sales@ambeed.com

Structure Search

List Search MOL Search Structure Search

Hello, Sign in

Home Cart 0 Sign in

X

[ CAS No. 7206-70-4 ]

{[proInfo.proName]} ,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 7206-70-4

Chemical Structure| 7206-70-4

Chemical Structure| 7206-70-4

Structure of 7206-70-4 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Bulk Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 100K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 7206-70-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 7206-70-4 ]

SDS Specification

Alternatived Products of [ 7206-70-4 ]

Product Details of [ 7206-70-4 ]

CAS No. :	7206-70-4	MDL No. :	MFCD00038794
Formula :	C₈H₈ClNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RVEATKYEARPWRE-UHFFFAOYSA-N
M.W :	201.61	Pubchem ID :	81626
Synonyms :

Calculated chemistry of [ 7206-70-4 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	49.31
TPSA :	72.55 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.04 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.21
Log Po/w (XLOGP3) :	2.1
Log Po/w (WLOGP) :	1.64
Log Po/w (MLOGP) :	0.22
Log Po/w (SILICOS-IT) :	1.16
Consensus Log Po/w :	1.26

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.62
Solubility :	0.481 mg/ml ; 0.00239 mol/l
Class :	Soluble
Log S (Ali) :	-3.25
Solubility :	0.112 mg/ml ; 0.000557 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.16
Solubility :	1.39 mg/ml ; 0.0069 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.59

Safety of [ 7206-70-4 ]

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

Application In Synthesis of [ 7206-70-4 ]

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

Upstream synthesis route of [ 7206-70-4 ]
Downstream synthetic route of [ 7206-70-4 ]

[ 7206-70-4 ] Synthesis Path-Upstream 1~12

1
[ 20896-27-9 ]
[ 7206-70-4 ]

Yield	Reaction Conditions	Operation in experiment
91.4%	With water; potassium hydroxide In methanolReflux; Large scale	(3) the above-mentioned the resulting 4-amino-5-chloro-2-methoxybenzoic acid methyl ester and potassium hydroxide the mole ratio is that 1 : 2.2 in 7 liters of methanol and water (volume ratio of 5:2) backflow mixing in the mixed solution of 2 more than an hour, then adding activated carbon to decolorize reflux 30 minutes, followed by activated carbon filter is removed, and then reducing the the solvent turns on lathe , and adding an aqueous solution of aqueous, dropping 3mol/L PH value adjusted with hydrochloric acid to 5, a white solid separated out from the aqueous solution, filtering and drying to obtain 1.93 kg of 4-amino-5-chloro-2-methoxybenzoic acid, can be very susceptible to hydrogen spectrogram see Figure 1, the yield is 91.4percent.

Reference： [1] Patent: CN105237422, 2016, A, . Location in patent: Paragraph 0018; 0022
[2] Organic Preparations and Procedures International, 1992, vol. 24, # 1, p. 64 - 66
[3] Journal of Molecular Structure, 1988, vol. 172, p. 381 - 394

2
[ 4093-31-6 ]
[ 7206-70-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	With hydrogenchloride In ethanol; water	EXAMPLE 14 2-methoxy-4-amino-5-chloro benzoic acid 25.75 grs (0.1 mol) methyl 2-methoxy-4-acetamido-5-chlorobenzoate were introduced into a 500 ml flask, suspended in 100 ml ethanol. 40 grs NaOH, dissolved in 150 cc of water, were added and the mixture was heated under reflux for 2.5 hours. The mixture was diluted with water and made acid with concentrated HCl. The white solid which precipitated was collected and recrystallized from methanol. Weight: 17 grs m.p. = 213°-215° C. Yield = 84percent.

Reference： [1] Patent: US4138492, 1979, A,
[2] Patent: US2005/49416, 2005, A1, . Location in patent: Page/Page column 11
[3] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493

3
[ 24201-13-6 ]
[ 7206-70-4 ]

Reference： [1] Patent: WO2005/23808, 2005, A2, . Location in patent: Page/Page column 37-38

4
[ 65-49-6 ]
[ 7206-70-4 ]

Reference： [1] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493
[2] Patent: CN105237422, 2016, A,

5
[ 27492-84-8 ]
[ 7206-70-4 ]

Reference： [1] Organic Preparations and Procedures International, 1992, vol. 24, # 1, p. 64 - 66

6
[ 4093-29-2 ]
[ 7206-70-4 ]

Reference： [1] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493

7
[ 4093-28-1 ]
[ 7206-70-4 ]

Reference： [1] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493

8
[ 4136-97-4 ]
[ 7206-70-4 ]

Reference： [1] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493

9
[ 7206-70-4 ]
[ 100-36-7 ]
[ 54769-22-1 ]
[ 364-62-5 ]

Reference： [1] Patent: US4242507, 1980, A,

10
[ 7206-70-4 ]
[ 364-62-5 ]

Reference： [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 21, p. 3166 - 3170

11
[ 7206-70-4 ]
[ 4093-31-6 ]

Reference： [1] Patent: US2012/277224, 2012, A1,

12
[ 7206-70-4 ]
[ 98446-49-2 ]

Yield	Reaction Conditions	Operation in experiment
15%	With silver carbonate; copper dichloride; palladium dichloride In tetrahydrofuran at 110℃; for 24 h;	General procedure: A mixture of carboxylic acid (1 equiv., 0.5 mmol), CuBr2 or CuCl2 (2 equiv., 1 mmol), Ag2CO3 (1 equiv., 0.5 mmol) and PdCl2 (0.1 equiv.) was heated inTHF (3 mL) under reflux at 110 oC for 24 h. After the reaction finished, the mixture was evaporated under vacuum and purified by columnchromatography to afford the desired product.

Reference： [1] Tetrahedron Letters, 2013, vol. 54, # 24, p. 3079 - 3081

[ 7206-70-4 ] Synthesis Path-Downstream 1~68

1
[ 20896-27-9 ]
[ 7206-70-4 ]

Yield	Reaction Conditions	Operation in experiment
91.4%	With water; potassium hydroxide; In methanol;Reflux; Large scale;	(3) the above-mentioned the resulting 4-amino-5-chloro-2-methoxybenzoic acid methyl ester and potassium hydroxide the mole ratio is that 1 : 2.2 in 7 liters of methanol and water (volume ratio of 5:2) backflow mixing in the mixed solution of 2 more than an hour, then adding activated carbon to decolorize reflux 30 minutes, followed by activated carbon filter is removed, and then reducing the the solvent turns on lathe , and adding an aqueous solution of aqueous, dropping 3mol/L PH value adjusted with hydrochloric acid to 5, a white solid separated out from the aqueous solution, filtering and drying to obtain 1.93 kg of 4-amino-5-chloro-2-methoxybenzoic acid, can be very susceptible to hydrogen spectrogram see Figure 1, the yield is 91.4%.

Reference： [1]Patent: CN105237422,2016,A .Location in patent: Paragraph 0018; 0022
[2]Organic Preparations and Procedures International,1992,vol. 24,p. 64 - 66
[3]Journal of Molecular Structure,1988,vol. 172,p. 381 - 394

2
[ 7206-70-4 ]
[ 40987-24-4 ]
[ 126645-66-7 ]

Reference： [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 1406 - 1413

3
[ 7206-70-4 ]
[ 110859-47-7 ]
[ 112885-23-1 ]

Reference： [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 1406 - 1413

4
[ 7206-70-4 ]
[ 112914-13-3 ]
[ 112885-17-3 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 616 - 624

5
[ 7206-70-4 ]
[ 541-41-3 ]
[ 150007-96-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 0℃; for 2h;	Step 2: ClCO2Et (92 muL, 0.96 mmol) was added dropwise to a solution of 51 (247 mg, 0.86 mmol) and Et3N (121 muL, 0.88 mmol) in THF (5 mL) at 0 C, and the reaction mixture was stirred for 2 h. A solution of 50 (194 mg, 0.96 mmol) in THF (1 mL) was then added dropwise via cannula and the reaction was allowed to warm to rt over 16 h. The insoluble residue was filtered, and the filtrate was concentrated in vacuo. Purification via flash column chromatography (eluent CH2Cl2/MeOH/Et3N, 96:3:1) gave 40 as a colourless oil (205 mg, 64% from 49, >99:1 dr); +3.3 (c 1.0 in CHCl3); numax (ATR) 3576, 3525, 3469, 3326, 3006, 2970, 2929, 2856, 1738, 1629; deltaH (500 MHz, CDCl3) 1.79-1.92 (2H, m, C(5)H2), 1.95-2.05 (2H, m, C(2')H2), 2.16-2.29 (2H, m, C(2)HA, C(6)HA), 2.50-2.61 (2H, m, C(1')H2), 2.76-2.88 (1H, m, C(6)HB), 3.01-3.16 (1H, m, C(2)HB), 3.44 (3H, s, OMe), 3.44-3.47 (1H, m, C(3)H), 3.89 (3H, s, OMe), 3.93-4.01 (2H, m, C(3')H2), 4.17-4.25 (1H, m, C(4)H), 4.37 (2H, s, NH2), 6.30 (1H, s, C(3)H), 6.80-6.87 (2H, m, C(2)H, C(6)H), 6.93-7.00 (2H, m, C(3)H, C(5)H), 8.11 (1H, s, C(6)H), 8.21 (1H, d, J 8.2, CONH); deltaC (125 MHz, CDCl3) 26.8 (C(2')), 27.8 (C(5)), 48.0 (C(4)), 51.9 (C(6)), 53.6 (C(2)), 55.2 (C(1')), 56.0, 57.0 (2× OMe), 66.9 (C(3')), 76.7 (C(3)), 97.9 (C(3)), 111.6 (C(1)), 112.9 (C(5)), 115.4 (d, J 7.6, C(2), C(6)), 115.7 (d, J 22.9, C(3), C(5)), 133.1 (C(6)), 146.5 (C(4)), 155.1 (d, J 1.9, C(1)), 157.2 (d, J 238, C(4)), 157.5, 163.7 (C(2), C(1)CONH); deltaF (470 MHz, CDCl3) 124.2 (C(4)F); m/z (ESI+) 466 ([M(35Cl)+H]+, 100%); HRMS (ESI+) C23H3035ClFN3O4+ ([M(35Cl)+H]+) requires 466.1903; found 466.1902.

Reference： [1]Journal of Medicinal Chemistry,1981,vol. 24,p. 1224 - 1230
[2]Journal of Molecular Structure,1988,vol. 172,p. 381 - 394
[3]Chemical and Pharmaceutical Bulletin,1992,vol. 40,p. 202 - 211
[4]Journal of Medicinal Chemistry,1993,vol. 36,p. 3166 - 3170
[5]European Journal of Medicinal Chemistry,1996,vol. 31,p. 231 - 239
[6]Journal of medicinal chemistry,1996,vol. 39,p. 2764 - 2772
[7]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 424 - 436
[8]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 788 - 790
[9]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 189 - 192
[10]Tetrahedron,2012,vol. 68,p. 3263 - 3275
[11]Journal of labelled compounds and radiopharmaceuticals,2015,vol. 58,p. 342 - 348

6
[ 7206-70-4 ]
[ 1738-76-7 ]
(4-Amino-5-chloro-2-methoxy-benzoylamino)-acetic acid benzyl ester [ No CAS ]

Reference： [1]Il Farmaco,1994,vol. 49,p. 805 - 808

7
[ 7206-70-4 ]
[ 77-78-1 ]
[ 20896-27-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate In dimethyl sulfoxide for 4h; Heating;

Reference： [1]Ohmori; Maeno; Hidaka; Nakato; Matsumoto; Tada; Hattori; Sakamoto; Tsukamoto; Usuda; Mase [Journal of medicinal chemistry, 1996, vol. 39, # 14, p. 2764 - 2772]

8
[ 7206-70-4 ]
[ 168466-84-0 ]
4-amino-<i>N</i>-(1-benzyl-piperidin-3-yl)-5-chloro-2-methoxy-benzamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3293 - 3296

9
[ 7206-70-4 ]
[ 168466-85-1 ]
4-amino-<i>N</i>-(1-benzyl-piperidin-3-yl)-5-chloro-2-methoxy-benzamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3293 - 3296

10
[ 7206-70-4 ]
[ 144222-22-0 ]
[ 188973-04-8 ]

Yield	Reaction Conditions	Operation in experiment
96%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine;benzotriazol-1-ol; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h;	Step 5: Preparation of tertiary butyl 4-((4-amino-5-chloro-2-methoxybenzamido)methyl)piperidine-1-carboxylate (compound of formula 10) <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (compound of formula 9) (16.6g, 82.28mmol) was dissolved in dimethylformamide (166mL) and the solution was cooled to 0. Then, tertiary butyl 4-(aminomethyl)piperidine-1-carboxylate (21.16g, 98.74mmol), triethylamine (11.56mL, 246.84mmol), N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (EDC, 20.51g, 106.96mmol), and 1-hydroxybenzotriazole (HOBT, 16.68g, 123.42mmol) were added thereto. The reaction mixture was warmed to room temperature, stirred for 4 hours, and extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound (31.4g, 96%). 1H NMR (CDCl3, 400MHz): delta 8.08 (s, 1H), 7.76-7.70 (m, 1H), 6.27 (s, 1H), 4.37 (s, 2H), 4.16-4.04 (m, 2H), 3.88 (s, 3H), 3.34-3.26 (m, 2H), 2.74-2.60 (m, 2H), 1.80-1.63 (m, 3H), 1.42 (s, 9H), 1.20-1.10 (m, 2H).
64.1%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;	To a mixture of 4-aminomethyl-l- (tert-butoxycarbonyl) piperidine (10.0 g, 46.7 mmol) , 4-amino-5-chloro-2~ methoxybenzoic acid (9.41 g, 46.7 mmol) and NEt3 (6.80 ml, 46.7 mmol) in DMF (100 ml) were added l-ethyl-3- [3- (dimethylamino)propyl] carbodiimide hydrochloride (EDC) (9.39 g, 46.7 mmol) and 1-hydroxybenzotriazole (HOBT) (6.62 g, 46.7 mmol) at 00C. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The resulting residue was added H2O (100 ml) and extracted with EtOAc. The combined organic extracts were washed with aqueous K2CO3 and dried over Na2SO4. The solvent was removed in vacuo and the residue separated with flash chromatography (SiO2, EtOAc) to give the expected product as a white solid (11.91 g, 64.1%).1H-NMR (200 MHz, CDCl3) :delta 8.06 (s, 1 H), 7.77 (t, 1 H), 6.33 (s, 1 H), 4.64 (s, 2 H), 4.08 (d, 2 H), 3.86 (s, 3 EPO <DP n="51"/>H) , 3.30 (t, 2 H), 2.67 (t, 2 H), 1.78-1.66 (m, 3 H), 1.43 (s, 9 H) , 1.24-1.11 (m, 2 H)
64.1%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 0 - 20℃;	Example 29 Synthesis of 4-amino-N- (tert-butoxycarbonyl) piperidin-4-ylmethyl]-5-chloro-2- methoxybenzamide A mixture of 4-aminomethyl-1-(tert-butoxycarbonyl) piperidine (10.0 g, 46.7 mmol), 4- amino-5-chloro-2-methoxybenzoic acid (9.41 g, 46.7 mmol) and NEt3 (6.80 ml, 46.7 mmol) in DMF (100 ml) were added 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (EDC) (9.39 g, 46.7 mmol) and 1-hydroxybenzotriazole (HOBT) (6.62 g, 46.7 mmol) at 0 C. The reaction mixture was stirred to room temperature overnight and concentrated in vacuo. The resulting residue was added H2O (100 ml) and extracted with EtOAc. The combined organic extracts were washed with aqueous K2CO3 and dried over Na2S04. The solvent was removed in vacuo and the residue separated with flash chromatography (SiO2, EtOAc) to give the expected product as a white solid (11.91 g, 64.1 %). 'H-NMR (200 MHz, CDCl3) : 8 8.06 (s, 1 H), 7.77 (t, 1 H), 6.33 (s, 1 H), 4.64 (s, 2 H), 4.08 (d, 2 H), 3.86 (s, 3 H), 3.30 (t, 2 H), 2.67 (t, 2 H), 1.78-1. 66 (m, 3 H), 1.43 (s, 9 H), 1.24-1. 11 (m, 2 H)

1,1'-Carbonyldiimidazole (1.61 g, 9.91 mmol) was added to a solution of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (2.0 g, 9.91 mmol) in dimethylformamide (5 ml). After stirring for 5 min. at room temperature, solution of N-tert-butyloxycarbonyl-4-(aminomethyl)piperidine (1.77 g, 8.26 mmol) in dimethylformamide (5 ml) was added and the reaction mixture was heated at 55 C. After 23 h, the product was extracted into ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. Flash chromatography of the crude product with 2:1, ethyl acetate/hexanes as the eluant gave N-tert-butyloxycarbonyl-4-(4-amino-5-chloro-2-methoxyphenylcarbonylaminomethyl)piperidine (2.63 g) as a foam.

Reference： [1]Patent: WO2011/132901,2011,A2 .Location in patent: Page/Page column 14-15
[2]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 4225 - 4234
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 3172 - 3187
[4]Patent: WO2007/7072,2007,A1 .Location in patent: Page/Page column 49-50
[5]Patent: WO2005/61483,2005,A2 .Location in patent: Page/Page column 49
[6]Patent: US6339087,2002,B1 .Location in patent: Page column 57-58
[7]Journal of Medicinal Chemistry,2009,vol. 52,p. 5330 - 5343

11
[ 64-17-5 ]
[ 7206-70-4 ]
[ 35019-78-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With hydrogenchloride; at 65℃; for 6h;High pressure;	Ethyl 4-amino-5-chloro-2-methoxybenzoate. A solution of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (6.6 g, 0.031 mol) in hydrogen chloride 1.25M in Ethanol (250 mL, 0.31mol) was stirred in a pressure vessel for 6h at 65C. The reaction mixture was basified with sodium hydroxide 2N and extracted with methylene chloride. The organic layer was washed with water, dried and filtered. The solvent was removed under reduced pressure giving the title compound as a white solid (78%), which was used in the next step without further purification. LRMS (m/z): 230(M+1)+.
		Intermediate 37.Ethyl 4-amino-5-chloro-2-methoxybenzoate.A solution of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (6.6 g, 0.031 mol) in hydrogen chloride 1.25M in Ethanol (250 mL, 0.31 mol) was stirred in a pressure vessel for 6h at 65C. The reaction mixture was basified with sodium hydroxide 2N and extracted with methylene chloride. The organic layer was washed with water, dried and filtered. The solvent was removed under reduced pressure giving the title compound as a white solid (78%), which was used in the next step without further purification.LRMS (m/z): 230(M+1 )+.

Reference： [1]Patent: EP2386555,2011,A1 .Location in patent: Paragraph 0125
[2]Journal of Medicinal Chemistry,2004,vol. 47,p. 6973 - 6982
[3]Patent: WO2011/141180,2011,A1 .Location in patent: Page/Page column 37

12
[ 7206-70-4 ]
[ 24190-74-7 ]

Yield	Reaction Conditions	Operation in experiment
92%	With pyridine; SULFAMIDE; for 2.5h;Heating / reflux;	Step i; 4-Amino-5-chloro-2-methoxybenzamide; <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (commercially available) (600mg, 2.98 mmol) was added to sulfamide (715 mg; 7.44 mmol, 2.5 equiv) and the mixture was then dissolved in pyridine (2.9 ml) and heated under nitrogen atmosphere for 2.5 hours. Reaction mixture was allowed to cool to ambient temperature and the pyridine was removed in vacuo. The resulting solids were washed with 10% MeOH in dichloromethane. Filtered and dried to afford a cream solid 550mg; 92%.
92%	With pyridine; sulfonamide; for 2.5h;Inert atmosphere; Heating;	<strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (commercially available) (600mg, 2.98 mmol) was added to sulfamide (715 mg; 7.44 mmol, 2.5 equiv) and the mixture was then dissolved in pyridine (2.9 mL) and heated under nitrogen atmosphere for 2.5 hours. Reaction mixture was allowed to cool to ambient temperature and the pyridine was removed in vacuo. The resulting solids were washed with 10% MeOH in dichloromethane. Filtered and dried to afford a cream solid 550 mg, 92%.
92%	With pyridine; SULFAMIDE; for 2.5h;Heating / reflux;	Step i <n="79"/>4-Amino-5-chloro-2-methoxybenzamide<strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (commercially available) (600mg, 2.98 mmol) was added to sulfamide (715 mg; 7.44 mmol, 2.5 equiv) and the mixture was then dissolved in pyridine (2.9 ml) and heated under nitrogen atmosphere for 2.5 hours. Reaction mixture was allowed to cool to ambient temperature and the pyridine was removed in vacuo. The resulting solids were washed with 10% MeOH in dichloromethane. Filtered and dried to afford a cream solid 550mg; 92%.

Reference： [1]Patent: WO2009/30871,2009,A1 .Location in patent: Page/Page column 45-46
[2]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 6770 - 6789
[3]Patent: WO2007/104944,2007,A1 .Location in patent: Page/Page column 77-78

13
[ 7206-70-4 ]
[ 4774-14-5 ]
[ 1000068-63-2 ]

Yield	Reaction Conditions	Operation in experiment
	With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 135℃; for 4h;Heating / reflux;	2,6-dichloropyrazine (0.40 g, 2.7 mmol), <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (0.60 g, 3.0 mmol), NaOtBu (0.52 g, 5.3 mmol), Xantphos (45 mg, 0.08 mmol) and Pd2(dba)3 (25 mg, 0.027 mmol) were stirred in dry dioxane (10 rnL). The reaction mixture was refluxed at 135 0C for 4 hours, then allowed to attain rt. The mixture was concentrated under reduced pressure to give crude 5- chloro-4-[(6-chloropyrazin-2-yl)amino]-2-methoxybenzoic acid. Half of the ob- tained crude 5-chloro-4-[(6-chloropyrazin-2-yl)amino]-2-methoxybenzoic acid (theoretically containing 421 mg, 1.34 mmol) was dissolved in DME/ water. [1- (tert-Butoxycarbonyl)-H-indol-2-yl]boronic acid (350 mg, 1.34 mmol), NaHCO3 (394 mg, 4.69 mmol) and Pd(PPh3)4 (31 mg, 0.03 mmol) were added. The reaction mixture was stirred at 100 0C for 7 h and at rt for 8 hours. MeOH (5mL) was added followed by filtration and concentration in vacuo. The residue was dissolved in EtOAc (15 mL) and 1 M aq NaOH (20 mL). The phases were separated, and the aqueous layer was extracted with EtOAc (15 mL). The water phase was acidified with 1 M HCl (aq) and extracted with EtOAc (10 mL). The combined organic phases were concentrated and the remaining material was dissolved in DCM/TFA (4: 1, 10 mL) and stirred for 5 h at rt. The solvent was evaporated, and the residue was purified by preparative HPLC (YMC ODS-AQ, 0.1% TFA-MeCN) to give 5-chloro-4-[6-(5-fluoro- lH-indol-2-yl)pyrazin-2- yl]amino}-2-methoxybenzoic acid (26 mg). To 5-chloro-4-[6-(5-fluoro- lH-indol-2-yl)pyrazin-2-yl]amino}-2- methoxybenzoic acid (13 mg, 0.03 mmol) in dry DMF (1.5 mL) were addedNEt3 (14 muL, 0.09 mmol), 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane- 2,4,6-trioxide (50% in EtOAc, 75 muL, 0.13 mmol) and piperazine (81 mg, 0.95 <n="144"/>mmol). The mixture was stirred at rt over night. TBTU (2 eq) was added and the reaction mixture was stirred over night. 1 drop of water was added and the mixture was concentrated in vacuo. Purification was performed by preparative HPLC (ACE C8, 0.1% TFA, MeCN) to give the title compound (2 mg). MS (ESI+) for C24H22C1FN6O2 m/z 481 (M+H)+. HPLC 97%(System A), 98%(System B). MS (ESI+) calcd for C24H22ClFN6O2 480.1477, found 480.1469.

Reference： [1]Patent: WO2007/147874,2007,A1 .Location in patent: Page/Page column 142-143

14
[ 96-50-4 ]
[ 7206-70-4 ]
[ 851202-80-7 ]

Yield	Reaction Conditions	Operation in experiment
32%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); 1,2-dichloro-ethane; at 60℃;	4-Amino-5-chloro-2-methoxy-benzoic acid (19.8 mmol)) was dissolved in DMF (10 mL) and 1, 2-dichloroethane (80 mL). DIPEA (19.8 mmol), 1- (3-dimethylamino- propyl)-3-ethyl-carbodiimide hydrochloride (19.8 mmol), 1-hydroxybenzotriazole (19.8 mmol) and 2-amino thiazole (19.8 mmol) was added and the reaction mixture was stirred at 60 C over night. The volume was reduced in vacuo, and water (60 mL) was added. The mixture was extracted with ethyl acetate, the organic phase was washed with NH4C1 (aq. , sat. ), dried over MgS04, filtered and evaporated. The crude product was re-crystallized from ethyl acetate. Yield: 32% 1H NMR (D6-DMSO) : 3.94 (s, 3H); 6.30 (s, 2H); 6.56 (s, 1H); 7.23 (d, 1H); 7.49 (d, 1H) ; 7.76 (s, 1H); 11.05 (br s, 1H).
32%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; N,N-dimethyl-formamide; at 60℃;	4-Amino-5-chloro-2-methoxy-benzoic acid (19.8 mmol) ) was dissolved in DMF (10 mL) and 1,2-dichloroethane (80 mL). DIPEA (19.8 mmol), l-(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride (19.8 mmol), 1-hydroxybenzotriazole (19.8 mmol) and 2- aminothiazole (19.8 mmol) was added and the reaction mixture was stirred at 60 0C over night. The volume was reduced in vacuo, and water (60 mL) was added. The mixture was extracted with ethyl acetate, the organic phase was washed with NH4Cl (aq., sat.), dried over MgSO4, filtered and evaporated. The crude product was re-crystallized from ethyl acetate. Yield: 32% IH NMR (D6-DMSO): 3.94 (s, 3H); 6.30 (s, 2H); 6.56 (s, IH); 7.23 (d, IH); 7.49 (d, IH); 7.76 (s, lH); 11.05 (br s, IH).

Reference： [1]Patent: WO2005/39572,2005,A1 .Location in patent: Page/Page column 26
[2]Patent: WO2006/114093,2006,A1 .Location in patent: Page/Page column 38

15
[ 4093-31-6 ]
[ 7206-70-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	With hydrogenchloride; In ethanol; water;	EXAMPLE 14 2-methoxy-4-amino-5-chloro benzoic acid 25.75 grs (0.1 mol) methyl 2-methoxy-4-acetamido-5-chlorobenzoate were introduced into a 500 ml flask, suspended in 100 ml ethanol. 40 grs NaOH, dissolved in 150 cc of water, were added and the mixture was heated under reflux for 2.5 hours. The mixture was diluted with water and made acid with concentrated HCl. The white solid which precipitated was collected and recrystallized from methanol. Weight: 17 grs m.p. = 213-215 C. Yield = 84%.
	With potassium hydroxide; In ethanol; water;Heating / reflux;	Stage B Preparation of 4-amino-5-chloro-2-methoxybenzoic acid Methyl 4-acetamido-5-chloro-2-methoxybenzoate is dissolved in ethanol and aqueous potassium hydroxide added. The solution is refluxed for a short time, cooled and concentrated hydrochloric acid added. The resulting precipitate is filtered off, washed with water and dried to give the title compound as a white solid.

Reference： [1]Patent: US4138492,1979,A
[2]Patent: US2005/49416,2005,A1 .Location in patent: Page/Page column 11
[3]Letters in drug design and discovery,2012,vol. 9,p. 489 - 493

16
[ 7206-70-4 ]
[ 18107-18-1 ]
[ 20896-27-9 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; hexane; toluene at 0 - 20℃; for 16h;	47 Methyl 4-Amino-5-chloro-2-methoxybenzoate Preparation 47 Methyl 4-Amino-5-chloro-2-methoxybenzoate To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (1.008 g, 5.0 mmol) in a mixture of toluene (9 mL) and methanol (1 mL) at 0° C. was added (trimethylsilyl)diazomethane (2.0 M in hexane, 3.0 mL, 6.0 mmol) dropwise. The reaction mixture was then warmed to room temperature and stirred for 16 h. Excess (trimethylsilyl)diazomethane was quenched by adding acetic acid until the bright yellow color of the reaction mixture disappeared. The mixture was then concentrated in vacuo to give the title compound as an off-white solid, which was used without further purification.
	Stage #1: 4-amino-5-chloro-2-methoxybenzoic acid; diazomethyl-trimethyl-silane With acetic acid In methanol; hexane; toluene at 0 - 20℃; for 16h; Stage #2: With acetic acid In methanol; hexane; toluene	1 Methyl 4-Amino-5-chloro-2-methoxybenzoate To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (1.008 g, 5.0 mmol) in a mixture of toluene (9 mL) and methanol (1 mL) at 0° C. was added (trimethylsilyl)diazomethane (2.0 M in hexane, 3.0 mL, 6.0 mmol) dropwise. The reaction mixture was then warmed to room temperature and stirred for 16 h. Excess (trimethylsilyl)diazomethane was quenched by adding acetic acid until the bright yellow color of the reaction mixture disappeared. The mixture was then concentrated in vacuo to give the title compound as an off-white solid, which was used without further purification.

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2005/113417, 2005, A1 Location in patent: Page/Page column 46
[2]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2006/35931, 2006, A1 Location in patent: Page/Page column 12

17
[ 24201-13-6 ]
[ 7206-70-4 ]

Yield	Reaction Conditions	Operation in experiment
		Methyl 4-acetamido-5-chloro-2-methoxybenzoate is dissolved in ethanol and aqueous potassium hydroxide added. The solution is refluxed for a short time, cooled and concentrated hydrochloric acid added. The resulting precipitate is filtered off, washed with water and dried to give the title compound as a white solid.

Reference： [1]Patent: WO2005/23808,2005,A2 .Location in patent: Page/Page column 37-38

18
[ 847605-31-6 ]
[ 7206-70-4 ]
4-amino-5-chloro-N-({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)-2-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h;	To a solution of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (200 mg, 0.99 mmol) in N, N-dimethylformamide (10 mL) were added 4-[4-(aminomethyl) piperidin-1-yl] methyl} tetrahydro-2H-pyran~4-ol as prepared in 1 (2) and 1 (4) (340 mg, 1. 48 mmol), diethyl phosphorocyanidate (241 mg, 1.48 mmol) and NN-diisopropylethylamine (191 mg, 1.48 mmol) at room temperature, and the mixture was stirred at room temperature for 18 h. Then, the mixture was concentrated in vacuo to give yellow oil. The residual yellow oil was chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% ammonium hydroxide (v/v/v=30/l/0. 1) to give 371 mg (91%) of the title compound as a white solid. The solid was washed with dichloromethane/diethyl ether (v/v=1/20, 20 mL) and collected by filtration to give 350 mg (86%) of the title compound as a white solid. MS (ESI) m/z: 412 (M+H) +, 410 (M-H)-. m. p.: 164. 3 DEG C IR (KBr) v : 3456,3402, 3315,2943, 2927,2858, 1629,1596, 1541,1498, 1309,1263, 1180,1105, 1089,985, 842 cm 1. lH-NMR (DMSO-d6, 300MHz) 8 ppm: 8.11 (1 H, s), 7.74 (1 H, br. ), 6.30 (1 H, br. ), 4.37 (2 H, br. ), 3.90 (3 H, s), 3.80-3. 75 (5 H, m), 3.32 (2 H, t, J=6. 4 Hz), 2. 89-2. 84 (2 H, m), 2.38-2. 31 (4 H, m), 1.75-1. 20 (8 H, m). A signal due to OH was not observed. Anal. Calcd. for C2oH3oN304Cl : C, 58. 32 ; H, 7. 34 ; N, 10.20. Found: C, 58. 04 ; H, 7. 47 ; N, 9.89.

Reference： [1]Patent: WO2005/92882,2005,A1 .Location in patent: Page/Page column 40,41

19
[ 7206-70-4 ]
[ 20896-27-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With methanol; thionyl chloride; for 16h;Reflux;	To a solution of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (20.0 g, 99.2 mmol) in methanol (250 mL) was added thionyl chloride (7.2 mL, 99.2 mmol). The reaction was refluxed for 16 h then concentrated in vacuo. Purification by silica gel chromatography (0-90% ethyl acetate/hexanes) provided methyl 4-amino-5-chloro-2-methoxybenzoate (21.3 g, quantitative yield). LC/MS m/z 216.3 [M+H]+
	With thionyl chloride; In methanol; sodium hydroxide; diethyl ether;	Step A. 4-Amino-5-chloro-2-methoxy-benzoic acid methyl ester <strong>[7206-70-4]4-Amino-5-chloro-2-methoxy benzoic acid</strong> (50.0 g, 248 mmol) was suspended in methanol (500 mL) and the slurry cooled to 0 C. Thionyl chloride (54.3 mL, 744 mmol) was then added dropwise over the course of 20 minutes. Initially, a clear solution formed, which subsequently turned to a white suspension. The reaction was warmed to room temperature and stirred for 3 hours. The methanol was evaporated and the resulting slurry suspended in diethyl ether (1 L). The solid was filtered and rinsed thoroughly with diethyl ether to afford the title compound (50.9 g) as the hydrochloride salt. The salt was suspended in 1 N sodium hydroxide and stirred vigorously for 30 minutes. Filtration and thorough rinsing with water afforded the title compound free base as a white solid, m.p. 136-137 C. 1H NMR (DMSO-d6, 400 MHz): delta7.57 (s, 1H), 6.43 (s, 1H), 6.14 (s, 2H), 3.7 (s, 3H), 3.67 (s, 3H). Anal. Calcd. for C9H10CINO3: C 50.13, H 4.67, N 6.50. Found: C 49.85, H 4.46, N 6.65. MS [(+)-APCl, m/z]: 216 [M+H]+. Calcd for C9H11CINO3: 216.0428.
	With thionyl chloride; In methanol; sodium hydroxide; diethyl ether;	Step A. 4-Amino-5-chloro-2-methoxy-benzoic acid methyl ester <strong>[7206-70-4]4-Amino-5-chloro-2-methoxy benzoic acid</strong> (50.0 g, 248 mmol) was suspended in methanol (500 mL) and the slurry cooled to 0 C. Thionyl chloride (54.3 mL, 744 mmol) was then added dropwise over the course of 20 minutes. Initially, a clear solution formed, which subsequently turned to a white suspension. The reaction was warmed to room temperature and stirred for 3 hours. The methanol was evaporated and the resulting slurry suspended in diethyl ether (1 L). The solid was filtered and rinsed thoroughly with diethyl ether to afford the title compound (50.9 g) as the hydrochloride salt. The salt was suspended in 1 N aqueous NaOH and stirred vigorously for 30 minutes. Filtration and thorough rinsing with water afforded the title compound free base as a white solid, m.p. 136-137 C. 1H NMR (DMSO-d6, 400 MHz): delta 7.57 (s, 1H), 6.43 (s, 1H), 6.14 (s, 2H), 3.71 (s, 3H), 3.67 (s, 3H). Anal. Calcd. for C9H10ClNO3: C 50.13, H 4.67, N 6.50. Found: C 49.85, H 4.46, N 6.65. MS [(+)-APCl, m/z]: 216 [M+H+. Calcd. for C9H11ClNO3: 216.0428.

	With thionyl chloride; In methanol; sodium hydroxide; diethyl ether;	Step A. 4-Amino-5-chloro-2-methoxy-benzoic acid methyl ester <strong>[7206-70-4]4-Amino-5-chloro-2-methoxy benzoic acid</strong> (50.0 g, 248 mmol) was suspended in methanol (500 mL) and the slurry cooled to 0 C. Thionyl chloride (54.3 mL, 744 mmol) was then added dropwise over the course of 20 minutes. The initially clear solution turned to a white suspension. The reaction was warmed to room temperature and stirred for 3 hours. The methanol was evaporated and the resulting slurry suspended in diethyl ether (1 L). The solid was filtered and rinsed thoroughly with diethyl ether to afford the title compound (50.9 g) as the hydrochloride salt. The salt was suspended in 1 N sodium hydroxide and stirred vigorously for 30 minutes. Filtration and thorough rinsing with water afforded the title compound free base as a white solid, m.p. 136-137 C. 1H NMR (DMSO-d6,400 MHz): delta 7.57 (s, 1H), 6.43 (s, 1H), 6.14 (s, 2H), 3.71 (s, 3H), 3.67 (s, 3H). Anal. Calcd. for C9 H10ClNO3: C 50.13, H 4.67, N 6.50. Found: C 49.85, H 4.46, N 6.65 MS [(+)-APCI, m/z]: 216 [M+H]+. Calc'd for C9H11ClNO3: 216.0428.
	With thionyl chloride; In methanol; sodium hydroxide; diethyl ether;	Step A. 4-Amino-5-chloro-2-methoxy-benzoic Acid Methyl Ester <strong>[7206-70-4]4-Amino-5-chloro-2-methoxy benzoic acid</strong> (50.0 g, 248 mmol) was suspended in methanol (500 mL) and the slurry cooled to 0 C. Thionyl chloride (54.3 mL, 744 mmol) was then added dropwise over the course of 20 minutes. Initially, a clear solution formed, which subsequently turned to a white suspension. The reaction was warmed to room temperature and stirred for 3 hours. The solvent was evaporated and the resulting slurry suspended in diethyl ether (1 L). The solid was filtered and rinsed thoroughly with diethyl ether to afford the title compound (50.9 g) as the hydrochloride salt. The salt was suspended in 1 N sodium hydroxide and stirred vigorously for 30 minutes. Filtration and thorough rinsing with water afforded the free base as a white solid, m.p. 136-137 c. 1H NMR (DMSO-d6, 400 MHz): delta 7.57 (s, 1H), 6.43 (s, 1H), 6.14 (s, 2H), 3.71 (s, 3H), 3.67 (s, 3H). Anal. Calcd. for C9H10ClNO3: C, 50.13; H, 4.67; N, 6.50. Found: C, 49.85; H, 4.46; N, 6.65. MS [(+)-APCI, m/z]: 216 [M+H]+. Calcd. for C9H11ClNO3: 216.0428.
	In methanol;	Step 1. Methyl 2-methoxy-4-amino-5-chlorobenzoate HCl gas is bubbled through a suspension of <strong>[7206-70-4]2-methoxy-4-amino-5-chlorobenzoic acid</strong> (39 g) in methanol (600 ml) while cooled in an ice bath for 20 minutes. The mixture is evaporated affording the desired product as a solid which is used in the next step.
	With hydrogenchloride; In methanol;	EXAMPLE 8 METHYL 2-METHOXY-4-AMINO-5-CHLOROBENZOATE To a solution of 50 g of <strong>[7206-70-4]2-methoxy-4-amino-5-chlorobenzoic acid</strong> in 500 ml of methanol is added HCl gas until all the material dissolves. Stirring is continued overnight, the solvent removed, ether added, filtered, dried over magnesium sulfate and evaporated to dryness to obtain methyl 2-methoxy-4-amino-5-chlorobenzoate which is used directly in the next step.

Reference： [1]Patent: US2010/168094,2010,A1 .Location in patent: Page/Page column 66
[2]Patent: WO2005/121132,2005,A1 .Location in patent: Page/Page column 229-230
[3]Patent: US2003/4159,2003,A1
[4]Patent: US2003/55046,2003,A1
[5]Patent: US2002/183311,2002,A1
[6]Patent: US2002/198196,2002,A1
[7]Patent: US4920219,1990,A
[8]Patent: US4863921,1989,A

20
[ 67-56-1 ]
[ 7206-70-4 ]
[ 20896-27-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With thionyl chloride; at 80℃; for 5h;	Step 1. Methyl 4-amino-5-chloro-2-methoxybenzoate A solution of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (30 g, 148.80 mmol) and thionyl chloride (35.1 g, 296.95 mmol) in methanol (400 mL) was stirred 5 hours at 80 C. The reaction mixture was concentrated in vacuo, diluted with water (200 mL), extracted with ethyl acetate (2*200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 4-amino-5-chloro-2-methoxybenzoate as a pink solid (31.3 g, 97%). LC/MS (ES, m/z): [M+H]+ 216.0 1H-NMR (300 MHz, CDCl3) delta 7.84 (s, 1H), 6.30 (s, 1H), 3.85 (s, 3H), 3.84 (s, 3H)
94%	With thionyl chloride; for 3h;Reflux;	General procedure: To a stirred solution of benzoic acid derivatives (1.0 eq.) in MeOH (5 mL/mmol) at 0C was added dropwise SOCl2 (2.0 eq.) and the resulting mixture was refluxed for 3h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was dissolved with ethyl acetate, washed with a saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the title compounds 17 and 18. Methyl 4-amino-5-chloro-2-methoxy-benzoate (17). The compound was prepared from <strong>[7206-70-4]4-amino-5-chloro-2-methoxy-benzoic acid</strong> (1.0 g, 5.0 mmol), according to procedure E, and refluxing the reaction for 3h, 17 was obtained as white solid (94% yield); mp 139C; 1H NMR (CDCl3, 400 MHz) delta 7.83 (s, 1H), 6.28 (s, 1H), 4.48 (br s, 2H), 3.83 (s, 3H), 3.82 (s, 3H); 13C NMR (CDCl3, 100 MHz) delta 165.4 (CO), 160.4 (Cq), 148.0 (Cq), 133.6 (CH), 110.1 (Cq), 109.7 (Cq), 98.3 (CH), 56.2 (CH3), 51.8 (CH3); MS m/z [M+H]+ 216.42/218.44; IR (neat, cm-1) nu 3448, 3365, 3235, 2984, 2939, 1712, 1633, 1602, 1244, 1107, 696.
		To a solution of 4-amino-5-chloro-2-methoxyberzoic acid (1.008 g, 5.0 mmol) in a mixture of toluene (9 mL) and methanol (1 mL) at 0 C. was added (trimethylsilyl)diazomethane (2.0 M in hexane, 3.0 mL, 6.0 mmol) dropwise. The reaction mixture was then warmed to room temperature and stirred for 16 h. Excess (trimethylsilyl)diazomethane was quenched by adding acetic acid until the bright yellow color of the reaction mixture disappeared. The mixture was then concentrated in vacuo to give the title compound as an off-white solid, which was used without further purification.

Reference： [1]Patent: US2012/277224,2012,A1 .Location in patent: Page/Page column 59
[2]European Journal of Medicinal Chemistry,2019,vol. 162,p. 234 - 248
[3]Patent: US2006/35933,2006,A1 .Location in patent: Page/Page column 30-31

21
[ 7206-70-4 ]
[ 473264-13-0 ]

Yield	Reaction Conditions	Operation in experiment
19%		Example 42 5-Chloro-4-iodo-2-methoxybenzoic acid To a stirred solution of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (5 g, 24.8 mmol) in water (10 mL) at 0 C., concentrated sulfuric acid (50 mL) was added. Then a solution of NaNO2 (1.9 g, 27.3 mmol) in water (10 mL) was added dropwise while keeping the internal temperature around 0 C. KI (4.5 g, 27.3 mmol) and I2 (3.5 g, 13.64 mmol) were dissolved in water and added dropwise to the stirred reaction mixture. The reaction was stirred at 5 C. for 2 h and then extracted with ethyl acetate. The organic layer was washed with water, Na2SO3 (aq, 10%) and brine, dried over anhydrous Na2SO4 and concentrated in vacuo to afford desired product (1.55 g, 19% yield). ESI-MS m/z: 311.1[M+H]+.
19%	With sulfuric acid; iodine; potassium iodide; sodium nitrite; In water; at 0 - 5℃; for 2h;	To a stirred solution of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (5 g, 24.8 mmol) in water (10 mL) at 0C, concentrated sulfuric acid (50 mL) was added. Then a solution of NaNO2 (1.9 g, 27.3 mmol) in water (10 mL)was added dropwisewhile keeping the internal temperature around 0C. KI (4.5 g, 27.3 mmol) and 12(3.5 g,13.64 mmol) were dissolved in water and added dropwise to the stirred reaction mixture. The reaction was stirred at 5C for 2 h and then extracted with ethyl acetate. The organic layer was washed with water, Na2503 (aq, 10%) and brine, dried over anhydrous Na2SO4 and concentrated in vacuo to afford desired product (1.55 g, 19% yield). ESI-MS mlz: 311.1 [M+H].
	With potassium iodide; iodine; sodium nitrite; In water;	Step A. 4-Iodo-5-chloro-2-methoxy Benzoic Acid A stirred solution of 4-amino-5-chloro-2-methoxy benzoic acid (12.25 g, 60.8 mmol) in water (136 mL) and concentrated sulfuric acid (34 mL) was cooled to 0 C. in a flask fitted with an overhead stirrer. A solution of sodium nitrite (4.62 g, 66.9 mmol) in water (26 mL) was added dropwise while keeping the internal temperature around 0 C. Potassium iodide (11.11 g, 66.9 mmol) and iodine (4.24 g, 33.5 mmol) were dissolved in water (130 mL) and added dropwise to the stirred reaction mixture. After 2 hours the reaction was extracted with ethyl acetate. The organic extracts were then washed with 10% sodium thiosulfate and brine, then dried over magnesium sulfate, filtered and evaporated to dryness to yield 11.32 g of the title compound, m.p. 150-151 C. This material was used without further purification. 1H NMR (DMSO-d6, 400 MHz): delta 13.03 (br, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 3.82 (s, 3H). MS [(-)-APCI, m/z]: 311 [M-H]-. Anal. Calcd. for C8H6CllO3: C 30.75, H 1.94. Found: C 31.28, H 1.78.

With potassium iodide; iodine; sodium nitrite; In water;

Step A. 4-Iodo-5-chloro-2-methoxy benzoic acid A stirred solution of 4-amino-5-chloro-2-methoxy benzoic acid (12.25 g, 60.8 mmol) in water (136 mL) and concentrated sulfuric acid (34 mL) was cooled to 0 C. in a flask fitted with an overhead stirrer. A solution of sodium nitrite (4.62 g, 66.9 mmol) in water (26 mL) was added dropwise while keeping the internal temperature around 0 C. Potassium iodide (11.11 g, 66.9 mmol) and iodine (4.24g, 33.5 mmol) were dissolved in water (130 mL) and added dropwise to the stirred reaction mixture. After 2 hours the reaction was extracted with ethyl acetate. The organic extracts were then washed with 10% sodium thiosulfate and brine, then dried over magnesium sulfate, filtered and evaporated to dryness to yield 11.32 g of the title compound, m.p. 150-151 C. This material was used without further purification. 1H NMR (DMSO-d6, 400 MHz): delta13.03 (br, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 3.82 (s, 3H). MS [(-)-APCI, m/z]: 311 [M-H]- Anal. Calcd. for C8H6ClIO3: C, 30.75; H, 1.94. Found: C, 31.28; H, 1.78.

Reference： [1]Patent: US2014/288045,2014,A1 .Location in patent: Paragraph 0632
[2]Patent: WO2016/44772,2016,A1 .Location in patent: Paragraph 329; 330
[3]Patent: US2003/18026,2003,A1
[4]Patent: US2003/55047,2003,A1

22
[ 7206-70-4 ]
[ 6638-79-5 ]
4-amino-5-chloro-N,2-dimethoxy-N-methylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%		1,1?-Carbonyldiimidazole (17.4 g, 105.8 mmol) was added portionwise to a solution of carboxylic acid 2 (20.0 g, 96.2 mmol) in DMF(100 mL) at r.t. After 1 h, N,O-dimethylhydroxylamine hydrochloride (12.2 g, 125.1 mmol) and Et3N (13.43 mL, 96.2 mmol) were added at r.t. and the reaction mixture was stirred for an additional 20 h. The reaction was quenched with sat. aq NH4Cl (100 mL) and extracted with EtOAc (4 × 80 mL). The combined organic layers were washed with brine (4 × 200 mL) and dried (MgSO4). After filtration, the solvent was removed under vacuum and the crude residue was triturated in Et2O and the resulting solid was collected by filtration to afford compound 10, which was used without further purification in the next step; yield: 19.7 g (80 mmol, 84%); white solid; mp 134-135 C. 1H NMR (CDCl3, 300 MHz): delta = 7.19 (s, 1 H), 6.29 (s, 1 H), 4.21 (br s, 2H), 3.78 (s, 3 H), 3.60 (s, 3 H), 3.26 (s, 3 H). 13C NMR (CDCl3, 75 MHz): delta = 156.0, 145.1, 129.0, 115.6, 110.3, 98.6,61.1, 56.0. HRMS (ESI+): m/z [M + H]+ calcd for C10H14ClN2O3: 245.0693; found: 245.0694. Anal. Calcd for C10H13ClN2O3: C, 49.1; H, 5.4; N, 11.4. Found: C, 49.21; H, 5.37; N, 11.49.
	With triethylamine; 1,1'-carbonyldiimidazole; In N,N-dimethyl-formamide;	Example 2 N-Methoxy-N-methyl-4-amino-5-chloro-2-methoxybenzamide The following is the preparation of a compound of Formula III in which R1 is chloro and R3 is methoxy. 4-Amino-5-chloro-2-methoxybenzoic acid (10.1 g, 50 mmol) was dissolved in DMF (50 mL). Carbonyldiimidazole (8.9 g, 55 mmol) was added to the solution and the mixture was stirred for 15 minutes. Triethylamine (7 mL, 5.1 g, 50 mmol) and N,O-dimethylhydroxylamine hydrochloride (6.3 g, 65 mmol) were added and the mixture was stirred for 12 hours. The mixture was then diluted with water and extracted into ethyl acetate. The ethyl acetate extract was washed with 5% HCl, with water, and then with brine. The extract was dried over sodium sulfate and then evaporated. Crystallization from ethyl acetate gave N-methoxy-N-methyl-4-amino-5-chloro-2-methoxybenzamide (10 g, 41 mmol), m.p. 134-135 C.

Reference： [1]Synthesis,2017,vol. 49,p. 2057 - 2062
[2]Patent: US5763458,1998,A

23
[ 7206-70-4 ]
[ 20059-73-8 ]
[ 541-41-3 ]
[ 122892-34-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; triethylamine; In chloroform;	EXAMPLE 5 4-Amino-5-chloro-N-[4-[2-(dimethylamino)ethoxy]benzyl]-2-methoxybenzamide To a cooled suspension of 2.49 g of 4-amino-5-chloro-2-methoxybenzoic acid in 15 ml of chloroform were successively added dropwise 1.26 g of triethylamine and 1.35 g of ethyl chloroformate with stirring. The mixture was stirred at the same temperature for 30 minutes. Next, to the mixture was added a solution of 2.00 g of <strong>[20059-73-8]4-[2-(dimethylamino)ethoxy]benzylamine</strong> in 10 ml of chloroform with stirring. The mixture was stirred at room temperature for 14 hours and the solvent was evaporated. 10% Hydrochloric acid was added to the residue and the aqueous solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with chloroform. The extract was washed with water, dried, and evaporated. The residue was washed with ether to give 3.87 g of slightly brownish crystals, which were recrystallized from ethanol to give colorless needles, m.p. 147-148 C. Analysis for C19 H24 ClN3 O3: Calculated %: C, 60.39; H, 6.40; N, 11.12. Found %: C, 60.28; H, 6.46; N, 11.12.
	With hydrogenchloride; triethylamine; In chloroform;	Example 5 4-Amino-5-chloro-N-[4-[2-(dimethylamino)ethoxy]benzyl]-2-methoxybenzamide To a cooled suspension of 2.49 g of 4-amino-5-chloro-2-methoxy-benzoic acid in 15 ml of chloroform were successivly added dropwise 1.26 g of triethylamine and 1.35 g of ethyl chloroformate with stirring. The mixture was stirred at the same temperature for 30 minutes. Next, to the mixture was added a solution of 2.00 g of <strong>[20059-73-8]4-[2-(dimethylamino)ethoxy]benzylamine</strong> in 10 ml of chloroform with stirring. The mixture was stirred at room temperature for 14 hours and the solvent was evaporated. 10% Hydrochloric acid was added to the residue and the aqueous solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with chloroform. The extract was washed with water, dried, and evaporated. The residue was washed with ether to give 3.87 g of slightly brownish crystals, which were recrystallized from ethanol to give colorless needles, m.p. 147-148C. Analysis for C19H24ClN3O3:

Reference： [1]Patent: US4983633,1991,A
[2]Patent: EP306827,1991,B1

24
[ 7206-70-4 ]
[ 541-41-3 ]
[ 18471-40-4 ]
[ 61694-71-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane;	EXAMPLE 51 In 20 ml. of dichloromethane was suspended 1.1 g. of 4-amino-5-chloro-2-methoxybenzoic acid and then 0.75 ml. of triethylamine was added to the suspension to form a solution. After cooling the solution to a temperature of from -20 to -25 C., 0.55 ml. of ethyl chlorocarbonate was added to the solution with stirring followed by further stirring for one hour at the same temperature. Thereafter, a solution of 0.97 g. of 1-benzyl-3-aminopyrrolidine in 5 ml. of dichloromethane was added dropwise to the mixture at the same temperature as above followed by stirring for 30 minutes at the same temperature and then the mixture was allowed to stand overnight at room temperature. After the reaction was over, the reaction mixture was washed -- with water, a diluted aqueous sodium hydroxide solution, and then water, successively and dried, and then the solvent was distilled off under a reduced pressure. The residue formed was triturated with a small amount of ether to form crystals, which were recovered by filtration, washed with a small amount of ether and recrystallized from a mixture of benzene and n- hexane to provide 1.2 g. of the white crystals of N-(1-benzyl-3-pyrrolidinyl)-4-amino-5-chloro-2-methoxybenzamide. Melting point: 116-118 C. Elemental analysis for C19 H22 N3 O2 Cl:
	With triethylamine; In dichloromethane;	EXAMPLE 51 In 20 ml. of dichloromethane was suspended 1.1 g. of 4-amino-5-chloro-2-methoxybenzoic acid and then 0.75 ml. of triethylamine was added to the suspension to form a solution. After cooling the solution to a temperature of from -20 C. to -25 C., 0.55 ml. of ethyl chlorocarbonate was added to the solution with stirring followed by further stirring for one hour at the same temperature. Thereafter, a solution of 0.97 g. of 1-benzyl-3-aminopyrrolidine in 5 ml. of dichloromethane was added dropwise to the mixture at the same temperature as above followed by stirring for 30 minutes at the same temperature and then the mixture was allowed to stand overnight at room temperatue. After the reaction as over, the reaction mixture was washed with water, a diluted aqueous sodium hydroxide solution, and then water, successively and dried, and then the solvent was distilled off under a reduced pressure. The residue formed was triturated with a small amount of ether to form crystals, which were covered by filtration, washed with a small amount of ether and recrystallized from a mixture of benzene and n-hexane to provide 1.2 g. of the white crystals of N-(1-benzyl-3-pyrrolidinyl)-4-amino-5-chloro-2-methoxybenzamide. Melting point: 116-118 C. Elemental analysis for C19 H22 N3 O2 Cl:

Reference： [1]Patent: US4097487,1978,A
[2]Patent: US4197243,1980,A

25
[ 7206-70-4 ]
[ 541-41-3 ]
[ 60407-35-4 ]
[ 61694-72-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane;	EXAMPLE 52 In 30 ml. of dichloromethane was suspended 1.0 g. of 4-amino-5-chloro-2-methoxybenzoic acid and then 0.75 ml. of triethylamine was added to the suspension to form a solution. After cooling the solution to a temperature of from -20 to -25 C., 0.55 ml. of ethyl chlorocarbonate was added to the solution with stirring followed by further stirring for one hour at the same temperature. Then, a solution of 0.95 g. of 3-amino-1-benzyl-piperidine in 5 ml. of dichloromethane was added dropwise to the mixture at the same temperature as above followed by stirring for 30 minutes at the same temperature and then the mixture was further stirred for 30 minutes at room temperature. After the reaction was over, the reaction mixture was washed -- with water, a diluted aqueous sodium hydroxide solution, and then water successively, and dried, and then the solvent was distilled off under a reduced pressure. To the oily residue formed was added a small amount of ether to form crystals, which were recovered by filtration and recrystallized from a mixture of acetone and n-hexane to provide 1.6 g. of N-(benzyl-3-piperidinyl)-4-amino-5-chloro-2-methoxybenzamide. Melting point: 165 C. Elemental analysis for C20 H24 N3 O2 Cl:
	With triethylamine; In dichloromethane;	EXAMPLE 52 In 30 ml. of dichloromethane was suspended 1.0 g. of 4-amino-5-chloro-2-methoxybenzoic acid and then 0.75 ml. of triethylamine was added to the suspension to form a solution. After cooling the solution to a temperature of from -20 C. to -25 C., 0.55 ml. of ethyl chlorocarbonate was added to the solution with stirring followed by further stirring for one hour at the same temperature. Then, a solution of 0.95 g. of 3-amino-1-benzyl-piperidine in 5 ml. of dichloromethane was added dropwise to the mixture at the same temperature as above followed by stirring for 30 minutes at the same temperatures and then the mixture was further stirred for 30 minutes at room temperature. After the reaction was over, the reaction mixture was washed with water, a diluted aqueous sodium hydroxide solution, and then water successively, and dried, and then the solvent was distilled off under a reduced pressure. To the oily residue formed was added a small amount of ether to form crystals, which were recovered by filtration and recrystallized from a mixture of acetone and n-hexane to provide 1.6 g. of N-(1-benzyl-3-piperidinyl)-4-amino-5-chloro-2-methoxybenzamide. Melting point: 165 C. Elemental analysis for C20 H24 N3 O2 Cl:

Reference： [1]Patent: US4097487,1978,A
[2]Patent: US4197243,1980,A

26
[ 7206-70-4 ]
[ 14165-27-6 ]
[ 61694-37-9 ]

Yield	Reaction Conditions	Operation in experiment
		15 EXAMPLE 15 EXAMPLE 15 By following general method B using 1.0 g. of 4-amino-5-chloro-2-methoxybenzoic acid and 1.2 g. of N,N-dibenzylethylenediamine, 1.5 g. of N-[2-(N',N'-dibenzylamino)ethyl]-4-amino-5-chloro-2-methoxybenzamide was obtained. Melting point: 133° C. (recrystallized from toluene). Elemental analysis for C27 H26 N3 O2 Cl:
		15 EXAMPLE 15 EXAMPLE 15 By following general method B using 1.0 g. of 4-amino-5-chloro-2-methoxybenzoic acid and 1.2 g. of N,N-dibenzylethylenediamine, 1.5 g. of N-[2-(N',N'-dibenzylamino)ethyl]-4-amino-5-chloro-2-methoxy-benzamide was obtained. Melting point: 133° C. (recrystallized from toluene). Elemental analysis for C27 H26 N3 O2 Cl:

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US4097487, 1978, A
[2]Current Patent Assignee: ASTELLAS PHARMA INC. - US4197243, 1980, A

27
[ 7206-70-4 ]
[ 87120-72-7 ]
[ 768370-78-1 ]

Yield	Reaction Conditions	Operation in experiment
74%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h;	To a solution of 4-amino-5-chloro-2-(methyloxy)benzoic acid (1.16g, 5.79mmol; available commercially from e.g. Aldrich) in DCM (12OmL) was added 1 ,1 -dimethylethyl 4-amino-1-piperidinecarboxylate (1.74g, 8.69mmol; available commercially from e.g. Fluka), EDC (1.21g, 11.58mmol) and DMAP (142mg, 1.16mmol). The mixture was stirred under argon at room temperature for 2h. After this time, LCMS showed that the reaction mixture contained 81 % desired product. The reaction mixture was transferred to a separating funnel and 10OmL sodium bicarbonate was added. The DCM layer was separated using a phase separation cartridge. The resulting oil was purified on a 100g silica column eluting with 0-95% EtOAc/pentane. Appropriate fractions were combined and evaporated to give the desired product as a white solid (D22) (1.63g, 74%). deltaH (CDCI3, 400MHz) 1.35-1.45 (2H, m), 1.47 (9H, s), 1.95-2.03 (2H, m), 2.95-3.05 (2H, m), 3.89 (3H, s), 3.93- 4.07 (2H, m), 4.08-4.20 (1 H, m, integration masked by EtOAc), 4.38 (2H, s), 6.29 (1 H, s), 7.33 (1 H, d, J = 7.6Hz), 8.10 (1 H, s) Mass Spectrum: Ci8H2SCIN3O4 requires 383/385; found 384/386 (MH+)

Reference： [1]Patent: WO2007/68739,2007,A1 .Location in patent: Page/Page column 31
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 5330 - 5343

28
[ 207405-68-3 ]
[ 7206-70-4 ]
C₂₀H₂₈ClN₃O₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 5330 - 5343

29
[ 7206-70-4 ]
[ 192130-34-0 ]
C₁₉H₂₉ClN₄O₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 5330 - 5343

30
[ 7206-70-4 ]
[ 1132683-09-0 ]
[ 1132683-10-3 ]

Yield	Reaction Conditions	Operation in experiment
23.6%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	4-Amino-5-chloro-2-methoxy-benzoic acid (0.277 g, 1.37 mmol) was dissolved in 20 mL of dichloromethane with stirring, and added with (S)-6-(2-aminomethyl-morpholin-4-yl)-hexanoic acid ethyl ester 2b (0.294 g, 1.14 mmol) and 1-ethyl-3-(3-dimethyl-propyl)carbodiimide hydrochloride (0.437 g, 2.28 mmol). The reaction mixture was reacted overnight at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. 400 mL of dichloromethane was added. The mixture was washed successively with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (S)-5-{2-[(4-amino-5-chloro-2-methoxy-benzoylamino)-methyl]-morpholin-4-yl}-hexanoic acid ethyl ester 2c (0.119 g, yield 23.6%) as a white solid. MS m/z (ESI): 442.3 [M+1]. 1H NMR (CDCl3, 400 MHz) delta 8.09 (s, 1H), 7.9 (m, 1H), 6.28 (s, 1H), 4.4 (s, 2H), 4.14-4.09 (q, 2H), 3.88 (s, 3H), 3.88 (m, 1H), 3.71-3.65 (m, 3H), 3.39-3.35 (m, 1H), 2.81-2.78 (m, 1H), 2.67 (m, 1H), 2.33-2.27 (m, 4H), 2.09-2.08 (m, 1H), 1.91-1.86 (m, 1H), 1.65-1.61 (m, 2H), 1.49-1.47 (m, 2H), 1.34-1.33 (m, 2H), 1.26-1.23 (t, 3H).
23.6%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	4-Amino-5-chloro-2-methoxy-benzoic acid (0.277 g, 1.37 mmol) was dissolved in 20 mL of dichloromethane with stirring, and added with (S)-6-(2-aminomethyl-morpholin-4-yl)-hexanoic acid ethyl ester 2b (0.294 g, 1.14 mmol) and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (0.437 g, 2.28 mmol). The reaction mixture was reacted overnight at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. 400 mL of dichloromethane was added. The mixture was washed successively with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (S)-6-{2-[(4-amino-5-chloro-2-methoxy-benzoylamino)-methyl]-morpholin-4-yl}-hexanoic acid ethyl ester 2c (0.119 g, yield 23.6%) as a white solid.MS m/z (ESI): 442.3 [M+1].1H NMR (CDCl3, 400 MHz) delta 8.09 (s, 1H), 7.9 (m, 1H), 6.28 (s, 1H), 4.4 (s, 2H), 4.14-4.09 (q, 2H), 3.88 (s, 3H), 3.88 (m, 1H), 3.71-3.65 (m, 3H), 3.39-3.35 (m, 1H), 2.81-2.78 (m, 1H), 2.67 (m, 1H), 2.33-2.27 (m, 4H), 2.09-2.08 (m, 1H), 1.91-1.86 (m, 1H), 1.65-1.61 (m, 2H), 1.49-1.47 (m, 2H), 1.34-1.33 (m, 2H), 1.26-1.23 (t, 3H).

Reference： [1]Patent: EP2189451,2010,A1 .Location in patent: Page/Page column 12
[2]Patent: US2010/210640,2010,A1 .Location in patent: Page/Page column 11

31
[ 7206-70-4 ]
[ 1132683-22-7 ]
[ 1132683-24-9 ]

Yield	Reaction Conditions	Operation in experiment
17.3%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 5h;	4-Amino-5-chloro-2-methoxy-benzoic acid (0.484 g, 2.4 mmol) was dissolved in 20 mL of dichloromethane with stirring, and added with (R)-6-(2-aminomethyl-morpholin-4-yl)-hexanoic acid ethyl ester 4i (0.516 g, 2.0 mmol) and 1-ethyl-3-(3-dimethyl-propyl)carbodiimide hydrochloride (0.767 g, 4.0 mmol). The reaction mixture was reacted for 5 hours at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was added with 100 mL of saturated sodium bicarbonate solution, and extracted with dichloromethane (200 mL×3). The combined organic phase was washed successively with water and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (R)-5-{2-[(4-amino-5-chloro-2-methoxy-benzoylamino)-methyl]-morpholin-4-yl}-hexanoic acid ethyl ester 4j (153 mg, yield 17.3%) as a white solid. MS m/z (ESI): 442.7 [M+1]. 1H NMR (CDCl3, 400 MHz) delta 8.09 (s, 1H), 7.9 (m, 1H), 6.28 (s, 1H), 4.4 (s, 2H), 4.14-4.09 (q, 2H), 3.88 (s, 3H), 3.88 (m, 1H), 3.71-3.65 (m, 3H), 3.39-3.35 (m, 1H), 2.81-2.78 (m, 1H), 2.67 (m, 1H), 2.33-2.27 (m, 4H), 2.09-2.08 (m, 1H), 1.91-1.86 (m, 1H), 1.65-1.61 (m, 2H), 1.49-1.47 (m, 2H), 1.34-1.33 (m, 2H), 1.26-1.23 (t, 3H).
17.3%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 5h;	4-Amino-5-chloro-2-methoxy-benzoic acid (0.484 g, 2.4 mmol) was dissolved in 20 mL of dichloromethane with stirring, and added with (R)-6-(2-aminomethyl-morpholin-4-yl)-hexanoic acid ethyl ester 4i (0.516 g, 2.0 mmol) and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (0.767 g, 4.0 mmol). The reaction mixture was reacted for 5 hours at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was added with 100 mL of saturated sodium bicarbonate solution, and extracted with dichloromethane (200 mL×3). The combined organic phase was washed successively with water and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (R)-6-{2-[(4-amino-5-chloro-2-methoxy-benzoylamino)-methyl]-morpholin-4-yl}-hexanoic acid ethyl ester 4j (153 mg, yield 17.3%) as a white solid.MS m/z (ESI): 442.7 [M+1].1H NMR (CDCl3, 400 MHz) delta 8.09 (s, 1H), 7.9 (m, 1H), 6.28 (s, 1H), 4.4 (s, 2H), 4.14-4.09 (q, 2H), 3.88 (s, 3H), 3.88 (m, 1H), 3.71-3.65 (m, 3H), 3.39-3.35 (m, 1H), 2.81-2.78 (m, 1H), 2.67 (m, 1H), 2.33-2.27 (m, 4H), 2.09-2.08 (m, 1H), 1.91-1.86 (m, 1H), 1.65-1.61 (m, 2H), 1.49-1.47 (m, 2H), 1.34-1.33 (m, 2H), 1.26-1.23 (t, 3H).

Reference： [1]Patent: EP2189451,2010,A1 .Location in patent: Page/Page column 15-16
[2]Patent: US2010/210640,2010,A1 .Location in patent: Page/Page column 14

32
[ 7206-70-4 ]
[ 1132683-28-3 ]
[ 1132683-29-4 ]

Yield	Reaction Conditions	Operation in experiment
45%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h;	(R)-6-(2-Aminomethyl-morpholin-4-yl)-pentanoic acid ethyl ester 5b (0.241 g, 1.0 mmol) was dissolved in 20 mL of dichloromethane with stirring, and added with <strong>[7206-70-4]4-amino-5-chloro-2-methoxy-benzoic acid</strong> (0.242 g, 1.2 mmol) and 1-ethyl-3-(3-dimethyl-propyl)carbodiimide hydrochloride (0.383 g, 2.0 mmol). The reaction mixture was stirred for 3 hours at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was added with 100 mL of saturated sodium bicarbonate solution, and extracted with ethyl acetate (200 mL×3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (R)-5-{2-[(4-amino-5-chloro-2-methoxy-benzoylamino)-methyl]-morpholin-4-yl}-pentanoic acid ethyl ester 5c (162 mg, yield 45%) as a white solid. MS m/z (ESI): 428.3 [M+1].
45%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h;	(R)-5-(2-Aminomethyl-morpholin-4-yl)-pentanoic acid ethyl ester 5b (0.241 g, 1.0 mmol) was dissolved in 20 mL of dichloromethane with stirring, and added with <strong>[7206-70-4]4-amino-5-chloro-2-methoxy-benzoic acid</strong> (0.242 g, 1.2 mmol) and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (0.383 g, 2.0 mmol). The reaction mixture was stirred for 3 hours at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was added with 100 mL of saturated sodium bicarbonate solution, and extracted with ethyl acetate (200 mL×3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (R)-5-{2-[(4-amino-5-chloro-2-methoxy-benzoylamino)-methyl]-morpholin-4-yl}-pentanoic acid ethyl ester 5c (162 mg, yield 45%) as a white solid.MS m/z (ESI): 428.3 [M+1].

Reference： [1]Patent: EP2189451,2010,A1 .Location in patent: Page/Page column 17
[2]Patent: US2010/210640,2010,A1 .Location in patent: Page/Page column 15

33
[ 7206-70-4 ]
[ 1132683-31-8 ]
[ 1132683-32-9 ]

Yield	Reaction Conditions	Operation in experiment
69.8%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h;	(R)-6-(2-Aminomethyl-morpholin-4-yl)-butyric acid ethyl ester 6b (0.199 g, 0.865 mmol) was dissolved in 20 mL of dichloromethane with stirring, and added with <strong>[7206-70-4]4-amino-5-chloro-2-methoxy-benzoic acid</strong> (0.209 g, 1.038 mmol) and 1-ethyl-3-(3-dimethyl-propyl)carbodiimide hydrochloride (0.332 g, 1.73 mmol). The reaction mixture was stirred for 3 hours at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The mixture was added with 100 mL of saturated sodium bicarbonate solution, and extracted with ethyl acetate (200 mL×3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (R)-5-{2-[(4-amino-5-chloro-2-methoxy-benzoylamino)-methyl]-morpholin-4-yl}-butyric acid ethyl ester 6c (0.25 g, yield 69.8%) as a colorless transparent viscous solid. MS m/z (ESI): 414.2 [M+1].
69.8%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h;	(R)-4-(2-Aminomethyl-morpholin-4-yl)-butyric acid ethyl ester 6b (0.199 g, 0.865 mmol) was dissolved in 20 mL of dichloromethane with stirring, and added with <strong>[7206-70-4]4-amino-5-chloro-2-methoxy-benzoic acid</strong> (0.209 g, 1.038 mmol) and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (0.332 g, 1.73 mmol). The reaction mixture was stirred for 3 hours at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The mixture was added with 100 mL of saturated sodium bicarbonate solution, and extracted with ethyl acetate (200 mL×3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (R)-4-{2-[(4-amino-5-chloro-2-methoxy-benzoylamino)-methyl]-morpholin-4-yl}-butyric acid ethyl ester 6c (0.25 g, yield 69.8%) as a colorless transparent viscous solid.MS m/z (ESI): 414.2 [M+1].

Reference： [1]Patent: EP2189451,2010,A1 .Location in patent: Page/Page column 18
[2]Patent: US2010/210640,2010,A1 .Location in patent: Page/Page column 16-17

34
[ 7206-70-4 ]
[ 1335036-28-6 ]
[ 76352-16-4 ]

Yield	Reaction Conditions	Operation in experiment
51.8%		General procedure: A solution of aromatic acid (5 mmol), ethyl chloroformate (0.5 mL, 5 mmol) and triethylamine (0.75 mL, 5 mmol) in anhydrous DMF (30 mL) was stirred for 30 min at 0 C. Subsequently, a solution of amine 3a, 3b or 3c (5 mmol) in anhydrous DMF (5 mL) was added dropwise. The cooling bath was removed and stirring was continued for 24 h. The solvent was evaporated in vacuo and the residue was dissolved in CH2Cl2 (30 mL). The solution was washed with a 5% aqueous solution of Na2CO3, dried with magnesium sulphate, filtered, and the solvent was evaporated in vacuo. The residue was recrystallised (for solid compounds), purified by column chromatography or treated with the appropriate acid to form crystalline salts (for oily compounds), as described below.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 4474 - 4488

35
[ 7206-70-4 ]
[ 1335036-30-0 ]
[ 1335036-68-4 ]

Yield	Reaction Conditions	Operation in experiment
74%		General procedure: A solution of aromatic acid (5 mmol), ethyl chloroformate (0.5 mL, 5 mmol) and triethylamine (0.75 mL, 5 mmol) in anhydrous DMF (30 mL) was stirred for 30 min at 0 C. Subsequently, a solution of amine 3a, 3b or 3c (5 mmol) in anhydrous DMF (5 mL) was added dropwise. The cooling bath was removed and stirring was continued for 24 h. The solvent was evaporated in vacuo and the residue was dissolved in CH2Cl2 (30 mL). The solution was washed with a 5% aqueous solution of Na2CO3, dried with magnesium sulphate, filtered, and the solvent was evaporated in vacuo. The residue was recrystallised (for solid compounds), purified by column chromatography or treated with the appropriate acid to form crystalline salts (for oily compounds), as described below.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 4474 - 4488

36
[ 7206-70-4 ]
[ 503433-37-2 ]
[ 81098-60-4 ]

Reference： [1]Tetrahedron Asymmetry,2011,vol. 22,p. 1591 - 1593

37
[ 7206-70-4 ]
[ 86720-98-1 ]

Yield	Reaction Conditions	Operation in experiment
13%		Intermediate 52.5-chloro-4-hydroxy-2-methoxybenzoic acid.To a suspension of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (25 g; 0.12 mol) in 125 ml of water was added tetrafluoroboric acid (40.5 ml of 48 % aqueous solution). The white cake was then cooled to 0C and NaN02 (9.41 g in 75 mL of H20) was added drop wise and the whole stirred at that temperature for 30 minutes. The white precipitate was collected by filtration. The diazonium salt was suspended in glacial AcOH (1250 mL) and the resulting suspension was stirred at 100 C for 1 hour (it became a brown solution). It was allowed to stand at RT for two more hours. The solvent was removed under reduced pressure and the brown oily residue suspended in brine (1250 ml) and extracted with EtOAC (3x400 ml). The combined organic layers were dried over magnesium sulphate, filtered and evaporated under reduced pressure to give brown oil. Purification by preparative reversed-phase HPLC (Et20/EtOH 0/100 to 40/60) afforded 3.0 g (13 %) of a red solid.LRMS (m/z): 203(M+1 )+.
13%		5-chloro-4-hydroxy-2-methoxybenzoic acid. To a suspension of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (25 g; 0.12 mol) in 125 ml of water was added tetrafluoroboric acid (40.5 ml of 48 % aqueous solution). The white cake was then cooled to 0C and NaNO2 (9.41 g in 75 mL of H2O) was added drop wise and the whole stirred at that temperature for 30 minutes. The white precipitate was collected by filtration. The diazonium salt was suspended in glacial AcOH (1250 mL) and the resulting suspension was stirred at 100 C for 1 hour (it became a brown solution). It was allowed to stand at RT for two more hours. The solvent was removed under reduced pressure and the brown oily residue suspended in brine (1250 ml) and extracted with EtOAC (3x400 ml). The combined organic layers were dried over magnesium sulphate, filtered and evaporated under reduced pressure to give brown oil. Purification by preparative reversed-phase HPLC (Et2O/EtOH 0/100 to 40/60) afforded 3.0 g (13 %) of a red solid. LRMS (m/z): 203(M+1)+.
		Intermediate 153.5-chloro-4-hydroxy-2-methoxybenzoic acid methyl ester.To a suspension of 10 g (48 mmol) of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> in 50 ml H20 was added HBF4 (16.2 mL, 48% aqueous solution). The white cake was then cooled to 0 C and NaN02 (3.76 g in 30 mL of H20) was added dropwise (addition funnel, 10 minutes). The suspension became bright yellow. It was stirred at that temperature for 30 minutes. The white precipitate was collected by filtration to isolate a diazonium salt (wet weight: 12.97 g). The diazonium salt was suspended in glacial AcOH (500 mL) and the resulting suspension was stirred at 100 C for 1 hour (it became a brown solution). It was allowed to stand at RT for two additional hours.The solvent was removed under reduced pressure and the brown oily residue suspended in brine (500 mL) and extracted with EtOAC (3x300 mL). The combined organic layers were dried, filtered and evaporated under reduced pressure to give a brown oil which was treated with 0.5M NaOH in MeOH (150 mL) and stirred at RT for 90 min. It was stirred at RT for 3 hr. The solvent was evaporated and the residue redisolved in H20 (250 mL). The aqueous solution was acidified to pH=2 with 5N HCI and extracted with CH2CI2 (3x250 mL). A solid precipitated which was filtered, washed with Et20 and dried in the oven (45 C, 90 min) to give 4.3 g of a dark-brown solid which was directly purified by column chromatography on a Merck column (80g silica, Luer fitting) using the SP1 system with CH2CI2 (A) and CH2CI2/EtOAc 8:2(B) as eluents (0% to 25% B in 19 column volumes and 25% to 60% B in 10 CV, 100 mL/min). The appropriate fractions were collected and the solvent removed to afford 2.9 g (27% yield) of a pale red solid.

Reference： [1]Patent: WO2011/141180,2011,A1 .Location in patent: Page/Page column 43
[2]Patent: EP2386555,2011,A1 .Location in patent: Paragraph 0144
[3]Patent: WO2011/141180,2011,A1 .Location in patent: Page/Page column 84-85

38
cis-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate [ No CAS ]
[ 7206-70-4 ]
cis-tert-butyl 4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-fluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		To a solution of 0.97 g (4.82 mmol) of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> in 25 mL of dry DMF was added 0.70 g (6.88 mmol) of triethylamine at room temperature under N2-atmosphere. After stirring for 10 min at rt, a solution of 0.52 g (4.82 mmol) of ethyl chloroformate in 1 mL of DMF was added dropwise at rt and stirring was continued for 30 min. Then 0.65 g (4.82 mmol) of hydroxybenzotriazole was added as a solid in one portion at rt and the solution was stirred for 30 min. Subsequently, a solution of 1.0 g (4.59 mmol) of amine 10 in 3 mL of DMF was added dropwise at rt and the reaction mixture was stirred overnight at rt. Afterwards, the mixture was poured in 100 mL of brine and extracted with EtOAc (4x 30 mL). The combined organic fraction was washed with brine, dried over MgS04, filtered and evaporated under reduced pressure. The crude mixture was subjected to flash silicagel chromatography (hex/EtOAc/Et3N 1 : 1 :0.1; Rf = 0.01) to yield 1.25 g (68%) of pure tert-butyl 4-(4- amino-5-chloro-2-methoxybenzoylamino)-3-fluoropiperidine-l-carboxylate 11 as a solid. Mp 198-199C.1H MR (CDC13): delta 1.35 (9H, s); 1.44-1.77 (2H, m); 2.77-2.98 (1H, m); 3.81 (3H, s); 4.04-4.32 (4H, m); 4.42 (2H, s(br)); 4.65 (1H, d, J = 48.9 Hz); 6.23 (1H, s); 7.95 (1H, s(br)); 8.01 (1H, s). 19F NMR (CDC13): delta -203.5 to -204.5 (IF, m). 13C NMR (CDC13): delta 26.6, 28.5 (3x), 42.3 (br), 46.5 (br), 48.6 (d, J = 17.3 Hz), 52.2, 80.1, 87.9 (d, J = 176.5 Hz), 97.9, 111.6, 112.0, 133.1, 147.1, 155.2, 157.7, 164.0. IR (ATR, cm"1): v = 3470, 3393, 3310, 1697, 1637, 1612, 1534, 1420. MS (ES+) mlz (%): 402/404 (M+H+, 100).
68%		Synthesis of cis-tert-butyl 4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-fluoropiperidine-1-carboxylate 11 [0058] To a solution of 0.97 g (4.82 mmol) of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> in 25 mL of dry DMF was added 0.70 g (6.88 mmol) of triethylamine at room temperature under N2-atmosphere. After stirring for 10 min at rt, a solution of 0.52 g (4.82 mmol) of ethyl chloroformate in 1 mL of DMF was added dropwise at rt and stirring was continued for 30 min. Then 0.65 g (4.82 mmol) of hydroxybenzotriazole was added as a solid in one portion at rt and the solution was stirred for 30 min. Subsequently, a solution of 1.0 g (4.59 mmol) of amine 10 in 3 mL of DMF was added dropwise at rt and the reaction mixture was stirred overnight at rt. Afterwards, the mixture was poured in 100 mL of brine and extracted with EtOAc (4×30 mL). The combined organic fraction was washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture was subjected to flash silicagel chromatography (hex/EtOAc/Et3N 1:1:0.1; Rf=0.01) to yield 1.25 g (68%) of pure tert-butyl 4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-fluoropiperidine-1-carboxylate 11 as a solid. Mp 198-199 C. 1H NMR (CDCl3): delta 1.35 (9H, s); 1.44-1.77 (2H, m); 2.77-2.98 (1H, m); 3.81 (3H, s); 4.04-4.32 (4H, m); 4.42 (2H, s(br)); 4.65 (1H, d, J=48.9 Hz); 6.23 (1H, s); 7.95 (1H, s(br)); 8.01 (1H, s). 19F NMR (CDCl3): delta -203.5 to -204.5 (1F, m). 13C NMR (CDCl3): delta 26.6, 28.5 (3×), 42.3 (br), 46.5 (br), 48.6 (d, J=17.3 Hz), 52.2, 80.1, 87.9 (d, J=176.5 Hz), 97.9, 111.6, 112.0, 133.1, 147.1, 155.2, 157.7, 164.0. IR (ATR, cm-1): nu=3470, 3393, 3310, 1697, 1637, 1612, 1534, 1420. MS (ES+) m/z (%): 402/404 (M+H+, 100).

Reference： [1]Patent: WO2012/28614,2012,A1 .Location in patent: Page/Page column 14-15
[2]Patent: US2013/172386,2013,A1 .Location in patent: Paragraph 0054; 0058

39
[ 7206-70-4 ]
trans-4-amino-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
trans-tert-butyl 4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-fluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%		To a solution of 0.41 g (2.02 mmol) of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> in 10 mL of dry DMF was added 0.29 g (2.89 mmol) of triethylamine at room temperature under N2-atmosphere. After stirring for 10 min at rt, a solution of 0.22 g (2.02 mmol) of ethyl chloroformate in 2 mL of DMF was added dropwise at rt and stirring was continued for 30 min, while the temperature was maintained at rt (cooling with waterbath at rt). Then 0.27 g (2.02 mmol) of hydroxybenzotriazole was added as a solid in one portion at rt and the solution was stirred for 30 min. Subsequently, a solution of 0.42 g (1.93 mmol) of amine 5 in 3 mL of DMF was added dropwise at rt and the reaction mixture was stirred overnight at rt. Afterwards, the mixture was poured in 20 mL of brine and extracted with EtOAc (3x 25 mL). The combined organic fraction was washed with brine, dried over MgS04, filtered and evaporated under reduced pressure. The crude mixture was subjected to flash silicagel chromatography (hex/EtOAc/Et3N 1 : 1 :0.1) to yield 0.72 g (93%) of pure traws-tert-butyl 4-(4-amino-5-chloro-2- methoxybenzoylamino)-3-fluoropiperidine-l-carboxylate 6 as a solid. 1H MR(CDC13): delta 1.47 (9H, s); 2.17-2.28 (1H, m); 2.96-3.19 (2H, m); 3.74 (1H, dm, J = 13.7 Hz); 3.90 (3H, s); 3.92-4.40 (3H, m); 4.45 (1H, ddt, J = 4.4 Hz, 8.3 Hz, J = 48.4 Hz); 6.30 (1H, s); 7.82 (1H, d, J = 7.2 Hz); 8.08 (1H, s). 19F MR (CDC13): delta -189.0 (d, J = 44.7 Hz). 13C NMR (CDC13): delta 28.4 (3x), 29.1 (br), 41.5 (br), 45.6 (br), 50.1 (br), 56.4, 80.4, 88.2 (d, J = 182.3 Hz), 97.9, 111.8, 112.1, 133.2, 147.1, 154.7, 157.6; 164.5. IR (ATR, cm"1): v = 3478, 3378, 1683, 1619, 1593, 1420, 1247, 1146. MS (ES+) mlz (%): 346/48 (M+H+, 100); 402/404 (M+H+, 60).
93%		Synthesis of trans-tert-butyl 4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-fluoropiperidine-1-carboxylate 6 To a solution of 0.41 g (2.02 mmol) of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> in 10 mL of dry DMF was added 0.29 g (2.89 mmol) of triethylamine at room temperature under N2-atmosphere. After stirring for 10 min at rt, a solution of 0.22 g (2.02 mmol) of ethyl chloroformate in 2 mL of DMF was added dropwise at rt and stirring was continued for 30 min, while the temperature was maintained at rt (cooling with waterbath at rt). Then 0.27 g (2.02 mmol) of hydroxybenzotriazole was added as a solid in one portion at rt and the solution was stirred for 30 min. Subsequently, a solution of 0.42 g (1.93 mmol) of amine 5 in 3 mL of DMF was added dropwise at rt and the reaction mixture was stirred overnight at rt. Afterwards, the mixture was poured in 20 mL of brine and extracted with EtOAc (325 mL). The combined organic fraction was washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture was subjected to flash silicagel chromatography (hex/EtOAc/Et3N 1:1:0.1) to yield 0.72 g (93%) of pure trans-tert-butyl 4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-fluoropiperidine-1-carboxylate 6 as a solid. 1H NMR (CDCl3): delta 1.47 (9H, s); 2.17-2.28 (1H, m); 2.96-3.19 (2H, m); 3.74 (1H, dm, J=13.7 Hz); 3.90 (3H, s); 3.92-4.40 (3H, m); 4.45 (1H, ddt, J=4.4 Hz, 8.3 Hz, J=48.4 Hz); 6.30 (1H, s); 7.82 (1H, d, J=7.2 Hz); 8.08 (1H, s). 19F NMR (CDCl3): delta -189.0 (d, J=44.7 Hz). 13C NMR (CDCl3): delta 28.4 (3), 29.1 (br), 41.5 (br), 45.6 (br), 50.1 (br), 56.4, 80.4, 88.2 (d, J=182.3 Hz), 97.9, 111.8, 112.1, 133.2, 147.1, 154.7, 157.6; 164.5. IR (ATR, cm-1): nu=3478, 3378, 1683, 1619, 1593, 1420, 1247, 1146. MS (ES+) m/z (%): 346/48 (M+H+, 100); 402/404 (M+H+, 60).

Reference： [1]Patent: WO2012/28614,2012,A1 .Location in patent: Page/Page column 12
[2]Patent: US2013/172386,2013,A1 .Location in patent: Paragraph 0044; 0048

40
[ 7206-70-4 ]
[ 1361191-19-6 ]
[ 1361191-20-9 ]

Yield	Reaction Conditions	Operation in experiment
71%		In a dry 50 mL flask, 0.44 g (2.2 mmol; 1.1 equiv) of 4-amino-5-chloro-2- methoxybenzoic acid and 0.30 g (3 mmol; 1.5 equiv) of triethylamine were dissolved in 25 mL of dimethylformamide and stirred during 10 minutes at room temperature. Then the mixture was cooled to 0C and 0.24 g (2.2 mmol; 1.1 equiv) of ethyl chloroformate was added and stirred during 30 minutes at room temperature. Then 0.29 g (2.2 mmol; 1.1 equiv) of 1-hydroxybenzotriazole was added and stirred during 30 minutes at room temperature. Then 0.57 g of 3,3-difluoro-l-[3-(4-fluorophenoxy)propyl]piperidin-4- amine 16 was added and the mixture was stirred at room temperature during 15 hours. After evaporation of the solvent in vacuo, the crude oil was redissolved in EtOAc and poured in 50 mL of brine and extracted with EtOAc (4 x 50 mL). The organic phases were washed with brine and dried over MgS04. After filtration of the solids and evaporation of the solvent under vacuum, the crude oil was purified via flash chromatography (hexane/EtOAc 3 :7, Rf = 0.35) yielding 0.66 g (1.4 mmol; 71% yield) of pure 4-amino-5 -chloro-N- {3,3 -difluoro- 1 - [3 -(4-fluorophenoxy)propyl]piperidin-4- yl}-2-methoxybenzamide 17 as white crystals. M.p. = 125.8 C (hexane/EtOH 1 : 1). 1H MR (CDC13): delta 1.70 (1H, ddd, J = 24.8 Hz, 12.7 Hz, 3.9 Hz, CFLHb); 1.93 (2H, quintet, J = 6.6 Hz, CH2); 2.01-2.12 (1H, m, CHaHb); 2.21 (1H, t, J = 11.8 Hz,NCHaHb); 2.34 (1H, ddd, J = 28.8 Hz, 11.3 Hz, 1.7 Hz, NCFLHbCF2); 2.50-2.69 (2H, m, NCH2); 2.92 (1H, d, J = 1 1.8 Hz, NCHaHb); 3.19 (1H, td, J = 11.3 Hz, 4.4 Hz, NCHaHbCF2); 3.86 (3H, s, OCH3); 3.96 (2H, t, J = 6.6 Hz, OCH2); 4.43 (3H, s(broad), NCH and NH2); 6.26 (1H, s, CHar); 6.81 (2H, dd, J = 8.8 Hz, 4.4 Hz, 2 CHar); 6.94 (2H, t, J = 8.8 Hz, 2 CHar); 8.03 (1H, s(broad), NH); 8.06 (1H, s, CHar). 19F NMR (CDCI3): delta -107.6 (IF, d, J = 240.7 Hz, CFaFb); -116.9 (IF, d(broad), J = 240.7 Hz, CFaFb); -124.0 (IF, tt, J = 7.9 Hz, 4.0 Hz, CarF). 13C NMR (CDC13): delta 26.8 (CHj, ^); 29.6 (d, J = 5.8 Hz, CH2); 50.2 (t, J = 19.6 Hz, NCH); 51.5 (NCH2); 53.9 (NCH2, ^1); 56.2 (OCH3); 58.0 (dd, J = 29.4 Hz, 23.7 Hz, NCH2CF2); 66.3 (OCH2); 97.8 (CHar); 111.6 (CarCO); 111.9 (CarCl); 115.4 (d, J = 8.1 Hz, 2 x CHar); 115.7 (d, J = 23.1 Hz, 2 x CHar); 118.9 (t, J = 245.8 Hz, CF2); 133.1 (CHar); 147.1 (CarNH2); 155.0 (d, J = 2.3 Hz, OCar); 157.2 (d, J = 237.7 Hz, CarF); 157.6 (CarOMe); 164.4 (C=0). IR (ATR, cm"1): v = 3480; 3398; 3329; 3194; 2964; 2886; 2818; 1641; 1614; 1584; 1538; 1506; 1462; 1318; 1247; 1208; 1146; 1124; 1074; 1037; 982; 910; 822; 753; 681. MS (ES+) mlz (%): 472/474 (M+H+, 100).
71%		Example 3 Synthesis of 4-amino-5-chloro-N-{3,3-difluoro-1-[3-(4-fluorophenoxy)propyl]-piperidin-4-yl}-2-methoxybenzamide 17 In a dry 50 mL flask, 0.44 g (2.2 mmol; 1.1 equiv) of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> and 0.30 g (3 mmol; 1.5 equiv) of triethylamine were dissolved in 25 mL of dimethylformamide and stirred during 10 minutes at room temperature. Then the mixture was cooled to 0 C. and 0.24 g (2.2 mmol; 1.1 equiv) of ethyl chloroformate was added and stirred during 30 minutes at room temperature. Then 0.29 g (2.2 mmol; 1.1 equiv) of 1-hydroxybenzotriazole was added and stirred during 30 minutes at room temperature. Then 0.57 g of 3,3-difluoro-1-[3-(4-fluorophenoxy)propyl]piperidin-4-amine 16 was added and the mixture was stirred at room temperature during 15 hours. After evaporation of the solvent in vacuo, the crude oil was redissolved in EtOAc and poured in 50 mL of brine and extracted with EtOAc (450 mL). The organic phases were washed with brine and dried over MgSO4. After filtration of the solids and evaporation of the solvent under vacuum, the crude oil was purified via flash chromatography (hexane/EtOAc 3:7, Rf=0.35) yielding 0.66 g (1.4 mmol; 71% yield) of pure 4-amino-5-chloro-N-{3,3-difluoro-1-[3-(4-fluorophenoxy)propyl]piperidin-4-yl}-2-methoxybenzamide 17 as white crystals. M.p.=125.8 C. (hexane/EtOH 1:1). 1H NMR (CDCl3): delta 1.70 (1H, ddd, J=24.8 Hz, 12.7 Hz, 3.9 Hz, CHaHb); 1.93 (2H, quintet, J=6.6 Hz, CH2); 2.01-2.12 (1H, m, CHaHb); 2.21 (1H, t, J=11.8 Hz, NCHaHb); 2.34 (1H, ddd, J=28.8 Hz, 11.3 Hz, 1.7 Hz, NCHaHbCF2); 2.50-2.69 (2H, m, NCH2); 2.92 (1H, d, J=11.8 Hz, NCHaHb); 3.19 (1H, td, J=11.3 Hz, 4.4 Hz, NCHaHbCF2); 3.86 (3H, s, OCH3); 3.96 (2H, t, J=6.6 Hz, OCH2); 4.43 (3H, s(broad), NCH and NH2); 6.26 (1H, s, CHar); 6.81 (2H, dd, J=8.8 Hz, 4.4 Hz, 2CHar); 6.94 (2H, t, J=8.8 Hz, 2CHar); 8.03 (1H, s(broad), NH); 8.06 (1H, s, CHar). 19F NMR (CDCl3): delta -107.6 (1F, d, J=240.7 Hz, CFaFb); -116.9 (1F, d(broad), J=240.7 Hz, CFaFb); -124.0 (1F, tt, J=7.9 Hz, 4.0 Hz, CarF). 13C NMR (CDCl3): delta 26.8 (CH2, alkyl); 29.6 (d, J=5.8 Hz, CH2); 50.2 (t, J=19.6 Hz, NCH); 51.5 (NCH2); 53.9 (NCH2, alkyl); 56.2 (OCH3); 58.0 (dd, J=29.4 Hz, 23.7 Hz, NCH2CF2); 66.3 (OCH2); 97.8 (CHar); 111.6 (CarCO); 111.9 (CarCl); 115.4 (d, J=8.1 Hz, 2CHar); 115.7 (d, J=23.1 Hz, 2*CHar); 118.9 (t, J=245.8 Hz, CF2); 133.1 (CHar); 147.1 (CarNH2); 155.0 (d, J=2.3 Hz, OCar); 157.2 (d, J=237.7 Hz, CarF); 157.6 (CarOMe); 164.4 (C=O). IR (ATR, cm-1): nu=3480; 3398; 3329; 3194; 2964; 2886; 2818; 1641; 1614; 1584; 1538; 1506; 1462; 1318; 1247; 1208; 1146; 1124; 1074; 1037; 982; 910; 822; 753; 681. MS (ES+) m/z (%): 472/474 (M+H+, 100).

Reference： [1]Patent: WO2012/28614,2012,A1 .Location in patent: Page/Page column 19-20
[2]Patent: US2013/172386,2013,A1 .Location in patent: Paragraph 0070

41
[ 7206-70-4 ]
[ 2827-56-7 ]
4-amino-5-chloro-N-(2,4-dioxo-l-imidazolidinyl)-2-methoxybenzene [ No CAS ]

Reference： [1]Medicinal Chemistry,2010,vol. 6,p. 344 - 354

42
[ 7206-70-4 ]
[ 81098-60-4 ]

Reference： [1]Tetrahedron,2012,vol. 68,p. 3263 - 3275

43
[ 4093-29-2 ]
[ 7206-70-4 ]

Reference： [1]Letters in drug design and discovery,2012,vol. 9,p. 489 - 493

44
[ 4093-28-1 ]
[ 7206-70-4 ]

Reference： [1]Letters in drug design and discovery,2012,vol. 9,p. 489 - 493

45
[ 7206-70-4 ]
[ 4093-31-6 ]

Reference： [1]Patent: US2012/277224,2012,A1

46
[ 7206-70-4 ]
[ 1374829-47-6 ]
[ 1401423-42-4 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 9416 - 9433

47
[ 773837-37-9 ]
[ 7206-70-4 ]
copper(l) cyanide [ No CAS ]
5-chloro-4-cyano-2-methoxybenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		To a suspension of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (4.Og, 1 9.8mmol) in water (66mL) was added concentrated hydrogen chloride (6.6mL of a 35% solution in water, 79.2mmol) and the resulting mixture was cooled to 0C with vigorous stirring. Then, a solution of sodium nitrite (1 .95g, 28.3mmol) in water (6mL) was added dropwise while maintaining the internal temperature below 4C. After 5 mm, the mixture containing the diazonium salt was slowly added, through an addition funnel and maintaining the temperature below 5C, over a mechanically stirred solution of copper cyanide (2.4g, 26.8mmol) and sodium cyanide (3.7g, 75.Smmol) in water (2OmL, this solution was freshly prepared from a suspension of the copper cyanide in water and slow addition of sodium cyanide while keeping the temperature below 40 C and allowed to cool to rt). Once the addition was finished, the reaction mixture was allowed to warm to rt and vigorous stirring was maintained for 4 hours. Then, water and hydrogen chloride (SN) were added to the mixture and the aqueous phase was extracted with ethyl acetate. The whole mixture was filtered to remove the solids and the phases were separated. The aqueous phase was further extracted twice with ethyl acetate and the combined organic extracts were washed with brine, dried, decolorized with active carbon, filtered and concentrated to dryness to afford the title compound as light yellow solid (3.Og, 70%).LRMS (mlz): 210 (M-1)-
62%		To a solution of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (4g, 0.019mol) in water (60ml_) was added hydrochloric acid (35%, 0.63ml_) and the mixture was stirred vigorously and cooled to 5C. Then a solution of sodium nitrite (1 .92g, 0.027mol) in water (6 mL) was added dropwise. The mixture was stirred for some minutes and then a previously formed solution of copper cyanide (2.32g, 0.026mol) and sodium cyanide (3.65g, 0.074mol) in water (20ml_) was added dropwise maintaining a low temperature. Once the addition was finished the reaction mixture was stirred 1 hour at room temperature. The pH of the aqueous phase was adjusted to 3 and ethyl acetate was added into the mixture and the organic layer was washed with water, dried, filtered and the solvent was removed under reduced pressure giving the title compound (2.93g, 62%).
62%		Intermediate 54.5-chloro-4-cyano-2-methoxybenzoic acidTo a solution of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (4g, 0.019mol) in water (60ml_) was added hydrochloric acid (35%, 0.63ml_) and the mixture was stirred vigorously and cooled to 5C. Then a solution of sodium nitrite (1 .92g, 0.027mol) in water (6 mL) was added dropwise. The mixture was stirred for some minutes and then a previously formed solution of copper cyanide (2.32g, 0.026mol) and sodium cyanide (3.65g, 0.074mol) in water (20ml_) was added dropwise maintaining a low temperature. Once the addition was finished the reaction mixture was stirred 1 hour at room temperature. The pH of the aqueous phase was adjusted to 3 and ethyl acetate was added into the mixture and the organic layer was washed with water, dried, filtered and the solvent was removed under reduced pressure giving the title compound (2.93g, 62%).LRMS (m/z): 212 (M+1 )+

Reference： [1]Patent: WO2014/95920,2014,A1 .Location in patent: Page/Page column 157
[2]Patent: WO2013/68552,2013,A1 .Location in patent: Page/Page column 61
[3]Patent: WO2013/68554,2013,A1 .Location in patent: Page/Page column 71

48
[ 204580-28-9 ]
[ 7206-70-4 ]
[ 1441173-24-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; at 20℃; for 1h;	General procedure: Step 2: 4-Amino-N-(2-((fer/-butyldimethylsilyl)oxy)ethyl)-5-chloro-2-methoxy- N-methylbenzamide 4-Amino-5-chloro-2-methoxybenzoic acid (3.0 g, 14.9 mmol), DIPEA (3.84 g, 29.8 mmol) and HATU (6.80 g, 17.9 mmol) were stirred at room temperature for 20 min in dichloromethane (180 mL). 2-((reri-butyldimethylsilyl)oxy)-N-methylethanamine (3.12 g, 16.4 mmol) was added, then the reaction was stirred for 1 h after which time analysis by LCMS indicated the reaction was complete. The dichloromethane was removed and the resulting residue partitioned between ethyl acetate and water. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were concentrated and the resulting residue was triturated with ethyl acetate- petroleum ether (1 : 1). The solid was collected by filtration and discarded. The supernatant was retained and concentrated to afford a crude product that was used directly in the next step (2.0 g, 36%).

Reference： [1]Patent: WO2013/79505,2013,A1 .Location in patent: Page/Page column 62-63

49
[ 7206-70-4 ]
[ 98446-49-2 ]

Yield	Reaction Conditions	Operation in experiment
15%	With silver carbonate; copper dichloride; palladium dichloride; In tetrahydrofuran; at 110℃; for 24h;	General procedure: A mixture of carboxylic acid (1 equiv., 0.5 mmol), CuBr2 or CuCl2 (2 equiv., 1 mmol), Ag2CO3 (1 equiv., 0.5 mmol) and PdCl2 (0.1 equiv.) was heated inTHF (3 mL) under reflux at 110 oC for 24 h. After the reaction finished, the mixture was evaporated under vacuum and purified by columnchromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 3079 - 3081

50
[ 110-72-5 ]
[ 7206-70-4 ]
[ 27260-19-1 ]

Yield	Reaction Conditions	Operation in experiment
Ca. 62%		[0166] Synthesis of Ethylethylencdiamine-4-Amino-5-Chloro-2-Methoxybenzoic Acid Amide (Compound 6)[0167] To a DMF solution of 4-amino-5-choro-2-methoxybenzoic acid (1.8 g, ?-8.9 mmol) and methylmorpholine (-2.7 g, --26.8 mmol), CDMT was added(---1 .6 g, --8.9 mmol) and the reaction mixture was stirred at room temperature for -1 hour. Thereafter, Nethylethlenediamine (-1.6 g, -17.9 mmol) was then added. The reaction mixture was stirred at room temperature overnight (-19 h), and HPLC indicated that the reaction was complete. DCM was added to the reaction mixture and the DCM solution was washed with O.IN NaOH/NaCl aqueous solution three times. After all solvents were removed, the product mixture was loaded on a silica gel column and eluted with DCM/Methanol in a Biotage. A white solid was obtained (--1.5 g, -5.5 mmol, -62% isolated yield). LC-MS: calc: 271.1; found: 271.1. Proton NMR also confirmed that it was the desired ethylethlenediamine-4- amino-5-chloro-2-methoxybenzoic acid amide (Compound 6).

Reference： [1]Patent: WO2014/43707,2014,A1 .Location in patent: Paragraph 0166; 0167

51
[ 7206-70-4 ]
[ 6530-09-2 ]
(R)-zacopride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.9%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 24h;	The same procedures as described in Preparative Example 2 were conducted, and a compound represented by Formula 91, that is, (R)-3-aminoquinuclidine hydrochloride (44.90 mg, 0.225 mmol) and a compound represented by Formula 149, that is, <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (50.01 mg, 0.248 mmol) were used according to reaction scheme 78. As a result, a benzamide compound represented by Formula 78 was obtained as a desired product (WZ-047; 54.40 mg, 77.9% yield). [0342] Analysis data of the produced benzamide compound is provided as follows. 1H-NMR (MeOD-d4) d 1.64(m, 1H), 1.80(m, 3H), 1.99(m, 1H), 2.54(m, 1H), 2.88(m, 5H), 3.95(s, 3H), 4.09(m, 1H), 6.53(s, 1H), 7.79(m, 1H).

Reference： [1]Patent: EP2786986,2014,A2 .Location in patent: Paragraph 0340-0342

52
[ 7206-70-4 ]
[ 6530-09-2 ]
(S)-zacopride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 24h;	The same procedures as described in Preparative Example 2 were conducted, and a compound represented by Formula 91, that is, (S)-3-aminoquinuclidine hydrochloride (44.90 mg, 0.225 mmol) and a compound represented by Formula 149, that is, <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (50.01 mg, 0.248 mmol) were used according to Formula 79. A benzamide compound represented by Formula 79 was obtained as a desired product (WZ-049; 47.50 mg, 68.0% yield). [0345] Analysis data of the produced benzamide compound is provided as follows. 1H-NMR (MeOD-d4) d 1.64(m, 1H), 1.80(m, 3H), 1.99(m, 1H), 2.64(m, 1H), 2.78(m, 1H), 2.86(m, 2H), 2.91(m, 2H), 3.95(s, 3H), 4.09(m, 1H), 6.53(s, 1H), 7.79(s, 1H).

Reference： [1]Patent: EP2786986,2014,A2 .Location in patent: Page/Page column 0343-0345

53
C-(octahydroquinolizin-1-yl)methylamine dihydrochloride [ No CAS ]
[ 7206-70-4 ]
C₁₈H₂₆ClN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.2%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 24h;	The same procedures as described in Preparative Example 2 were conducted, and a compound represented by Formula 150, that is, C-(octahydroquinolizin-1-yl)methylamine dihydrochloride (24.90 mg, 0.103 mmol) and a compound represented by Formula 149, that is, <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (22.84 mg, 0.114 mmol) were used according to reaction scheme 77. As a result, a benzamide compound represented by Formula 77 was obtained as a desired product (WZ-044; 24.40 mg, 67.2% yield). [0339] Analysis data of the produced benzamide compound is provided as follows. 1H-NMR (MeOD-d4) d 1.33(m, 1H), 1.46(m, 2H), 1.54(m, 4H), 1.82(m, 3H), 2.06(m, 1H), 2.84(m, 1H), 3.41(m, 2H), 3.87(s, 3H), 6.47(s, 1H), 7.75(s, 1H).

Reference： [1]Patent: EP2786986,2014,A2 .Location in patent: Paragraph 0337-0339

54
4-aminomethyl-1-methylpiperidin-4-ol hydrochloride [ No CAS ]
[ 7206-70-4 ]
C₁₅H₂₂ClN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50.3%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 24h;	The same procedures as described in Preparative Example 2 were conducted, and a compound represented by Formula 151, that is, 4-aminomethyl-1-methylpiperidin-4-ol hydrochloride (58.90 mg, 0.271 mmol) and a compound represented by Formula 149, that is, <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (60.02 mg, 0.298 mmol) were used according to reaction scheme 80. As a result, a benzamide compound represented by Formula 80 was obtained as a desired product (WZ-055; 44.70 mg, 50.3% yield). [0348] Analysis data of the produced benzamide compound is provided as follows. 1H-NMR (MeOD-d4) d 1.75(m, 4H), 2.51 (s, 3H), 2.79(m, 2H), 2.88(m, 2H), 3.45(s, 2H), 3.97(s, 3H), 6.51(s, 1H), 7.83(s, 1H).

Reference： [1]Patent: EP2786986,2014,A2 .Location in patent: Paragraph 0346-0348

55
[ 7206-70-4 ]
[ 6148-64-7 ]
ethyl 3-(4-amino-5-chloro-2-methoxyphenyl)-3-oxo-propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		To a solution of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong>(5.00 g, 24.8 mmol, 1.0 eq.) in THF (200 mL, 0.12 M) was added CDI(4.42 g, 27.3 mmol, 1.1 eq.) portionwise. The mixture was stirred atrt for 4 h. Then, ethyl potassium malonate (5.06 g, 29.7 mmol, 1.2eq.) and MgCl2 (2.83 g, 29.7 mmol, 1.2 eq.) were added portionwisely.The resulting mixture was stirred 16 h at 40 C.Solvent were evaporated under vacuum. The residue wasdiluted with water and then extracted with DCM three times. Organicslayers were combined and washed with NaHCO3 sat. solution,then brine, and dried over MgSO4. Solvent was evaporatedunder vacuum to afford a crude product which was purified onsilica gel column (Cyclohexane/EtOAc from 100:0 to 60:40). Thecompound was obtained as a light yellow powder (3.76 g, 60%yield).1H NMR (CDCl3, 400 MHz) d 7.92 (s, 1H), 6.23 (s, 1H), 4.55 (s,2H), 4.17 (q, J 7.1 Hz, 2H), 3.87 (s, 2H), 3.82 (s, 3H), 1.23 (t,J 7.1 Hz, 3H)13C NMR (CDCl3, 100 MHz) d 189.6, 168.6, 159.9,148.7, 132.5, 117.3, 111.7, 97.0, 60.8, 55.4, 50.5, 14.2 MS m/z [MH]272.51 IR (neat, cm1) n 3463, 3363, 3223, 2983, 1725, 1648, 1622,1573, 1479, 1457 1326, 1220, 837, 654 Mp 117 C. Spectral andanalytical data matched with literature [21].

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3172 - 3187
[2]European Journal of Medicinal Chemistry,2019,vol. 182
[3]European Journal of Medicinal Chemistry,2016,vol. 121,p. 283 - 293

56
[ 7206-70-4 ]
(1-(cyclohexylmethyl)piperidin-4-yl)methanol [ No CAS ]
[1-(cyclohexylmethyl)-4-piperidyl]methyl 4-amino-5-chloro-2-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%		Using N2the 89 mg of CDI (0.55mmol) adding to the containing <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (101 mg) suspension of the new distillation 3mlTHF (tetrahydrofuran). The reaction medium is stirred at room temperature 24 hours, then adding new distillation 2mlTHF of 106 mg of (1 - (cyclohexyl methyl) piperidin-4-yl) methanol (0.50mmol) solution, then adding 21mgNaH (0.55mmol). Stirring at room temperature after a weekend, THF evaporation. The residue dissolved in AcOEt, washed with water, then using MgSO4drying. After concentrating, the residue purified on silica gel (gradient elution: DCM100% than AcOEt100%), the resulting product of the yield is 31%.

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3172 - 3187
[2]Patent: CN105705488,2016,A .Location in patent: Paragraph 0369; 0370; 0371; 0372; 0373; 0374; 0375; 0376

57
[ 7206-70-4 ]
copper(l) cyanide [ No CAS ]
5-chloro-4-cyano-2-methoxybenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		Intermediate 66. 5-chloro-4-cyano-2-methoxybenzoic acid To a suspension of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (4.0g, 19.8mmol) in water (66mL) was added concentrated hydrogen chloride (6.6mL of a 35% solution in water, 79.2mmol) and the resulting mixture was cooled to 0C with vigorous stirring. Then, a solution of sodium nitrite (1 .95g, 28.3mmol) in water (6mL) was added dropwise while maintaining the internal temperature below 4C. After 5 min, the mixture containing the diazonium salt was slowly added, through an addition funnel and maintaining the temperature below 5C, over a mechanically stirred solution of copper cyanide (2.4g, 26.8mmol) and sodium cyanide (3.7g, 75.5mmol) in water (20ml_, this solution was freshly prepared from a suspension of the copper cyanide in water and slow addition of sodium cyanide while keeping the temperature below 40 C and allowed to cool to rt). Once the addition was finished, the reaction mixture was allowed to warm to rt and vigorous stirring was maintained for 4 hours. Then, water and hydrogen chloride (5N) were added to the mixture and the aqueous phase was extracted with ethyl acetate. The whole mixture was filtered to remove the solids and the phases were separated. The aqueous phase was further extracted twice with ethyl acetate and the combined organic extracts were washed with brine, dried, decolorized with active carbon, filtered and concentrated to dryness to afford the title compound as light yellow solid (3.0g, 70%). LRMS (m/z): 210 (M-1 )-

Reference： [1]Patent: WO2016/46390,2016,A1 .Location in patent: Page/Page column 63-64

58
[ 7206-70-4 ]
[ 6148-64-7 ]
ethyl 3-(4-amino-5-fluoro-2-methoxy-phenyl)-3-oxopropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With magnesium chloride; In tetrahydrofuran; at 40℃; for 48h;	The 533 mg of CDI (3.29mmol) adding to the containing 603 mg of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (2.99mmol) is distilled of a suspension of 30mlTHF in.10stirring the mixture at room temperature for 6 hours. Next, each adding 611 mg of 3-ethyl-3-oxo-b ester sylvite (3.59mmol) and 342 mg of MgCl2(3.59mmol). The reaction mixture in 40 C lower stirring 2 days. Using 30mlEt2O expansion solution, water for sequentially, NaHCO3saturated solution of NaCl saturated solution and washing. Using MgSO4after drying, evaporating the organic phase, the purification of a crude product on silica gel (gradient elution: CH/AcOEt8/2 to 7/3), the resulting 507 mg of 3 - (4-amino-5-chloro-2-methoxyphenyl) - 3-oxo-ethyl ester in the yield of 62%.

Reference： [1]Patent: CN105705488,2016,A .Location in patent: Paragraph 0417; 0418; 0419; 0420; 0421; 0422; 0423; 0424

59
[ 7206-70-4 ]
1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine hydrochloride [ No CAS ]
[ 1342815-16-0 ]

Yield	Reaction Conditions	Operation in experiment
98%		(0163) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in dichloromethane (10 mL) and cooled to C. N-methyl morpholine (0.12 g) and isobutyl chloroformate (0.16 g) were sequentially added to the solution and stirred for 3 hours. A reaction solution was prepared by sequentially adding triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine hydrochloride (0.31 g) thereto. The temperature of the reaction solution was elevated and the solution was stirred under reflux. After 4 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes and a layer was separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (3 mL) were added to the collected organic layers to extract the aqueous layer. 1N sodium hydroxide (4 mL) was added to the aqueous layer, and the extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with sodium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22 C. for 18 hours to obtain the titled compound (0.39 g; yield: 98%). (0164) 1H NMR (400 MHz, CDCl3) delta 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Reference： [1]Patent: US2016/185751,2016,A1 .Location in patent: Paragraph 0163-0164

60
[ 7206-70-4 ]
1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine [ No CAS ]
[ 1342815-16-0 ]

Yield	Reaction Conditions	Operation in experiment
100%		(0173) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in acetonitrile (10 mL). Carbonyldiimidazole (0.19 g) was added to the solution and stirred at 19-22 C. for 4 hours. After triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine (0.27 g) were sequentially added thereto, the temperature of the resulting solution was elevated. Then the solution was stirred under reflux. After 21 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes, and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (4 mL) were added to the collected organic layers to extract the aqueous layer. 2N sodium hydroxide (about 4 mL) was added to the aqueous layer to adjust pH of about 10. The extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with anhydrous magnesium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22 C. for 17 hours to obtain the titled compound (0.41 g; yield: 100%). (0174) 1H NMR (400 MHz, CDCl3) delta 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)
100%		4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in acetonitrile (10 mL). Carbonyldiimidazole (0.19 g) was added to the solution and stirred at 19-22 C. for 4 hours. After triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine (0.27 g) were sequentially added thereto, the temperature of the resulting solution was elevated. Then the solution was stirred under reflux. After 21 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes, and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (4 mL) were added to the collected organic layers to extract the aqueous layer. 2N sodium hydroxide (about 4 mL) was added to the aqueous layer to adjust pH of about 10. The extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with anhydrous magnesium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22 C. for 17 hours to obtain the titled compound (0.41 g; yield: 100%).

Reference： [1]Patent: US2016/185751,2016,A1 .Location in patent: Paragraph 0173-0174
[2]Patent: KR101595183,2016,B1 .Location in patent: Paragraph 0208-0209

61
[ 7206-70-4 ]
1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine oxalate [ No CAS ]
[ 1342815-16-0 ]

Yield	Reaction Conditions	Operation in experiment
90%		(0165) 4-Amino-5-chloro-2-methoxybenzoic acid (0.2 g) was dissolved in dichloromethane (10 mL) and cooled to C. N-methyl morpholine (0.12 g) and isobutyl chloroformate (0.16 g) were sequentially added to the solution and stirred for 3 hours. A reaction solution was prepared by sequentially adding triethylamine (0.2 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine oxalate (0.37 g) thereto, and the temperature of the reaction solution was elevated. The reaction solution was stirred under reflux. After 4 hours of stirring, water (10 ml) was added thereto, stirred for 5 minutes, and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (3 mL) were added to the collected organic layers to extract the aqueous layer. 1N sodium hydroxide (4 mL) was added to the aqueous layer and the extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with sodium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22 C. for 18 hours to obtain the titled compound (0.36 g; yield: 90%). (0166) 1H NMR (400 MHz, CDCl3) delta 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Reference： [1]Patent: US2016/185751,2016,A1 .Location in patent: Paragraph 0165-0166

62
[ 7206-70-4 ]
1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine succinate [ No CAS ]
[ 1342815-16-0 ]

Yield	Reaction Conditions	Operation in experiment
90%		(0169) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in dichloromethane (10 mL) and cooled to C. N-methyl morpholine (0.12 g) and isobutyl chloroformate (0.16 g) were sequentially added to the solution and stirred for 3 hours. A reaction solution was prepared by sequentially adding triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine succinate (0.41 g) thereto. The temperature of the reaction solution was elevated and the stirring was performed under reflux. After 14 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (3 mL) were added to the collected organic layers to extract the aqueous layer. 1N sodium hydroxide (4 mL) was added to the aqueous layer and the extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with sodium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22 C. for 18 hours to obtain the titled compound (0.36 g; yield: 90%). (0170) 1H NMR (400 MHz, CDCl3) delta 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Reference： [1]Patent: US2016/185751,2016,A1 .Location in patent: Paragraph 0169-0170

63
[ 7206-70-4 ]
1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine citrate [ No CAS ]
[ 1342815-16-0 ]

Yield	Reaction Conditions	Operation in experiment
88%		(0167) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in dichloromethane (10 mL) and cooled to C. N-methyl morpholine (0.12 g) and isobutyl chloroformate (0.16 g) were sequentially added to the solution and stirred for 3 hours. A reaction solution was prepared by sequentially adding triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine citrate (0.49 g) thereto. The temperature of the reaction solution was elevated and the reaction solution was stirred under reflux. After 14 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (3 mL) were added to the collected organic layers to extract the aqueous layer. 1N sodium hydroxide (4 mL) was added to the aqueous layer and the extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with sodium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22 C. for 18 hours to obtain the titled compound (0.35 g; yield: 88%). (0168) 1H NMR (400 MHz, CDCl3) delta 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Reference： [1]Patent: US2016/185751,2016,A1 .Location in patent: Paragraph 0167-0168

64
[ 7206-70-4 ]
[ 110102-86-8 ]

Reference： [1]Organic Letters,2017,vol. 19,p. 5505 - 5508
[2]Journal of Organic Chemistry,2018,vol. 83,p. 14362 - 14384

65
[ 595-40-4 ]
[ 7206-70-4 ]
(+)-N-(4-amino-5-chloro-2-methoxybenzoyl)-L-isovaline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 50℃; for 2.0h;	To a suspension of 4-amino-5-chloro-2-methoxybenzoic acid (310 mg, 0.50 mmol), triethylamine (0.43 mL, 3.1 mmol) and (S)-alpha-ethylalanine monohydrate (200 mg, 1.5 mmol) in DMF (1.5 mL), HATU (700 mg, 1.8 mmol) was added, followed by stirring at 50 C. for 2 hours. After completion of the reaction, the reaction solution was diluted with DMSO and purified by HPLC [elution solvent: 0.1% formic acid-containing aqueous solution/0.1% formic acid-containing acetonitrile=73/27-45/55 (V/V)] to obtain 450 mg (45%) of the title compound in the form of a solid. (0321) 1H-NMR (400 MHz, CD3OD) delta: 0.84 (3H, t, J=7.3 Hz), 1.64 (3H, s), 1.87-1.96 (1H, m), 2.27-2.36 (1H, m), 3.95 (3H, s), 6.52 (1H, s), 7.79 (1H, s). (0322) MS m/z: 301, 303 [M+H]+. (0323) [alpha]D25 +20.73 (c 0.5, Methanol).

Reference： [1]Patent: US2019/365688,2019,A1 .Location in patent: Paragraph 0319-0323

66
[ 7206-70-4 ]
1-(3-(cyclopentyloxy)propyl)piperidine-4-amine hydrochloride [ No CAS ]
4-amino-5-chloro-N-(1-(3-(cyclopentyloxy)propyl)piperidin-4-yl)-2-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;	In a 100mL single-necked bottle, add <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (1.15g, 5.72mmol),1- (3- (cyclopentyloxy) propyl) piperidin-4-amine hydrochloride (980mg, 3.74mmol),N, N-dimethylformamide (15mL),Triethylamine (1.6mL, 11.6mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.5g, 7.85mmol)And 1-hydroxybenzotriazole (1g, 7.85mmol), and stirred at room temperature for 4 hours.The reaction was stopped, ethyl acetate (30 mL) and water (30 mL) were added, stirred for 10 minutes, separated, and the organic phase was concentrated. The residue was separated and purified by column chromatography (dichloromethane / methanol (v / v) = 30/1) )The title compound was obtained as a white solid (1.02g, 67%).

Reference： [1]Patent: CN110950843,2020,A .Location in patent: Paragraph 0222; 0231-0235

67
[ 7206-70-4 ]
ClH*C₁₂H₂₀N₄O₂S [ No CAS ]
C₂₀H₂₆ClN₅O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	Weigh 2- (2- (2- (4-aminopiperidin-1-yl) ethoxy) -4-methylthiazole-5-carboxamide hydrochloride (955mg, 2.67mmol),<strong>[7206-70-4]4-amino-5-chloro-2-methoxy-benzoic acid</strong> (490mg, 2.43mmol),N, N-dimethylformamide (20mL)And triethylamine (1mL, 7.29mmol) in a 100mL single-necked bottle,Then 1- (3-dimethylamidopropyl) -3-ethylcarbodiimide hydrochloride (565mg, 2.92mmol) was addedAnd 1-hydroxybenzotriazole (402mg, 2.92mmol), placed at room temperature and stirred for 16h to stop the reaction,Dichloromethane (20 mL) was added and washed with water (10 mL × 3). After concentration, the residue was separated by column chromatography (dichloromethane / methanol (v / v) = 20/1) to obtain the title compound as a white solid (620 mg , 55%).

Reference： [1]Patent: CN110950843,2020,A .Location in patent: Paragraph 0236; 0249-0253

68
[ 7206-70-4 ]
2-(3-(4-aminopiperidin-1-yl)propoxy)-4-methylthiazole-5-carboxamide hydrochloride [ No CAS ]
2-(3-(4-(4-amino-5-chloro-2-methoxybenzoylamino)piperidin-1-yl)propoxy)-4-methylthiazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	Weigh 2- (3- (4-aminopiperidin-1-yl) propoxy) -4-methylthiazole-5-carboxamide hydrochloride (434mg, 1.30mmol)And <strong>[7206-70-4]4-amino-5-chloro-2-methoxy-benzoic acid</strong> (250mg, 1.17mmol) in a 100mL single-necked bottle,Add N, N-dimethylformamide (10mL)And triethylamine (0.5mL, 3.0mmol),Then 1- (3-dimethylamidopropyl) -3-ethylcarbodiimide hydrochloride (272mg, 1.40mmol) was addedAnd 1-hydroxybenzotriazole (193mg, 1.40mmol), placed at room temperature and stirred for 16h to stop the reaction,Dichloromethane (20 mL) was added, the solution was separated and washed with water (10 mL × 3). After concentration, the residue was separated by column chromatography (dichloromethane / methanol (v / v) = 20/1) to obtain the title compound as a white solid (280 mg, 45%).

Reference： [1]Patent: CN110950843,2020,A .Location in patent: Paragraph 0254; 0262-0266

Same Skeleton Products

Related Products

Historical Records

Related Functional Groups of
[ 7206-70-4 ]

Aryls

[ 108282-38-8 ]

4-Amino-5-chloro-2-ethoxybenzoic acid

Similarity: 0.97

[ 145742-50-3 ]

4-Amino-5-chloro-2-methoxybenzaldehyde

Similarity: 0.92

[ 4093-31-6 ]

Methyl 4-acetamido-5-chloro-2-methoxybenzoate

Similarity: 0.88

[ 5043-81-2 ]

Methyl 3-amino-5-chloro-2-hydroxybenzoate

Similarity: 0.87

[ 84228-44-4 ]

Methyl 4-amino-3-chlorobenzoate

Similarity: 0.83

Chlorides

[ 108282-38-8 ]

4-Amino-5-chloro-2-ethoxybenzoic acid

Similarity: 0.97

[ 145742-50-3 ]

4-Amino-5-chloro-2-methoxybenzaldehyde

Similarity: 0.92

[ 4093-31-6 ]

Methyl 4-acetamido-5-chloro-2-methoxybenzoate

Similarity: 0.88

[ 5043-81-2 ]

Methyl 3-amino-5-chloro-2-hydroxybenzoate

Similarity: 0.87

[ 84228-44-4 ]

Methyl 4-amino-3-chlorobenzoate

Similarity: 0.83

Ethers

[ 108282-38-8 ]

4-Amino-5-chloro-2-ethoxybenzoic acid

Similarity: 0.97

[ 145742-50-3 ]

4-Amino-5-chloro-2-methoxybenzaldehyde

Similarity: 0.92

[ 4093-31-6 ]

Methyl 4-acetamido-5-chloro-2-methoxybenzoate

Similarity: 0.88

[ 3438-16-2 ]

5-Chloro-2-methoxybenzoic acid

Similarity: 0.80

[ 79025-26-6 ]

Methyl 2-amino-5-chloro-4-methoxybenzoate

Similarity: 0.80

Amines

[ 108282-38-8 ]

4-Amino-5-chloro-2-ethoxybenzoic acid

Similarity: 0.97

[ 145742-50-3 ]

4-Amino-5-chloro-2-methoxybenzaldehyde

Similarity: 0.92

[ 4093-31-6 ]

Methyl 4-acetamido-5-chloro-2-methoxybenzoate

Similarity: 0.88

[ 5043-81-2 ]

Methyl 3-amino-5-chloro-2-hydroxybenzoate

Similarity: 0.87

[ 84228-44-4 ]

Methyl 4-amino-3-chlorobenzoate

Similarity: 0.83

Carboxylic Acids

[ 108282-38-8 ]

4-Amino-5-chloro-2-ethoxybenzoic acid

Similarity: 0.97

[ 3438-16-2 ]

5-Chloro-2-methoxybenzoic acid

Similarity: 0.80

[ 79025-82-4 ]

2-Amino-5-chloro-4-methoxybenzoic acid

Similarity: 0.80

[ 123654-26-2 ]

4-Amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid

Similarity: 0.79

[ 57479-70-6 ]

4-Chloro-2-methoxybenzoic acid

Similarity: 0.79

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