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[ CAS No. 112108-73-3 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 112108-73-3

Chemical Structure| 112108-73-3

Chemical Structure| 112108-73-3

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Quality Control of [ 112108-73-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 112108-73-3 ]

SDS Specification

Alternatived Products of [ 112108-73-3 ]

Product Details of [ 112108-73-3 ]

CAS No. :	112108-73-3	MDL No. :	MFCD11110549
Formula :	C₇H₅ClFNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YXVJHZWHPLOEAP-UHFFFAOYSA-N
M.W :	189.57	Pubchem ID :	10103979
Synonyms :

Calculated chemistry of [ 112108-73-3 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	45.2
TPSA :	45.82 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) :	-5.45 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.66
Log Po/w (XLOGP3) :	2.83
Log Po/w (WLOGP) :	3.12
Log Po/w (MLOGP) :	2.22
Log Po/w (SILICOS-IT) :	1.2
Consensus Log Po/w :	2.21

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.1
Solubility :	0.15 mg/ml ; 0.00079 mol/l
Class :	Soluble
Log S (Ali) :	-3.45
Solubility :	0.0672 mg/ml ; 0.000355 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.06
Solubility :	0.164 mg/ml ; 0.000865 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.84

Safety of [ 112108-73-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302+H312+H332-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 112108-73-3 ]

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

Upstream synthesis route of [ 112108-73-3 ]
Downstream synthetic route of [ 112108-73-3 ]

[ 112108-73-3 ] Synthesis Path-Upstream 1~4

1
[ 452-73-3 ]
[ 112108-73-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	at -5 - 20℃;	b) Synthesis of the aromatic nitro compounds;: 55 g (380 mmol) 2-chloro-4-fluoro toluene are dissolved in 500 ml cone. sulfuric acid and cooled to-5 to 0 °C in an ice bath. To this solution, 50.6 g (500 mmol) KNO3 is added in portions within 1 h. The reaction mixture is allowed to warmed up to room temperature overnight and then poured onto ice. After customary workup, 60 g (81 percent) 27 (Rt. = 2.73 min (method C) ) is obtained as a yellow oil which crystallises in the refrigerator.
81%	at -5 - 20℃;	55 g (380 mmol) 2-Chloro-4-fluoro toluene are dissolved in 500 ml concentrated sulfuric acid and cooled to-5-0 °C in an ice bath. To this solution, 50.6 g (500 mmol) potassium nitrate are added in several portions within 1 h. The reaction mixture is warmed up to room temperature overnight and then poured onto ice. The yellow suspension is extracted 3x with 11 tert. - Butyl-methylether each time and the combined organic phases are washed neutral with NaHCO3-solution. The organic phase is stirred with Na2SO4 and 10 g charcoal, filtered and the filtrate is evaporated to dryness. Yield : 60 g (81 percent) 6, yellow oil, which crystallises in the refrigerator
81%	at -5 - 20℃;	55 g (380 mmol) 2-Chloro-4-fluoro toluene in 500 ml conc. Sulfuric acid are cooled to-5-0 °C gekuehlt and treated within one hour with 50.6 g (500 mmol) potassium nitrate in several portions. The reaction mixture is allowed to warm up to room temperature overnight and then poured onto ice. The yellow suspension is extracted 3x with 11 tert.-Butyl-methylether and the combined organic phases are washed neutral using NaHCO3-solution. The organic phase is stirred with Na2SO4 and 10 g charcoal, filtered and and the filtrate is evaporated. Yield : 60 g (81 percent) 25, yellow oil, crystallises in the refrigerator 0.55 g (2.81 mmol) 25 in DMF are treated with 0.59 g (3.38 mmol) N-Boc-N- methylaminoethanol and 2.11 g (6.47 mmol) cesium carbonate and stirred overnight at 50 °C. the reaction mixture is filtered and the filtrate is evaporated. The residue is taken up in ethylacetate, washed with water, dried using Na2SO4, filtered and evaporated. Yield : 0.94 g (97 percent), brown oil The thus obtained nitro compound is hydrogenated in THF at room temperature using H2 and Raney-Ni. The catalyst is removed by filtration and the filtrate is evaporated to dryness. Yield : 0.83 g (96 percent) 26, brown oil

51.2%	at 0 - 20℃; for 22 h;	2-Chloro-4-fluoro-1-methylbenzene (5.000 g, 34.585 mmol) and Potassium nitrate (4.371 g, 43.232 mmol) was added to a mixture of sulfuric acid (12.536 mL, 235.180 mmol) at 0 & The mixture was slowly added so that the internal temperature did not exceed 10 ° C, slowly raised to room temperature, and stirred for 22 hours.The reaction mixture was cooled in an ice bath and poured into 50 ml of water. After completion of the reaction, the mixture was extracted three times with 50 ml of ethyl acetate.The combined organic layers were washed with a saturated aqueous sodium chloride solution, and water was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure.The concentrate was purified by column chromatography (SiO2, 80 g cartridge; ethyl acetate / hexane = 0percent to 5percent) and concentrated to give 1-chloro-5-fluoro-2-methyl- , 51.2percent) as a pale yellow liquid.
80%	With KNO₃ In conc. H₂ SO₄	2-Chloro-4-fluoro-5-nitrotoluene. To a stirred solution of 2-chloro-4-fluorotoluene (2.000 g, 1.383 mmol, Aldrich, used as received) in conc. H₂ SO₄ (15.0 mL) at 0° C., KNO₃ (1.400 g, 1.385 mmol) was added in one lot. The resulting pale yellow solution was allowed to warm to 28° C. and stirred overnight at 28° C. It was then poured into ice (100 g) and extracted with ethyl acetate (2*100 mL). Ethyl acetate was dried over anhydrous Na₂ SO₄, removed under vacuum, and the resulting oil was dried further under vacuum to afford 2.085 g (80percent) of title compound as an oil, which was used as such for the next reaction; ¹ H NMR (CDCl₃): δ2.422 (s, 3H), 7.325 (d, 1H, J₁ =10.2 Hz), 7.973 (d, 1H, J₁ =5.2 Hz).
1.1 g	at -5 - 20℃; for 16 h;	Step 1: 1-chloro-5-fluoro-2-methyl-4-nitrobenzene 2-chloro-4-fluoro-1-methyl benzene (1.5g, 10.4mmol) and concentrated sulfuric acid (15mL) were added into a 50 mL reaction flask. The reaction mixture was cooled down to -5°C∼0°C and then potassium nitrate (1.4g, 13.8mmol) was added in batches at this temperature. The reaction mixture was slowly increased up to room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted by using ethyl acetate, and washed with saturated aqueous sodium bicarbonate and saturated brine, dried and concentrated. The crude product thus obtained was separated and purified by column chromatography (silica gel column, eluent: ethyl acetate / petroleum ether = 1:50) to obtain the title compound (yellow solid, 1.1g, 56percent). (MS: [M+1] none)

Reference： [1] Patent: WO2005/82853, 2005, A1, . Location in patent: Page/Page column 210-211
[2] Patent: WO2005/75425, 2005, A2, . Location in patent: Page/Page column 184-185
[3] Patent: WO2005/82862, 2005, A2, . Location in patent: Page/Page column 136
[4] Journal of Medicinal Chemistry, 2013, vol. 56, # 14, p. 5675 - 5690
[5] Patent: KR2016/147358, 2016, A, . Location in patent: Paragraph 0226-0228
[6] Patent: WO2005/85220, 2005, A1, . Location in patent: Page/Page column 71-72
[7] Journal of Organic Chemistry, 1995, vol. 60, # 18, p. 5838 - 5842
[8] Patent: US5631373, 1997, A,
[9] Patent: US4846875, 1989, A,
[10] Patent: US4846882, 1989, A,
[11] Patent: WO2008/73687, 2008, A2, . Location in patent: Page/Page column 30-31
[12] Patent: EP3150592, 2017, A1, . Location in patent: Paragraph 0106; 0107; 0108
[13] Patent: CN104447515, 2017, B, . Location in patent: Paragraph 0023-0025
[14] Patent: US2018/86706, 2018, A1, . Location in patent: Paragraph 0042-0045
[15] Patent: WO2007/107566, 2007, A1, . Location in patent: Page/Page column 84

