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[ CAS No. 13726-14-2 ] {[proInfo.proName]}

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DV 2D 3D

3d Animation Molecule Structure of 13726-14-2

Chemical Structure| 13726-14-2

Chemical Structure| 13726-14-2

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Quality Control of [ 13726-14-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 13726-14-2 ]

SDS Specification

Alternatived Products of [ 13726-14-2 ]

Product Details of [ 13726-14-2 ]

CAS No. :	13726-14-2	MDL No. :	MFCD00672967
Formula :	C₇H₈ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LNKBDFVSILQKSI-UHFFFAOYSA-N
M.W :	157.60	Pubchem ID :	13103692
Synonyms :

Calculated chemistry of [ 13726-14-2 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	42.35
TPSA :	35.25 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) :	-5.95 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.68
Log Po/w (XLOGP3) :	1.85
Log Po/w (WLOGP) :	1.94
Log Po/w (MLOGP) :	1.75
Log Po/w (SILICOS-IT) :	1.75
Consensus Log Po/w :	1.79

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.36
Solubility :	0.687 mg/ml ; 0.00436 mol/l
Class :	Soluble
Log S (Ali) :	-2.21
Solubility :	0.969 mg/ml ; 0.00615 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.77
Solubility :	0.268 mg/ml ; 0.0017 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.36

Safety of [ 13726-14-2 ]

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 [ 13726-14-2 ]

* 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 [ 13726-14-2 ]
Downstream synthetic route of [ 13726-14-2 ]

[ 13726-14-2 ] Synthesis Path-Upstream 1~13

1
[ 16817-43-9 ]
[ 13726-14-2 ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: With magnesium; ethylene dibromide In tetrahydrofuranInert atmosphere Stage #2: With C₁₀H₁₇NO In tetrahydrofuran; toluene at -78℃; for 3 h; Inert atmosphere	General procedure: To a flame-dried 25 mL round bottom flask was charged activated Mg (7.5 mmol, 1.5 eq.) and 5 mL anhydrous THF. To this suspension was added 2 drops of 1,2-dibromoethane. After 5 min, a solution of Aryl bromide (5 mmol, 1.0 eq.) in 5 mL anhydrous THF was slowly added to the suspension of Mg at room temperature. The reaction was mildly exothermic. The Grignard reagent was titrated and 1 mmol of this reagent was added to a flame-dried reaction vial. The solution was diluted with 3 mL anhydrous toluene and after cooling to the target temperature T, a solution of oxaziridine (1.2 mmol, 1.2 eq.) in 1 mL anhydrous toluene was added. The reaction was maintained at the targeted temperature T for time t before being quenched with saturated aqueous NH₄Cl. (The actual temperature/reaction time is listed for each substrate.)

Reference： [1] Nature Chemistry, 2017, vol. 9, # 7, p. 681 - 688
[2] Patent: US2018/57444, 2018, A1, . Location in patent: Paragraph 0098; 0134; 0135; 0184

2
[ 1009-36-5 ]
[ 13726-14-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	at 20℃; Inert atmosphere	Iron based nanomaterial (12 mg, 3.6percent) was placed into an oven dried 5 mL microwave reaction vial containing a PTFE-coated magnetic stir bar. The reaction vial was covered with a rubber septum and 0.5 mL aqueous solution of 2 wt.percent TPGS-750-M was added via syringe. The mixture was stirred at ft for 1 mm. The septum was opened and NaBH4 (57 mg, 1.5 mmol) was slowly added to the mixture. During addition NaB H4, reaction mixture was turned black with evolution of hydrogen gas. 1-Chloro-2-methoxy-4- nitrobenzene (187 mg, 1 mmol) was then added and the vial was filled argon and again covered. The contents were stirred vigorously until complete consumption of the starting material (about 4 h). The resulting mixture was extracted with EtOAc (0.4 mL x 2). The organic layer was then separated (with the aid of centrifuge, if needed) and dried over anhydrous Na2504, and the volatiles were removed under reduced pressure and purified by flash chromatography over silica gel with EtOAc/hexanes to obtain 4-chloro-3- methoxyaniline 54 (151 mg, 0.96 mmol, 96percent). Brown solid, mp 79-80 °C; ‘H NMR (400 MHz, DMSO) 6.98 (d, J= 8.4, 1H), 6.34 (d, J= 1.8, 1H), 6.16 (dd, J= 8.4, 1.9, 1H), 5.23 (s, 2H), 3.74 (s, 3H). GC-MS, mlz: 157 [Mj.
93%	at 20℃; for 2 h;	First, NaBH4 (1 mmol) was used as a reducing agent forthe conversion of Ag (+ 1) to Ag (0) in methanol at roomtemperature for 2 h. After that, the Ag/MMT was filtered andused as a catalyst. Then, in a typical procedure, a mixtureof 4-nitrophenol (0.1 mmol), KOH (0.15 mmol), isopropylalcohol (3 mL), and Ag/MMT catalyst (50 mg) 1.01 wtpercentwas stirred at room temperature for an appropriate time(Scheme 2). After the completion of the reaction (monitoredby GC), the catalyst was separated by filtration. The ensuingproduct was extracted with ethyl acetate and repeatedlywashed with water (3–4 times) to remove KOH. The resultingsolvent was evaporated to dryness in vacuum.
82%	With iron; ammonium chloride In tetrahydrofuran; methanol; water at 80℃;	4-Chloro-3-methoxy-phenylamine Ammonium chloride (14.3 g, 267 mmol) and iron powder (325 mesh, 14.9 g, 267 mmol) were dissolved in water (100 ml_). A solution of 2-chloro-5-nitroanisole (10 g, 53.3 mmol) in tetrahydrofuran (50 ml_) and methanol (50 ml_) was added. The mixture was stirred at 80⁰C overnight. The reaction mixture was cooled to room temperature and filtrated. The filtrate was extracted with ethyl acetate. The organic phases were washed with brine, dried over sodium sulphate filtrated and concentrated in vacuo to give 4-chloro-3- methoxy-phenylamine 6.9 g (82percent) as a grey solid.

82%	With iron; ammonium chloride In tetrahydrofuran; methanol; water at 80℃;	4-Chloro-3-methoxy-phenylamineAmmonium chloride (14.3 g, 267 mmol) and iron powder (325 mesh, 14.9 g, 267 mmol) were dissolved in water (100 ml_). A solution of 2-chloro-5-nitroanisole (10 g, 53.3 mmol) in tetrahydrofuran (50 ml_) and methanol (50 ml_) was added. The mixture was stirred at 80 ⁰C overnight. The reaction mixture was cooled to room temperature and filtrated. The filtrate was extracted with ethyl acetate. The organic phases were washed with brine, dried over sodium sulphate filtrated and concentrated in vacuo to give 4-chloro-3- methoxy-phenylamine 6.9 g (82percent) as a grey solid.
79.36%	Stage #1: With hydrogenchloride; tin(ll) chloride In methanol; water at 40 - 50℃; for 2 h; Stage #2: With sodium hydroxide In methanol; water at 20℃;	5-NITRO-2-CHLORO aniline (50.0 g, 0.289 mol) in 30 percent sulfuric acid (300 ml) was stirred at RT FOR 2 h. Sodium nitrite (21.0 g, 0.304 mol) in water (50 ml) was added slowly at 0°C and maintained at this temperature for 15 min. This diazotized solution was added slowly to dilute sulfuric acid (50 percent, 250 ML) at 110 °C. Stirring was continued for 15 min. After cooling to RT, ice water was added, the mixture extracted with ethylacetate, washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield 12.0 g, 24. 0 percent. [00162] To K2CO3 (23.84 g, 0.172 mol) and 2-chloro-5-nitrophenol (10.0 g, 0.0576 mol) in ACETONITRILE (100 ml) was added methyl iodide (19.60 g, 0.138 mol) at 0°C. The reaction mixture was warmed to RT and stirred overnight. Water was added and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield : 6.0 g, 55. 55 percent. [00163] 2-CHLORO-5-NITRO ANISOLE (6.0 g, 0.032 mol) in MEOH (45 ml) was added slowly to stannous chloride (15.1 g, 0.08 mol) in conc. HCI (110 ml) at 40 °C and the temperature was slowly raised to 50 ° C. Stirring was continued for 2h, the reaction cooled to RT, basified with 50 percent NAOH solution and extracted by ethyl acetate. The organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield : 4.0 g, 79.36 percent. [00164] To triethylamine (3.83 g, 0.037 mol) and 3-methoxy-4- chloro aniline (3.0 g, 0.0190 mol) in benzene (50 ML) was added trimethylacetylchloride (2.75 g, 0.022 mol) slowly at 0 °C. The temperature was raised to RT and stirred overnight. The reaction mixture was added to ice and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over NA2SO4 and concentrated. Yield : 3.7 g, 80.43 percent. [00165] To N-PIVALOYL-3-METHOXY-4-CHLOROANILINE (1.50 g, 0.0062 mol) in THF (30 ML) was added n-butyl lithium (1.0 g, 0.0156 mol) at 0 °C and the reaction stirred for 2 hr. After cooling to-70 °C, methyl isonicotinate (1.3 g, 0.0094 mol) in THF (12 ml) was added slowly. The reaction was warmed to rt and stirred overnight and then quenched with water and extracted with ether. The water layer was further extracted and the combined ether layers were washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield 0.50 g, 23. 25 percent. [00166] The protected ketone from step 5 (0.500g, 0. 0014MOL) was suspended in concentrated HCI (5 ml) at RT, then the temperature was raised to 95 °C and the mixture stirred over night. The mixture was cooled to RT, basified with 20 percent NAOH solution and extracted with DCM. The combined organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography using basic alumina to yield title compound (0.140 g, 37.33percent).
76.36%	Stage #1: With hydrogenchloride; tin(ll) chloride In methanol at 40 - 50℃; for 2 h; Stage #2: With sodium hydroxide In methanol; water at 20℃;	5-Nitro-2-chloro aniline (50.0 g, 0.289 mol) in 30 percent sulfuric acid (300 ml) was stirred at RT for 2 h. Sodium nitrite (21.0 g, 0.304 mol) in water (50 ml) was added slowly at 0°C. After 15 mins, this solution was added slowly to dilute sulfuric acid (50 percent, 250 ml) at 110 °C. Stirring was continued for 15 min. The reaction mixture was cooled to RT, ice water was added, extracted with ethylacetate, washed with water, brine and dried over NA2SO4. The phenol product obtained upon concentration was purified by column chromatography. Yield 12.0 g, 24.0 percent. [00153] K2CO3 (23.84 g, 0.172 mol) was added to 2-chloro-5- nitrophenol (10.0 g, 0.058 mol) in acetonitrile (100 ml) at RT. After cooling to 0 °C, methyl iodide (19.6 g, 0.138 mol) was added slowly and the reaction mixture stirred at RT overnight. Water (100 ml) was added and the aqueous layer extracted with ethyl acetate. The organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography to yield the ANISOLE (6.0 g, 55.55percent). [00154] 2-CHLORO-5-NITRO ANISOLE (6.0 g, 0.032 mol) in MEOH (45 ml) was added slowly to stannous chloride (15.1 g, 0.08 mol) in conc. HCI (110 ml) at 40 °C and the temperature was slowly raised to 50 ° C. Stirring was continued for 2 h. After cooling to RT, the reaction mixture was basified with 50 percent NAOH solution, extracted by ethyl acetate, washed with water, then brine and dried over NA2SO4. 3-METHOXY-4-CHLOROANILINE was obtained upon concentration and was purified further by column chromatography. Yield : 4.0 g, 79.36 percent. [00155] To 3-METHOXY-4-CHLOROANILINE (2.0 g, 0.0126 mol) in trichloroethylene (30 ml) was added BC13 (2.18 g, 1 M solution in DCM, 0.0188 mol) AT 0 °C. After stirring for 10 min, 4-CYANOPYRIDINE (1.6 g, 0.0153 mol) and AIC13 (2.35 g, 0.018 mol) were added and the temperature was raised to RT, with further stirring for 30 min. The temperature was raised further to 85 °C and maintained at the same temperature for 1 h. DCM was distilled off and the solution was stirred at 115 °C for 4 h and then at RT over night. 3N HCI was added at RT and the reaction mixture REFLUXED for 1.5 h. The reaction mixture was allowed to cool and made basic using NAOH (6 N), diluted with water and extracted with DCM, washed with water, brine and dried over NA2SO4. The crude title compound was obtained upon concentration and was purified by column chromatography. Yield : 0.50 g, 15 percent.
53%	With palladium 10% on activated carbon; hydrogen In ethyl acetate for 16 h;	Pd(C) (10percent, 142mg, 0.13mmol, 0.1 eq. Pd) was added to a solution of 1-chloro-2-methoxy-4-nitrobenzene (250mg, 1.33mmol, 1.0 eq.) in 10ml of EtOAc. The vessel was evacuated, backfilled with H₂, fitted with a H₂ balloon, and stirred for 16h. The suspension was filtered through a pad of Celite and concentrated. NMR indicated 5–10percent of the dehalogenated product; therefore, the crude product mixture was recrystallized from heptane with a minimal amount of CH₂Cl₂ to give the title compound as white crystals (111mg, 0.70mmol, 53percent yield). The ¹H spectrum was in accord with literature data [39].

