyl-5-nitrophenyl)methanol|97%
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Quality Control of [ 22474-47-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 22474-47-1 ]

CAS No. :	22474-47-1	MDL No. :	MFCD00229932
Formula :	C₈H₉NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IBQRNQSJJZLSTK-UHFFFAOYSA-N
M.W :	167.16	Pubchem ID :	3567085
Synonyms :

Calculated chemistry of [ 22474-47-1 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	46.36
TPSA :	66.05 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.14 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.52
Log Po/w (XLOGP3) :	1.66
Log Po/w (WLOGP) :	1.24
Log Po/w (MLOGP) :	0.68
Log Po/w (SILICOS-IT) :	-0.03
Consensus Log Po/w :	1.01

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.16
Solubility :	1.16 mg/ml ; 0.00692 mol/l
Class :	Soluble
Log S (Ali) :	-2.66
Solubility :	0.365 mg/ml ; 0.00218 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.99
Solubility :	1.72 mg/ml ; 0.0103 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.73

Safety of [ 22474-47-1 ]

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

Application In Synthesis of [ 22474-47-1 ]

* 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 [ 22474-47-1 ]
Downstream synthetic route of [ 22474-47-1 ]

[ 22474-47-1 ] Synthesis Path-Upstream 1~4

1
[ 22474-47-1 ]
[ 16634-91-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With pyridinium chlorochromate In dichloromethane at 55℃;	General procedure: Variant C: (0530) Adapting a literature known protocol (Corey and Suggs, Tetrahedron Lett., 1975, 16(31), 2647-2650; and Fujikawa, et al., J. Am. Chem. Soc., 2008, 130, 14533-14543), to a solution of the benzylic alcohol (20 mmol) in dichloromethane (DCM) (100 mL) is added commercial pyridinium chlorochromate (Pyr⁺CrO₃Cl⁻, PCC) (28-40 mmol). The reaction mixture is heated to reflux (55° C. oil bath temperature) for 1-4 hours. The reaction is monitored by TLC and/or LCMS to completion. The reaction is cooled to room temperature. Work-up and product isolation and purification are conducted as described for Variant B.
94%	With pyridinium chlorochromate In dichloromethaneReflux	General procedure: Variant C: Adapting a literature known protocol (Corey and Suggs, Tetrahedron Lett, 1975, 16(31), 2647-2650; and Fujikawa, et al., J. Am. Chem. Soc, 2008, 130, 14533- 14543), to a solution of the benzylic alcohol (20 mmol) in dichloromethane (DCM) (100 mL) is added commercial pyridinium chlorochr ornate (Pyr⁺Cr0₃Cl^~, PCC) (28-40 mmol). The reaction mixture is heated to reflux (55°C oil bath temperature) for 1-4 hours. The reaction is monitored by TLC and/or LCMS to completion. The reaction is cooled to room temperature. Work-up and product isolation and purification are conducted as described for Variant B. Following the General Procedure of Description 2 (Variant A), 2-methyl-5-nitro- benzaldehyde (lb) (Beech, J. Chem. Soc. I, 1967, 2374-2375) was prepared from 2-methyl-5- nitro-phenyl)methanol (la) (16.3 g, 97.3 mmol) in the presence of dimethylsulfoxide (DMSO) (56.8 mL, 62.6 g, 0.80 mol), triethylamine (TEA, Et₃N) (69.5 mL, 50.6 g, 0.50 mmol), and sulfur tri oxide pyridine complex (S0₃ pyridine) (47.8 g, 0.30 mol) in dichloromethane (600 mL). Purification by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (EtOAc/hexane = 1 :4, v/v) afforded 12.6 g (78percent yield) of the target compound (lb) as a yellow-beige solid. [0593] Following the General Procedure of Description 2 (Variant B), 2-methyl-5-nitro- benzaldehyde (lb) (Beech, J. Chem. Soc. I, 1967, 2374-2375) was prepared from 2-methyl-5- nitro-phenyl)methanol (la) (4.03 g, 24.1 mmol) in the presence of manganese dioxide (Mn0₂) (22 g, 254 mmol) in dichloromethane (DCM) (100 mL). Work-up afforded 3.56 g (89percent yield) of the target compound (lb) as a pale yellow to beige solid. The material was of sufficient purity to be used directly in the next step without further isolation and purification. [0594] Following the General Procedure of Description 2 (Variant C), 2-methyl-5-nitro- benzaldehyde (lb) (Beech, J. Chem. Soc. I, 1967, 2374-2375) was prepared from 2-methyl-5- nitro-phenyl)methanol (la) (5.00 g, 29.9 mmol) in the presence of pyridinium chlorochromate (PCC) (9.02 g, 41.9 mmol) in dichloromethane (DCM) (150 mL). Purification by silica gel column chromatography using mixtures of ethyl acetate (EtOAc) and hexane (EtOAc/hexane = 1 :4, v/v→ EtOAc/hexane = 1 :2, v/v) afforded 4.67 g (94percent yield) of the target compound (lb) as a yellow-beige solid. Rf. -0.76 (EtOAc/Hxn = 1 :2, v/v). 1H MR (300 MHz, CDC1₃): δ 10.32 (s, 1H), 8.65 (dd, J= 2.7 Hz, 1H), 8.31 (dd, J= 8.4, 2.4 Hz, 1H), 7.47 (d, J= 8.4 Hz, 1H), 2.79 (s, 3H) ppm. The compound is also commercially available.