2
[ 452-84-6 ]
[ 112108-73-3 ]

Yield	Reaction Conditions	Operation in experiment
61%	at -5℃; for 1 h;	1-Chloro-5-fluoro-2-methyl-4-nitrobenzene To a cooled (-5° C.) solution of 2-fluoro-5-methylaniline (1 equiv.) in concentrated H₂SO₄ (0.7 M) was added KNO₃ (1.3 equiv.) in several portions within 1 h. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into ice-water slowly, and extracted with MTBE, washed with saturated NaHCO₃ and brine, dried over Na₂SO₄, filtered and concentrated. The resulted residue was recrystallized from ethyl acetate and petroleum ether to afford 1-chloro-5-fluoro-2-methyl-4-nitrobenzene (61percent) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.00 (d, J=8.0 Hz, 1H), 7.35 (d, J=10.4 Hz, 1H), 2.45 (s, 3H).

Reference： [1] Patent: US2016/96841, 2016, A1, . Location in patent: Paragraph 0353

3
[ 67-63-0 ]
[ 112108-73-3 ]
[ 1032903-50-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	at 60℃; for 16 h;	2-Chloro-4-fluoro-5-nitrobenzene (25 g, 131 mmol) was dissolved in isopropanol (250 mL) and cesium carbonate(208 g, 659 mmol) was added thereto. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was cooled to room temperature and the reaction mixture was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate (250 mL) and then water (250 mL) was added. The separated organic phase was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (petroleum ether: ethyl acetate = 19: 1) to deliver a yellow solid 13-d (28.7 g, yield:95percent).1H-NMR (400MHz, DMSO-d6) δ: 7.90 (d, J=0.6Hz, 1H), 7.52 (s, 2H), 7. 86 (m, 1H), 2.30 (s, 3H), 1.27 (d, J=6Hz, 6H) ppm.
86.3%	at 20℃;	1.5 L of isopropanol, 1-chloro-5-fluoro-2-methyl-4-nitrobenzene (260 g)Potassium hydroxide (116g) was added to complete the reaction at a temperature of 20 ° C to monitor the disappearance of the raw materials. The stirring was stopped and the reaction solution was added to 5L of water overThe product was filtered and the filter cake was dried to give 1-chloro-5-isopropyloxy-2-methyl-4-nitrobenzene, 271 g, yield: 86.3percent.
82%	at 60℃;	The title compound 2-chloro-4-fluoro-5-nitrotoluene (i.e., compound 2-1, 14.2 g, 74.9 mmol) was dissolved in isopropanol (100.0 mL)Cesium carbonate (122.0 g, 374.4 mmol) was added,The reaction was carried out at 60 ° C overnight.After completion of the reaction, the mixture was concentrated to remove isopropanol,Poured into 500.0mL water, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, concentrated,Compound No. 2-2 (14.4 g) was obtained in a yield of 82.0percent.

82%	at 60℃;	The title compound 2-chloro-4-fluoro-5-nitrotoluene (i.e., Compound 2-1, 14.2 g, 74.9 mmol) was dissolved in isopropanol (100.0 mL), cesium carbonate (122.0 g, 374.4 mmol) The reaction mixture was concentrated at 60 ° C overnight. After completion of the reaction, the mixture was concentrated to remove isopropanol, poured into 500.0 mL of water, extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to give Compound 2-2 (14.3 g), yield: 82.0percent.
74.4%	at 60℃; for 24 h;	1-Chloro-5-fluoro-2-methyl-4-nitrobenzene (3.260 g, 17.197 mmol)Cesium carbonate (28.015 g, 85.984 mmol) was added to a solution ofPropanol (35 mL) at 60 ° C was stirred at the same temperature for 24 hours, and then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a paper filter to remove the solid. The solvent was removed from the filtrate under reduced pressure, water was poured into the resulting concentrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution,The water was removed with magnesium sulfate, filtered and concentrated under reduced pressure.The concentrate was purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 5percent) and concentrated to obtain 2.938 g (74.4percent) of 1-chloro-5-isopropoxy-2-methyl-4-nitrobenzene As a light brown solid.

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 14, p. 5675 - 5690
[2] Patent: EP3287463, 2018, A1, . Location in patent: Paragraph 0164; 0165
[3] Patent: CN106674084, 2017, A, . Location in patent: Paragraph 0026; 0027; 0028
[4] Patent: CN106336398, 2017, A, . Location in patent: Paragraph 0108; 0127; 0128; 0129
[5] Patent: CN106478700, 2017, A, . Location in patent: Paragraph 0093; 0108; 0109; 0110
[6] Patent: KR2016/147358, 2016, A, . Location in patent: Paragraph 0230-0232
[7] Patent: WO2008/73687, 2008, A2, . Location in patent: Page/Page column 31
[8] Patent: CN104447515, 2017, B, . Location in patent: Paragraph 0027-0029
[9] Patent: US2018/86706, 2018, A1, . Location in patent: Paragraph 0046-0049

4
[ 112108-73-3 ]
[ 1032903-63-1 ]

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 14, p. 5675 - 5690
[2] Patent: KR2016/147358, 2016, A,
[3] Patent: CN106478700, 2017, A,
[4] Patent: EP3287463, 2018, A1,

[ 112108-73-3 ] Synthesis Path-Downstream 1~88

1
[ 452-73-3 ]
[ 112108-73-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sulfuric acid; potassium nitrate; at -5 - 20℃;Product distribution / selectivity;	b) Synthesis of the aromatic nitro compounds;: 55 g (380 mmol) 2-chloro-4-fluoro toluene are dissolved in 500 ml cone. sulfuric acid and cooled to-5 to 0 C in an ice bath. To this solution, 50.6 g (500 mmol) KNO3 is added in portions within 1 h. The reaction mixture is allowed to warmed up to room temperature overnight and then poured onto ice. After customary workup, 60 g (81 %) 27 (Rt. = 2.73 min (method C) ) is obtained as a yellow oil which crystallises in the refrigerator.
81%	With sulfuric acid; potassium nitrate; at -5 - 20℃;	55 g (380 mmol) 2-Chloro-4-fluoro toluene are dissolved in 500 ml concentrated sulfuric acid and cooled to-5-0 C in an ice bath. To this solution, 50.6 g (500 mmol) potassium nitrate are added in several portions within 1 h. The reaction mixture is warmed up to room temperature overnight and then poured onto ice. The yellow suspension is extracted 3x with 11 tert. - Butyl-methylether each time and the combined organic phases are washed neutral with NaHCO3-solution. The organic phase is stirred with Na2SO4 and 10 g charcoal, filtered and the filtrate is evaporated to dryness. Yield : 60 g (81 %) 6, yellow oil, which crystallises in the refrigerator
81%	With sulfuric acid; potassium nitrate; at -5 - 20℃;	55 g (380 mmol) 2-Chloro-4-fluoro toluene in 500 ml conc. Sulfuric acid are cooled to-5-0 C gekuehlt and treated within one hour with 50.6 g (500 mmol) potassium nitrate in several portions. The reaction mixture is allowed to warm up to room temperature overnight and then poured onto ice. The yellow suspension is extracted 3x with 11 tert.-Butyl-methylether and the combined organic phases are washed neutral using NaHCO3-solution. The organic phase is stirred with Na2SO4 and 10 g charcoal, filtered and and the filtrate is evaporated. Yield : 60 g (81 %) 25, yellow oil, crystallises in the refrigerator 0.55 g (2.81 mmol) 25 in DMF are treated with 0.59 g (3.38 mmol) N-Boc-N- methylaminoethanol and 2.11 g (6.47 mmol) cesium carbonate and stirred overnight at 50 C. the reaction mixture is filtered and the filtrate is evaporated. The residue is taken up in ethylacetate, washed with water, dried using Na2SO4, filtered and evaporated. Yield : 0.94 g (97 %), brown oil The thus obtained nitro compound is hydrogenated in THF at room temperature using H2 and Raney-Ni. The catalyst is removed by filtration and the filtrate is evaporated to dryness. Yield : 0.83 g (96 %) 26, brown oil