Reference： [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8413 - 8426
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 31, p. 8979 - 8983[3] Angew. Chem., 2016, vol. 128, # 31, p. 9125 - 9129,5
[4] Patent: WO2017/106426, 2017, A1, . Location in patent: Paragraph 0079; 0080; 0081
[5] Journal of the Iranian Chemical Society, 2018, vol. 15, # 2, p. 281 - 291
[6] Patent: WO2009/77584, 2009, A1, . Location in patent: Page/Page column 14
[7] Patent: WO2009/77585, 2009, A1, . Location in patent: Page/Page column 14
[8] Patent: WO2004/46092, 2004, A2, . Location in patent: Page 53-55
[9] Patent: WO2004/46092, 2004, A2, . Location in patent: Page 50-51
[10] European Journal of Medicinal Chemistry, 2017, vol. 134, p. 415 - 427
[11] Chemische Berichte, 1899, vol. 32, p. 2623[12] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1899, p. 1625
[13] Bulletin of the Chemical Society of Japan, 1969, vol. 42, p. 3016 - 3017
[14] Bulletin de la Societe Chimique de France, 1966, p. 3311 - 3318
[15] Chimica Therapeutica, 1969, vol. 4, p. 334 - 343
[16] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 2, p. 211 - 214
[17] Environmental Toxicology and Chemistry, 2001, vol. 20, # 7, p. 1381 - 1389
[18] Patent: US2004/180878, 2004, A1, . Location in patent: Page/Page column 26

3
[ 1984-58-3 ]
[ 13726-14-2 ]

Reference： [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 19, p. 7076 - 7094
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8321 - 8327
[3] Journal of the American Chemical Society, 1953, vol. 75, p. 3196
[4] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4399 - 4426
[5] Patent: US2013/123258, 2013, A1, . Location in patent: Paragraph 0152; 0153; 0154

4
[ 1009-36-5 ]
[ 7439-89-6 ]
[ 13726-14-2 ]

Reference： [1] Patent: US4853410, 1989, A,
[2] Patent: EP230379, 1991, B1,

5
[ 97-52-9 ]
[ 13726-14-2 ]

Reference： [1] Environmental Toxicology and Chemistry, 2001, vol. 20, # 7, p. 1381 - 1389
[2] Chemische Berichte, 1899, vol. 32, p. 2623[3] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1899, p. 1625
[4] Bulletin of the Chemical Society of Japan, 1969, vol. 42, p. 3016 - 3017
[5] Bulletin de la Societe Chimique de France, 1966, p. 3311 - 3318

6
[ 1236162-19-8 ]
[ 13726-14-2 ]

Reference： [1] Tetrahedron Letters, 2010, vol. 51, # 30, p. 3876 - 3878

7
[ 1984-58-3 ]
[ 7664-41-7 ]
[ 13726-14-2 ]

Reference： [1] Journal of the American Chemical Society, 1953, vol. 75, p. 3196

8
[ 13726-14-2 ]
[ 16817-43-9 ]

Reference： [1] Journal of medicinal chemistry, 1967, vol. 10, # 6, p. 1008 - 1014

9
[ 75-17-2 ]
[ 13726-14-2 ]
[ 13726-16-4 ]

Reference： [1] Bulletin de la Societe Chimique de France, 1966, p. 3311 - 3318

10
[ 13726-14-2 ]
[ 13726-17-5 ]

Reference： [1] Bulletin de la Societe Chimique de France, 1966, p. 3311 - 3318

11
[ 13726-14-2 ]
[ 6358-06-1 ]

Reference： [1] Patent: US3948596, 1976, A,

12
[ 13726-14-2 ]
[ 13726-21-1 ]

Reference： [1] Bulletin de la Societe Chimique de France, 1966, p. 3311 - 3318

13
[ 13726-14-2 ]
[ 161949-50-4 ]

Reference： [1] Chemical Communications, 2006, # 4, p. 423 - 425

[ 13726-14-2 ] Synthesis Path-Downstream 1~74

1
[ 1009-36-5 ]
[ 13726-14-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium tetrahydroborate; water; at 20℃;Inert atmosphere;	Iron based nanomaterial (12 mg, 3.6%) was placed into an oven dried 5 mL microwave reaction vial containing a PTFE-coated magnetic stir bar. The reaction vial was covered with a rubber septum and 0.5 mL aqueous solution of 2 wt.% TPGS-750-M was added via syringe. The mixture was stirred at ft for 1 mm. The septum was opened and NaBH4 (57 mg, 1.5 mmol) was slowly added to the mixture. During addition NaB H4, reaction mixture was turned black with evolution of hydrogen gas. 1-Chloro-2-methoxy-4- nitrobenzene (187 mg, 1 mmol) was then added and the vial was filled argon and again covered. The contents were stirred vigorously until complete consumption of the starting material (about 4 h). The resulting mixture was extracted with EtOAc (0.4 mL x 2). The organic layer was then separated (with the aid of centrifuge, if needed) and dried over anhydrous Na2504, and the volatiles were removed under reduced pressure and purified by flash chromatography over silica gel with EtOAc/hexanes to obtain 4-chloro-3- methoxyaniline 54 (151 mg, 0.96 mmol, 96%). Brown solid, mp 79-80 C; ?H NMR (400 MHz, DMSO) 6.98 (d, J= 8.4, 1H), 6.34 (d, J= 1.8, 1H), 6.16 (dd, J= 8.4, 1.9, 1H), 5.23 (s, 2H), 3.74 (s, 3H). GC-MS, mlz: 157 [Mj.
93%	With isopropyl alcohol; potassium hydroxide; at 20℃; for 2h;Catalytic behavior;	First, NaBH4 (1 mmol) was used as a reducing agent forthe conversion of Ag (+ 1) to Ag (0) in methanol at roomtemperature for 2 h. After that, the Ag/MMT was filtered andused as a catalyst. Then, in a typical procedure, a mixtureof 4-nitrophenol (0.1 mmol), KOH (0.15 mmol), isopropylalcohol (3 mL), and Ag/MMT catalyst (50 mg) 1.01 wt%was stirred at room temperature for an appropriate time(Scheme 2). After the completion of the reaction (monitoredby GC), the catalyst was separated by filtration. The ensuingproduct was extracted with ethyl acetate and repeatedlywashed with water (3-4 times) to remove KOH. The resultingsolvent was evaporated to dryness in vacuum.
82%	With iron; ammonium chloride; In tetrahydrofuran; methanol; water; at 80℃;	4-Chloro-3-methoxy-phenylamine Ammonium chloride (14.3 g, 267 mmol) and iron powder (325 mesh, 14.9 g, 267 mmol) were dissolved in water (100 ml_). A solution of <strong>[1009-36-5]<strong>[1009-36-5]2-chloro-5-nitroanisol</strong>e</strong> (10 g, 53.3 mmol) in tetrahydrofuran (50 ml_) and methanol (50 ml_) was added. The mixture was stirred at 800C overnight. The reaction mixture was cooled to room temperature and filtrated. The filtrate was extracted with ethyl acetate. The organic phases were washed with brine, dried over sodium sulphate filtrated and concentrated in vacuo to give 4-chloro-3- methoxy-phenylamine 6.9 g (82%) as a grey solid.

82%	With iron; ammonium chloride; In tetrahydrofuran; methanol; water; at 80℃;	4-Chloro-3-methoxy-phenylamineAmmonium chloride (14.3 g, 267 mmol) and iron powder (325 mesh, 14.9 g, 267 mmol) were dissolved in water (100 ml_). A solution of <strong>[1009-36-5]<strong>[1009-36-5]2-chloro-5-nitroanisol</strong>e</strong> (10 g, 53.3 mmol) in tetrahydrofuran (50 ml_) and methanol (50 ml_) was added. The mixture was stirred at 80 0C overnight. The reaction mixture was cooled to room temperature and filtrated. The filtrate was extracted with ethyl acetate. The organic phases were washed with brine, dried over sodium sulphate filtrated and concentrated in vacuo to give 4-chloro-3- methoxy-phenylamine 6.9 g (82%) as a grey solid.
79.36%		5-NITRO-2-CHLORO aniline (50.0 g, 0.289 mol) in 30 % sulfuric acid (300 ml) was stirred at RT FOR 2 h. Sodium nitrite (21.0 g, 0.304 mol) in water (50 ml) was added slowly at 0C and maintained at this temperature for 15 min. This diazotized solution was added slowly to dilute sulfuric acid (50 %, 250 ML) at 110 C. Stirring was continued for 15 min. After cooling to RT, ice water was added, the mixture extracted with ethylacetate, washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield 12.0 g, 24. 0 %. [00162] To K2CO3 (23.84 g, 0.172 mol) and 2-chloro-5-nitrophenol (10.0 g, 0.0576 mol) in ACETONITRILE (100 ml) was added methyl iodide (19.60 g, 0.138 mol) at 0C. The reaction mixture was warmed to RT and stirred overnight. Water was added and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield : 6.0 g, 55. 55 %. [00163] 2-CHLORO-5-NITRO ANISOLE (6.0 g, 0.032 mol) in MEOH (45 ml) was added slowly to stannous chloride (15.1 g, 0.08 mol) in conc. HCI (110 ml) at 40 C and the temperature was slowly raised to 50 C. Stirring was continued for 2h, the reaction cooled to RT, basified with 50 % NAOH solution and extracted by ethyl acetate. The organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield : 4.0 g, 79.36 %. [00164] To triethylamine (3.83 g, 0.037 mol) and 3-methoxy-4- chloro aniline (3.0 g, 0.0190 mol) in benzene (50 ML) was added trimethylacetylchloride (2.75 g, 0.022 mol) slowly at 0 C. The temperature was raised to RT and stirred overnight. The reaction mixture was added to ice and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over NA2SO4 and concentrated. Yield : 3.7 g, 80.43 %. [00165] To N-PIVALOYL-3-METHOXY-4-CHLOROANILINE (1.50 g, 0.0062 mol) in THF (30 ML) was added n-butyl lithium (1.0 g, 0.0156 mol) at 0 C and the reaction stirred for 2 hr. After cooling to-70 C, methyl isonicotinate (1.3 g, 0.0094 mol) in THF (12 ml) was added slowly. The reaction was warmed to rt and stirred overnight and then quenched with water and extracted with ether. The water layer was further extracted and the combined ether layers were washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield 0.50 g, 23. 25 %. [00166] The protected ketone from step 5 (0.500g, 0. 0014MOL) was suspended in concentrated HCI (5 ml) at RT, then the temperature was raised to 95 C and the mixture stirred over night. The mixture was cooled to RT, basified with 20 % NAOH solution and extracted with DCM. The combined organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography using basic alumina to yield title compound (0.140 g, 37.33%).
76.36%		5-Nitro-2-chloro aniline (50.0 g, 0.289 mol) in 30 % sulfuric acid (300 ml) was stirred at RT for 2 h. Sodium nitrite (21.0 g, 0.304 mol) in water (50 ml) was added slowly at 0C. After 15 mins, this solution was added slowly to dilute sulfuric acid (50 %, 250 ml) at 110 C. Stirring was continued for 15 min. The reaction mixture was cooled to RT, ice water was added, extracted with ethylacetate, washed with water, brine and dried over NA2SO4. The phenol product obtained upon concentration was purified by column chromatography. Yield 12.0 g, 24.0 %. [00153] K2CO3 (23.84 g, 0.172 mol) was added to 2-chloro-5- nitrophenol (10.0 g, 0.058 mol) in acetonitrile (100 ml) at RT. After cooling to 0 C, methyl iodide (19.6 g, 0.138 mol) was added slowly and the reaction mixture stirred at RT overnight. Water (100 ml) was added and the aqueous layer extracted with ethyl acetate. The organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography to yield the ANISOLE (6.0 g, 55.55%). [00154] 2-CHLORO-5-NITRO ANISOLE (6.0 g, 0.032 mol) in MEOH (45 ml) was added slowly to stannous chloride (15.1 g, 0.08 mol) in conc. HCI (110 ml) at 40 C and the temperature was slowly raised to 50 C. Stirring was continued for 2 h. After cooling to RT, the reaction mixture was basified with 50 % NAOH solution, extracted by ethyl acetate, washed with water, then brine and dried over NA2SO4. 3-METHOXY-4-CHLOROANILINE was obtained upon concentration and was purified further by column chromatography. Yield : 4.0 g, 79.36 %. [00155] To 3-METHOXY-4-CHLOROANILINE (2.0 g, 0.0126 mol) in trichloroethylene (30 ml) was added BC13 (2.18 g, 1 M solution in DCM, 0.0188 mol) AT 0 C. After stirring for 10 min, 4-CYANOPYRIDINE (1.6 g, 0.0153 mol) and AIC13 (2.35 g, 0.018 mol) were added and the temperature was raised to RT, with further stirring for 30 min. The temperature was raised further to 85 C and maintained at the same temperature for 1 h. DCM was distilled off and the solution was stirred at 115 C for 4 h and then at RT over night. 3N HCI was added at RT and the reaction mixture REFLUXED for 1.5 h. The reaction mixture was allowed to cool and made basic using NAOH (6 N), diluted with water and extracted with DCM, washed with water, brine and dried over NA2SO4. The crude title compound was obtained upon concentration and was purified by column chromatography. Yield : 0.50 g, 15 %.
53%	With palladium 10% on activated carbon; hydrogen; In ethyl acetate; for 16h;	Pd(C) (10%, 142mg, 0.13mmol, 0.1 eq. Pd) was added to a solution of <strong>[1009-36-5]1-chloro-2-methoxy-4-nitrobenzene</strong> (250mg, 1.33mmol, 1.0 eq.) in 10ml of EtOAc. The vessel was evacuated, backfilled with H2, fitted with a H2 balloon, and stirred for 16h. The suspension was filtered through a pad of Celite and concentrated. NMR indicated 5-10% of the dehalogenated product; therefore, the crude product mixture was recrystallized from heptane with a minimal amount of CH2Cl2 to give the title compound as white crystals (111mg, 0.70mmol, 53% yield). The 1H spectrum was in accord with literature data [39].
	With hydrogen;nickel; In tetrahydrofuran; methanol; at 35℃; under 975.0980000000001 Torr; for 4h;Parr apparatus;	A mixture of 36 g of <strong>[1009-36-5]<strong>[1009-36-5]2-chloro-5-nitroanisol</strong>e</strong> and Raney nickel in 150 ml of MeOH and 200 ml of THF is hydrogenated in Parr apparatus for 4 hours, at 35 C. and under a pressure of 1.3 bar. The catalyst is filtered off on Celite and the filtrate is concentrated under vacuum. 28 g of the expected product are obtained, and are used without further purification.

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8413 - 8426
[2]Angewandte Chemie - International Edition,2016,vol. 55,p. 8979 - 8983
Angew. Chem.,2016,vol. 128,p. 9125 - 9129,5
[3]Patent: WO2017/106426,2017,A1 .Location in patent: Paragraph 0079; 0080; 0081
[4]Journal of the Iranian Chemical Society,2018,vol. 15,p. 281 - 291
[5]ChemCatChem,2020,vol. 12,p. 2426 - 2430
[6]Patent: WO2009/77584,2009,A1 .Location in patent: Page/Page column 14
[7]Patent: WO2009/77585,2009,A1 .Location in patent: Page/Page column 14
[8]Patent: WO2004/46092,2004,A2 .Location in patent: Page 53-55
[9]Patent: WO2004/46092,2004,A2 .Location in patent: Page 50-51
[10]European Journal of Medicinal Chemistry,2017,vol. 134,p. 415 - 427
[11]Chemische Berichte,1899,vol. 32,p. 2623
Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften,1899,p. 1625
[12]Bulletin of the Chemical Society of Japan,1969,vol. 42,p. 3016 - 3017
[13]Chimica Therapeutica,1969,vol. 4,p. 334 - 343
[14]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 211 - 214
[15]Environmental Toxicology and Chemistry,2001,vol. 20,p. 1381 - 1389
[16]Patent: US2004/180878,2004,A1 .Location in patent: Page/Page column 26

2
[ 1984-58-3 ]
[ 13726-14-2 ]

Yield	Reaction Conditions	Operation in experiment
	With Iron(III) nitrate nonahydrate; ammonia; sodium; In hexane; at -78 - -45℃; for 2h;	900 mL of ammonia was condensed at -78 C. 1 g of thinly shaven strips of sodium was added followed by 1.0 g of iron (III) nitrate nonahydrate. Upon disappearance of the deep blue color 25 g of thinly shaven strips of sodium was added. After 30 mins of stirring at -78 C., 50 g of 2,5-dichloroanisole was added as a solution in hexane (70 mL) dropwise and the reaction warmed to -45 C. for 2 hrs. Upon completion the ammonia was allowed to evaporate. The crude pot was then diluted in chloroform and 100 g of NH4Cl was added slowly. The combines were taken up in a separatory funnel and washed with water (3) followed by brine (1). The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting solid can be used without further purification. Yield: 99%. 1H NMR (400 MHz, DMSO) delta 6.98 (d, J=8.4, 1H), 6.34 (d, J=1.8, 1H), 6.16 (dd, J=8.4, 1.9, 1H), 5.23 (s, 2H), 3.74 (s, 3H). 13C NMR (101 MHz, DMSO) delta 154.90, 149.16, 129.68, 107.02, 106.74, 98.66, 55.38. HRMS (ESI) calculated for C7H8ClNO [M+H]+: 157.0367. found: 157.0361.