Reference： [1] Patent: US2015/218086, 2015, A1, . Location in patent: Paragraph 0529; 0530; 0573
[2] Patent: WO2017/24009, 2017, A1, . Location in patent: Paragraph 0560; 0592

2
[ 22474-47-1 ]
[ 98799-27-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With phosphorus tribromide In dichloromethane at 0℃;	General procedure: Adapting literature known protocols (Harrison and Diehl, Org. Synth., 1955, Coll. Vol. 3, 370), the benzylic alcohol (50 mmol) is dissolved in unhydrous dichloromethane (DCM) (about 100-150 mL) and the solution is cooled to about 00 (ice bath). To the solution is dropwise added a commercial 1.0 M solution of phosphorus tribromide (PBr₃) (50 mmol) and the resulting mixture is stirred for about 1-2 h at this temperature. The reaction is followed by TLC to completion. The reaction mixture is poured onto a mixture of crushed ice and a saturated sodium hydrogencarbonate solution. After phase separation, the aqueous phase is extracted with DCM or ethyl acetate (EtOAc) and the combined organic extracts are washed with a saturated aqueous solution of sodium hydrogencarbonate (NaHCO₃) (1×) and brine (1×), dried over anhydrous magnesium sulfate (MgSO₄), filtered, the filter residue is washed with DCM, and the combined organic filters are evaporated under reduced pressure. If needed, the crude material is purified by silica gel column chromatography or is re-crystallized. 2-(Bromomethyl)-1-methyl-4-nitro-benzene (3a) Following the General Procedure of Description 10, 2-(bromomethyl)-1-methyl-4-nitro-benzene (3a) was prepared through bromination of (2-methyl-5-nitro-phenyl)methanol (1a) (11.0 g, 65.8 mmol) (prepared as described in Example 1) dissolved in dichloromethane (DCM) (110 mL) with a solution of phosphorus tribromide (PBr₃) in (1.0 M PBr₃ in DCM) (65.8 mL). Aqueous work-up yielded 11.3 g (75percent yield) of a light yellow solid which was of sufficient purity to be used directly and without further isolation and purification in the next step. R_f=0.56 (EtOAc/Hxn=1:5 v/v). ¹H NMR (300 MHz, CDCl₃): δ 8.19 (d, J=2.4 Hz, 1H), 8.07 (dd, J=8.4, 2.7 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 4.53 (s, 2H), 2.52 (s, 2H) ppm. The spectroscopic data correspond to the data provided in the literature. The compound is also commercially available.
75%	With phosphorus tribromide In dichloromethane at 0℃;	General procedure: General Procedure for the Bromination of Benzylic Alcohols to Benzylic Bromides [0571] Adapting literature known protocols (Harrison and Diehl, Org. Synth., 1955, Coll. Vol. 3, 370), the benzylic alcohol (50 mmol) is dissolved in anhydrous dichloromethane (DCM) (about 100-150 mL) and the solution is cooled to about 0° (ice bath). To the solution is dropwise added a commercial 1.0 M solution of phosphorus tribromide (PBr₃) (50 mmol) and the resulting mixture is stirred for about 1-2 h at this temperature. The reaction is followed by TLC to completion. The reaction mixture is poured onto a mixture of crushed ice and a saturated sodium hydrogencarbonate solution. After phase separation, the aqueous phase is extracted with DCM or ethyl acetate (EtOAc) and the combined organic extracts are washed with a saturated aqueous solution of sodium hydrogencarbonate (NaHC0₃) (l x) and brine (l x), dried over anhydrous magnesium sulfate (MgS0₄), filtered, the filter residue is washed with DCM, and the combined organic filters are evaporated under reduced pressure. If needed, the crude material is purified by silica gel column chromatography or is re- crystallized; Following the General Procedure of Description 10, 2-(bromomethyl)-l-methyl-4- nitro-benzene (3a) was prepared through bromination of (2-methyl-5-nitro-phenyl)methanol (la) (11.0 g, 65.8 mmol) (prepared as described in Example 1) dissolved in dichloromethane (DCM) (110 mL) with a solution of phosphorus tribromide (PBr₃) in (1.0 M PBr₃ in DCM) (65.8 mL). Aqueous work-up yielded 11.3 g (75percent yield) of a light yellow solid (3a) which was of sufficient purity to be used directly and without further isolation and purification in the next step. Rf. -0.56 (EtOAc/Hxn = 1 :5, v/v). 1H MR (300 MHz, CDC1₃): δ 8.19 (d, J = 2.4 Hz, IH), 8.07 (dd, J= 8.4, 2.7 Hz, IH), 7.36 (d, J= 8.7 Hz, IH), 4.53 (s, 2H), 2.52 (s, 2H) ppm. The spectroscopic data correspond to the data provided in the literature. The compound is also commercially available.
55%	With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; for 12 h;	IF3a (0403) A mixture of IF2a (1.60 g, 9.58 mmol), CBr₄(3.81 g, 11.50 mmol) and Ph₃P (3.02 g, 11.50 mmol) in CH₂Cl₂(100 mL) was allowed to stir at rt for 12 h. After removal of the solvent, the residue was purified by flash column chromatography (EtOAc/hexanes) to afford IF3a as a white solid (1.22 g, 55percent). ¹H NMR (CDCl₃, 600 MHz) δ 8.20 (d, J=1.2 Hz, 1H), 8.08 (dd, J=8.4, 2.4 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H), 4.53 (s, 2H), 1.58 (s, 3H).