51.2%	With sulfuric acid; potassium nitrate; at 0 - 20℃; for 22h;	2-Chloro-4-fluoro-1-methylbenzene (5.000 g, 34.585 mmol) and Potassium nitrate (4.371 g, 43.232 mmol) was added to a mixture of sulfuric acid (12.536 mL, 235.180 mmol) at 0 & The mixture was slowly added so that the internal temperature did not exceed 10 C, slowly raised to room temperature, and stirred for 22 hours.The reaction mixture was cooled in an ice bath and poured into 50 ml of water. After completion of the reaction, the mixture was extracted three times with 50 ml of ethyl acetate.The combined organic layers were washed with a saturated aqueous sodium chloride solution, and water was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure.The concentrate was purified by column chromatography (SiO2, 80 g cartridge; ethyl acetate / hexane = 0% to 5%) and concentrated to give 1-chloro-5-fluoro-2-methyl- , 51.2%) as a pale yellow liquid.
2.085 g (80%)	With KNO3; In conc. H2 SO4;	2-Chloro-4-fluoro-5-nitrotoluene. To a stirred solution of 2-chloro-4-fluorotoluene (2.000 g, 1.383 mmol, Aldrich, used as received) in conc. H2 SO4 (15.0 mL) at 0 C., KNO3 (1.400 g, 1.385 mmol) was added in one lot. The resulting pale yellow solution was allowed to warm to 28 C. and stirred overnight at 28 C. It was then poured into ice (100 g) and extracted with ethyl acetate (2*100 mL). Ethyl acetate was dried over anhydrous Na2 SO4, removed under vacuum, and the resulting oil was dried further under vacuum to afford 2.085 g (80%) of title compound as an oil, which was used as such for the next reaction; 1 H NMR (CDCl3): delta2.422 (s, 3H), 7.325 (d, 1H, J1 =10.2 Hz), 7.973 (d, 1H, J1 =5.2 Hz).
	With sulfuric acid; potassium nitrate; In 1,2-dichloro-ethane;	Step A Synthesis of 2-chloro-4-fluoro-5-nitrotoluene Concentrated sulfuric acid (250 ml) was added to a stirred solution of 2-chloro-4-fluorotoluene (50.0 g, 0.346 mole) in ethylene dichloride (250 ml) at 0 C. Potassium nitrate (35.0 g, 0.346 mole) was then added slowly, maintaining the temperature below 10 C. The reaction was monitored by gas chromatography. Upon the disappearance of 2-chloro-4-fluorotoluene, the reaction mixture was poured into ice and extracted with methylene chloride. The dried organic layer was concentrated under reduced pressure to yield 60.0 g of 2-chloro-4-fluoro-5-nitrotoluene. This reaction was repeated several times.
	With sulfuric acid; potassium nitrate; In 1,2-dichloro-ethane;	Step A Synthesis of 2-chloro-4-fluoro-5-nitrotoluene To a mixture of 20.0 g (0.138 mole) of 2-chloro-4fluorotoluene in 50 ml of 1,2-dichloroethane which had been cooled to 0 C. was added 50 ml of concentrated sulfuric acid. While maintaining the temperature below 10 C., 14.0 g (0.138 mole) of potassium nitrate was added slowly to the mixture. After three hours the reaction mixture was poured into ice, and the resulting mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was passed through a silica gel column, eluding with heptane. Appropriate fractions were combined, and the solvent was evaporated under reduced pressure, yielding 13.0 g of 2-chloro-4-fluoro-5-nitrotoluene as a yellow solid. The nmr spectrum was consistent with the proposed structure.
	With sulfuric acid; potassium nitrate; at 0 - 20℃; for 1h;	To a solution of 100 g (0.7 mol) of 2-chloro-4-fluorotoluene in 250 ml of concentrated H2SO4 is added portion-wise 85 g (0.875 mol) of KNO3 at 00C (addition of the whole amount of KNO3 is finished in about 1 hour). The reddish mixture is slowly warmed-up at room temperature overnight and quenched over crushed ice and extracted with EtOAc. The organic layers are combined, dried over MgSO4 and concentrated. The crude oil is then purified over a large silica plug (eluent: 97/3 hexanes/EtOAc) to afford 2-chloro-4-fluoro-5-nitrotoluene as a pale yellow oil that solidifies upon standing. 1H NMR (CDCl3, 400 Mz): 7.97 (d, J = 8.0 Hz, IH), 7.32 (d, J = 10.4 Hz, IH), 2.43 (s, 3H).
1.1 g	With sulfuric acid; potassium nitrate; at -5 - 20℃; for 16h;	Step 1: 1-chloro-5-fluoro-2-methyl-4-nitrobenzene 2-chloro-4-fluoro-1-methyl benzene (1.5g, 10.4mmol) and concentrated sulfuric acid (15mL) were added into a 50 mL reaction flask. The reaction mixture was cooled down to -5C?0C and then potassium nitrate (1.4g, 13.8mmol) was added in batches at this temperature. The reaction mixture was slowly increased up to room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted by using ethyl acetate, and washed with saturated aqueous sodium bicarbonate and saturated brine, dried and concentrated. The crude product thus obtained was separated and purified by column chromatography (silica gel column, eluent: ethyl acetate / petroleum ether = 1:50) to obtain the title compound (yellow solid, 1.1g, 56%). (MS: [M+1] none)
	With sulfuric acid; nitric acid;Cooling with ice;	135ml concentrated sulfuric acid into the reaction bottle, Stirring under ice bath cooling, 43.4 g of fuming nitric acid was added dropwise. After dripping continue to stir 30min, Form mixed acid. And 315 ml of concentrated sulfuric acid (3.5 V) and 90.0 g of 2-chloro-4-fluoro-toluene were charged in another three-necked flask. Ice salt bath cooling, The mixed acid of nitric acid and sulfuric acid is added to the sulfuric acid solution of 2-chloro-4-fluoro-toluene, Continue to react 1 ~ 2 hours. The reaction solution was slowly added to the crushed ice to stir, Ethyl acetate was extracted twice. Combined with ethyl acetate, Washed twice with water, Saturated brine once. Organic phase concentrated to dry, To give 2-chloro-4-fluoro-5-nitro-toluene as an oil.
	With sulfuric acid; nitric acid;Cooling with ice;	EXAMPLE 1 Preparation of 2-chloro-4-fluoro-5-nitrotoluene 135 ml of concentrated sulfuric acid was added into the reaction flask, and cooled in an ice bath under stirring, 43.4g fuming nitric acid was then added therein dropwise. After the completion of addition, the mixture was stirred continuously for 30 min to form a mixed acid. Meanwhile, 315 ml of concentrated sulfuric acid and 90.0 g of 2-chloro-4-fluorotoluene were added in another three-necked flask. The abovementioned mixed acid of nitric acid and sulfuric acid was added to the sulfuric acid solution of 2-chloro-4-fluorotoluene under cooling in an ice-salt bath, and the reaction was continued for 1 to 2 hours. The reaction solution was slowly added to the crushed ice under stirring to quench, and then extracted with ethyl acetate twice. The ethyl acetate layers was combined, and washed twice with water and once with saturated brine. The organic phase was concentrated to dryness to give oily 2-chloro-4-fluoro-5-nitrotoluene. H NMR Data 1H NMR(CDCl3, 400 MHz): delta 7.95(d, 3.8, 1H), 7.51(d, 4.2, 1H), 2.45(s, 3H).
	With sulfuric acid; potassium nitrate; at 20℃; for 1h;	Description 84. 1-Chloro-5-fluoro-2-methyl-4-nitrobenzene (D84); A solution of 2-chloro-4-fluorotoluene (4.Og) in concentrated sulfuric acid (30ml) was treated portionwise with potassium nitrate (2.8g) at <20C (internal). After 1 h more stirring with ice cooling the mixture was poured onto ice and extracted with diethyl ether. Drying and evaporation gave the title compound, 4.5g.