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 7076 - 7094
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 8321 - 8327
[3]Journal of the American Chemical Society,1953,vol. 75,p. 3196
[4]Journal of Medicinal Chemistry,2011,vol. 54,p. 4399 - 4426
[5]Patent: US2013/123258,2013,A1 .Location in patent: Paragraph 0152; 0153; 0154

3
[ 463-71-8 ]
[ 13726-14-2 ]
[ 120222-86-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride

Reference： [1]Browne; Dyson [Journal of the Chemical Society, 1931, p. 3285,3299]

4
[ 13726-14-2 ]
[ 18113-07-0 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1914,vol. 405,p. 276
[2]Chimica Therapeutica,1969,vol. 4,p. 334 - 343

5
[ 75-17-2 ]
[ 13726-14-2 ]
[ 13726-16-4 ]

Reference： [1]Bulletin de la Societe Chimique de France,1966,p. 3311 - 3318

6
[ 13726-14-2 ]
[ 16817-43-9 ]

Reference： [1]Journal of medicinal chemistry,1967,vol. 10,p. 1008 - 1014

7
[ 553-82-2 ]
[ 7664-41-7 ]
sodium amide [ No CAS ]
petroleum ether [ No CAS ]
[ 2401-24-3 ]
[ 13726-14-2 ]
[ 95-03-4 ]

Reference： [1]Journal of the American Chemical Society,1953,vol. 75,p. 3196

8
[ 101094-85-3 ]
[ 13726-14-2 ]
(4-chloro-3-methoxy-phenyl)-(4-pyridin-4-ylmethyl-phthalazin-1-yl)-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2310 - 2323

9
[ 13726-14-2 ]
[ 79-44-7 ]
[ 28170-67-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With pyridine; dmap; In dichloromethane; at 20℃;Sealed tube;	General procedure: Anilines (1 mmol), N,N-dimethylcarbamoyl chloride (2 mmol), DMAP (1 mmol), and pyridine (4mmol) were sequentially added under air to a reaction tube equipped with a stir bar and aseptum. CH2Cl2 (2 mL) was added by syringe and the resulting mixture vigorously stirred for36-48 h at ambient temperature. After this time, the contents of the flask were extracted withEtOAc. The solution obtained was filtered through the plug of silica gel and anhydrous MgSO4,and then concentrated by rotary evaporation. The residue was purified by flash chromatography,eluting with hexane/EtOAc to afford the product.

Reference： [1]Beilstein Journal of Organic Chemistry,2016,vol. 12,p. 1040 - 1064
[2]Environmental Toxicology and Chemistry,2001,vol. 20,p. 1381 - 1389

10
[ 13726-14-2 ]
[ 214470-55-0 ]
4-(4-chloro-3-methoxy-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 3965 - 3977

11
[ 13726-14-2 ]
[ 161949-50-4 ]

Reference： [1]Chemical Communications,2006,p. 423 - 425

12
[ 13726-14-2 ]
[ 13726-17-5 ]

Reference： [1]Bulletin de la Societe Chimique de France,1966,p. 3311 - 3318

13
[ 13726-14-2 ]
[ 13726-21-1 ]

Reference： [1]Bulletin de la Societe Chimique de France,1966,p. 3311 - 3318

14
[ 13726-14-2 ]
[ 13726-18-6 ]

Reference： [1]Bulletin de la Societe Chimique de France,1966,p. 3311 - 3318

15
[ 100-48-1 ]
[ 13726-14-2 ]
[ 698395-64-1 ]

Yield	Reaction Conditions	Operation in experiment
15%		5-Nitro-2-chloro aniline (50.0 g, 0.289 mol) in 30 % sulfuric acid (300 ml) was stirred at RT for 2 h. Sodium nitrite (21.0 g, 0.304 mol) in water (50 ml) was added slowly at 0C. After 15 mins, this solution was added slowly to dilute sulfuric acid (50 %, 250 ml) at 110 C. Stirring was continued for 15 min. The reaction mixture was cooled to RT, ice water was added, extracted with ethylacetate, washed with water, brine and dried over NA2SO4. The phenol product obtained upon concentration was purified by column chromatography. Yield 12.0 g, 24.0 %. [00153] K2CO3 (23.84 g, 0.172 mol) was added to 2-chloro-5- nitrophenol (10.0 g, 0.058 mol) in acetonitrile (100 ml) at RT. After cooling to 0 C, methyl iodide (19.6 g, 0.138 mol) was added slowly and the reaction mixture stirred at RT overnight. Water (100 ml) was added and the aqueous layer extracted with ethyl acetate. The organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography to yield the ANISOLE (6.0 g, 55.55%). [00154] 2-CHLORO-5-NITRO ANISOLE (6.0 g, 0.032 mol) in MEOH (45 ml) was added slowly to stannous chloride (15.1 g, 0.08 mol) in conc. HCI (110 ml) at 40 C and the temperature was slowly raised to 50 C. Stirring was continued for 2 h. After cooling to RT, the reaction mixture was basified with 50 % NAOH solution, extracted by ethyl acetate, washed with water, then brine and dried over NA2SO4. 3-METHOXY-4-CHLOROANILINE was obtained upon concentration and was purified further by column chromatography. Yield : 4.0 g, 79.36 %. [00155] To 3-METHOXY-4-CHLOROANILINE (2.0 g, 0.0126 mol) in trichloroethylene (30 ml) was added BC13 (2.18 g, 1 M solution in DCM, 0.0188 mol) AT 0 C. After stirring for 10 min, 4-CYANOPYRIDINE (1.6 g, 0.0153 mol) and AIC13 (2.35 g, 0.018 mol) were added and the temperature was raised to RT, with further stirring for 30 min. The temperature was raised further to 85 C and maintained at the same temperature for 1 h. DCM was distilled off and the solution was stirred at 115 C for 4 h and then at RT over night. 3N HCI was added at RT and the reaction mixture REFLUXED for 1.5 h. The reaction mixture was allowed to cool and made basic using NAOH (6 N), diluted with water and extracted with DCM, washed with water, brine and dried over NA2SO4. The crude title compound was obtained upon concentration and was purified by column chromatography. Yield : 0.50 g, 15 %.

Reference： [1]Patent: WO2004/46092,2004,A2 .Location in patent: Page 50-51

16
[ 3282-30-2 ]
[ 13726-14-2 ]
N-[4-chloro-3-(methyloxy)phenyl]-2,2-dimethylpropanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine; In dichloromethane; at 0 - 20℃; for 2.5h;	Intermediate 15: lambda/-[4-chloro-3-(methyloxy)phenyll-2,2-dimethylpropanamidePivaloyl chloride (7.02 ml, 57 mmol) was added over a period of 20 minutes to a solution of 4-chloro-3-(methyloxy)aniline (commercially available) (9.0 g, 57 mmol) and TEA (8.74 ml, 63 mmol) in DCM (60 ml) at ice-bath temperature. The temperature was allowed to warm to room temperature and after 2.5 hours the reaction mixture was quenched with water. The mixture was extracted with DCM and the organic layers combined, dried (Na2SO4) and concentrated in vacuo. The crude <n="49"/>solid was triturated with diethyl ether to give the title compound (11.0 g, 80 %); (ES) m/z: 242.1 [MH+]; C12H16CINO2 requires 241.72.
80.43%	With triethylamine; In benzene; at 0 - 20℃;	5-NITRO-2-CHLORO aniline (50.0 g, 0.289 mol) in 30 % sulfuric acid (300 ml) was stirred at RT FOR 2 h. Sodium nitrite (21.0 g, 0.304 mol) in water (50 ml) was added slowly at 0C and maintained at this temperature for 15 min. This diazotized solution was added slowly to dilute sulfuric acid (50 %, 250 ML) at 110 C. Stirring was continued for 15 min. After cooling to RT, ice water was added, the mixture extracted with ethylacetate, washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield 12.0 g, 24. 0 %. [00162] To K2CO3 (23.84 g, 0.172 mol) and 2-chloro-5-nitrophenol (10.0 g, 0.0576 mol) in ACETONITRILE (100 ml) was added methyl iodide (19.60 g, 0.138 mol) at 0C. The reaction mixture was warmed to RT and stirred overnight. Water was added and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield : 6.0 g, 55. 55 %. [00163] 2-CHLORO-5-NITRO ANISOLE (6.0 g, 0.032 mol) in MEOH (45 ml) was added slowly to stannous chloride (15.1 g, 0.08 mol) in conc. HCI (110 ml) at 40 C and the temperature was slowly raised to 50 C. Stirring was continued for 2h, the reaction cooled to RT, basified with 50 % NAOH solution and extracted by ethyl acetate. The organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield : 4.0 g, 79.36 %. [00164] To triethylamine (3.83 g, 0.037 mol) and 3-methoxy-4- chloro aniline (3.0 g, 0.0190 mol) in benzene (50 ML) was added trimethylacetylchloride (2.75 g, 0.022 mol) slowly at 0 C. The temperature was raised to RT and stirred overnight. The reaction mixture was added to ice and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over NA2SO4 and concentrated. Yield : 3.7 g, 80.43 %. [00165] To N-PIVALOYL-3-METHOXY-4-CHLOROANILINE (1.50 g, 0.0062 mol) in THF (30 ML) was added n-butyl lithium (1.0 g, 0.0156 mol) at 0 C and the reaction stirred for 2 hr. After cooling to-70 C, methyl isonicotinate (1.3 g, 0.0094 mol) in THF (12 ml) was added slowly. The reaction was warmed to rt and stirred overnight and then quenched with water and extracted with ether. The water layer was further extracted and the combined ether layers were washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield 0.50 g, 23. 25 %. [00166] The protected ketone from step 5 (0.500g, 0. 0014MOL) was suspended in concentrated HCI (5 ml) at RT, then the temperature was raised to 95 C and the mixture stirred over night. The mixture was cooled to RT, basified with 20 % NAOH solution and extracted with DCM. The combined organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography using basic alumina to yield title compound (0.140 g, 37.33%).

Reference： [1]Patent: WO2008/37681,2008,A1 .Location in patent: Page/Page column 47-48
[2]Patent: WO2004/46092,2004,A2 .Location in patent: Page 53-55
[3]Journal of the American Chemical Society,2017,vol. 139,p. 12317 - 12324

17
[ 10421-85-9 ]
[ 13726-14-2 ]
[ 352277-98-6 ]

Yield	Reaction Conditions	Operation in experiment
	In dichlorobenzene, 1,2-; at 230℃; for 4.0h;Dean-Stark apparatus;	A mixture of 28 g of the compound obtained in the preceding step and 33.13 g of D,L-<strong>[10421-85-9]2-chloromandelic acid</strong> in 128 ml of 1,2-dichlorobenzene is heated at 230 C. for 4 hours, while removing the water formed using Dean-Stark apparatus. The reaction mixture is partially concentrated under vacuum and left to crystallize. The crystalline product formed is filtered off by suction and washed with iso ether. 40 g of the expected product are obtained

Reference： [1]Patent: US2004/180878,2004,A1 .Location in patent: Page/Page column 26

18
[ 532-55-8 ]
[ 13726-14-2 ]
[ 855531-26-9 ]

Yield	Reaction Conditions	Operation in experiment
98%		Benzoyl isothiocyanate (8.8 mL, 64 mmol) was added dropwise to a solution of 4-chloro- 3-methoxy-benzenamine (10 g, 63 mmol) in 160 mL THF. The mixture was stirred at room temperature for 40 minutes, volatiles were removed and the residue was dissolved in 400 mL methanol. A solution of potassium carbonate (26.3 g, 190 mmol) in 200 mL water was added and the mixture was stirred at room temperature for 90 minutes. The title product (13.5 g, 98%) precipitated after removal of 450 mL of the solvents. MS (m/e): 216.0, 218.0 (M+)

Reference： [1]Patent: WO2005/58887,2005,A1 .Location in patent: Page/Page column 49

19
[ 13726-14-2 ]
[ 178423-72-8 ]

Yield	Reaction Conditions	Operation in experiment
72%		Concentrated hydrochloric acid (12 mL) and a solution of sodium nitrite (1.7 g, 24.4 mmol) in water (8 mL) were added to a solution of 4-chloro-3-methoxy aniline (3.86 g, 24.4 mmol) in water (8 mL), at -10 C. The mixture was stirred for 30 minutes and was then added to solution of tin chloride (14.89 g, 66 mmol) in concentrated hydrochloric acid (24 mL) and water (24 mL), cooled to 0 C. The reaction mixture was stirred for 18 hours, allowing the temperature to rise to 25 C. The resulting precipitate was filtered off and the solid was re-crystallized from heptanes/ethyl acetate (33:66) to afford the title compound the title compound as white solid in 72% yield, 3 g

Reference： [1]Patent: US2006/35922,2006,A1 .Location in patent: Page/Page column 35

20
[ 79-04-9 ]
[ 13726-14-2 ]
2-chloro-N-(4-chloro-3-methoxyphenyl)-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 3. 2-Chloro-N-(4-chloro-3-methoxyphenyl)-acetamideChloroacetyl chloride (10 mmol) is added dropwise to a mixture of 4-chloro-3-methoxyaniline (1.57 g, 10 mmol), ethyl ether (30 mL) and NaHCO3 (saturated solution, 30 mL) at room temperature and under vigorous stirring. After 1 h at room temperature the layers are separated, the organic layer is washed with NaHCO3 (saturated solution, 2x30 mL), brine (2 x 30 mL), aqueous HC1 (1M, 30 mL), and brine (2 x 30 mL), and dried (MgSO4). The solvent is removed under reduced pressure to produce the title compound as an off-white solid. H-l NMR: 3.91 (s, 3H); 4.18 (s, 2H); 6.90 (dd, 1H); 7.30 (d, 1H); 7.46 (d, 1H); 8.22 (broad, 1H).

Reference： [1]Patent: WO2006/15279,2006,A1 .Location in patent: Page/Page column 45

21
[ 13726-14-2 ]
[ 6358-06-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen bromide; acetic acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate;	Preparation of 2-chloro-5-aminophenol 4.35 Moles (688 grams) of 2-chloro-5-amino anisole are introduced into 3.44 liters of hydrobromic acid (d = 1.49) to which has been added 1.38 liters of acetic acid. The resulting mixture is heated for 3 hours at reflux at which time it is cooled to 0°C. The 2-chloro-5-aminophenol hydrobromide that has precipitated is then filtered, introduced into 3 liters of ice water and neutralized with concentrated ammonia so as to precipitate 2-chloro-5-aminophenol. The desired product which is then filtered to provide a yield of 495 g exhibits, after drying, a melting point of 160°C.

Reference： [1]Patent: US3948596,1976,A

22
[ 13726-14-2 ]
[ 940948-33-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; In tetrahydrofuran; at -78 - 20℃; for 2.5h;	EXAMPLE 70 3-Bromo-4-chloro-5-methoxyphenylamine NBS (0.582 g, 3.27 mmol) was added to a solution of 4-chloro-3-methoxyphenylamine (0.468 g, 2.97 mmol) in THF (15 mL) at -78 C. The resulting mixture was stirred at -78 C. for 30 min and then at room temperature for 2 h. LC-MS showed the completion of the reaction. After evaporating the solvent, the residue was dissolved in dichloromethane, washed with water, dried over Na2SO4, and concentrated to afford the desired product. MS (ES+): m/z 235.99 (MH+, 35Cl, 79Br), 239.93 (MH+, 37Cl, 81Br). HPLC: tR=3.19 min (OpenLynx, polar-5 min).

Reference： [1]Patent: US2007/129364,2007,A1 .Location in patent: Page/Page column 97

23
HPF₆ [ No CAS ]
[ 450-89-5 ]
[ 3375-31-3 ]
[ 13726-14-2 ]
[ 865-48-5 ]
[ 57260-71-6 ]
[ 102392-11-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; sodium nitrite; In hydrogenchloride; dichloromethane; water; toluene; mineral oil;	1-(4-Fluoro-2-methoxy-phenyl)-piperazine: 4-Chloro-3-methoxy-aniline (25 g, 158 mmol) was dissolved in conc. HCl (160 mL) at 80 C., and the solution was cooled to -10 C. An aqueous solution of NaNO2 (12.04 g, 174.6 mmol) was added drop wise with stirring. After an additional 20 minutes, HPF6 (80 mL) was added with stirring, keeping the temperature at or below 0 C. After an additional 30 minutes, the solid was filtered and washed with cold water and an ether-methanol mixture (4:1), and dried overnight in vacuo. The solid was added in portions to mineral oil at 170 C. with stirring. After complete addition the mixture was cooled to ambient temperature, and 175 mL of 10% Na2CO3 was added slowly to it. The mixture was steam distilled, and the distillate was extracted with dichloromethane. The dichloromethane phase was washed with brine, dried with Na2SO4, filtered, and concentrated to give 2-Chloro-5-fluoroanisole. Following protocol A, Mono Boc-piperazine (7.64 g, 41.12 mmol), Pd (II) acetate (153 mg, 0.65 mmol), sodium tert. butoxide (4.61 g, 47 mmol) and BINAP (0.853 g, 1.37 mmol) were mixed together and stirred at rt in 100 mL dry toluene for 15 min under nitrogen atmosphere. <strong>[450-89-5]2-chloro-5-fluoroanisole</strong> (5.5 g, 34.2 mmol) in dry toluene (10 mL) was then added, and the mixture was refluxed for 20 hours. After cooling, the reaction mixture was filtered through a celite bed, followed by extensive washing with toluene. The toluene was concentrated, and the residue was extracted with ethyl acetate. The ethyl acetate was decanted, and was concentrated to obtain crude material that was taken directly to the next step. The crude compound from the previous step was dissolved in 20 mL of dichloromethane, and 2M HCl in dry ether (20 mL) was added to it. The reaction mixture was stirred overnight, and the solvent was evaporated. The residue was dissolved in water, and was washed once with ethyl acetate. The aqueous layer was basified with 10% sodium hydroxide solution to pH 12, and was extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1-(4-Fluoro-2-methoxy-phenyl)-piperazine as a white solid.

Reference： [1]Patent: US2004/162282,2004,A1

24
[ 69610-41-9 ]
[ 13726-14-2 ]
[ 1105706-96-4 ]

Yield	Reaction Conditions	Operation in experiment
68%		a) (S)-2-[(4-Chloro-3-methoxy-phenylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester To a solution of 4-chloro-3-methoxyaniline (1.57 g, 10.0 mmol) in methanol (27 ml) were added acetic acid (3 ml), N-(tert-butoxycarbonyl)-L-prolinal (2.40 g, 12.05 mmol) and sodium cyanoborohydride (1.56 g, 24.1 mmol). The resulting suspension was stirred for 2 hours at room temperature. Aqueous sodium bicarbonate solution (30 ml) was added and the mixture was extracted with ethyl acetate (3*20 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=70:30) to yield a light yellow oil (2.31 g, 68%); MS (ISP): 341.0, 342.9 ((M+H)+.).

Reference： [1]Patent: US2009/29962,2009,A1 .Location in patent: Page/Page column 10

25
[ 1000373-92-1 ]
[ 13726-14-2 ]
[ 1000372-61-1 ]

Yield	Reaction Conditions	Operation in experiment
8%	With sodium iodide; In ethylene glycol; at 130℃; for 6h;	A mixture of 181 mg of 2-bromo-N-[6-(2-bromo-2-methyl-propionyl)-4-trifluoromethyl-6H-pyrazolo[4',3':3,4]benzo[1,2-d]thiazol-2-yl]-2-methyl-propionamide, 211 mg of 4-chloro-3-methoxyaniline, 100 mg of sodium iodide and 4.0 ml of ethylene glycol was heated at 130C for 6 hours. The mixture was cooled to room temperature, water was added to the mixture, and the precipitated solid was collected by filtration. The crude product was purified by silica gel column chromatography (chloroform:methanol=100:1-10:1) to give 12 mg (yield: 8%) of the desired compound. MASS(ESI+) m/z= 484, 486 [M+H]+

Reference： [1]Patent: EP2045253,2009,A1 .Location in patent: Page/Page column 69

26
[ 3612-20-2 ]
[ 13726-14-2 ]
[ 1161413-01-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium tris(acetoxy)borohydride; sodium sulfate; In dichloromethane; at 20℃; for 12h;Inert atmosphere;	General procedure: N-Benzylpiperidone (1 g, 5.2 mmol, 1 equiv), 3, 4 difluoroaniline (0.52 mL, 5.2 mmol, 1 equiv) and sodium sulfate (3.7 g, 26.4 mmol, 5 equiv) were suspended in dichloromethane (20 mL). Sodium triacetoxyborohydride (1.3 g, 6.33 mmol, 1.2 equiv) was added and the reaction mixture was stirred at room temperature overnight. Aqueous sodium hydrogen carbonate was added followed by stirring for 30 min. The reaction mixture was extracted with dichloromethane and the combined organic phases were washed with brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The residue obtained upon evaporation of solvent was chromatographed over silica gel and eluted with 35% ethyl acetate/hexane to give the 26 as a light yellow colored solid (1.2 g, 75% yield).
46%		/V-Benzylpiperidone (7.9 ml_, 43,8 mmol), 4-chloro-3-methoxy-phenylamine (6.9 g, 43.8 mmol) and sodium sulphate (31.1 g, 218 mmol) were suspended in dichloromethane (250 ml_). Sodium triacetoxyborohydride (11.4 g, 52.5 mmol) was added and the reaction mixture was stirred at room temperature overnight. <n="16"/>Aqueous sodium hydrogencarbonate was added followed by stirring for 30 min. The mixture was extracted with dichloromethane and the combined organic phases were washed with brine, dried over sodium sulphate, filtrated and concentrated in vacuo. (1 -Benzyl-piperidin-4-yl)-(4-chloro-3-methoxy-phenyl)- amine was precipitated from ethyl acetate/heptane 6.7 g (46%) as a white solid.
46%		Example 2(1-Benzyl-piperidin-4-yl)-(4-chloro-3-methoxy-phenyl)-amine/V-Benzylpiperidone (7.9 ml_, 43,8 mmol), 4-chloro-3-methoxy-phenylamine (6.9 g, 43.8 mmol) and sodium sulphate (31.1 g, 218 mmol) were suspended in dichloromethane (250 ml_). Sodium triacetoxyborohydride (11.4 g, 52.5 mmol) was added and the reaction mixture was stirred at room temperature overnight.Aqueous sodium hydrogencarbonate was added followed by stirring for 30 min.The mixture was extracted with dichloromethane and the combined organic phases were washed with brine, dried over sodium sulphate, filtrated and <n="16"/>concentrated in vacuo. (1 -Benzyl-piperidin-4-yl)-(4-chloro-3-methoxy-phenyl)- amine was precipitated from ethyl acetate/heptane 6.7 g (46%) as a white solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6185 - 6194
[2]Patent: WO2009/77584,2009,A1 .Location in patent: Page/Page column 14-15
[3]Patent: WO2009/77585,2009,A1 .Location in patent: Page/Page column 14-15

27
[ 98-98-6 ]
[ 13726-14-2 ]
[ 1161205-04-4 ]

Yield	Reaction Conditions	Operation in experiment
53%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 20 - 50℃;	3 was synthesized in a similar procedure as described for 2 by using 4-chloro-3-methoxyaniline (400 mg, 2.54 mmol), 1 (312 mg, 2.54 mmol), HOBt·H2O (389 mg, 2.54 mmol), DIPEA (0.66 g, 5.08 mmol), EDC.HCl (730 mg, 3.81 mmol) and anhydrous 1,4-dioxane (30 mL). 3 was obtained as a pale yellow solid (325 mg, 1.34 mmol, 53 % yield); mp: 120 C. 1H NMR (500MHz, CDCl3) delta ppm 10.07 (s, 1H), 8.63 (d, J=4.0Hz, 1H), 8.29 (d, J=8.0Hz, 1H), 7.92 (ddd, J=7.6, 7.6, 1.6Hz, 1H), 7.81 (d, J=2.0Hz, 1H), 7.50 (dd, J=7.0Hz, 5.0Hz, 1H), 7.34 (d, J=8.5Hz, 1H), 7.09 (dd, J=9, 2.5Hz, 1H), 3.97 (s, 3H). 13C NMR (125MHz, CDCl3) delta ppm 162.41, 155.68, 149.85, 148.37, 138.17, 137.97, 130.47, 127.01, 122.72, 117.80, 112.45, 104.37. LC-MS, calcd for C13H11N2O2Cl: 262.05; obsd: 263.0 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5955 - 5962
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 4115 - 4118
[3]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3956 - 3960

28
[ 13726-14-2 ]
2-bromo-4-chloro-5-methoxyaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-Bromosuccinimide; In dichloromethane; at 5 - 20℃; for 3h;	A solution of 4-chloro-3-methoxy-aniline (7.00 g, 44.4 mmol) dissolved in dichloromethane (100 mL) at 5 C was treated portions with NBS (8.14 g, 45.7 mmol) over 1 hour, then warmed to 20 C and stirred at 20 C for 2 hours. On completion, a 5% aqueous Na2SO3 solution (100 mL) was added and the mixture was stirred for 10 minutes. The layers were separated and the organic layer was washed with water and saturated brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The getting residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give the title compound (9.00 g, 85% yield) as a dark brown solid.1H NMR (400MHz, CD3Cl) delta = 7.37 (s, 1H), 6.35 (s, 1H), 4.13 (br. s., 2H), 3.83 (s, 3H).
80%		A solution of 4-chloro-3-methoxyaniline (1.0 equivalent) dissolved in CH2CI2 (15 volumes) at 5 C was treated portion wise with N-bromosuccinimide (1.03 equivalents), warmed to 20 C and mixed for 5 minutes. A 5% aqueous Na2S03 solution (10 volumes) was added and the mixture was stirred for 10 minutes. The layers were separated and the organic layer was washed with water and saturated brine, dried (Na2S04), filtered and concentrated. The resulting solid was triturated with a minimal volume of heptane and the solid was collected by filtration and dried to constant mass (80 % yield).
1.8 g	With N-Bromosuccinimide; In dichloromethane; at 20℃; for 0.166667h;Cooling with ice; Inert atmosphere;	4-Chloro-3-Methoxyaniline(1.57 g, 10 mmol)Was dissolved in dichloromethane (15 mL)N-Bromosuccinimide (1.95 g, 1 l mmol) was added portionwise to the above solution under ice-cooling,After the addition, the reaction was allowed to warm to room temperature for 10 minutes.After completion of the reaction,The reaction was quenched by adding 5% aqueous sodium sulfite solution,The organic phase was separated,Respectively, with water,Washed with a saturated saline solution,Dried over anhydrous sodium sulfate,Filtered and concentrated under reduced pressure.The residue was diluted with a small amount of n-heptane,Precipitation of solid,The solid was collected by filtration to give 2-bromo-4-chloro-5-methoxyaniline (off-white solid, 1.8 g).

Reference： [1]Patent: WO2018/106636,2018,A1 .Location in patent: Paragraph 00266
[2]Patent: WO2012/87833,2012,A1 .Location in patent: Page/Page column 154
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 8413 - 8426
[4]Tetrahedron Letters,2010,vol. 51,p. 3876 - 3878
[5]Patent: CN103848785,2016,B .Location in patent: Paragraph 0171

29
[ 4755-77-5 ]
[ 13726-14-2 ]
C₁₁H₁₂ClNO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	General procedure: To a solution containing para-chloro-meta-fluoroaniline (10.0 g, 70.1 mmol) in 600 mL THF at 0 C was added Et3N (9.11 mL, 70.1 mmol) followed by ethyl oxalylchloride (7.70 mL, 70.1 mmol) dropwise over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 18 hrs. The reaction mixture was filtered and the filter cake was washed with one-300 mL portion of ethyl acetate. The organic phase was washed with two-100 mL portions of 1M HCl, dried over MgSO4, filtered, and concentrated to give the product. Recrystallization from hot Et2O gave 14.4 g (84%) of 27 as a colorless crystalline solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 91 - 101

30
[ 1198-44-3 ]
[ 13726-14-2 ]
[ 1312077-64-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: ethyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate; 4-chloro-m-anisidine With acetic acid In benzene at 100℃; Stage #2: In diphenylether Reflux;

Reference： [1]Location in patent: experimental part Cross, R. Matthew; Maignan, Jordany R.; Mutka, Tina S.; Luong, Lisa; Sargent, Justin; Kyle, Dennis E.; Manetsch, Roman [Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4399 - 4426]

31
[ 2942-59-8 ]
[ 13726-14-2 ]
[ 1432112-11-2 ]

Yield	Reaction Conditions	Operation in experiment
58%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Step 1 :Exp-4-g1Step 1 : preparation of 2-Chloro-N-(4-chloro-3-methoxyphenyl)pyridine-3- carboxamide (Exp-4-g3)[0100] Into a vessel containing a solution prepared by dissolving 1 g of 2- chloropyridine-3-carboxylic acid (Exp-4-gl, 6.37 mmol) and 1 g of 4-chloro-3- methoxy-phenylamine (Exp-4-g2, 6.4 mmol) in 30 mL of DMF was added 6.05 g 0- 7- Azabenzotriazol-l-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate (HATU, 15.9 mmol), and 1.93 g triethylamine (TEA, 19.1 mmol). The reaction mixture thus provided was stirred at ambient temperature (RT) overnight then the mixture was poured into cool water and the resulting mixture extracted with sufficient amounts of EtOAc to obtain the product from the reaction mixture. The organics were combined, washed with brine, dried over MgSC>4, filtered and concentrated under reduced pressure. The residue thus provided was purified on silica column chromatogram (PE:EtOAc = 50: 1-1 : 1) to give 1.1 g of Exp-4-g3 (calculated yield 58%).
58%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Into a vessel containing a solution prepared by dissolving 1 g of 2- chloropyridine-3-carboxylic acid (Exp-4-gl, 6.37 mmol) and 1 g of 4-chloro-3- methoxy-phenylamine (Exp-4-g2, 6.4 mmol) in 30 mL of DMF was added 6.05 g O-(7- Azabenzotriazol-l-y^-A .A.N'.N'-tetramethyluronium hexafluorophosphate (HATU, 15.9 mmol), and 1.93 g tnethylamine (TEA, 19.1 mmol). The reaction mixture thus provided was stirred at ambient temperature (RT) overnight then the mixture was poured into cool water and the resulting mixture extracted with sufficient amounts of EtOAc to obtain the product from the reaction mixture. The organics were combined, washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The residue thus provided was purified on silica column chromatogram (PE:EtOAc = 50: 1-1 :1) to give 1.1 g of Exp-4-g3 (calculated yield 58%).