Reference： [1] Patent: US2015/218086, 2015, A1, . Location in patent: Paragraph 0544; 0590
[2] Patent: WO2017/24009, 2017, A1, . Location in patent: Paragraph 0571; 0609
[3] Patent: US2016/376238, 2016, A1, . Location in patent: Paragraph 0395; 0403
[4] Patent: WO2010/122089, 2010, A1, . Location in patent: Page/Page column 72-73
[5] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 5, p. 527 - 532
[6] Journal of Medicinal Chemistry, 2014, vol. 57, # 10, p. 3939 - 3965

3
[ 22474-47-1 ]
[ 850449-93-3 ]

Reference： [1] Patent: WO2009/105712, 2009, A1,
[2] Patent: WO2005/34869, 2005, A2,

4
[ 22474-47-1 ]
[ 287119-83-9 ]

Reference： [1] Patent: WO2009/105712, 2009, A1,

[ 22474-47-1 ] Synthesis Path-Downstream 1~88

1
[ 58966-24-8 ]
[ 127-09-3 ]
[ 22474-47-1 ]

Reference： [1]Journal of Organic Chemistry,1957,vol. 22,p. 1043
[2]Patent: US2373438,1942,

2
[ 22474-47-1 ]
[ 111437-10-6 ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 3343 - 3356
[2]Patent: US2373438,1942,

3
[ 22364-41-6 ]
[ 22474-47-1 ]

Reference： [1]Pharmazie,1969,vol. 24,p. 87 - 94

4
[ 1975-52-6 ]
[ 22474-47-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With dimethylsulfide borane complex; In tetrahydrofuran; at 75℃;	General procedure: Adapting literature known protocols (Hay, et al., J. Chem. Soc., Perkin Trans. 1, 1999, 2759-2770; Fujikawa, et al., J. Am. Chem. Soc., 2008, 130, 14533-14543; Allen, et al., International Publication No. WO 2010/122089; and Gerspacher, et al., International Publication No. WO2008/031594), commercial borane dimethylsulfide (BH3.DMS, BH3.SMe2) (2.0 M in THF) (50 mL, 100 mmol) or borane tetrahydrofurane complex (BH3.THF) (1.0 M in THF) (100 mL, 100 mmol) is added dropwise at room temperature to a stirred solution of the nitrobenzoic acid (50 mmol) in anhydrous THF (250 mL). Optionally, the reaction is performed in the presence of trimethyl borate (B(OMe)3) (200 mmol). The solution is heated at reflux for 4-6 hours (75 C. oil bath temperature). The reaction is monitored by TLC and/or LCMS to completion. After cooling to about 5 C. (ice bath), the reaction is carefully quenched with a 1:1 (v/v) mixture of methanol (MeOH)/water (25 mL) followed by 5 N hydrochloric acid (HCl) (50 mL). The mixture is heated at about 50 C. for about 30-60 min and the majority of the volatile solvents are removed under reduced pressure. Water is added and the aqueous phase is extracted with ethyl acetate (3×). The combined organic extracts are successively washed with a saturated aqueous sodium hydrogencarbonate (NaHCO3) solution (1×) and with brine (1×), dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvents are evaporated to dryness under reduced pressure. If needed, the crude material is purified by silica gel column chromatography or is re-crystallized. (2-Methyl-5-nitro-phenyl)methanol (1a) Following the General Procedure of Description 1,2-methyl-5-nitro-phenyl)methanol (1a) was prepared from commercial 2-methyl-5-nitro benzoic acid (50.0 g, 276 mmol) with borane dimethylsulfide complex (2.0 M BH3.SMe2 in THF) (166 mL, 332 mmol) in anhydrous tetrahydrofuran (400 mL) to yield 44.0 g (?quantitative yield) of the target compound (1a) as a pale yellow solid which was of sufficient purity to be used directly in the next step without further isolation and purification. Rf: ?0.50 (EtOAc/Hxn=1:1 v/v). 1H NMR (300 MHz, CDCl3): delta 8.30 (d, J=2.4 Hz, 1H), 8.05 (dd, J=8.4, 2.4 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 4.78 (d, J=5.1 Hz, 2H), 2.41 (s, 3H), 1.87 (br. t, J=5.1 Hz, 1H) ppm. The compound is also commercially available.
100%	With dimethylsulfide borane complex; In tetrahydrofuran;Reflux;	General procedure: General Procedure for the Reduction of Benzoic Acids to Benzylic Alcohols [0557] Adapting literature known protocols (Hay, et al., J. Chem. Soc, Perkin Trans. 1, 1999, 2759-2770; Fujikawa, et al., J. Am. Chem. Soc, 2008, 130, 14533-14543; Allen, et al., International Application Publication No. WO 2010/122089; and Gerspacher, et al., International Application Publication No. WO2008/031594), commercial borane dimethylsulfide (BH3 DMS, BH3 SMe2) (2.0 M in THF) (50 mL, 100 mmol) or borane tetrahydrofurane complex (BH3 THF) (1.0 M in THF) (100 mL, 100 mmol) is added dropwise at room temperature to a stirred solution of the nitrobenzoic acid (50 mmol) in anhydrous THF (250 mL). Optionally, the reaction is performed in the presence of trimethyl borate (B(OMe)3) (200 mmol). The solution is heated at reflux for 4-6 hours (~75C oil bath temperature). The reaction is monitored by TLC and/or LCMS to completion. After cooling to about 5C (ice bath), the reaction is carefully quenched with a 1 : 1 (v/v) mixture of methanol (MeOH)/water (25 mL) followed by 5 N hydrochloric acid (HC1) (50 mL). The mixture is heated at about 50C for about 30-60 min and the majority of the volatile solvents are removed under reduced pressure. Water is added and the aqueous phase is extracted with ethyl acetate (3 chi). The combined organic extracts are successively washed with a saturated aqueous sodium hydrogencarbonate (NaHC03) solution (l x) and with brine (l x), dried over anhydrous magnesium sulfate (MgS04), filtered, and the solvents are evaporated to dryness under reduced pressure. If needed, the crude material is purified by silica gel column chromatography or is re-crystallized. Following the General Procedure of Description 1, 2-methyl-5-nitro- phenyl)methanol (la) was prepared from commercial 2-methyl-5-nitro benzoic acid (50.0 g, 276 mmol) with borane dimethylsulfide complex (2.0 M BH3 SMe2 in THF) (166 mL, 332 mmol) in anhydrous tetrahydrofuran (400 mL) to yield 44.0 g (-quant, yield) of the target compound (la) as a pale yellow solid which was of sufficient purity to be used directly in the next step without further isolation and purification. Rf: -0.50 (EtOAc/Hxn = 1 : 1, v/v). 1H MR (300 MHz, CDC13): delta 8.30 (d, J= 2.4 Hz, 1H), 8.05 (dd, J= 8.4, 2.4 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 4.78 (d, J= 5.1 Hz, 2H), 2.41 (s, 3H), 1.87 (br. t, J= 5.1 Hz, 1H) ppm.
95%	With borane; potassium carbonate; In tetrahydrofuran; water;	1. (2-Methyl-5-nitrophenyl)methanol 2-Methyl-5-nitrobenzoic acid (2.00 g, 11.0 mmol) was warmed under nitrogen, dissolved in anhydrous THF (25 mL), and treated with a 1N solution of borane in THF (16.5 mL). After stirring 18 hours at ambient temperature the reaction was quenched with a solution of potassium carbonate (1.8 g, 13 mmol) in water (50 mL), and the THF removed in vacuo. The remaining aqueous solution was extracted with DCM, and the organic layer washed with pH 7 buffer and brine, dried over sodium sulfate, and filtered. The evaporated filtrate gave the title compound as a pale yellow solid (1.76 g, 95%). 1H NMR (300 MHz, CDCl3) delta 8.29 (d, 1H, J=2.5 Hz), 8.04 (dd, 1H, J=8.3 Hz, 2.5 Hz), 7.31 (d, 1H, J=8.31 Hz), 4.77 (d, 2H, J=5.5 Hz), 2.41 (s, 3H), 2.09 (t, 1H, J=5.6 Hz).