Reference： [1]Patent: WO2005/82853,2005,A1 .Location in patent: Page/Page column 210-211
[2]Patent: WO2005/75425,2005,A2 .Location in patent: Page/Page column 184-185
[3]Patent: WO2005/82862,2005,A2 .Location in patent: Page/Page column 136
[4]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 1514 - 1517
[5]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690
[6]Patent: KR2016/147358,2016,A .Location in patent: Paragraph 0226-0228
[7]Patent: WO2005/85220,2005,A1 .Location in patent: Page/Page column 71-72
[8]Journal of Organic Chemistry,1995,vol. 60,p. 5838 - 5842
[9]Patent: US5631373,1997,A
[10]Patent: US4846875,1989,A
[11]Patent: US4846882,1989,A
[12]Patent: WO2008/73687,2008,A2 .Location in patent: Page/Page column 30-31
[13]Patent: EP3150592,2017,A1 .Location in patent: Paragraph 0106; 0107; 0108
[14]Patent: CN104447515,2017,B .Location in patent: Paragraph 0023-0025
[15]Patent: US2018/86706,2018,A1 .Location in patent: Paragraph 0042-0045
[16]Patent: WO2007/107566,2007,A1 .Location in patent: Page/Page column 84

2
[ 6000-44-8 ]
[ 112108-73-3 ]
N-(5'-Chloro-4'-methyl-2'-nitrophenyl)glycine sodium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.005 g (37%)	In water; N,N-dimethyl-formamide;	N-(5'-Chloro-4'-methyl-2'-nitrophenyl)glycine sodium salt. To a stirred solution of <strong>[112108-73-3]2-chloro-4-fluoro-5-nitrotoluene</strong> (2.080 g, 10.97 mmol, as prepared above) in DMF (11.0 mL) at 70 C., was added dropwise, a solution of sodium glycinate (1.065 g, 10.97 mmol, Aldrich, used as received) in water (11.0 mL). The resulting suspension was stirred overnight at 70 C., cooled to room temperature, and the resulting red solid was filtered, washed with acetone (35 mL), and dried under vacuum to give 1.005 g (37%) of the pure (1 H NMR) title compound as a red powder; 1 H NMR (DMSO-d6): delta2.184 (s, 3H), 3.396 (d, 2H, J=4.2 Hz), 6.852 (s, 1H), 7.991 (s, 1H), 8.671 (s, 1H).

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 5838 - 5842
[2]Patent: US5631373,1997,A

3
[ 112108-73-3 ]
[ 170098-87-0 ]

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 5838 - 5842

4
[ 112108-73-3 ]
6-chloro-7-methyl-5-nitro-1,4-dihydroquinoxaline-2,3-dione [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 5838 - 5842

5
[ 2955-88-6 ]
[ 112108-73-3 ]
[ 862874-06-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 50℃;	5 mmol 2-Chloro-4-fluoro-5-nitrotoluene, 5-7.5 mmol substituted 2-amino ethanol (R (CH2) 20H) and 11.5-12. 5 mmol cesiumcarbonate are dissolved in DMF and stirred at room temperature or 50-80 C until a full conversion is achieved. Depending from from the reaction route chosen, the reaction mixture is worked up according the following variants: Variant A: the reaction mixture is filtered and the residue rinsed with ethyl acetate. The filtrate is diluted with ethyl acetate, washed 3x with water and 1 x with brine, dried over Na2SO4, filtered and evaporated. The residue is purified by column chromatography (silica gel, eluent : DCM/MeOH 0-5% in 45min). Variant B: the reaction mixture is filtered by suction and rinsed with little DMF. The filtrate is evaporated. The oily residue is taken up in 100 ml water and extracted 3x with acyl acetate. The combined organic phases are washed 2x with water and 1x with brine, dried over Na2SO4, and evaporated. The residue is purified by column chromatography (silica gel, eluent : DCM/MeOH 0-5% in 45min). Variant C: the reaction mixture is filtered by suction and rinsed with little DMF. The filtrate is evaporated. The oily residue is taken up in 100 ml water and extracted 3x with acyl acetate. The combined organic phases are washed 2x with water and 1x with brine, dried over Na2SO4, and evaporated. Substituents, reaction conditions and yields : 7c: R = (CH2) 2N (CH2) 4; 50 C, over night, working up procedure: C, 87 %, red-brown solid 7d: R = (CH2) 2N (CH3) 2 ; 50 C, overnight, working up procedure: C, 93 %, brown oil 7e: R = (CH2) 2N (C2H5) 2; 50 C, overnight, working up procedure: B, 72 %, yellow oil 7f: R = (CH2) 2N (CH2) 20 (CH2) 2 ; 50 C, overnight, working up procedure: B, 71 %, brown crystals 7g: R = (CH2) 2N (CH2) 2NBoc (CH2) 2; 50 OC, overnight, working up procedure: C, 90 %, brown oil

Reference： [1]Patent: WO2005/75425,2005,A2 .Location in patent: Page/Page column 187-188

6
[ 3891-07-4 ]
[ 112108-73-3 ]
[ 862874-00-8 ]

Yield	Reaction Conditions	Operation in experiment
24%	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 5.5h;	8 g (42.2 mmol) 2-chloro-4-fluoro-5-nitro toluene 31 are dissolved in DMF, treated with 8.07 g (42.2 mmol) N- (2-hydroxyethyl) phthalimide and 27.5 g (84.4 mmol) cesium carbonate and stirred for 5.5 h at 80 C. Then, the reaction mixture was cooled to room temperature. After customary workup, 3.65 g (24 %) of the substitution product is obtained as a pale yellow solid.
24%	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 50℃; for 5.5h;	8 g (42.2 mmol) 2-Chloro-4-fluoro-5-nitrotoluene are dissolved in DMF, treated with 8.07 g (42.2 mmol) N- (2-Hydroxyethyl) phthalimide and 27.5 g (84.4 mmol) cesium carbonate and stirred at 80 C for 5.5 h. The reaction mixture is cooled to room temperature, filtered by suction and washed with DMF. The filtrate is evaporated to dryness. The residue is taken up in ethyl acetate, washed 3x with water and 1x with brine, dried over Na2SO4, filtered and evaporated. The residue is digested with diethylether/MTB-ether (1: 1), filtered by suction, washed with ethyl acetate/MTB-ether (1: 1) and dried in vacuo. Yield : 3.65 g (24 %), pale yellow solid

Reference： [1]Patent: WO2005/82853,2005,A1 .Location in patent: Page/Page column 215
[2]Patent: WO2005/75425,2005,A2 .Location in patent: Page/Page column 185

7
[ 57561-39-4 ]
[ 112108-73-3 ]
[ 862874-04-2 ]