Reference： [1]Patent: WO2013/60029,2013,A1 .Location in patent: Paragraph 0100
[2]Patent: WO2013/63100,2013,A1 .Location in patent: Paragraph 0100

32
[ 1432112-16-7 ]
[ 13726-14-2 ]
[ 1432112-19-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 3h;Inert atmosphere; Reflux;	Step 3: Preparation of N-(4-Chloro-3-methoxyphenyl)-l-(4-methoxybenzyl)-lH- pyrazolo[3,4-b]pyrazin-3-amine (Exp-5-g25)[0106] Into a vessel containing 3 mL of dioxane was added 60 mg of Exp-5-g24 prepared in Step 2 (0.19 mmol), 31 mg of 4-chloro-3-methoxy-phenylamine (0.2 mmol), 18 mg of Pd2dba3 (0.02 mmol), 23 mg of Xantphos (0.04 mmol) and 130 mg Cs2C03 (0.4 mmol). The reaction mixture thus provided was maintained under an N2 atmosphere, refluxed for 3 hours, then cooled to ambient temperature, filtered and concentrated under reduced pressure. The residue thus provided was purified by Prep-TLC (PE:EtOAc = 1 :2) yielding 65 mg of Exp-5-g25 (calculated yield 70 %).
70%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 3h;Inert atmosphere; Reflux;	Into a vessel containing 3 mL of dioxane was added 60 mg of Exp-5-g24 prepared in Step 2 (0.19 mmol), 31 mg of 4-chloro-3-methoxy-phenylamine (0.2 mmol), 18 mg of Pd2dba3 (0.02 mmol), 23 mg of Xantphos (0.04 mmol) and 130 mg Cs2C03 (0.4 mmol). The reaction mixture thus provided was maintained under an 2 atmosphere, refluxed for 3 hours, then cooled to ambient temperature, filtered and concentrated under reduced pressure. The residue thus provided was purified by Prep-TLC (PE:EtOAc = 1 :2) yielding 65 mg of Exp-5-g25 (calculated yield 70 %).

Reference： [1]Patent: WO2013/60029,2013,A1 .Location in patent: Paragraph 0106
[2]Patent: WO2013/63100,2013,A1 .Location in patent: Paragraph 0106

33
[ 1432111-98-2 ]
[ 13726-14-2 ]
[ 1432112-01-0 ]

Yield	Reaction Conditions	Operation in experiment
66%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 4h;Inert atmosphere; Reflux;	Step 3: Preparation of N-(4-Chloro-3-methoxyphenyl)-l-(4-methoxybenzyl)-lH- yrazolof 4, 3-b]pyridin-3-amine (Exp- 1 -g4)[0088] Into a vessel containing 1.5 mL dioxane was placed 63 mg of the crude Exp-1- g3 prepared in Step 2 (0.2 mmol). To the vessel was added 39 mg of 4-chloro-3- methoxy-phenylamine (0.25 mmol), 18 mg Pd2dba3 (0.02 mmol), 23 mg Xantphos (0.04 mmol) and 130 mg Cs2C03 (0.4 mmol). The reaction mixture thus provided was refluxed under a nitrogen atmosphere for 4 hours, then filtered and concentrated under reduced pressure. The residue was subjected to Prep-TLC (PE:EtOAc = 2: 1) to obtain Exp-l-g4 (52 mg, 66 %).
66%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 4h;Inert atmosphere; Reflux;	Into a vessel containing 1.5 mL dioxane was placed 63 mg of the crude Exp-1- g3 prepared in Step 2 (0.2 mmol). To the vessel was added 39 mg of 4-chloro-3- methoxy-phenylamine (0.25 mmol), 18 mg Pd2dba3 (0.02 mmol), 23 mg Xantphos (0.04 mmol) and 130 mg CS2CO3 (0.4 mmol). The reaction mixture thus provided was refluxed under a nitrogen atmosphere for 4 hours, then filtered and concentrated under reduced pressure. The residue was subjected to Prep-TLC (PE:EtOAc = 2: 1) to obtain Exp-l-g4 (52 mg, 66 %).

Reference： [1]Patent: WO2013/60029,2013,A1 .Location in patent: Paragraph 0088
[2]Patent: WO2013/63100,2013,A1 .Location in patent: Paragraph 0088

34
[ 42883-45-4 ]
[ 13726-14-2 ]
[ 1428967-91-2 ]

Yield	Reaction Conditions	Operation in experiment
18%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 180℃; for 0.5h;Microwave irradiation;	General procedure: A mixture of an a-halogenoketone, an amine and a base (DIPEA or triethylamine) in a solvent (e.g. DMF, ethanol, acetonitrile, dioxane or THF) was irradiated in a microwave oven at 100C to 200C (more in particular at 120 to 200 C) for 5 to 180 min. (more in particular for 15 to 120 min). The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel. 2-((4-Chloro-3-methoxyphenyl)amino)-1-(1 /-/-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1 /-/-indol-3-yl)-2-phenylethanone (0.104 g; 0.386 mmol), 3-methoxy-4-chloroaniline (0.105 g; 0.666 mmol) and DIPEA (0.200 mL; 1.148 mmol) in DMF (2 mL), irradiated in a microwave oven at 180 C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane furnished 0.027g (18%) of the desired compound as a white solid. ESI/APCI(+): 391 , 393 (M+H); 413, 415 (M+Na). ESI/APCI(-): 389, 391 (M-H). 1H NMR (CDCI3) delta 8.65 (1 H, br s); 8.40 (1 H, m); 7.95-8.1 1 (2H, m); 7.50-7.53 (2H, m); 7.24-7.53 (5H, m); 7.05 (1 H, d); 6.18-6.28 (2H, m); 5.70 (1 H, s); 3.79 (3H, s).

Reference： [1]Patent: WO2013/45516,2013,A1 .Location in patent: Page/Page column 129; 133

35
[ 887144-94-7 ]
[ 13726-14-2 ]
[ 1558046-40-4 ]

Yield	Reaction Conditions	Operation in experiment
62%	With tris[2-phenylpyridinato-C2,N]iridium(III); In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; Irradiation;	Ir (ppy) 3 (2 mg) and DMF (1 ml) were added to the reaction flask under nitrogen or argon atmosphere and then irradiated with a blue LED band (7 W) at room temperature until complete conversion of the trivalent iodine reagent was completed. 10 ml of a saturated aqueous Na2C03 solution was added thereto, and the mixture was extracted three times with ethyl acetate. The organic layer was washed once with saturated brine, and the organic layer was dried over anhydrous Na2S04. Column chromatography (eluent: petroleum ether 60-90: ethyl acetate = 20: 1-10: 1) afforded the product in a yield of 62%

Reference： [1]Patent: CN103553857,2016,B .Location in patent: Paragraph 0039-0040
[2]Organic Letters,2014,vol. 16,p. 1768 - 1771

36
[ 13726-14-2 ]
[ 1354745-52-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: toluene-4-sulfonic acid / benzene / 6 h / Reflux; Dean-Stark 2.1: dowtherm A / 0.33 h / 250 °C 3.1: iodine; potassium iodide; N-butylamine / water; N,N-dimethyl-formamide / 12 h / 20 °C 4.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 50 °C 4.2: 8 h / 50 °C 5.1: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / water; N,N-dimethyl-formamide / 18 h / 85 °C / Molecular sieve 6.1: acetic acid; hydrogen bromide / water / 24 h / 90 °C
	Multi-step reaction with 5 steps 1.1: toluene-4-sulfonic acid / benzene / 24 h / Reflux; Dean-Stark 1.2: 0.75 h / 250 °C 2.1: sodium hydrogencarbonate; iodine / methanol / 336 h / 20 °C 3.1: potassium carbonate / N,N-dimethyl-formamide / 72 h / 20 °C 4.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 24 h / Inert atmosphere; Heating 5.1: acetic acid; hydrogen bromide / water / 68 h / 90 °C
	Multi-step reaction with 5 steps 1.1: toluene-4-sulfonic acid / benzene / 24 h / Reflux; Dean-Stark 1.2: 0.75 h / 250 °C 2.1: sodium hydrogencarbonate; bromine / methanol 3.1: potassium carbonate / N,N-dimethyl-formamide / 72 h / 20 °C 4.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 24 h / Inert atmosphere; Heating 5.1: acetic acid; hydrogen bromide / water / 68 h / 90 °C

Reference： [1]Nilsen, Aaron; Miley, Galen P.; Forquer, Isaac P.; Mather, Michael W.; Katneni, Kasiram; Li, Yuexin; Pou, Sovitj; Pershing, April M.; Stickles, Allison M.; Ryan, Eileen; Kelly, Jane Xu; Doggett, J. Stone; White, Karen L.; Hinrichs, David J.; Winter, Rolf W.; Charman, Susan A.; Zakharov, Lev N.; Bathurst, Ian; Burrows, Jeremy N.; Vaidya, Akhil B.; Riscoe, Michael K. [Journal of Medicinal Chemistry, 2014, vol. 57, # 9, p. 3818 - 3834]
[2]Pou, Sovitj; Dodean, Rozalia A.; Frueh, Lisa; Liebman, Katherine M.; Gallagher, Rory T.; Jin, Haihong; Jacobs, Robert T.; Nilsen, Aaron; Stuart, David R.; Doggett, J. Stone; Riscoe, Michael K.; Winter, Rolf W. [Organic Process Research and Development, 2021, vol. 25, # 8, p. 1841 - 1852]
[3]Pou, Sovitj; Dodean, Rozalia A.; Frueh, Lisa; Liebman, Katherine M.; Gallagher, Rory T.; Jin, Haihong; Jacobs, Robert T.; Nilsen, Aaron; Stuart, David R.; Doggett, J. Stone; Riscoe, Michael K.; Winter, Rolf W. [Organic Process Research and Development, 2021, vol. 25, # 8, p. 1841 - 1852]

37
[ 13726-14-2 ]
[ 98-47-5 ]
[ 1236162-18-7 ]

Yield	Reaction Conditions	Operation in experiment
7.03 g		Step 1: 6-Chloro-7-methoxyquinoline A solution of sulfuric acid (35 mL) in water (35 mL) was treated with 3-nitrobenzenesulfonic acid (35.1 g, 159 mmol) and glycerol (80 ml, 1.1 mol) to give a thick grey suspension. The suspension was heated to 75 C. and 4-chloro-3-methoxyaniline (25.0 g, 159 mmol) was added. The mixture was stirred at 140 C. for 1 h. Additional quantities of water (35 mL), sulfuric acid (35 mL) and glycerol (40 mL) were added and the reaction was stirred an additional 2 h at 140 C. The solution was cooled to room temperature, poured onto ice, and the pH was adjusted to 13 by addition of concentrated ammonium hydroxide. The mixture was extracted with EtOAc (3*) and the extracts were washed with brine, dried over Na2SO4 and concentrated.

Reference： [1]Patent: US2014/206661,2014,A1 .Location in patent: Paragraph 0347; 0348

38
[ 13726-14-2 ]
[ 100-51-6 ]
[ 1308401-08-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	With heptahydrido bis(tricyclohexylphosphine)rheniume(VII); carbon monoxide; at 150℃; under 1140.08 Torr;	General procedure: The mixture of aniline 1 (1.2 mmol), alcohol (0.4 mmol), and ReH7(PCy3)2 (10 mol %,18 mg) were added into the flask. Then, anisole (0.5 mL) was added. The flask was evacuated and backfilled with CO (1.5 atm). The reaction mixture was vigorously stirred at 150 oC under for 20-36 h. After the reaction finished, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 × 5 mL), the combined organic phases were dried over anhydrous Na2SO4 and the solvent was evaporated under vacuum. After removing the solvents in vacuum, the residue was purified by flash column chromatography on silica gel or preparative TLC on GF254to afford the desired amination products.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 4172 - 4174

39
[ 13726-14-2 ]
[ 61700-61-6 ]
[ 1619884-58-0 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6679 - 6703

40
[ 704-91-6 ]
[ 13726-14-2 ]
N-(4-chloro-3-methoxyphenyl)-1H-indazole-6-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6679 - 6703

41
[ 1448419-29-1 ]
[ 13726-14-2 ]
C₂₂H₁₉ClN₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	With triethylamine; sodium iodide; In 1-methyl-pyrrolidin-2-one; at 130℃;	Example 26 [00349] A mixture of 26 (0.25 mmol), 3-chloro-4-methoxyaniline (0.75 mmol), TEA (0.75 mmol) and Nal (0.025 mmol) in NMP (2mL) was heated to 130 C and stirred overnight. The mixture was diluted with AcOEt (10 mL) and washed with H20 (2x lOmL). The organic layers were dried over Na2S04, filtered and evaporated under reduce pressure. Flash Chromatography (eluent: 5% MeOH in AcOEt) gave the desired product T (10% yield). MS ESI (m/z) 407 (M+H)

Reference： [1]Patent: WO2015/9930,2015,A2 .Location in patent: Paragraph 00348-00350
[2]Patent: US10626113,2020,B2 .Location in patent: Page/Page column 42

42
ethyl 3-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)butanoate [ No CAS ]
[ 13726-14-2 ]
[ 1354745-52-0 ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: ethyl 3-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)butanoate; 4-chloro-m-anisidine With acetic acid In benzene at 110℃; Dean-Stark; Stage #2: In toluene at 260℃; for 0.05h; Microwave irradiation;
30%	Stage #1: ethyl 3-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)butanoate; 4-chloro-m-anisidine With acetic acid In benzene for 18h; Inert atmosphere; Reflux; Dean-Stark; Stage #2: In toluene at 255℃; for 0.05h; Inert atmosphere; Microwave irradiation;

Reference： [1]Namelikonda, Niranjan K.; Monastyrskyi, Andrii; Manetsch, Roman [European Journal of Organic Chemistry, 2017, vol. 2017, # 23, p. 3328 - 3334]
[2]Monastyrskyi, Andrii; Namelikonda, Niranjan K.; Manetsch, Roman [Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2513 - 2520]

43
[ 1346549-25-4 ]
[ 13726-14-2 ]
N-[4-chloro-3-(methyloxy)phenyl]-6-(tetrahydro-2H-pyran-4-ylthio)-4-quinolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.9%	With hydrogenchloride; In ethanol; at 80℃; for 72h;	A mixture of 4-chloro-6-(tetrahydro-2H-pyran-4-ylthio)quinoline (1.4 g, 5.00 mmol), 4-chloro-3-(methyloxy)aniline (0.789 g, 5.00 mmol) and ethanol (16.68 ml) was treated with concentrated HCl (1 drop) and at 80 C for 3d. The reaction was cooled to rt, poured into diethylether (300 mL) and filtered to provide crude product (1g). The material was partitioned between ethyl acetate and sat. sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (1x) and the combined organic extracts were washed with brine (1x), dried over magnesium sulfate, dry-loaded onto silica gel and purified via column chromatography (ISCO-Rf, 40g column, 0-10% methanol/DCM) to afford N-[4-chloro-3-(methyloxy)phenyl]-6-(tetrahydro-2H-pyran-4-ylthio)-4-quinolinamine (700 mg, 1.746 mmol, 34.9 % yield) as a brown oil. 1H NMR (400 MHz, DMSO-d6) delta ppm 9.07 (s, 1 H), 8.48 (d, J=5.3 Hz, 1 H), 8.41 (d, J=1.8 Hz, 1 H), 7.85 (d, J=8.8 Hz, 1 H), 7.70 - 7.79 (m, 1 H), 7.43 (d, J=8.6 Hz, 1 H), 7.12 (d, J=2.3 Hz, 1 H), 7.06 (d, J=5.3 Hz, 1 H), 6.96 (dd, J=8.5, 2.4 Hz, 1 H), 3.81 - 3.90 (m, 5 H), 3.63 - 3.67 (m, 1 H), 3.40 (td, J=11.2, 2.4 Hz, 2 H), 1.84 - 1.94 (m, 2 H), 1.48 - 1.62 (m, 2 H). MS (m/z) 401(M+H)+.

Reference： [1]Patent: EP2566477,2015,B1 .Location in patent: Paragraph 0237; 0239

44
[ 402-69-7 ]
[ 13726-14-2 ]
N-(4-chloro-3-methoxyphenyl)-6-fluoro-2-picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 20 - 50℃;	General procedure: The synthesis was carried out by using the synthetic method a. To a solution of 2-picolinic acid (0.871 g,7.08 mmol), N-hydroxybenzotriazolehydrate (HOBt.H2O,1.084 g, 7.08 mmol), diisopropylethylamine(DIPEA, 1.83 g, 14.17mmol) and N-(3-methylaminopropyl)-N?-ethylcarbodiimidehydrochloride (EDCHCl, 2.036 g, 10.63mmol) in anhydrous 1,4-dioxane (60 mL) was added 3-fluoro-3-methoxyanilline (1.00 g, 7.08 mmol) at room temperature. The mixture was heated to 50 oC and stirred overnight. To the reaction mixture was added 300 mL of dichloromethane, and sequentially washed with water (3 x100 mL). After the organic layer was separated and concentrated, the reaction mixture was purified by silica-gel chromatography (hexane/ethyl acetate) to give the product as a pale-yellow solid (1.559 g, 6.33mmol, 89.4percent yield).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3956 - 3960

45
[ 637-87-6 ]
[ 13726-14-2 ]
4-chloro-N-(4-chlorophenyl)-3-methoxyaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35.2%	With palladium diacetate; sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate; In toluene; at 110℃; for 12h;Inert atmosphere;	Step 1 : 4-choro-3-methoxy aniline (2.0 g, 12.6 mmol), 1-chloro-4-iodobenzene (3.33 g, 13.9 mmol, and sodium-tert-butoxide (6.04 g, 63 mmol) were taken in toluene (15 mL). The resulting mixture was purged with nitrogen, added Pd(OAc)2 (0.141 g, 0.63 mmol), [HPtBu3][BF4] ( 0.255 g, 0.88 mmol) and heated at 110 C for 12 h. After completion of the reaction, the reaction mixture was filtered through celite bed and concentrated under vacuum. The residue obtained was diluted with ethyl acetate (200 mL) washed with water, brine solution and dried over anhydrous Na2S04. The organic phase was concentrated and purified by the column chromatography (230-400 size mesh) to get the white solid 4-chloro-N-(4_chlorophenyl)-3- methoxy aniline (1.2 g, 35.2%). 1H NMR (400 MHz, DMSO-d6): delta 8.46 (s, 1H), 7.22-7.28 (m, 3H), 7.08-7.10 (m, 2H), 6.75 (s, 1H), 6.64 (d, J = 8.68 Hz, 1H), 3.80 (s, 3H).

Reference： [1]Patent: WO2016/827,2016,A1 .Location in patent: Page/Page column 83

46
[ 50-00-0 ]
[ 13726-14-2 ]
(4-chloro-3-methoxyphenyl)-N-methylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%		Step 1(4-Chloro-3-methoxy-phenyl)-methyl-amineIn a 50 mL flask are added 4-Chloro-3-methoxy-phenylamine (907 mg), sodium methoxide (1.56 g), 10 mL anhydrous methanol, and paraformaldehyde (690 mg). Reaction mixture is then stirred overnight at room temperature. Then, paraformaldehyde (173 mg) and sodium methoxyde (311 mg) are added, and reaction mixture is heated at reflux for 1 hour. Sodium borohydride (436 mg) is then added, and reaction mixture is stirred at reflux for 4 hours. Once back at room temperature, mixture is partially evaporated, and KOH aq 1M (50 mL) is then added. The obtained suspension is extracted by Et20, organic phase is dried over Na2S04 and evaporated. The obtained residue is purified by flash chromatography (cHex to cHex/EtOAc 8/2) to give 650 mg of the expected product (66 %).MS [M+H]+ m/z = 171.9 1H-NMR (DMSO- 6) : delta (ppm) 2.66 (d, J = 4.9 Hz, 3H) ; 3.77 (s, 3H) ; 5.80 (q, J = 4.9 Hz, 1H) ; 6.09 (dd, J = 2.5 Hz, J = 8.7 Hz, 1H) ; 6.25 (d, J = 2.4 Hz, 1H) ; 7.04 (d, J = 8.7 Hz, 1H).

Reference： [1]Patent: WO2015/189330,2015,A1 .Location in patent: Page/Page column 39; 40
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

47
[ 145729-61-9 ]
[ 13726-14-2 ]
2-chloro-5-propyl-N<SUP>4</SUP>-(3-methoxy-4-chlorophenyl)pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 67h;Reflux;	General procedure: Procedure B: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below.
27%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 67h;Reflux;	This was prepared from MAl-039 (0.262 g) and 3-methoxy-4-chloroaniline (0.227 g) using procedure B (reaction time, 67 h) to give the title compound as a white solid (0.116 g, 27%). Mp: 142-142 C. lH NMR (400 MHz, DMSO-ifc): delta 10.04 (s, 1H, disappeared on D20 shake), 8.43 (s, 1H), 7.66 (s, 1H), 7.31 (s, 1H), 7.30 (s, 1H), 3.82 (s, 3H), 2.54 (t, / = 7.5 Hz, 2H), 1.58 (sextet, / = 7.5 Hz, 2H), 0.92 (t, / = 7.5 Hz, 3H). HPLC-MS (ESI+): m/z 314.1 [70%, (M35C137 +], 312.1 [100%, (M35C135C1+H)+]. Procedure B A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below.

Reference： [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 77; 102
[2]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 186; 212

48
[ 13544-44-0 ]
[ 13726-14-2 ]
2-chloro-5-iodo-N<SUP>4</SUP>-(3-methoxy-4-chlorophenyl)pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 1h;Reflux;	General procedure: Procedure B: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below.
90%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 1h;Reflux;	This was prepared from <strong>[13544-44-0]2,4-dichloro-5-iodopyrimdine</strong>(0.550 g) and 3-methoxy-4-chloroaniline (0.315 g) using procedure B (reaction time, 1 h) to give the title compound as a gray solid (0.708 g, 90%). Mp: 190-192 C (dec). lH NMR (400 MHz, DMSO-ifc): delta 8.94 (s, 1H, disappeared on D20 shake ), 8.59 (s, 1H), 7.43 (d, / = 2.3 Hz, 1H), 7.41 (d, / = 8.6 Hz, 1H), 7.21 (dd, / = 8.6, 2.3 Hz, 1H), 3.84 (s, 3H). HPLC-MS (ESI+): m/z 397.9 [78%, (M35C137C1+H)+], 395.9 [100%, (M35C135C1+H)+].

Reference： [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 77; 102
[2]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 186; 212

49
[ 5424-21-5 ]
[ 13726-14-2 ]
2-chloro-N<SUP>4</SUP>-(4-chloro-3-methoxyphenyl)-6-methylpyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 72h;Reflux;	General procedure: Procedure B: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below.

Reference： [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 77; 83

50
[ 514843-12-0 ]
[ 13726-14-2 ]
2-chloro-5-methylethyl-N⁴-[3-methoxy-4-chlorophenyl]-pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 36h;Reflux;	General procedure: Procedure B: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below.

Reference： [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 77; 106-107

51
[ 1240390-28-6 ]
[ 13726-14-2 ]
2-chloro-N<SUP>4</SUP>-(4-chloro-3-methoxyphenyl)-5-carbamoylpyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 12.5h;Reflux;	General procedure: Procedure B: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below.
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 12.5h;Reflux;	A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below. 2-Chloro-^V4-(4-chloro-3-methoxyphenyl)-5-carbamoylpyrimidin-4-amine (SG2- 132): This was prepared from SG2-138 (0.096 g) and 4-chloro-3-methoxyaniline (0.079 g) using procedure B (reaction time, 12.5 h). Water (2 mL) was added and the precipitate was filtered, washed with water (1 x 10 mL) and hexanes (1 x 10 mL), and dried to give the title compound as a brown solid (0.110 g, 49%; 52% purity based on HPLC-MS) and used in the next step without further purification. HPLC-MS (ESI+): m/z 315.0 [30%, (M37C1+H)+], 313.0 [40%, (M35C1+H)+].

Reference： [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 77; 91
[2]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 186; 201

52
[ 5750-76-5 ]
[ 13726-14-2 ]
2,5-dichloro-N<SUP>4</SUP>-(4-chloro-3-methoxyphenyl)pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 12h;Reflux;	General procedure: Procedure B: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below.
82%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 12h;Reflux;	A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below. 2,5-Dichloro-/Y4-(4-chloro-3-methoxyphenyl)pyrimidin-4-amine (SG1-168): This was prepared from 2,4,5-trichloropyrimidine (0.500 g), 4-chloro-3-methoxyaniline (0.451 g), and DIPEA (0.570 mL) using procedure B (reaction time, 12 h). The solvent was removed and EtOAc (20 mL) was added. The organic layer was extracted with water (20 mL). The aqueous layer was re-extracted with EtOAc (20 mL). The organic layers were combined and washed with water and brine (20 mL each), dried (Na2S04) and concentrated under reduced pressure. The resulting dark purple oil was triturated using EtOAc/hexanes to give the title compound as a light purple solid (0.680 g, 82%). Mp: 136-138 C. NMR (400 MHz, DMSO-ifc): delta 9.57 (s, 1H, disappeared on D20 shake), 8.41 (s, 1H), 7.49 (d, / = 2.2 Hz, 1H), 7.41 (d, / = 8.6 Hz, 1H), 7.28 (dd, / = 8.6, 2.2 Hz, 1H), 3.82 (s, 3H). HPLC-MS (ESI+): m/z 308.1 [40%, (M35C137C137C1+H)+], 306.1 [98%, (M35C135C137C1+H)+], 304.0 [100%, (M35C135C135C1+H)+].

Reference： [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 77; 78
[2]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 186-187

53
[ 1780-32-1 ]
[ 13726-14-2 ]
2-chloro-N-(4-chloro-3-methoxyphenyl)-5,6-dimethylpyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 85℃; for 23.5h;Microwave irradiation; Sealed tube;	2-Chloro-iV-(4-chloro-3-methoxyphenyl)-5,6-dimethylpyrimidin-4-amine (RJ1-034): A mixture of RJ1-008 (0.354 g, 2.0 mmol), 4-chloro-3-methoxyaniline (0.331 g, 2.1 mmol), DIPEA (0.42 mL, 2.4 mmol), and iPrOH (2 mL) was added to a 5 mL microwave vial which was then sealed and placed in a hot oil bath at 85 C with stirring. After 23.5 hours, DMAP (0.024 g, 0.2 mmol) was added as no significant reaction was observed by TLC or LC/MS. After 3.5 days, the vial was removed from the oil bath and the reaction mixture was concentrated before being dissolved in EtOAc (20 mL) and washed with water (20 mL). The aqueous layer was re-extracted with EtOAc (20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and concentrated. The residue was then dissolved in EtOAc and purified via flash chromatography, and the desired product was collected at hexane/EtOAc 22-25% to give RJ1-034 as a yellow-orange solid (0.117 g, 20%). m.p. = 162 C (decomposed). NMR (400 MHz, DMSO-) delta 8.78 (s, 1H), 7.49 (d, J= 2.3 Hz, 1H), 7.35 (d, J= 8.6 Hz, 1H), 7.28 (dd, J= 8.6, 2.3 Hz, 1H), 3.82 (s, 3H), 2.32 (s, 3H), 2.14 (s, 3H). LRMS (ESI+) m/z 298.1 (M35C1+H)+, 300.0 (M37C1+H)+; HRMS (ESI+) m/z calculated for C13H13CI2N3O (M+H)+ 298.05084, found 298.04992.
20%		A mixture of RJ1-008 (0.354 g, 2.0 mmol), 4-chloro-3-methoxyaniline (0.331 g, 2.1 mmol), DIPEA (0.42 mL, 2.4 mmol), and iPrOH (2 mL) was added to a 5 mL microwave vial which was then sealed and placed in a hot oil bath at 85 C with stirring. After 23.5 hours, DMAP (0.024 g, 0.2 mmol) was added as no significant reaction was observed by TLC or LC/MS. After 3.5 days, the vial was removed from the oil bath and the reaction mixture was concentrated before being dissolved in EtOAc (20 mL) and washed with water (20 mL). The aqueous layer was re-extracted with EtOAc (20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and concentrated. The residue was then dissolved in EtOAc and purified via flash chromatography, and the desired product was collected at hexane/EtOAc 22-25% to give RJ1-034 as a yellow-orange solid (0.117 g, 20%). m.p. = 162 C (decomposed). NMR (400 MHz, DMSO-ifc) delta 8.78 (s, 1H), 7.49 (d, / = 2.3 Hz, 1H), 7.35 (d, / = 8.6 Hz, 1H), 7.28 (dd, / = 8.6, 2.3 Hz, 1H), 3.82 (s, 3H), 2.32 (s, 3H), 2.14 (s, 3H). LRMS (ESI+) m/z 298.1 (M35C1+H)+, 300.0 (M37C1+H)+; HRMS (ESI+) m/z calculated for C13H13CI2N3O (M+H)+ 298.05084, found 298.04992.

Reference： [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 95-96
[2]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 205

54
[ 51940-64-8 ]
[ 13726-14-2 ]
ethyl 2-chloro-4-(4-chloro-3-methoxyphenylamino)pyrimidine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 85℃; for 17h;Microwave irradiation; Sealed tube;	Ethyl 2-chloro-4-(4-chloro-3-methoxyphenylamino)pyrimidine-5-carboxylate (RJ1- 061): A mixture of <strong>[51940-64-8]ethyl 2,4-dichloropyrimidine-5-carboxylate</strong> (0.442 g, 2.0 mmol), 4-chloro-3- methoxyaniline (0.331 g, 2.1 mmol), DIPEA (0.42 mL, 2.4 mmol), and iPrOH (2 mL) was added to a 5 mL microwave vial which was then sealed and placed in a hot oil bath with stirring at 85 C overnight for 17 hours. At this point, a brown solid had formed and this was then washed with iPrOH (10 mL), water (10 mL), iPrOH (10 mL), and hexanes (10 mL) to yield RJ1-061 as a brown solid (0.570 g, 83%). m.p. = 119 C (decomposed). XH NMR (400 MHz, DMSO-) delta 10.27 (s, 1H), 8.81 (s, 1H), 7.48 (d, J= 2.3 Hz, 1H), 7.43 (d, J= 8.6 Hz, 1H), 7.28 (dd, J= 8.6, 2.3 Hz, 1H), 4.37 (q, J= 7.1 Hz, 2H), 3.85 (s, 3H), 1.34 (t, J= 7.1 Hz, 3H). LRMS (ESI+) m/z 342.1 (MC135C135+H)+, 344.0 (MC135C137+H)+, 346.0 (MC137C137+H)+; (ESI-) m/z 339.3 (MC135C135-H)-; HRMS (ESI+) m/z calculated for C14H13CI2N3O3 (M+H)+ 342.04067, found 342.04100.
83%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 85℃; for 17h;Sealed tube;	A mixture of <strong>[51940-64-8]ethyl 2,4-dichloropyrimidine-5-carboxylate</strong> (0.442 g, 2.0 mmol), 4-chloro-3- methoxyaniline (0.331 g, 2.1 mmol), DIPEA (0.42 mL, 2.4 mmol), and iPrOH (2 mL) was added to a 5 mL microwave vial which was then sealed and placed in a hot oil bath with stirring at 85 C overnight for 17 hours. At this point, a brown solid had formed and this was then washed with iPrOH (10 mL), water (10 mL), iPrOH (10 mL), and hexanes (10 mL) to yield RJ1-061 as a brown solid (0.570 g, 83%). m.p. = 119 C (decomposed). NMR (400 MHz, DMSO-ifc) delta 10.27 (s, 1H), 8.81 (s, 1H), 7.48 (d, / = 2.3 Hz, 1H), 7.43 (d, / = 8.6 Hz, 1H), 7.28 (dd, / = 8.6, 2.3 Hz, 1H), 4.37 (q, / = 7.1 Hz, 2H), 3.85 (s, 3H), 1.34 (t, / = 7.1 Hz, 3H). LRMS (ESI+) m/z 342.1 (MC135C135+H)+, 344.0 (MC135C137+H)+, 346.0 (MC137C137+H)+; (ESI-) m/z 339.3 (MC135C135-H)-; HRMS (ESI+) m/z calculated for C14H13CI2N3O3 (M+H)+ 342.04067, found 342.04100.

Reference： [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 99
[2]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 209

55
[ 13726-14-2 ]
[ 34171-40-9 ]
2-chloro-5-ethyl-N<SUP>4</SUP>-(3-methoxy-4-chlorophenyl)pyrimidin-4-amine [ No CAS ]
5-ethyl-N⁴,N²-bis-[4-chloro-3-methoxyphenyl]pyrimidine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%; 9%	In methanol; water; at 45℃; for 16h;	General procedure: Procedure A: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.) and substituted aniline (1.15 equiv.) in MeOH/water (1 : 1.5, 0.2 M) was stirred at 45 C. The reaction time is indicated below. Upon cooling to ambient temperature, the desired product precipitated and was filtered, washed with MeOH/water (1 : 1.5, 20 mL), and dried.
23%; 9%	In methanol; water; at 45℃; for 384h;	This was prepared from MA1-012 (0.531 g) and 3-methoxy-4-chloroaniline (0.473 g) using procedure A (reaction time, 16 h) to give the title compound as a white solid (0.202 g, 23%). Mp: 143-144 C. lH NMR (400 MHz, DMSO-ifc): delta 8.93 (s, IH, disappeared on D20 shake), 8.07 (s, IH), 7.53 (d, / = 2.3 Hz, IH), 7.37 (d, / = 8.6 Hz, IH), 7.31 (dd, / = 8.6, 2.3 Hz, IH), 3.83 (s, 3H), 2.61 (q, J = 7.4 Hz, 2H), 1.17 (t, / = 7.4 Hz, 3H). HPLC-MS (ESI+): m/z 300.1 [70%, (M37C135C1+H)+], m/z 298.1 [100%, (M35C135C1+H)+]. Further elution gave the bis- adddition side product MA1-025B (109 mg, 9%) as a yellow solid, Mp: 201 C (dec). HPLC: 99% [tR = 8.1 min, 65% MeOH, 35% water (with 0.1% TFA), 20 min]. lH NMR (400 MHz, DMSO-ifc): delta 9.20 (s, IH, disappeared on D20 shake), 8.48 (s, IH, 40% reduced on D20 shake), 7.97 (s, IH), 7.56 (d, / = 2.3 Hz, IH), 7.43 (d, / = 2.3 Hz, IH), 7.38 (dd, / = 8.6, 2.3 Hz, IH), 7.32 (d, / = 8.7 Hz, IH) 7.29 (dd, / = 8.6, 2.3 Hz, IH), 7.15 (d, / = 8.7 Hz, IH), 3.74 (s, 3H), 3.60 (s, 3H), 2.57 (q, / = 7.4 Hz, 2H), 1.18 (t, / = 7.4 Hz, 3H). HPLC-MS (ESI+): m/z 421.1 [70%, (M37C135C1+H)+], 419.2 [100%, (M35C135C1+H)+]. LC-MS (ESI+): 421.1 [70%, (M37C135C1+H)+], 419.1 [100%, (M35C135C1+H)+]. HRMS (ESI+): m/z calcd for C20H20CI2N4O2 (M+H)+ 1035.Pr ocedure A: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.) and substituted aniline (1.15 equiv.) in MeOH/water (1 : 1.5, 0.2 M) was stirred at 45 C. The reaction time is indicated below. Upon cooling to ambient temperature, the desired product precipitated and was filtered, washed with MeOH/water (1 : 1.5, 20 mL), and dried. 2,5-Dichloro-/Y4-(4-[/Y-(l,l-dimethylethyl)sulfamoyl]phenyl)pyrimidin-4-amine (SG1-182): This was prepared from 2,4,5-trichloropyrimidine (0.500 g) and SG1-177 (0.715 g) using procedure A (stirred for 4 d). The crude solid was purified via flash chromatography (S1O2) eluting with hexanes/EtOAc (0: 10 to 4:6 v/v) to provide the title compound as a tangerine-colored solid (0.590 g, 58%). Mp: 180-181 C. NMR (400 MHz, DMSO-ifc): delta 9.73 (s, IH, disappeared on D20 shake), 8.46 (s, IH), 7.80 (s, 4H), 7.48 (s, IH, disappeared on D20 shake), 1.09 (s, 9H). HPLC-MS (ESI+): m/z 773.1 [10%, (MCl35Cl37+M35Cl35Cl+Na)+], 379.1 [10%, (MC137C137+H)+], 377.1 [70%, (MC135C137+H)+], 375.1 [100%, (M35C135C1+H)+].

Reference： [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 77; 100
[2]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 186; 210

56
[ 1780-31-0 ]
[ 13726-14-2 ]
[ 936092-35-2 ]

Yield	Reaction Conditions	Operation in experiment
30%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 13h;Reflux;	General procedure: Procedure B: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below.
30%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 13h;Reflux;	General procedure: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below. 2-Chloro-/Y4-(4-chloro-3-methoxyphenyl)-5-methylpyrimidin-4-amine (SG1-173-01): This was prepared from 2,4-dichloro-5-methylpyrimidine (1.00 g), 4-chloro-3- methoxyaniline (1.02 g), and DIPEA (1.28 mL) using procedure B (reaction time, 13 h). The solvent was removed and EtOAc (40 mL) was added. The organic layer was extracted with water (40 mL). The aqueous layer was re-extracted with EtOAc (40 mL). The organic layers were combined, washed with water and brine (40 mL each), dried (Na2S04), and concentrated under reduced pressure. The resulting residue was purified via column chromatography (S1O2) eluting with hexanes/EtOAc (0: 10 to 4:6 v/v) to give the title compound as an off-white solid (0.530 g, 30%). Mp: 132-134 C. NMR (400 MHz, DMSO-ifc): delta 8.90 (s, 1H, disappeared on D20 shake), 8.07 (s, 1H), 7.54 (s, 1H), 7.38 (d, / = 8.7 Hz, 1H), 7.33 (d, / = 8.7 Hz, 1H), 3.83 (s, 3H), 2.16 (s, 3H). HPLC-MS (ESI+): m/z 286.1 [70%, (M35C137C1+H)+], 284.1 [100%, (M35C135C1+H)+].

Reference： [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 77; 78
[2]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 186; 187

57
[ 108-24-7 ]
[ 13726-14-2 ]
[ 98446-55-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 3h;	To a solution of 4-chloro-3-methoxyaniline (50 g, 317 mmol) and DIPEA (110 mL, 635 mmol) in CH2CI2 (700 mL) was added acetic anhydride (36 mL, 381 mmol) drop wise at 0 C and the reaction mixture was stirred at room temperature for 3 h. The reaction then was quenched with water (250 mL) and the organic layer was separated. The aqueous layer was extracted with CH2CI2 (100 mL x 3). The combined organic layers were dried (Na2S04), concentrated and purified by flash chromatography with CELCb/MeOH to give N-(4-chloro-3-methoxy phenyl)acetamide (71 g, quantitative yield) as a white solid.
100%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 3h;	Step-1: N-(4-chloro-3-methoxyphenyl)acetamide [0112] To a solution of 4-chloro-3-methoxyaniline (50 g, 317 mmol) and DIPEA (110 mL, 635 mmol) in CH2Cl2 (700 mL) was added acetic anhydride (36 mL, 381 mmol) drop wise at 0 C and the reaction mixture was stirred at room temperature for 3 h. The reaction then was quenched with water (250 mL) and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (100 mL x 3). The combined organic layers were dried (Na2SO4), concentrated and purified by flash chromatography with CH2Cl2/MeOH to give N- (4-chloro-3-methoxy phenyl)acetamide (71 g, quantitative yield) as a white solid.
100%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 3h;	To a solution of 4-chloro-3-methoxyaniline (50 g, 3 i 7 mmol) and DIPEA (i iO mE, 635 mmol) in CH2C12 (700 mE) was added acetic anhydride (36 mE, 38i mmol) drop wise at 00 C. and the reaction mixture was stirred at room temperature for 3 h. The reaction then was quenched with water (250 mE) and the organic layer was separated. The aqueous layer was extracted with CH2C12 (iOO mEx3). The combined organic layers were dried (Na2504), concentrated and purified by flash chromatography with CH2C12/MeOH to give N-(4-chloro-3-methoxy phenyl)acetamide (7i g, quantitative yield) as a white solid.

Reference： [1]Patent: WO2016/44782,2016,A1 .Location in patent: Paragraph 0123
[2]Patent: WO2016/171755,2016,A1 .Location in patent: Paragraph 0112
[3]Patent: US2016/311818,2016,A1 .Location in patent: Paragraph 0489; 0490
[4]Journal of Medicinal Chemistry,2019,vol. 62,p. 6575 - 6596

58
[ 68790-38-5 ]
[ 13726-14-2 ]
t-butyl 2-(4-chloro-3-methoxyphenylcarbamoyl)phenylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	To a solution of 2-t-butoxycarbonylaminobenzoic acid (115 mg, 0.485 mmol) in DMF (2.0 mL) was added a solution of 4-chloro-3-methoxyaniline (82.2 mg, 0.522 mmol), HOBt (70.0 mg, 0.518 mmol), EDCI·HCl (104 mg, 0.542 mmol) and DIEA (90.0 muL, 0.522 mmol) in DMF (1.0 mL). The resulting mixture was stirred at r.t. overnight. After completion of the reaction, AcOEt was added. The organic layer was washed with water and brine, dried, and concentrated to give the title compound as a pale yellow paste, which was used for the next step without further purification.

Reference： [1]Chemical and Pharmaceutical Bulletin,2014,vol. 62,p. 979 - 988

59
2-(2-(adamantan-1-yl)-1H-indol-3-yl)-2-oxoacetyl chloride [ No CAS ]
[ 13726-14-2 ]
N-(4-chloro-3-methoxyphenyl)-2-(2-(adamantan-1-yl)-1H-indol-3-yl)-2-oxoacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In toluene; for 4h;	General procedure: A dry 50 mL capacity carousel reaction tube was charged with compound 3 (1.5 mmol), and this starting material was dissolved in dry ether (12 mL). Oxalyl chloride (1.65 mmol) was added and the mixture stirred at room temperature for 2 h, the solid was filtered off. Then compound 4 was used, without purification, for the next reaction. To a solution of 4 (1 mmol) and a substituted amine (1 mmol) in toluene (10 mL) was added K2CO3 (1.0 mmol), and the mixture stirred at room temp. After completion of the reaction, the mixture was concentrated and purified by column chromatography using appropriate mixtures of CH2Cl2/MeOH to give compounds 5a-y.

Reference： [1]Molecules,2016,vol. 21

60
4-chloro-6-[(1,1-dimethylethyl)sulfonyl]-7-(methyloxy)quinazoline [ No CAS ]
[ 13726-14-2 ]
6-(tert-butylsulfonyl)-N-(4-chloro-3-rnethoxyphenyl)-7-rnethoxyquinazolin-4-arnine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ethanol; water; at 80℃; for 1h;	General procedure: In a flask was combined 4-chloro-6-[(1,1-dimethylethyl)sulfonyl]-7-(methyloxy)quinazoline (100 mg, 0.32 mmol), 5-fluoro-1H-pyrazolo[3,4-b)]pyridin-3-amine (58 mg, 0.38 mmol) in NMP (1 mL). The reaction mixture was heated at 80C for 1h. The solution was allowed to cool to rt. The solid was filtered out and remaining solution was concentrated and residue was purified by HPLC to provide 20 mg of the title compound. MS:m/z: 431 [M+H]+; 1H NMR (400 MHz, DMSO-d6) delta 1.24 - 1.36 (s, 9 H), 3.98 (s, 3 H), 7.27 (s., 1 H), 8.02 (s, J = 8.72, 2.65 Hz, 1 H), 8.42 (s, 1 H), 8.54 (s, 2 H), 9.04 (s, 1 H).

Reference： [1]Patent: EP2744501,2016,B1 .Location in patent: Paragraph 0241; 0242

61
[ 89711-08-0 ]
[ 13726-14-2 ]
C₁₄H₂₁ClN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium cyanoborohydride; In chloroform; at 20℃;	General procedure: Compounds 2-19 were synthesized by reductive alkylation ofcommercially available anilines with N-Boc-2-aminoacetaldehydeand benzoylation with 2,4-dichlorobenzoyl chloride with subsequentremoval of Boc-protecting group with 4 N HCl in dioxane.Compound precipitated from hexane/ dioxane reaction mixtureas HCl salt.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 1571 - 1584

62
[ 1780-31-0 ]
[ 13726-14-2 ]
2-chloro-N<SUP>4</SUP>-(4-chloro-3-methoxyphenyl)-6-methylpyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 72h;Reflux;	A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below. 2-Chloro-/Y4-(4-chloro-3-methoxyphenyl)-6-methylpyrimidin-4-amine (SG2-053-01): This was prepared from 2,4-dichloro-6-methylpyrimidine (0.326 g), 4-chloro-3-methoxyaniline (0.331 mg), and DIPEA (0.420 mL) using procedure B (reaction time, 3 d). Ethyl acetate (15 mL) was added to the mixture which was then washed with water (15 mL). The aqueous layer was re-extracted with EtOAc (15 mL). The organic layers were combined, washed with water and brine (15 mL each), dried (Na2S04), and concentrated under reduced pressure. The resulting residue was purified via column chromatography (S1O2) eluting with hexanes/EtOAc (2:8 to 3:4 v/v) to give the title compound as an off-white solid (0.334 g, 59%). Mp: 168-169 C. NMR (400 MHz, DMSO-ifc): delta 10.02 (s, 1H, disappeared on D20 shake), 7.44 (d, / = 1.7 Hz, 1H), 7.36 (d, / = 8.6 Hz, 1H), 7.17 (dd, / = 8.6, 1.7 Hz, 1H), 6.59 (s, 1H), 3.83 (s, 3H), 2.28 (s, 3H). HPLC-MS (ESI+): m/z 286.1 [70%, (M35C137C1+H)+], 284.1 [100%, (M35C135C1+H)+].

Reference： [1]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 186; 192

63
[ 6160-65-2 ]
[ 13726-14-2 ]
[ 120222-86-8 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile at 100℃; for 0.166667h; Inert atmosphere; Sealed tube; Microwave irradiation;	5.4 General procedure for method B for synthesis of thioureas General procedure: To thiocarbonyldiimidazole (1 eq.) in dried MeCN (0.1-0.2M), the appropriate aniline (1 eq.) was added. The reaction vial was purged with N2, sealed, and stirred at 100°C for 10min in a microwave reactor. The appropriate amine was added, and the reaction vessel was heated to 100°C for 10min. After attaining rt, the reaction mixture was diluted with EtOAc and washed three times with NaHCO3 (aq., sat.), dried over Na2SO4, filtered and concentrated. Recrystallization from an appropriate solvent or solvent mixture gave the desired compound.

Reference： [1]Knutsson, Sofie; Kindahl, Tomas; Engdahl, Cecilia; Nikjoo, Dariush; Forsgren, Nina; Kitur, Stanley; Ekström, Fredrik; Kamau, Luna; Linusson, Anna [European Journal of Medicinal Chemistry, 2017, vol. 134, p. 415 - 427]

64
[ 873203-37-3 ]
[ 141-97-9 ]
[ 13726-14-2 ]
[ 1354745-52-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-iodo-4-(4-(trifluoromethoxy)-phenoxy)benzene; ethyl acetoacetate With copper(l) iodide; caesium carbonate; 2-Phenylphenol In tetrahydrofuran at 70℃; for 30h; Schlenk technique; Sealed tube; Inert atmosphere; Stage #2: 4-chloro-m-anisidine With acetic acid In benzene at 100℃; for 24h; Dean-Stark; Stage #3: In diphenylether at 260℃; for 0.25h;

Reference： [1]Namelikonda, Niranjan K.; Monastyrskyi, Andrii; Manetsch, Roman [European Journal of Organic Chemistry, 2017, vol. 2017, # 23, p. 3328 - 3334]

65
[ 16817-43-9 ]
[ 13726-14-2 ]

Yield	Reaction Conditions	Operation in experiment
62%		General procedure: To a flame-dried 25 mL round bottom flask was charged activated Mg (7.5 mmol, 1.5 eq.) and 5 mL anhydrous THF. To this suspension was added 2 drops of 1,2-dibromoethane. After 5 min, a solution of Aryl bromide (5 mmol, 1.0 eq.) in 5 mL anhydrous THF was slowly added to the suspension of Mg at room temperature. The reaction was mildly exothermic. The Grignard reagent was titrated and 1 mmol of this reagent was added to a flame-dried reaction vial. The solution was diluted with 3 mL anhydrous toluene and after cooling to the target temperature T, a solution of oxaziridine (1.2 mmol, 1.2 eq.) in 1 mL anhydrous toluene was added. The reaction was maintained at the targeted temperature T for time t before being quenched with saturated aqueous NH4Cl. (The actual temperature/reaction time is listed for each substrate.)

Reference： [1]Nature Chemistry,2017,vol. 9,p. 681 - 688
[2]Patent: US2018/57444,2018,A1 .Location in patent: Paragraph 0098; 0134; 0135; 0184

66
[ 13726-14-2 ]
[ 5659-93-8 ]
N,N’-bis-(4-chloro-3-methoxyphenyl)-2,2-dimethylmalonic diamide [ No CAS ]

Reference： [1]Organic Letters,2018,vol. 20,p. 6785 - 6788

67
[ 1239969-34-6 ]
[ 13726-14-2 ]
N₄-(4-chloro-3-methoxyphenyl)-N₂-(4-methoxyphenyl)pyridine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl acetamide; water; at 150℃; for 1h;	General procedure: An aqueous solution of cesium carbonate (130 mg, 0.4 mmol) in water (300 ul) was dispensed into each well containing a pre-mixed solution of 4-chloro-N-(4-methoxyphenyl)pyridin-2-amine (58.8 mg, 0.2mmol), respective aniline (0.26 mmol), xantphos (13.9 mg, 0.024mmol) and palladium (II) acetate (3.6 mg, 0.016 mmol) in DMA (1.25 ml). The resultant plate was placed on a pre-heated SOPHAS base plate set at 150 oC and shaken for 1 hour. The plate was cooled to room temperature and MP-TMT resin (90 mg) added to each well prior to shaking overnight at room temperature. The following day each well was transferred to a 48 well filter plate, washing through with an extra aliquot of DMA (200 ul) before a final centrifuge. The crude filtrates were then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5mu silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford required N2-(4-methoxyphenyl)-N4-[aryl]pyridine-2,4-diamine (23-42%)

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 6900 - 6904

68
(R)-2-(4-(6-fluoroquinolin-4-yl)phenyl)-3-(2-methoxyphenyl)propanoic acid [ No CAS ]
[ 13726-14-2 ]
(R)‐N‐(4‐chloro‐3‐methoxyphenyl)‐2‐[4‐(6‐fluoroquinolin‐4‐yl)phenyl]‐3‐(2‐methoxyphenyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a solution of compound 5 (15 mg, 0.037 mmol) in DMF (3 mL)4-Chloro-3-methoxyaniline (6.2 mg, 0.04 mmol) was added.HATU (17 mg, 0.045 mmol) and TEA (7.5 mg, 0.074 mmol),Stir at room temperature for 2 hours,It was poured into water (10 mL) and extracted with ethyl acetate (2×5 mL).The organic phase was separated and washed with saturated aqueous NaCI (2×).The organic phase was separated and dried over anhydrous Na2SO4, filtered and concentrated.The residue was purified by silica gel column chromatography.Elution with ethyl acetate/petroleum ether (1:2) gave the desired compound I-8 (11 mg, 55%).

Reference： [1]Patent: CN110218182,2019,A .Location in patent: Paragraph 0143-0146

69
[ 13726-14-2 ]
[ 262851-26-3 ]

Yield	Reaction Conditions	Operation in experiment
0.385 g	Stage #1: 4-chloro-m-anisidine With hydrogenchloride; sodium nitrite In water at -5 - 0℃; for 0.5h; Stage #2: With tin(ll) chloride In water at 0 - 20℃;

Reference： [1]Haffner, Curt D.; Charnley, Adam K.; Aquino, Christopher J.; Casillas, Linda; Convery, Máire A.; Cox, Julie A.; Elban, Mark A.; Goodwin, Nicole C.; Gough, Peter J.; Haile, Pamela A.; Hughes, Terry V.; Knapp-Reed, Beth; Kreatsoulas, Constantine; Lakdawala, Ami S.; Li, Huijie; Lian, Yiqian; Lipshutz, David; Mehlmann, John F.; Ouellette, Michael; Romano, Joseph; Shewchuk, Lisa; Shu, Arthur; Votta, Bartholomew J.; Zhou, Huiqiang; Bertin, John; Marquis, Robert W. [ACS Medicinal Chemistry Letters, 2019, vol. 10, # 11, p. 1518 - 1523]

70
2,6-dichloro-9-(cyclopropylmethyl)-9H-purine [ No CAS ]
[ 13726-14-2 ]
2-chloro-N-(4-chloro-3-methoxyphenyl)-9-(cyclopropylmethyl)-9H-purin-6-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 110℃; for 12h;	General procedure: To a solution of 2 (100 mg, 0.411 mmol), aniline (154 mg, 0.411 mmol) and DIPEA (0.15 mL, 0.822 mmol) in n-butanol (20 mL) were added, and the mixture was stirred at 110 C for 12 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by silica gel chromatography using a polarity mobile phase (acetone/dichloromethane, 10:100) to give product 3a.

Reference： [1]Bioorganic Chemistry,2019

71
[ 13726-14-2 ]
C₇H₇⁽²⁾HClNO [ No CAS ]

Reference： [1]Organic Letters,2020

72
[ 87-13-8 ]
[ 13726-14-2 ]
ethyl 6-chloro-4-hydroxy-7-methoxyquinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.51%	In diphenylether; at 100 - 280℃; for 8h;	A stirred solution of 4-chi oro-3-methoxy-aniline (92, 5 g, 31.73 mmol) and diethyl 2- (ethoxymethylene)propanedioate (77, 10.29 g, 47.59 mmol, 9.53 mL) was heated to 100C and stirred for 2 hours and then further heated to 165 C and stirred for an additional hour. Diphenyl ether (50.0 mL) was added to the resulting solution and the reaction was heated to 280 C and stirred for 5 hours. The resulting reaction mixture was cooled to room temperature, pet ether (250 mL) was added and the reaction was stirred for 10 minutes at room temperature. The resulting solid was filtered, washed with pet ether and dried under vacuum to yield ethyl 6-chloro-4- hydroxy-7-methoxy-quinoline-3-carboxylate (93, 8.0 g, 28.40 mmol, 89.51% yield) as an off white solid. LCMS (ES+): m/z 282 [M + H]+

Reference： [1]Patent: WO2020/51235,2020,A1 .Location in patent: Page/Page column 267; 282-283

73
[ 460086-95-7 ]
[ 13726-14-2 ]
1-(7-((4-chloro-3-methoxyphenyl)amino)benzofuran-2-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 120℃; for 10h;	4.1.2 General procedures for the synthesis of compounds 15, A1-A17 and B1-B7 General procedure: To a solution of compounds 10, 12 or 14 (0.84mmol, 1.0 equiv) in toluene (10mL) were added the corresponding aniline (0.76mmol, 0.9 equiv), Cs2CO3 (1.176mmol, 1.4 equiv), BINAP (0.084mmol, 0.1 equiv), and Pd(OAc)2 (0.084mmol, 0.1 equiv) at room temperature. The reaction mixture was allowed to stir at 120°C for about 10h and monitored by TLC. After cooling to room temperature, diluted with ethyl acetate, washed with brine and dried with sodium sulfate. The solution was concentrated in vacuo, then loaded on silica gel, and purified by silica gel chromatography with petroleum/ethyl acetate as eluent to give the compounds 15, A1-A17 and B1-B7.

Reference： [1]Feng, Kai-Rui; Gao, Dingding; Lin, Guo-Qiang; Shi, Xin-Wei; Tian, Ping; Wang, Feng; Zhang, Jian-Wei; Zhao, Jia-Ying; Zhou, Jian [Bioorganic and Medicinal Chemistry, 2020, vol. 28, # 24]

74
ethyl 3-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)-phenyl)butanoate [ No CAS ]
C₂₆H₂₃ClF₃NO₅ [ No CAS ]
[ 13726-14-2 ]
[ 1354745-52-0 ]

Yield	Reaction Conditions	Operation in experiment
57%	Stage #1: ethyl 3-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)-phenyl)butanoate; 4-chloro-m-anisidine With toluene-4-sulfonic acid In cyclohexane for 44h; Reflux; Dean-Stark; Stage #2: C₂₆H₂₃ClF₃NO₅ at 250℃; for 0.583333h;

Reference： [1]Pou, Sovitj; Dodean, Rozalia A.; Frueh, Lisa; Liebman, Katherine M.; Gallagher, Rory T.; Jin, Haihong; Jacobs, Robert T.; Nilsen, Aaron; Stuart, David R.; Doggett, J. Stone; Riscoe, Michael K.; Winter, Rolf W. [Organic Process Research and Development, 2021, vol. 25, # 8, p. 1841 - 1852]

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2,4-Dichloro-5-methoxyaniline

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5-Chloro-2,4-dimethoxyaniline

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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