94%		IF2a To a mixture of carboxylic acid IF1a (1.81 g, 10.0 mmol) and N-methylmorpholine (1.11 g, 11.0 mmol) in THF (20 mL) at 0 C. was added ethyl chloroformate (1.19 g, 11.0 mmol). The mixture was allowed to stir at 0 C. for an additional 30 min and filtered. The insoluble salt was washed with THF (5 mL*3). To the filtrate was added NaBH4 (1.13 g, 30 mmol) and the resulting mixture was then stirred at rt for 2 h. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous K2CO3, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexanes) to afford compound IF2a as a colorless oil (1.60 g, 94%). 1H NMR (CDCl3, 600 MHz) delta 8.31 (d, J=2.4 Hz, 1H), 8.06 (dd, J=8.1, 2.7 Hz, 1H), 7.32 (d, J=9.0 Hz, 1H), 4.79 (d, J=4.8 Hz, 2H), 1.57 (s, 3H).
		Methyl 2-(5-amino-2-methylphenyl)acetate (7); [0124] 2-Methyl-5-nitrobenzoic acid 9 (125 g, 690 mmol) is dissolved in anhydrous THF (1.25 L). After adding borane (517 mL of a 2 M solution in THF, 1.04 mol), the reaction is stirred at rt for 18 h. The reaction is quenched using an aqueous solution of potassium carbonate (112.5 g in 2.5 L). After removing THF in vacuo, the aqueous solution is extracted with DCM and the combined organic layer is washed with brine and dried over sodium sulfate. After filtering and removing the solvent in vacuo, the product 10 is obtained as a pale yellow solid. 1H NMR (300MHz, CDCl3) delta 8.29 (d, J = 3 Hz, IH), 8.50 (m, IH), 7.29 (m, IH), 4.78 (s, 2H), 2.41 (s, 3H).
		To a solution of 2-methyl-5-nitrobenzoic acid (3.0 g, 16.6 mmol, Acros) in THF (60 ml) at ambient temperature under nitrogen was added dropwise 1.0 M borane- tetrahydrofuran complex (33.1 ml, 33.1 mmol, Aldrich). The solution was heated to 80 0C for 1.5 h. To the solution at ambient temperature was slowly added methanol (20 ml) and then heated to 80 0C for 30 min. The solvent was removed in vacuo to leave an oil. The residue was dissolved in methanol (approximately 30 ml) and the solvent removed in vacuo to give (2-methyl-5-nitrophenyl)methanol as a yellow solid (3.18 g).
		[00121] 2-Methyl-5-nitrobenzoic acid 9 (125 g, 690 mmol) was dissolved in anhydrous THF (1.25 L). After adding borane (517 mL of a 2 M solution in THF, 1.04 mol), the reaction was stirred at rt for 18 h. The reaction was quenched using an aqueous solution of potassium carbonate (112.5 g in 2.5 L). After removing THF in vacuo, the aqueous solution was extracted with DCM and the combined organic layer was washed with brine and dried over sodium sulfate. After filtering and removing the solvent in vacuo, the product 10 was obtained as a pale yellow solid. 1H NMR (300MHz, CDCl3) delta 8.29 (d, J = 3 Hz, IH), 8.50 (m, IH), 7.29 (m, IH), 4.78 (s, 2H), 2.41 (s, 3H).
	With borane-THF; In tetrahydrofuran; at 20℃; for 18h;	2-Methyl-5-nitrobenzoic acid (5. 0g, 27. 5mmol) is dissolved in 50mL anhydrous THF. After adding 41.3mL 1M borane in THF solution (41.3mmol), the reaction is stirred in RT for 18 hours. The reaction is quenched by a solution of potassium carbonate (4. 5g) in 100mL water. After removing THF under vacuum, the aqueous solution is extracted with DCM and the combined organic layer is washed by brine and dried over sodium sulfate. After filtering and removing the solvent under the vacuum, the final product compound (12) (2-methyl-5-nitrophenyl) -methanol is the pale yellow solid, 4.3g.