Yield	Reaction Conditions	Operation in experiment
97%	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 50℃;	0.55 g (2.81 mmol) 2-Chloro-4-fluoro-5-nitrotoluene are dissolved in DMF, treated with 0.59 g (3.38 mmol) N-Boc-N-methylaminoethanol and 2.11 g (6.47 mmol) cesium carbonate and stirred at 50 C overnight. The reaction mixture is filtered by suction and the filtrate is evaporated. The residue is taken up in ethyl acetate, washed several times with water, dried over Na2SO4, filtered and then evaporated to dryness. Yield : 0.94 g (97 %) 7b, brown oil
97%	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 50℃;	55 g (380 mmol) 2-Chloro-4-fluoro toluene in 500 ml conc. Sulfuric acid are cooled to-5-0 C gekuehlt and treated within one hour with 50.6 g (500 mmol) potassium nitrate in several portions. The reaction mixture is allowed to warm up to room temperature overnight and then poured onto ice. The yellow suspension is extracted 3x with 11 tert.-Butyl-methylether and the combined organic phases are washed neutral using NaHCO3-solution. The organic phase is stirred with Na2SO4 and 10 g charcoal, filtered and and the filtrate is evaporated. Yield : 60 g (81 %) 25, yellow oil, crystallises in the refrigerator 0.55 g (2.81 mmol) 25 in DMF are treated with 0.59 g (3.38 mmol) N-Boc-N- methylaminoethanol and 2.11 g (6.47 mmol) cesium carbonate and stirred overnight at 50 C. the reaction mixture is filtered and the filtrate is evaporated. The residue is taken up in ethylacetate, washed with water, dried using Na2SO4, filtered and evaporated. Yield : 0.94 g (97 %), brown oil The thus obtained nitro compound is hydrogenated in THF at room temperature using H2 and Raney-Ni. The catalyst is removed by filtration and the filtrate is evaporated to dryness. Yield : 0.83 g (96 %) 26, brown oil

Reference： [1]Patent: WO2005/75425,2005,A2 .Location in patent: Page/Page column 186-187
[2]Patent: WO2005/82862,2005,A2 .Location in patent: Page/Page column 136

8
[ 110-91-8 ]
[ 112108-73-3 ]
[ 864272-41-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	In tetrahydrofuran; at 50℃;	1.0 g (5.27 mmol) 27 are dissolved in 500 pi THF, treated with 469 pi (5.27 mmol) morpholine and stirred overnight at 50C. After customary workup, 1.2 g (78%) 35 (Rt. = 2.42 min (method E) ) is obtained as a brown oil.

Reference： [1]Patent: WO2005/82853,2005,A1 .Location in patent: Page/Page column 216

9
[ 1126-09-6 ]
[ 112108-73-3 ]
[ 864272-42-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 50℃; for 2.0h;	1.0 g (5.23 mmol) 27 are dissolved in 500 pi THF, treated with 913 pl (5.80 mmol) ethyl-4-piperidine carboxylate and 808 ul (4.75 mmol) N-ethyl-N, N- diisopropyl amine and stirred for 2 h at 50C. After customary workup, 1.7 g (88%) 36 (Rt. = 3.05 min (method E) ) is obtained as a brown oil.

Reference： [1]Patent: WO2005/82853,2005,A1 .Location in patent: Page/Page column 216-217

10
[ 123-90-0 ]
[ 112108-73-3 ]
[ 864272-43-5 ]

Yield	Reaction Conditions	Operation in experiment
87%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 50℃; for 2.0h;	1.0 g (5.27 mmol) 27 are dissolved in 500 pi THF, treated with 612 ul (5.81 mmol) thiomorpholine and 808 pi (4.75 mmol) N-ethyl-N, N-diisopropyl amine and stirred for 2 h at 50C. After customary workup, 1.4 g (87%) 37 (Rt. = 2.93 min (method E) ) is obtained as a brown oil.

Reference： [1]Patent: WO2005/82853,2005,A1 .Location in patent: Page/Page column 217

11
[ 109384-19-2 ]
[ 112108-73-3 ]
[ 862874-11-1 ]

Reference： [1]Patent: WO2005/85220,2005,A1 .Location in patent: Page/Page column 72-73

12
[ 108-01-0 ]
[ 112108-73-3 ]
[ 862874-07-5 ]

Reference： [1]Patent: WO2005/85220,2005,A1 .Location in patent: Page/Page column 71-72

13
[ 142-25-6 ]
[ 112108-73-3 ]
[ 864272-40-2 ]

Yield	Reaction Conditions	Operation in experiment
73%	In dimethyl sulfoxide; at 50℃; for 2.0h;	1.0 g (5.27 mmol) 27 are dissolved in 500 Xul DMSO, treated with 556 mg (5.27 mmol) N, N, N'-trimethylethylen diamine and stirred for 2 h at 50C. After customary workup, 1.3 g (73%) 34 (Rt. = 1.65 min (method C) ) is obtained as an orange resinous residue

Reference： [1]Patent: WO2005/82853,2005,A1 .Location in patent: Page/Page column 216

14
[ 112108-73-3 ]
[ 116759-33-2 ]

Yield	Reaction Conditions	Operation in experiment
93%	With hydrogenchloride; iron; In ethanol; water; at 80℃; for 1.5h;	To a solution of <strong>[112108-73-3]1-chloro-5-fluoro-2-methyl-4-nitrobenzene</strong> (5a) (23.0 g, 121 mmol) in EtOH/H2O (200 mL, 1:1) was added 12 M HCl (10.1 mL, 121 mmol). The mixture was heated to 80 C. and Fe (23.7 g, 425 mmol) was added slowly over a period of 30 minutes. The mixture was stirred at the same temperature for 1 h. LCMS analysis indicated the starting material was consumed and the desired product was formed. The mixture was cooled to 25 C., diluted with ethyl acetate (300 mL), and basified to pH=8?9 with saturated aqueous NaHCO3. The layers were filtered separated, and the aqueous layer was extracted with ethyl acetate (2*300 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 4-chloro-2-fluoro-5-methylaniline (5b) as a yellow solid (18.0 g, 93% yield). 1H NMR (400 MHz, DMSO-d6) delta 7.08 (d, J=11.1 Hz, 1H), 6.69 (d, J=9.6 Hz, 1H), 5.20 (s, 2H), 2.15 (s, 3H). LCMS (ESI) m/z 160, 162 (M+H).
93%	With hydrogenchloride; iron; In ethanol; water; at 80℃; for 1.5h;	To a solution of <strong>[112108-73-3]1-chloro-5-fluoro-2-methyl-4-nitrobenzene</strong> (54) (23.0 g, 121 mmol) in EtOH/H2O (200 mL, 1:1) was added 12 M HCl (10.1 mL, 121 mmol). The mixture was heated at 80 C. and Fe (23.7 g, 425 mmol) was added slowly over a period of 30 minutes. The mixture was stirred at the same temperature for 1 hour. LCMS indicated the starting material was consumed and the desired product was formed. Then, the mixture was cooled to 25 C., diluted with EtOAc (300 mL) and acidified to pH=8-9 with saturated aqueous NaHCO3. The layers were filtered, separated and the aqueous layer was extracted with EtOAc (2*300 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure and gave 4-chloro-2-fluoro-5-methylaniline (55) as a yellow solid (18.0 g, 93% yield). 1H NMR (400 MHz, DMSO-d6) delta 7.08 (d, J=11.1 Hz, 1H), 6.69 (d, J=9.6 Hz, 1H), 5.20 (s, 2H), 2.15 (s, 3H). LCMS (ESI) m/z 160, 162 (M+H).
32%	With hydrogenchloride; iron; In ethanol; for 3.0h;Reflux;	4-Chloro-2-fluoro-5-methylaniline To a suspension of <strong>[112108-73-3]1-chloro-5-fluoro-2-methyl-4-nitrobenzene</strong> (1 equiv) in EtOH (2 M) was added Fe (5 equiv.), followed by concentrated HCl(2 M). The reaction was refluxed for 3 h. The reaction was filtered through a pad of celite. The filtrate was concentrated. The resulting residue was purified by column chromatography to afford 4-chloro-2-fluoro-5-methylaniline (32%) as a purple solid. 1H NMR (400 MHz, CDCl3) delta ppm: 7.41 (d, J=7.03 Hz, 1H), 6.97-7.13 (m, 2H), 2.33 (s, 3H).