Reference： [1]Patent: US2015/218086,2015,A1 .Location in patent: Paragraph 0524; 0570
[2]Patent: WO2017/24009,2017,A1 .Location in patent: Paragraph 0557; 0591
[3]Patent: US2002/61872,2002,A1
[4]Patent: US2016/376238,2016,A1 .Location in patent: Paragraph 0395; 0396
[5]Journal of Medicinal Chemistry,1996,vol. 39,p. 3343 - 3356
[6]Patent: WO2008/51757,2008,A1 .Location in patent: Page/Page column 33
[7]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5004 - 5008
[8]Patent: WO2010/122089,2010,A1 .Location in patent: Page/Page column 72
[9]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 527 - 532
[10]Journal of Medicinal Chemistry,2014,vol. 57,p. 3939 - 3965
[11]Patent: WO2009/105712,2009,A1 .Location in patent: Page/Page column 37
[12]Patent: WO2005/34869,2005,A2 .Location in patent: Page/Page column 41

5
[ 22474-47-1 ]
[ 180136-13-4 ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 3343 - 3356

6
[ 22474-47-1 ]
[ 180136-14-5 ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 3343 - 3356

7
[ 22474-47-1 ]
N-[3-((Z)-2-Cyano-2-pyridin-3-yl-vinyl)-4-methyl-phenyl]-3-cyclohexyl-propionamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 3343 - 3356

8
[ 22474-47-1 ]
N-{3-[2-cyano-2-(4-hydroxyphenyl)vinyl]-4-methylphenyl}-3-cyclohexylpropionamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 3343 - 3356

9
[ 22474-47-1 ]
N-[3-((Z)-2-Benzo[1,3]dioxol-5-yl-2-cyano-vinyl)-4-methyl-phenyl]-3-cyclohexyl-propionamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 3343 - 3356

10
[ 99-99-0 ]
[ 22474-47-1 ]

Reference： [1]Journal of Organic Chemistry,1957,vol. 22,p. 1043

11
[ 6970-77-0 ]
[ 22474-47-1 ]

Reference： [1]Pharmazie,1969,vol. 24,p. 87 - 94

12
[ 22364-38-1 ]
[ 22474-47-1 ]

Reference： [1]Pharmazie,1969,vol. 24,p. 87 - 94

13
[ 22364-40-5 ]
[ 22474-47-1 ]

Reference： [1]Pharmazie,1969,vol. 24,p. 87 - 94

14
[ 22474-47-1 ]
[ 124-63-0 ]
[ 409082-10-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 1h;	(2-Methyl-5-nitrophenyl)methanol 10 (96 g, 574 mmol) is dissolved in anhydrous DCM (2.5 L), cooled to 0 0C, treated with methanesulfonyl chloride (72 g, 632 mmol) and di-isopropylethylamine (89 g, 689 mmol) for 30 minutes. The reaction is warmed to rt and stirred for another 30 minutes. It is quenched by adding water (600 mL). The organic layer is washed with brine, dried over sodium sulfate and filtered. After removing the solvent in vacuo, the product 11 is isolated as yellow oil and used in the next step without further purification.
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 1h;	[00122] (2-Methyl-5-nitrophenyl)methanol 10 (96 g, 574 mmol) was dissolved in anhydrous DCM (2.5 L), cooled to 0 0C, treated with methanesulfonyl chloride (72 g, 632 mmol) and diisopropylethylamine (89 g, 689 mmol) for 30 minutes. The reaction was warmed to rt and stirred for another 30 minutes. It was quenched by adding water (600 mL). The organic layer was washed with brine, dried over sodium sulfate and filtered. After removing the solvent in vacuo, the product 11 was isolated as yellow oil and was used in the next step without further purification.
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 1h;	(2-methyl-5-nitrophenyl) -methanol (4.3g, 25. 7mmol) is dissolved in 100mL anhydrous DCM and cooled down to 0 C and treated with methanesulfonyl chloride (3.22g, 28. 3mmol) and DIEA (5. 36mL, 30. 8mmol) for 30 minutes. The reaction is warmed up to the room temperature and stirred for another 30 minutes. The reaction is quenched by adding 30mL water. The organic layer is washed with brine and dried over sodium sulfate and filtered. After removing the solvent under the vacuum, the final product compound (13) (2-methyl-5-nitrophenyl) -methyl methylsulfonate is the yellow oil, 6.2g.

Reference： [1]Patent: WO2008/51757,2008,A1 .Location in patent: Page/Page column 33
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5004 - 5008
[3]Patent: WO2009/105712,2009,A1 .Location in patent: Page/Page column 37-38
[4]Patent: WO2005/34869,2005,A2 .Location in patent: Page/Page column 41

15
[ 22474-47-1 ]
[ 98799-27-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With phosphorus tribromide; In dichloromethane; at 0℃;	General procedure: Adapting literature known protocols (Harrison and Diehl, Org. Synth., 1955, Coll. Vol. 3, 370), the benzylic alcohol (50 mmol) is dissolved in unhydrous dichloromethane (DCM) (about 100-150 mL) and the solution is cooled to about 00 (ice bath). To the solution is dropwise added a commercial 1.0 M solution of phosphorus tribromide (PBr3) (50 mmol) and the resulting mixture is stirred for about 1-2 h at this temperature. The reaction is followed by TLC to completion. The reaction mixture is poured onto a mixture of crushed ice and a saturated sodium hydrogencarbonate solution. After phase separation, the aqueous phase is extracted with DCM or ethyl acetate (EtOAc) and the combined organic extracts are washed with a saturated aqueous solution of sodium hydrogencarbonate (NaHCO3) (1×) and brine (1×), dried over anhydrous magnesium sulfate (MgSO4), filtered, the filter residue is washed with DCM, and the combined organic filters are evaporated under reduced pressure. If needed, the crude material is purified by silica gel column chromatography or is re-crystallized. 2-(Bromomethyl)-1-methyl-4-nitro-benzene (3a) Following the General Procedure of Description 10, 2-(bromomethyl)-1-methyl-4-nitro-benzene (3a) was prepared through bromination of (2-methyl-5-nitro-phenyl)methanol (1a) (11.0 g, 65.8 mmol) (prepared as described in Example 1) dissolved in dichloromethane (DCM) (110 mL) with a solution of phosphorus tribromide (PBr3) in (1.0 M PBr3 in DCM) (65.8 mL). Aqueous work-up yielded 11.3 g (75% yield) of a light yellow solid which was of sufficient purity to be used directly and without further isolation and purification in the next step. Rf=0.56 (EtOAc/Hxn=1:5 v/v). 1H NMR (300 MHz, CDCl3): delta 8.19 (d, J=2.4 Hz, 1H), 8.07 (dd, J=8.4, 2.7 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 4.53 (s, 2H), 2.52 (s, 2H) ppm. The spectroscopic data correspond to the data provided in the literature. The compound is also commercially available.
75%	With phosphorus tribromide; In dichloromethane; at 0℃;	General procedure: General Procedure for the Bromination of Benzylic Alcohols to Benzylic Bromides [0571] Adapting literature known protocols (Harrison and Diehl, Org. Synth., 1955, Coll. Vol. 3, 370), the benzylic alcohol (50 mmol) is dissolved in anhydrous dichloromethane (DCM) (about 100-150 mL) and the solution is cooled to about 0 (ice bath). To the solution is dropwise added a commercial 1.0 M solution of phosphorus tribromide (PBr3) (50 mmol) and the resulting mixture is stirred for about 1-2 h at this temperature. The reaction is followed by TLC to completion. The reaction mixture is poured onto a mixture of crushed ice and a saturated sodium hydrogencarbonate solution. After phase separation, the aqueous phase is extracted with DCM or ethyl acetate (EtOAc) and the combined organic extracts are washed with a saturated aqueous solution of sodium hydrogencarbonate (NaHC03) (l x) and brine (l x), dried over anhydrous magnesium sulfate (MgS04), filtered, the filter residue is washed with DCM, and the combined organic filters are evaporated under reduced pressure. If needed, the crude material is purified by silica gel column chromatography or is re- crystallized; Following the General Procedure of Description 10, 2-(bromomethyl)-l-methyl-4- nitro-benzene (3a) was prepared through bromination of (2-methyl-5-nitro-phenyl)methanol (la) (11.0 g, 65.8 mmol) (prepared as described in Example 1) dissolved in dichloromethane (DCM) (110 mL) with a solution of phosphorus tribromide (PBr3) in (1.0 M PBr3 in DCM) (65.8 mL). Aqueous work-up yielded 11.3 g (75% yield) of a light yellow solid (3a) which was of sufficient purity to be used directly and without further isolation and purification in the next step. Rf. -0.56 (EtOAc/Hxn = 1 :5, v/v). 1H MR (300 MHz, CDC13): delta 8.19 (d, J = 2.4 Hz, IH), 8.07 (dd, J= 8.4, 2.7 Hz, IH), 7.36 (d, J= 8.7 Hz, IH), 4.53 (s, 2H), 2.52 (s, 2H) ppm. The spectroscopic data correspond to the data provided in the literature. The compound is also commercially available.
55%	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 12h;	IF3a (0403) A mixture of <strong>[22474-47-1]IF2a</strong> (1.60 g, 9.58 mmol), CBr4 (3.81 g, 11.50 mmol) and Ph3P (3.02 g, 11.50 mmol) in CH2Cl2 (100 mL) was allowed to stir at rt for 12 h. After removal of the solvent, the residue was purified by flash column chromatography (EtOAc/hexanes) to afford IF3a as a white solid (1.22 g, 55%). 1H NMR (CDCl3, 600 MHz) delta 8.20 (d, J=1.2 Hz, 1H), 8.08 (dd, J=8.4, 2.4 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H), 4.53 (s, 2H), 1.58 (s, 3H).