With hydrogen; In acetic acid;

Step B Synthesis of 4-chloro-2-fluoro-5-methylaniline A solution of <strong>[112108-73-3]2-chloro-4-fluoro-5-nitrotoluene</strong> (30.0 g, 0.158 mole) in glacial acetic acid (150 ml) was added to a 250 ml Parr bottle which contained platinum IV oxide (0.4 g). The Parr bottle was placed on a Parr hydrogenation apparatus and charged with hydrogen. The reaction mixture was allowed to shake until hydrogen absorption ceased. The catalyst was removed by vacuum filtration. The filtrate containing 4-chloro-2-fluoro-5-methylaniline was used in the following step. This reaction was repeated several times.

Reference： [1]Patent: US2019/248767,2019,A1 .Location in patent: Paragraph 0219; 0220
[2]Patent: US2019/233440,2019,A1 .Location in patent: Paragraph 0252; 0253
[3]Patent: US2016/96841,2016,A1 .Location in patent: Paragraph 0354
[4]Patent: US4846875,1989,A

15
1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinamine dihydrochloride [ No CAS ]
[ 112108-73-3 ]
N-(4-chloro-5-methyl-2-nitrophenyl)-1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 20.0h;	Description 99. lambda/-(4-Chloro-5-methyl-2-nitrophenyl)-1 -[frans-4-(ethyloxy)-1 - methylcyclohexylj^-piperidinamine (D99); A stirred solution of 1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinamine (D68 free base, 170mg, 0.71 mmole) in dimethylformamide (4ml) at room temperature under argon was treated with diisopropylethylamine (0.18ml, LOmmole) followed by 1-chloro-4-fluoro- 2-methyl-5-nitrobenzene (D84, 190mg, LOmmole) and heated at 8O0C for 20hrs. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with dichloromethane. The extract was dried, concentrated under vacuum and the residue chromatographed on silica gel (10g) eluting with 0-10% <n="94"/>methanol/dichloromethane to afford the title compound as an orange solid (210mg, 72%). MH+ 410.1H NMR D(CDCI3, 400 MHz): 0.94 (3H, s), 1.20 (3H, t), 1.40-1.70 (8H, m), 1.80-1.90 (2H, m), 2.07 (2H, br d), 2.28-2.40 (2H, m), 2.37 (3H, s), 2.90-3.00 (2H, m), 3.35-3.42 (1 H, m), 3.42-3.55 (3H, m), 6.71 (1 H, s), 8.06 (1 H, d), 8.16 (1 H, s).

Reference： [1]Patent: WO2007/107566,2007,A1 .Location in patent: Page/Page column 92-93

16
1-(trans-4-ethoxycyclohexyl)piperidin-4-amine [ No CAS ]
[ 112108-73-3 ]
trans-N-(5-chloro-4-methyl-2-nitrophenyl)-1-(4-ethoxycyclohexyl)-4-piperidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 50℃; for 18.0h;	Description 85. frans-lambda/-(5-Chloro-4-methyl-2-nitrophenyl)-1 -(4-ethoxycyclohexyl)-4- piperidinamine (D85); A stirred solution of <strong>[112108-73-3]1-chloro-5-fluoro-2-methyl-4-nitrobenzene</strong> (D84, 0.2Og) in dimethylformamide (5ml) at room temperature under argon was treated with diisopropylethylamine (0.7ml) and frans-1 -[4-(ethoxy)cyclohexyl]-4-piperidinamine dihydrochloride (D20, 0.3g) and heated at 5O0C for 18h. The cooled reaction was diluted with ethyl acetate and washed three times with water then dried, evaporated and the residue crystallised from diethyl ether to give the title compound (0.10g).

Reference： [1]Patent: WO2007/107566,2007,A1 .Location in patent: Page/Page column 84

17
[ 67-63-0 ]
[ 112108-73-3 ]
[ 1032903-50-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With caesium carbonate; at 60℃; for 16.0h;	2-Chloro-4-fluoro-5-nitrobenzene (25 g, 131 mmol) was dissolved in isopropanol (250 mL) and cesium carbonate(208 g, 659 mmol) was added thereto. The reaction mixture was stirred at 60 C for 16 hours. The reaction mixture was cooled to room temperature and the reaction mixture was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate (250 mL) and then water (250 mL) was added. The separated organic phase was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (petroleum ether: ethyl acetate = 19: 1) to deliver a yellow solid 13-d (28.7 g, yield:95%).1H-NMR (400MHz, DMSO-d6) delta: 7.90 (d, J=0.6Hz, 1H), 7.52 (s, 2H), 7. 86 (m, 1H), 2.30 (s, 3H), 1.27 (d, J=6Hz, 6H) ppm.
86.3%	With potassium hydroxide; at 20℃;	1.5 L of isopropanol, <strong>[112108-73-3]1-chloro-5-fluoro-2-methyl-4-nitrobenzene</strong> (260 g)Potassium hydroxide (116g) was added to complete the reaction at a temperature of 20 C to monitor the disappearance of the raw materials. The stirring was stopped and the reaction solution was added to 5L of water overThe product was filtered and the filter cake was dried to give 1-chloro-5-isopropyloxy-2-methyl-4-nitrobenzene, 271 g, yield: 86.3%.
82%	With caesium carbonate; at 60℃;	The title compound <strong>[112108-73-3]2-chloro-4-fluoro-5-nitrotoluene</strong> (i.e., compound 2-1, 14.2 g, 74.9 mmol) was dissolved in isopropanol (100.0 mL)Cesium carbonate (122.0 g, 374.4 mmol) was added,The reaction was carried out at 60 C overnight.After completion of the reaction, the mixture was concentrated to remove isopropanol,Poured into 500.0mL water, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, concentrated,Compound No. 2-2 (14.4 g) was obtained in a yield of 82.0%.

82%	With caesium carbonate; at 60℃;	The title compound <strong>[112108-73-3]2-chloro-4-fluoro-5-nitrotoluene</strong> (i.e., Compound 2-1, 14.2 g, 74.9 mmol) was dissolved in isopropanol (100.0 mL), cesium carbonate (122.0 g, 374.4 mmol) The reaction mixture was concentrated at 60 C overnight. After completion of the reaction, the mixture was concentrated to remove isopropanol, poured into 500.0 mL of water, extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to give Compound 2-2 (14.3 g), yield: 82.0%.
74.4%	With caesium carbonate; at 60℃; for 24.0h;	1-Chloro-5-fluoro-2-methyl-4-nitrobenzene (3.260 g, 17.197 mmol)Cesium carbonate (28.015 g, 85.984 mmol) was added to a solution ofPropanol (35 mL) at 60 C was stirred at the same temperature for 24 hours, and then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a paper filter to remove the solid. The solvent was removed from the filtrate under reduced pressure, water was poured into the resulting concentrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution,The water was removed with magnesium sulfate, filtered and concentrated under reduced pressure.The concentrate was purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 5%) and concentrated to obtain 2.938 g (74.4%) of 1-chloro-5-isopropoxy-2-methyl-4-nitrobenzene As a light brown solid.
	With caesium carbonate; at 60℃;	To a solution of 25 g (0.131 mol) of <strong>[112108-73-3]2-chloro-4-fluoro-5-nitrotoluene</strong> in 250 ml of 2- propanol is added 208 g (0.659 mol, 5 eq.) of Cs2CO3. The mixture is stirred at 6O0C overnight and most of the 2-propanol is evaporated under reduced pressure. Water is added and the solution is extracted with EtOAc. The organic layers are combined, dried over MgSO4, concentrated and the crude product filtrated over a silica plug (eluent: 95/5 hexanes/EtOAc) to afford 2-chloro-4-/,sopropoxy-5-nitrotoluene as a pale yellow fluffy solid.
	With potassium carbonate; for 40.0h;Reflux;	2-chloro-4-fluoro-5-nitro-toluene was dissolved in 1200 ml of isopropanol and 2 L of a three-necked flask was added. Add 429 g of anhydrous potassium carbonate powder. Stir under the temperature to reflux. The reaction was kept under reflux for ~ 40 hours. Concentrate to remove most of the isopropanol. Add 2L of water, And extracted twice with ethyl acetate. The ethyl acetate layer was combined, Washed. Concentrated ethyl acetate, To give a brown 2-chloro-4-isopropoxy _5_ nitro - toluene.
	With potassium carbonate; for 40.0h;Reflux;	EXAMPLE 2 Preparation of 2-chloro-4-isopropyoxy-5-nitrotoluene <strong>[112108-73-3]2-chloro-4-fluoro-5-nitrotoluene</strong> was dissolved in 1200 ml of isopropanol and the solution was added in a 2 L of a three-necked flask. 429 g of anhydrous potassium carbonate powder was added therein. The mixture was heated to reflux under stirring. The reaction was conducted for about 40 hours under reflux. Most of the isopropanol was removed via concentration. 2 L of water was added and the mixture was extracted with ethyl acetate twice. The ethyl acetate layer was combined and washed with water. Ethyl acetate layer was concentrated to give 2-chloro-4-isopropoxy-5-nitrotoluene as a brown substance. H NMR Data 1H NMR (CDCl3): delta7.71(s, 1H), 7.07(s, 1H), 4.61(m, 1H), 2.34(s, 3H), 1.40(d, 3.2, 6H).

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690
[2]Patent: EP3287463,2018,A1 .Location in patent: Paragraph 0164; 0165
[3]Patent: CN106674084,2017,A .Location in patent: Paragraph 0026; 0027; 0028
[4]Patent: CN106336398,2017,A .Location in patent: Paragraph 0108; 0127; 0128; 0129
[5]Patent: CN106478700,2017,A .Location in patent: Paragraph 0093; 0108; 0109; 0110
[6]Patent: KR2016/147358,2016,A .Location in patent: Paragraph 0230-0232
[7]Patent: WO2008/73687,2008,A2 .Location in patent: Page/Page column 31
[8]Patent: CN104447515,2017,B .Location in patent: Paragraph 0027-0029
[9]Patent: US2018/86706,2018,A1 .Location in patent: Paragraph 0046-0049

18
[ 112108-73-3 ]
C₃₄H₄₆ClN₅O₅S*(x)ClH [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

19
[ 112108-73-3 ]
[ 1032903-62-0 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690
[2]Patent: CN106336398,2017,A
[3]Patent: CN104447515,2017,B
[4]Patent: CN106478700,2017,A
[5]Patent: CN106674084,2017,A

20
[ 112108-73-3 ]
[ 1032903-63-1 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690
[2]Patent: KR2016/147358,2016,A
[3]Patent: CN106478700,2017,A
[4]Patent: EP3287463,2018,A1

21
[ 112108-73-3 ]
[ 1445894-90-5 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

22
[ 112108-73-3 ]
[ 1032903-66-4 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

23
[ 112108-73-3 ]
[ 1445894-93-8 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

24
[ 112108-73-3 ]
5-chloro-N<SUP>2</SUP>-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N<SUP>4</SUP>-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690
[2]Patent: KR2016/147358,2016,A

25
[ 112108-73-3 ]
[ 1445894-96-1 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

26
[ 112108-73-3 ]
[ 1445894-97-2 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

27
[ 112108-73-3 ]
[ 1032901-06-6 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

28
[ 112108-73-3 ]
[ 1445895-03-3 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

29
[ 112108-73-3 ]
[ 1445895-04-4 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

30
[ 112108-73-3 ]
2-[4-(4-{5-chloro-4-[2-(propane-2-sulfonyl)phenylamino]pyrimidin-2-ylamino}-5-isopropoxy-2-methylphenyl)piperidin-1-yl]ethanol hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

31
[ 112108-73-3 ]
5-chloro-N₂-(2-isopropoxy-4-(1-(2-methoxyethyl)piperidin-4-yl)-5-methylphenyl)-N₄-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

32
[ 112108-73-3 ]
5-chloro-N₂-(2-isopropoxy-5-methyl-4-(1-(1-methylpiperidin-4-yl)piperidin-4-yl)phenyl )-N₄-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

33
[ 112108-73-3 ]
[ 1445895-08-8 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

34
[ 112108-73-3 ]
2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)acetic acid hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

35
[ 112108-73-3 ]
2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)acetamide hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

36
[ 112108-73-3 ]
[ 1190399-47-3 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

37
[ 112108-73-3 ]
N₂-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N₄-(2-(isopropylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

38
[ 112108-73-3 ]
N₂-(2-isopropoxy-5-methyl-4-(1-ethylpiperidin-4-yl)phenyl)-N₄-(2-(isopropylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine trifluoroacetic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

39
[ 112108-73-3 ]
[ 1445895-25-9 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

40
[ 112108-73-3 ]
[ 1445895-27-1 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

41
[ 112108-73-3 ]
5-chloro-N₂-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N₄-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

42
[ 112108-73-3 ]
2-((5-chloro-2-((2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

43
[ 112108-73-3 ]
4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-2-one trifluoroacetic acid salt [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

44
[ 112108-73-3 ]
[ 1445894-99-4 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

45
[ 112108-73-3 ]
[ 1445895-01-1 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

46
[ 112108-73-3 ]
[ 1032903-65-3 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

47
[ 112108-73-3 ]
[ 1445894-91-6 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

48
[ 112108-73-3 ]
[ 1445894-92-7 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

49
[ 112108-73-3 ]
[ 1035230-24-0 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

50
[ 112108-73-3 ]
C₁₆H₂₄N₂O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

51
[ 112108-73-3 ]
[ 1032903-64-2 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690
[2]Patent: KR2016/147358,2016,A

52
[ 112108-73-3 ]
C₃₄H₄₇N₅O₅S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

53
[ 112108-73-3 ]
C₃₄H₄₄ClN₅O₅S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

54
[ 2919-23-5 ]
[ 112108-73-3 ]
[ 1445894-86-9 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5675 - 5690

55
[ 452-84-6 ]
[ 112108-73-3 ]

Yield	Reaction Conditions	Operation in experiment
61%	With sulfuric acid; potassium nitrate; at -5℃; for 1.0h;	1-Chloro-5-fluoro-2-methyl-4-nitrobenzene To a cooled (-5 C.) solution of 2-fluoro-5-methylaniline (1 equiv.) in concentrated H2SO4 (0.7 M) was added KNO3 (1.3 equiv.) in several portions within 1 h. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into ice-water slowly, and extracted with MTBE, washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The resulted residue was recrystallized from ethyl acetate and petroleum ether to afford 1-chloro-5-fluoro-2-methyl-4-nitrobenzene (61%) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta ppm: 8.00 (d, J=8.0 Hz, 1H), 7.35 (d, J=10.4 Hz, 1H), 2.45 (s, 3H).