With phosphorus tribromide; In dichloromethane; at 20℃;Inert atmosphere; Cooling with ice;

To a slight suspension of <strong>[22474-47-1](2-methyl-5-nitrophenyl)methanol</strong> (2.0 g, 12 mmol) in DCM (20 ml) in an ice-water bath under nitrogen was a added a solution of phosphorus tribromide (1.13 ml_, 12 mmol, Aldrich) in DCM (20 ml). The resulting solution was allowed to warm to ambient temperature and stirred for 45 min. The solution was poured onto a mixture of ice-water (50 ml) and saturated sodium hydrogen carbonate (50 ml). The biphasic mixture was diluted with dichloromethane (50 ml) and the phases separated. The aqueous phase was extracted with dichloromethane (20 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to give 2-(bromomethyl)-1-methyl-4-nitrobenzene as a pale yellow solid (1.81 g).

Reference： [1]Patent: US2015/218086,2015,A1 .Location in patent: Paragraph 0544; 0590
[2]Patent: WO2017/24009,2017,A1 .Location in patent: Paragraph 0571; 0609
[3]Patent: US2016/376238,2016,A1 .Location in patent: Paragraph 0395; 0403
[4]Patent: WO2010/122089,2010,A1 .Location in patent: Page/Page column 72-73
[5]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 527 - 532
[6]Journal of Medicinal Chemistry,2014,vol. 57,p. 3939 - 3965

16
[ 16634-91-6 ]
[ 22474-47-1 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 3673 - 3679

17
[ 22474-47-1 ]
[ 1569736-78-2 ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 527 - 532

18
[ 22474-47-1 ]
[ 1569736-97-5 ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 527 - 532

19
[ 22474-47-1 ]
2-[(cyclopentylsulfanyl)methyl]-1-methyl-4-nitrobenzene [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 527 - 532

20
[ 124358-24-3 ]
[ 22474-47-1 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3939 - 3965

21
[ 22474-47-1 ]
[ 1606169-48-5 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3939 - 3965

22
[ 22474-47-1 ]
[ 1606169-58-7 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3939 - 3965

23
[ 22474-47-1 ]
[ 1606168-49-3 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3939 - 3965

24
[ 22474-47-1 ]
[ 1606168-71-1 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3939 - 3965

25
[ 22474-47-1 ]
[ 1606168-83-5 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3939 - 3965

26
[ 22474-47-1 ]
[ 1606168-99-3 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3939 - 3965

27
[ 22474-47-1 ]
[ 1606169-00-9 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3939 - 3965

28
[ 22474-47-1 ]
[ 1606169-01-0 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3939 - 3965

29
[ 22474-47-1 ]
diethyl 2-acetamido-2-[(2-methyl-5-nitro-phenyl)methyl]propanedioate [ No CAS ]

Reference： [1]Patent: US2015/218086,2015,A1
[2]Patent: WO2017/24009,2017,A1

30
[ 13292-87-0 ]
[ 1975-52-6 ]
[ 22474-47-1 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	Step I: (2-Methyl-5-nitro-phenyl)methanol (5i) Following the General Procedure of Description 6, 2-methyl-5-nitro-phenyl)methanol (5i) was prepared from commercial 2-methyl-5-nitro benzoic acid (50.0 g, 276 mmol) with borane dimethylsulfide complex (2.0 M BH3.SMe2 in THF) (166 mL, 332 mmol) in anhydrous tetrahydrofuran (400 mL) to yield 44.0 g (?quantitative yield) of the target compound (5i) as a pale yellow solid which was of sufficient purity to be used directly in the next step without further isolation and purification procedures. Rf: ?0.50 (EtOAc/Hxn=1:1 v/v). 1H NMR (300 MHz, CDCl3): delta 8.30 (d, J=2.4 Hz, 1H), 8.05 (dd, J=8.4, 2.4 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 4.78 (d, J=5.1 Hz, 2H), 2.41 (s, 3H), 1.87 (br. t, J=5.1 Hz, 1H) ppm.

Reference： [1]Patent: US2015/218085,2015,A1

31
[ 22474-47-1 ]
3-amino-3-(2-methyl-5-nitrophenyl)propanoic acid [ No CAS ]

Reference： [1]Patent: US2015/218086,2015,A1
[2]Patent: WO2017/24009,2017,A1

32
[ 22474-47-1 ]
[ 16634-91-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With pyridinium chlorochromate; In dichloromethane; at 55℃;	General procedure: Variant C: (0530) Adapting a literature known protocol (Corey and Suggs, Tetrahedron Lett., 1975, 16(31), 2647-2650; and Fujikawa, et al., J. Am. Chem. Soc., 2008, 130, 14533-14543), to a solution of the benzylic alcohol (20 mmol) in dichloromethane (DCM) (100 mL) is added commercial pyridinium chlorochromate (Pyr+CrO3Cl-, PCC) (28-40 mmol). The reaction mixture is heated to reflux (55 C. oil bath temperature) for 1-4 hours. The reaction is monitored by TLC and/or LCMS to completion. The reaction is cooled to room temperature. Work-up and product isolation and purification are conducted as described for Variant B.
94%	With pyridinium chlorochromate; In dichloromethane;Reflux;	General procedure: Variant C: Adapting a literature known protocol (Corey and Suggs, Tetrahedron Lett, 1975, 16(31), 2647-2650; and Fujikawa, et al., J. Am. Chem. Soc, 2008, 130, 14533- 14543), to a solution of the benzylic alcohol (20 mmol) in dichloromethane (DCM) (100 mL) is added commercial pyridinium chlorochr ornate (Pyr+Cr03Cl~, PCC) (28-40 mmol). The reaction mixture is heated to reflux (55C oil bath temperature) for 1-4 hours. The reaction is monitored by TLC and/or LCMS to completion. The reaction is cooled to room temperature. Work-up and product isolation and purification are conducted as described for Variant B. Following the General Procedure of Description 2 (Variant A), 2-methyl-5-nitro- benzaldehyde (lb) (Beech, J. Chem. Soc. I, 1967, 2374-2375) was prepared from 2-methyl-5- nitro-phenyl)methanol (la) (16.3 g, 97.3 mmol) in the presence of dimethylsulfoxide (DMSO) (56.8 mL, 62.6 g, 0.80 mol), triethylamine (TEA, Et3N) (69.5 mL, 50.6 g, 0.50 mmol), and sulfur tri oxide pyridine complex (S03 pyridine) (47.8 g, 0.30 mol) in dichloromethane (600 mL). Purification by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (EtOAc/hexane = 1 :4, v/v) afforded 12.6 g (78% yield) of the target compound (lb) as a yellow-beige solid. [0593] Following the General Procedure of Description 2 (Variant B), 2-methyl-5-nitro- benzaldehyde (lb) (Beech, J. Chem. Soc. I, 1967, 2374-2375) was prepared from 2-methyl-5- nitro-phenyl)methanol (la) (4.03 g, 24.1 mmol) in the presence of manganese dioxide (Mn02) (22 g, 254 mmol) in dichloromethane (DCM) (100 mL). Work-up afforded 3.56 g (89% yield) of the target compound (lb) as a pale yellow to beige solid. The material was of sufficient purity to be used directly in the next step without further isolation and purification. [0594] Following the General Procedure of Description 2 (Variant C), 2-methyl-5-nitro- benzaldehyde (lb) (Beech, J. Chem. Soc. I, 1967, 2374-2375) was prepared from 2-methyl-5- nitro-phenyl)methanol (la) (5.00 g, 29.9 mmol) in the presence of pyridinium chlorochromate (PCC) (9.02 g, 41.9 mmol) in dichloromethane (DCM) (150 mL). Purification by silica gel column chromatography using mixtures of ethyl acetate (EtOAc) and hexane (EtOAc/hexane = 1 :4, v/v? EtOAc/hexane = 1 :2, v/v) afforded 4.67 g (94% yield) of the target compound (lb) as a yellow-beige solid. Rf. -0.76 (EtOAc/Hxn = 1 :2, v/v). 1H MR (300 MHz, CDC13): delta 10.32 (s, 1H), 8.65 (dd, J= 2.7 Hz, 1H), 8.31 (dd, J= 8.4, 2.4 Hz, 1H), 7.47 (d, J= 8.4 Hz, 1H), 2.79 (s, 3H) ppm. The compound is also commercially available.

Reference： [1]Patent: US2015/218086,2015,A1 .Location in patent: Paragraph 0529; 0530; 0573
[2]Patent: WO2017/24009,2017,A1 .Location in patent: Paragraph 0560; 0592

33
[ 22474-47-1 ]
tert-butyl (3S)-3-(tert-butoxycarbonylamino)-5-(2-methyl-5-nitrophenyl)pent-4-enoate [ No CAS ]

Reference： [1]Patent: US2015/218086,2015,A1

34
[ 22474-47-1 ]
C₁₄H₁₇NO₅S [ No CAS ]
C₂₂H₂₄N₂O₇S [ No CAS ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 4418 - 4421

35
[ 22474-47-1 ]
N-(3-(((5-carbamoylpyridin-3-yl)oxy)methyl)-4-methylphenyl)nicotinamide [ No CAS ]

Reference： [1]Patent: US2016/376238,2016,A1

36
[ 22474-47-1 ]
C₁₅H₁₄N₂O₅ [ No CAS ]

Reference： [1]Patent: US2016/376238,2016,A1

37
[ 22474-47-1 ]
C₁₅H₁₆N₂O₃ [ No CAS ]

Reference： [1]Patent: US2016/376238,2016,A1

38
[ 22474-47-1 ]
C₁₄H₁₅N₃O₂ [ No CAS ]

Reference： [1]Patent: US2016/376238,2016,A1

39
[ 22474-47-1 ]
methyl 3-amino-3-(2-methyl-5-nitrophenyl)propanoate hydrochloride [ No CAS ]

Reference： [1]Patent: WO2017/24009,2017,A1

40
[ 22474-47-1 ]
methyl 3-benzyloxycarbonylamino-3-(2-methyl-5-nitrophenyl)propanoate [ No CAS ]

Reference： [1]Patent: WO2017/24009,2017,A1

41
[ 22474-47-1 ]
methyl 3-(5-amino-2-methyl-phenyl)-3-benzyloxycarbonylamino-propanoate [ No CAS ]

Reference： [1]Patent: WO2017/24009,2017,A1

42
[ 22474-47-1 ]
methyl 3-benzyloxycarbonylamino-3-[5-[bis(2-chloroethyl)amino]-2-methylphenyl]propanoate [ No CAS ]

Reference： [1]Patent: WO2017/24009,2017,A1

43
[ 22474-47-1 ]
3-amino-3-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]propanoic acid [ No CAS ]

Reference： [1]Patent: WO2017/24009,2017,A1

44
[ 22474-47-1 ]
[ 409082-11-7 ]