Reference： [1]Patent: US2016/96841,2016,A1 .Location in patent: Paragraph 0353

56
[ 112108-73-3 ]
1-chloro-5-fluoro-4-isothiocyanato-2-methylbenzene [ No CAS ]

Reference： [1]Patent: US2016/96841,2016,A1

57
[ 112108-73-3 ]
(1s,4s)-4-(8-(4-chloro-2-fluoro-5-methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide [ No CAS ]

Reference： [1]Patent: US2016/96841,2016,A1

58
[ 112108-73-3 ]
[ 1032903-52-8 ]

Reference： [1]Patent: KR2016/147358,2016,A
[2]Patent: EP3287463,2018,A1

59
[ 112108-73-3 ]
[ 1032900-25-6 ]

Reference： [1]Patent: KR2016/147358,2016,A
[2]Patent: CN104447515,2017,B
[3]Patent: US2018/86706,2018,A1
[4]Patent: US2018/86706,2018,A1

60
[ 112108-73-3 ]
N<SUP>2</SUP>-(4-((2'S,6'R)-1'-benzyl-2',6'-dimethyl-1,4'-bipiperidin-4-yl)-2-isopropoxy-5-methylphenyl)-5-chloro-N<SUP>4</SUP>-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine [ No CAS ]

Reference： [1]Patent: KR2016/147358,2016,A

61
[ 112108-73-3 ]
N<SUP>2</SUP>-(4-((2'RS,6'RS)-1'-benzyl-2',6'-dimethyl-1,4'-bipiperidin-4-yl)-2-isopropoxy-5-methylphenyl)-5-chloro-N<SUP>4</SUP>-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine [ No CAS ]

Reference： [1]Patent: KR2016/147358,2016,A

62
[ 112108-73-3 ]
[ 1032903-51-7 ]

Reference： [1]Patent: KR2016/147358,2016,A

63
[ 112108-73-3 ]
(2R,6S)-tert-butyl 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-2,6-dimethyl-5,6-dihydropyridin-1(2H)-carboxylate [ No CAS ]

Reference： [1]Patent: KR2016/147358,2016,A

64
[ 112108-73-3 ]
(2R,6R)-tert-butyl 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-2,6-dimethyl-5,6-dihydropyridin-1(2H)-carboxylate [ No CAS ]

Reference： [1]Patent: KR2016/147358,2016,A

65
[ 112108-73-3 ]
(2S,6R)-tert-butyl 4-(4-amino-5-isopropoxy-2-methylphenyl)-2,6-dimethylpiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: KR2016/147358,2016,A

66
[ 112108-73-3 ]
(2R,6R)-tert-butyl 4-(4-amino-5-isopropoxy-2-methylphenyl)-2,6-dimethylpiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: KR2016/147358,2016,A

67
[ 112108-73-3 ]
(2S,6R)-tert-butyl 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)-2,6-dimethylpiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: KR2016/147358,2016,A

68
[ 112108-73-3 ]
(2R,6R)-tert-butyl 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)-2,6-dimethylpiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: KR2016/147358,2016,A

69
[ 112108-73-3 ]
5-chloro-N<SUP>2</SUP>-(4-((2S,6R)-2,6-dimethylpiperidin-4-yl)-2-isopropoxy-5-methylphenyl)-N<SUP>4</SUP>-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine [ No CAS ]

Reference： [1]Patent: KR2016/147358,2016,A

70
[ 112108-73-3 ]
5-chloro-N<SUP>2</SUP>-(4-((2R,6R)-2,6-dimethylpiperidin-4-yl)-2-isopropoxy-5-methylphenyl)-N<SUP>4</SUP>-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine [ No CAS ]

Reference： [1]Patent: KR2016/147358,2016,A

71
[ 112108-73-3 ]
5-chloro-N<SUP>2</SUP>-(2-isopropoxy-5-methyl-4-((2S,6R)-1,2,6-trimethylpiperidin-4-yl)phenyl)-N<SUP>4</SUP>-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine [ No CAS ]

Reference： [1]Patent: KR2016/147358,2016,A

72
[ 112108-73-3 ]
5-chloro-N<SUP>2</SUP>-(2-isopropoxy-5-methyl-4-((2R,6R)-1,2,6-trimethylpiperidin-4-yl)phenyl)-N<SUP>4</SUP>-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine [ No CAS ]

Reference： [1]Patent: KR2016/147358,2016,A

73
[ 112108-73-3 ]
1-((2S,6R)-4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)-2,6-dimethylpiperidin-1-yl)-2-methylpropan-2-ol [ No CAS ]

Reference： [1]Patent: KR2016/147358,2016,A

74
[ 112108-73-3 ]
5-chloro-N<SUB>2</SUB>-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N<SUB>4</SUB>-(2-(propane-2-sulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride [ No CAS ]

Reference： [1]Patent: CN104447515,2017,B
[2]Patent: US2018/86706,2018,A1
[3]Patent: US2018/86706,2018,A1

75
[ 112108-73-3 ]
4-(5-(propan-2-yloxy)-2-methyl-4-nitro-phenyl)-1-benzyl-pyridinium bromide [ No CAS ]

Reference： [1]Patent: CN104447515,2017,B
[2]Patent: US2018/86706,2018,A1

76
[ 112108-73-3 ]
2-isopropoxy-5-methyl-4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-phenylamine [ No CAS ]

Reference： [1]Patent: CN104447515,2017,B
[2]Patent: US2018/86706,2018,A1

77
[ 112108-73-3 ]
2-isopropoxy-5-methyl-4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenylamine dihydrochloride salt [ No CAS ]

Reference： [1]Patent: CN104447515,2017,B
[2]Patent: US2018/86706,2018,A1

78
[ 112108-73-3 ]
5-chloro-N²-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl]-N⁴-[2-(isopropylsulfonyl)phenyl]pyrimidine-2,4-diamine dihydrochloride [ No CAS ]

Reference： [1]Patent: CN104447515,2017,B
[2]Patent: CN106674084,2017,A
[3]Patent: US2018/86706,2018,A1
[4]Patent: US2018/86706,2018,A1

79
[ 112108-73-3 ]
C₃₁H₃₉BClN₅O₅ [ No CAS ]

Reference： [1]Patent: CN106478700,2017,A

80
[ 112108-73-3 ]
7-((5-chloro-2-((2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)benzo[c][1,2]oxaborol-1(3H)-ol [ No CAS ]

Reference： [1]Patent: CN106478700,2017,A

81
[ 112108-73-3 ]
1-benzyl-4-(5-isopropyloxy-2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine [ No CAS ]

Reference： [1]Patent: CN106674084,2017,A

82
[ 112108-73-3 ]
7-(2,3-dihydro-1-benzofuran-7-yl)-N-[5-methyl-4-(piperidin-4-yl)-2-isopropoxyphenyl]-6-methylthieno[3,2-d]pyrimidin-2-amine [ No CAS ]

Reference： [1]Patent: EP3287463,2018,A1

83
[ 112108-73-3 ]
C₃₄H₄₂N₄O₃S [ No CAS ]

Reference： [1]Patent: EP3287463,2018,A1

84
[ 112108-73-3 ]
C₃₅H₄₂N₄O₄S [ No CAS ]

Reference： [1]Patent: EP3287463,2018,A1

85
[ 112108-73-3 ]
7-(2-methylphenyl)-N-[5-methyl-4-(piperidin-4-yl)-2-isopropoxyphenyl]-6-methylthieno[3,2-d]pyrimidin-2-amine [ No CAS ]

Reference： [1]Patent: EP3287463,2018,A1

86
[ 112108-73-3 ]
5-chloro-1-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1,3-dihydro-2H-benzimidazol-2-one [ No CAS ]

Reference： [1]Patent: WO2007/107566,2007,A1

87
[ 112108-73-3 ]
6-chloro-5-methyl-1-[1-(trans-4-ethoxycyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2007/107566,2007,A1

88
[ 112108-73-3 ]
5-chloro-1-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2007/107566,2007,A1

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere