[ CAS No. 57946-56-2 ] {[proInfo.proName]}

Name: 57946-56-2|4-Chloro-2-fluoroaniline|98%
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SKU: A618085
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Quality Control of [ 57946-56-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 57946-56-2 ]

Product Details of [ 57946-56-2 ]

CAS No. :	57946-56-2	MDL No. :	MFCD00010625
Formula :	C₆H₅ClFN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CSFDTBRRIBJILD-UHFFFAOYSA-N
M.W :	145.56	Pubchem ID :	93898
Synonyms :

Calculated chemistry of [ 57946-56-2 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	35.81
TPSA :	26.02 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.72 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.6
Log Po/w (XLOGP3) :	2.07
Log Po/w (WLOGP) :	2.49
Log Po/w (MLOGP) :	2.51
Log Po/w (SILICOS-IT) :	2.21
Consensus Log Po/w :	2.17

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.54
Solubility :	0.42 mg/ml ; 0.00288 mol/l
Class :	Soluble
Log S (Ali) :	-2.25
Solubility :	0.827 mg/ml ; 0.00568 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.91
Solubility :	0.179 mg/ml ; 0.00123 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.37

Safety of [ 57946-56-2 ]

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

Application In Synthesis of [ 57946-56-2 ]

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

Upstream synthesis route of [ 57946-56-2 ]
Downstream synthetic route of [ 57946-56-2 ]

[ 57946-56-2 ] Synthesis Path-Upstream 1~18

1
[ 57946-56-2 ]
[ 4146-24-1 ]

Reference： [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 9, p. 3141 - 3152
[2] Patent: WO2015/55994, 2015, A1,

2
[ 399-31-5 ]
[ 57946-56-2 ]
[ 59280-70-5 ]

Reference： [1] Patent: US4111681, 1978, A,
[2] Patent: US4124374, 1978, A,
[3] Patent: US4059434, 1977, A,
[4] Patent: US3958976, 1976, A,
[5] Patent: US4033751, 1977, A,
[6] Patent: US4042373, 1977, A,
[7] Patent: US3992189, 1976, A,

3
[ 700-37-8 ]
[ 57946-56-2 ]

Reference： [1] Patent: CN104163764, 2016, B, . Location in patent: Paragraph 0050-0053

4
[ 59280-70-5 ]
[ 57946-56-2 ]

Reference： [1] Heterocyclic Communications, 2008, vol. 14, # 6, p. 397 - 404
[2] Patent: US5041155, 1991, A,
[3] Patent: US4818275, 1989, A,

5
[ 348-54-9 ]
[ 57946-56-2 ]

Reference： [1] Beilstein Journal of Organic Chemistry, 2012, vol. 8, p. 744 - 748
[2] Journal of Organic Chemistry, 2017, vol. 82, # 14, p. 7529 - 7537

6
[ 446-30-0 ]
[ 57946-56-2 ]

Reference： [1] Patent: US4243819, 1981, A,

7
[ 106-47-8 ]
[ 57946-56-2 ]
[ 367-22-6 ]
[ 2613-33-4 ]
[ 2613-30-1 ]

Reference： [1] Journal of Fluorine Chemistry, 2005, vol. 126, # 4, p. 661 - 667

8
[ 446-30-0 ]
[ 57946-56-2 ]

Reference： [1] Collection of Czechoslovak Chemical Communications, 1979, vol. 44, # 7, p. 2139 - 2155

9
[ 57946-56-2 ]
[ 1996-29-8 ]

Reference： [1] Patent: WO2003/105853, 2003, A1, . Location in patent: Page 58

10
[ 57946-56-2 ]
[ 1996-29-8 ]

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

11
[ 106-47-8 ]
[ 57946-56-2 ]
[ 367-22-6 ]
[ 2613-33-4 ]
[ 2613-30-1 ]

Reference： [1] Journal of Fluorine Chemistry, 2005, vol. 126, # 4, p. 661 - 667

12
[ 57946-56-2 ]
[ 14791-78-7 ]

Reference： [1] Organic Letters, 2015, vol. 17, # 23, p. 5934 - 5937
[2] Organic Letters, 2013, vol. 15, # 14, p. 3734 - 3737

13
[ 57946-56-2 ]
[ 151-50-8 ]
[ 57381-51-8 ]

Reference： [1] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 5, p. 1357 - 1364

14
[ 57946-56-2 ]
[ 216393-67-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With silver(II) sulfate; iodine In ethanol at 20℃; for 2 h;	Step 1: synthesis of 4-chloro-2-fluoro-6-iodoaniline To a solution of 4-chloro-2-fluoroaniline (1.15 g, 7.9 mmol) in 125 mL of ethanol added silversulphate (1.7 g, 8.3 mmol), then followed by addition of ‘2 (2.1 g, 8.3 mmol) in portions. Afterthe addition was completed, the mixture was stirred at RT for 2 hours. The mixture was filtered through celite and the filtration was evaporated to give dark oil which was dissolved in 125 mL of DCM. The solution was washed with 2M sodium hydroxide (40 mL x 2), saturated Na25203 (40 mL x 2) and water (40 mL x 2). The resulting solution was dried over Mg504 and thenevaporated to give the crude 4-chloro-2-fluoro-6-iodoaniline as dark oil (2.1 g, yield: 98percent).
87%	With iodine; silver sulfate In ethanol at 20℃; for 1.5 h;	4-Chloro-2-fluoroaniline (2.9 g, 20 mmol) was dissolved in ethanol (200 mL). Silver sulphate (6.22 g, 20 mmol) was added and then iodine (5.08 g, 20 mmol) was added in small portions. After the addition was complete the reaction mixture was stirred at ambient temperature for 90min. The reaction mixture was filtered through Celite and evaporated to leave a dark oil which was taken up in DCM (200 mL). and washed with 2M sodium hydroxide (2 x 50 mL), saturated sodium thiosulphate (2x50 mL) and water (2x50 mL). The solution was dried (MgSO₄) and evaporated to leave the title compound as a dark oil (4.73g, 87percent).¹H NMR (400 MHz, DMSO-d₆) δ 5.30 (2H, s), 7.25 - 7.29 (IH, m), 7.47 (IH, t)

Reference： [1] Patent: WO2014/9302, 2014, A1, . Location in patent: Page/Page column 119
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5088 - 5109
[3] Patent: WO2006/82400, 2006, A1, . Location in patent: Page/Page column 56
[4] Patent: US2015/158879, 2015, A1, . Location in patent: Paragraph 0581; 0582
[5] Patent: US2016/200741, 2016, A1, . Location in patent: Paragraph 0582-0583

15
[ 57946-56-2 ]
[ 141337-26-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: With hydrogenchloride; sodium nitrite In water; acetic acid at 0℃; for 0.666667 h; Stage #2: With sulfur dioxide; copper(l) chloride In water; acetic acid at 0 - 20℃; for 1 h; Stage #3: at 0 - 20℃;	Compound 53. 2-fluoro-4-chloroaniline (22.90 g, 151 mmol) was dissolved in 120 mL of AcOH and 80 mL of concentrated HCl was added with stirring. The reaction mixture was cooled to 0 C. and a solution of NaNO2 (27.2 g, 0.4 mol) dissolved in 40 mL of H2O was added over 10 min. The reaction mixture was stirred for 30 min at 0 C. In a separate flask, 500 mg of CuCl was dissolved in 200 mL of AcOH. The flask was cooled to 0 C. and SO2 gas was bubbled into the solution for 40 minutes. The contents of the "aniline" flask were added to the contents of the second flask over 20 minutes causing a vigorous evolution of gas. After the addition was complete, the ice bath was removed, and the reaction mixture was allowed to warm to rt. The reaction mixture was poured into 500 g of chipped ice and the resulting solids were collected, washed and dried to give 26.1 g (73percent) of compound 53.

Reference： [1] Patent: US2003/232859, 2003, A1, . Location in patent: Page 56
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 22, p. 9539 - 9553

16
[ 57946-56-2 ]
[ 141337-26-0 ]

Yield	Reaction Conditions	Operation in experiment
87.1%	With hydrogenchloride; acetic acid; sodium nitrite In water	a 4-Chloro-2-fluorobenzenesulfonyl chloride In a mixture, maintained at -10° C., of 75 ml HCl 10N and 22 ml acetic acid, 32.5 g (223 mmoles) of commercial 4-chloro-2-fluoroaniline, and 16.7 g (241 mmoles) of sodium nitrite in solution in 26 ml water are added. This reaction mixture is added by fractions to a solution maintained at 10° C. of 220 ml acetic acid saturated with SO₂ and containing 5.5 g (56.3 mmoles) of cuprous (I) chloride (I). Stirring is continued 1/2 hour at room temperature, before pouring over a ice-water mixture and extracting with ether. The organic phase is washed with a solution saturated with NaHCO₃, dried over Na₂ SO₄ and concentrated. After distillation, there is obtained 44.5 g (yield=87.1percent) of a pale yellow liquid which crystallizes. b.p._0.1 =81° C. M.P.=36°-8° C. I.R. (film): ν (SO₂)=1375 cm^-1; (SO₂)=1175 cm^-1. N.M.R. (CDCl₃): δ=7.1-7.5 (2H,m); 7.7-8.1 (1H,m).

Reference： [1] Patent: US5387709, 1995, A,

17
[ 57946-56-2 ]
[ 20277-69-4 ]
[ 832755-13-2 ]

Reference： [1] Chinese Journal of Chemistry, 2017, vol. 35, # 11, p. 1661 - 1664

18
[ 24424-99-5 ]
[ 57946-56-2 ]
[ 956828-47-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	for 48 h; Reflux	A solution of 4-chloro-2-fluoroaniline (2 g, 13.74 mmol) and di-tert-butyl dicarbonate (6.4 mL, 27.6 mmol) in 1,4-dioxane (50 mL) was stirred at reflux for 2 days. The solvent was then evaporated. The resulting oil was diluted with MeOH, water, and aqueous ammonium hydroxide solution (10 mL each) and vigorously stirred for 45 minutes. The organic lower layer was separated. The organic material was diluted with EtOAc (50 mL), and washed with water (50 mL), 3.6percent aqueous HCl solution (250 mL), saturated aqueous NaHCO₃ solution (50 mL), and then again with water (250 mL). The organic layer was dried (MgSO₄), filtered, and evaporated under reduced pressure to provide tert-butyl(4-chloro-2-fluorophenyl)carbamate (3.0011 g, 12.22 mmol, 89percent yield) as a reddish liquid that solidified on standing. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 9.12 (s, 1H), 7.63 (t, J=8.65 Hz, 1H), 7.42 (dd, J=10.85, 2.35 Hz, 1H), 7.18-7.24 (m, 1H), 1.45 (s, 9H). LCMS (Method 1): m/z 246 [M+H]⁺.
89%	for 48 h; Reflux	Step-1: tert-Butyl (4-chloro-2-fluorophenyl)carbamate. [0131] A solution of 4-chloro-2-fluoroaniline (2 g, 13.74 mmol) and di-tert-butyl dicarbonate (6.4 mL, 27.6 mmol) in 1,4-dioxane (50 mL) was stirred at reflux for 2 days. The solvent was then evaporated. The resulting oil was diluted with MeOH, water, and aqueous ammonium hydroxide solution (10 mL each) and vigorously stirred for 45 minutes. The organic lower layer was separated. The organic material was diluted with EtOAc (50 mL), and washed with water (50 mL), 3.6percent aqueous HCl solution (2 x 50 mL), saturated aqueous NaHCO₃ solution (50 mL), and then again with water (2 x 50 mL). The organic layer was dried (MgSO₄), filtered, and evaporated under reduced pressure to provide tert- butyl (4-chloro-2-fluorophenyl)carbamate (3.0011 g, 12.22 mmol, 89percent yield) as a reddish liquid that solidified on standing.¹H NMR (300 MHz, DMSO-d₆): δ ppm 9.12 (s, 1 H), 7.63 (t, J = 8.65 Hz, 1 H), 7.42 (dd, J = 10.85, 2.35 Hz, 1 H), 7.18-7.24 (m, 1 H), 1.45 (s, 9 H). LCMS (Method 1): m/z 246 [M+H]⁺.
89%	for 48 h; Reflux	A solution of 4-chloro-2-fluoroaniline (2 g, 13.74 mmol) and di-tert-butyl dicarbonate (6.4 mE, 27.6 mmol) in 1 ,4-dioxane (50 mE) was stirred at reflux for 2 days. The solvent was then evaporated. The resulting oil was diluted with MeOH, water, and aqueous ammonium hydroxide solution (10 mE each) and vigorously stirred for 45 minutesThe organic lower layer was separated. The organic material was diluted with EtOAc (50 mE), and washed with water (50 mE), 3.6percent aqueous HC1 solution (2x50 mE), saturated aqueous NaHCO3 solution (50 mE), and then again with water (2x50 mE). The organic layer was dried (Mg504), filtered, and evaporated under reduced pressure to provide tert-butyl (4-chloro-2-fluorophenyl)carbamate (3.0011 g, 12.22 mmol, 89percent yield) as a reddish liquid that solidified on standing. ‘H NMR (300 MHz, DMSO-d5): ö ppm 9.12 (s, 1H), 7.63 (t, J=8.65 Hz, 1H), 7.42 (dd, J=i0.85, 2.35 Hz, 1H), 7.18-7.24 (m, 1H), 1.45 (s, 9H). ECMS (Method 1):mlz 246 [M+H].

Reference： [1] Patent: US2016/83365, 2016, A1, . Location in patent: Paragraph 0648; 0649; 0650
[2] Patent: WO2016/171755, 2016, A1, . Location in patent: Paragraph 0131
[3] Patent: US2016/311818, 2016, A1, . Location in patent: Paragraph 0541; 0542; 0543

[ 57946-56-2 ] Synthesis Path-Downstream 1~86

1
[ 57946-56-2 ]
[ 151-50-8 ]
[ 57381-51-8 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 1357 - 1364

2
[ 446-30-0 ]
[ 57946-56-2 ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1979,vol. 44,p. 2139 - 2155

3
[ 57946-56-2 ]
[ 87-13-8 ]
[ 185012-16-2 ]

Yield	Reaction Conditions	Operation in experiment
	at 115 - 120℃; 30-60 min; Yield given;

Reference： [1]Podanyi, Benjamin; Kereszturi, Geza; Vasvari-Debreczy, Lelle; Chinoin, Istvan Hermecz; Toth, Gabor [Magnetic Resonance in Chemistry, 1996, vol. 34, # 11, p. 972 - 978]

4
[ 57946-56-2 ]
7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride [ No CAS ]
7-benzyloxy-4-(4-chloro-2-fluorophenylamino)-6-methoxyquinazoline hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	In isopropyl alcohol;	The starting material was prepared as follows: A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.2 g, 3.6 mmol), (prepared as described for the starting material in Example 1), and <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (444 mul, 4 mmol) in isopropanol (40 ml) was heated at reflux for 1.5 hours. The mixture was allowed to cool, the precipitate was collected by filtration, washed with isopropanol then ether and dried under vacuum to give 7-benzyloxy4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (1.13 g, 71%). m.p. 239-242 C. 1 H NMR Spectrum: (DMSOd6) 4.0(s, 3H); 5.36(s, 2H); 7.39-7.52(m, 9H); 8.1(s, 1H); 8.75(s, 1H) MS - ESI: 410 [MH]+ Elemental analysis: Found C 59.2 H 4.3 N 9.4 C22 H17 N3 O2 ClF HCl Requires C 59.2 H 4.1 N 9.4%
71%	In isopropyl alcohol;	A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.2 g, 3.5 mmol) and <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (444 mul, 4 mmol) in isopropanol (40 ml) was refluxed for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with isopropanol then ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (1.13 g, 71%). m.p. 239-242 C. 1H NMR Spectrum: (DMSOd6) 4.0(s, 3H); 5.36(s, 2H); 7.39-7.52(m, 9H); 8.1(s, 1H); 8.75(s, 1H) MS-ESI: 410 [MH]+
64%	In isopropyl alcohol;	The starting material was prepared as follows: A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.34 g, 4 mmol), (prepared as described for the starting material in Example 1), and <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (444 mu, 4 mmol) in isopropanol (40 ml) was refluxed for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with isopropanol then ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (1.13 g, 64%). m.p. 239-242 C. 1 H NMR Spectrum: (DMSOd6) 4.0(s, 3H); 5.36(s, 2H); 7.39-7.52(m, 9H); 8.1(s, 1H); 8.75(s, 1H) MS - ESI: 410 [MH]+ Elemental analysis: Found C 59.2 H 4.3 N 9.4 C22 H17 N3 C1FO2 1HCl Requires C 59.2 H 4.1 N 9.41%

64%

In isopropyl alcohol; for 1.5h;Heating / reflux;

A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.2g, 4mmol), (prepared as described in WO 97/22596, Example 1), and [57946-56-2]4-chloro-2-fluoroaniline (444mul, 4mmol) in 2-propanol (40ml) was heated at reflux for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with 2-propanol then ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (1.13g, 64%). m.p. 239-242C 1H NMR Spectrum: (DMSOd6) 4.0(s, 3H); 5.36(s, 2H); 7.39-7.52(m, 9H); 8.1(s, 1H); 8.75(s, 1H) MS - ESI: 410 [MH]+

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 5369 - 5389
[2]Patent: US5962458,1999,A
[3]Patent: US6291455,2001,B1
[4]Patent: US6362336,2002,B1 .Location in patent: Example 24
[5]Patent: US5962458,1999,A
[6]Patent: EP1244647,2006,B1 .Location in patent: Page/Page column 25
[7]Patent: US6362336,2002,B1 .Location in patent: Example 15

5
[ 57946-56-2 ]
[ 214470-55-0 ]
[ 214485-81-1 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of 2.0 g of <strong>[214470-55-0]4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile</strong>, 1.46 g of 4-chloro-2-fluoroaniline, 0.925 g of pyridine hydrochloride, and 125 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 1 h. The mixture was cooled and added to 1000 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 2.61 g of 4-(4-chloro-2-fluoro-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 139-141 C; mass spectrum (electrospray, m/e): M+H 357.9.
		A mixture of 2.0 g of <strong>[214470-55-0]4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile</strong>, 1.46 g of 4-chloro-2 -fluoroaniline, 0.925 g of pyridine hydrochloride, and 125 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 1 h. The mixture was cooled and added to 1000 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 2.61 g of 4-(4-chloro-2-fluoro-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 139-141C; mass spectrum (electrospray, m/e): M+H 357.9.

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 3244 - 3256
[2]Journal of Medicinal Chemistry,2001,vol. 44,p. 822 - 833
[3]Patent: EP1950201,2008,A1 .Location in patent: Page/Page column 62
[4]Patent: EP973746,2003,B1 .Location in patent: Page/Page column 77

6
[ 57946-56-2 ]
[ 108-24-7 ]
[ 59280-70-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	In acetic acid; at 20℃; for 2h;	A solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (5.0 g, 34.3 mmol) in acetic acid (3 mL) was treated with acetic anhydride (6.45 mL, 68.7 mmol) and stirred at RT for 2 h. The mixture was poured onto ice water, stirred for 2 h and the resulting solid collected via filtration and dried to afford N-(4-chloro-2-fluorophenyl)acetamide (6.12 g, 95% yield). 1H NMR (400 MHz, DMSO-d6): delta 9.80 (s, 1H), 7.91 (t, J=8.7 Hz, 1H), 7.45 (dd, J=10.8, 2.4 Hz, 1H), 7.22 (d, J=8.9 Hz, 1H), 2.07 (s, 3H).
95%	With acetic acid; at 20℃; for 2h;	Example A45: A solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (5.0 g, 34.3 mmol) in aceticacid (3 mL) was treated with acetic anhydride (6.45 mL, 68.7 mmol) and stirred at RT for 2h. The mixture was poured onto ice water, stirred for 2 hand the resulting solid collected viafiltration and dried to afford N-( 4-chloro-2-fluorophenyl)acetamide (6.12 g, 95% yield). 1HNMR (400 MHz, DMSO-d6): 8 9.80 (s, 1 H), 7.91 (t, J = 8.7 Hz, 1 H), 7.45 (dd, J = 10.8, 2.4Hz, 1 H), 7.22 (d, J = 8.9 Hz, 1 H), 2.07 (s, 3 H).
	In acetic acid; at 20℃; for 3h;	To a solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (50.0 g, 344 mmol) in AcOH (3OmL) is added Ac2O (60 ml_) and the reaction is stirred at room temperature for 2 hours. The mixture is poured into ice water (500 mL) to give a solid precipitate. The mixture is stirred for an additional 1 hour at room temperature. The solid is filtered and washed with water and hexanes, then air dried to give lambda/-(4-chloro-2-fluorophenyl) acetamide

Reference： [1]Patent: US8461179,2013,B1 .Location in patent: Page/Page column 56
[2]Patent: WO2013/184119,2013,A1 .Location in patent: Paragraph 0169
[3]Journal of Medicinal Chemistry,2005,vol. 48,p. 3141 - 3152
[4]Patent: WO2008/2853,2008,A2 .Location in patent: Page/Page column 25

7
[ 106-47-8 ]
[ 57946-56-2 ]
[ 367-22-6 ]
[ 2613-33-4 ]
[ 2613-30-1 ]

Reference： [1]Journal of Fluorine Chemistry,2005,vol. 126,p. 661 - 667

8
[ 57946-56-2 ]
[ 4755-77-5 ]
N-(2-fluoro-4-chlorophenyl)oxalamic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
> 90%	With triethylamine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	General procedure: To a solution containing para-chloro-meta-fluoroaniline (10.0 g, 70.1 mmol) in 600 mL THF at 0 C was added Et3N (9.11 mL, 70.1 mmol) followed by ethyl oxalylchloride (7.70 mL, 70.1 mmol) dropwise over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 18 hrs. The reaction mixture was filtered and the filter cake was washed with one-300 mL portion of ethyl acetate. The organic phase was washed with two-100 mL portions of 1M HCl, dried over MgSO4, filtered, and concentrated to give the product. Recrystallization from hot Et2O gave 14.4 g (84%) of 27 as a colorless crystalline solid.

Reference： [1]Synthesis,2006,p. 807 - 812
[2]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 91 - 101

9
[ 57946-56-2 ]
[ 4146-24-1 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 3141 - 3152
[2]Patent: WO2015/55994,2015,A1

10
[ 57946-56-2 ]
[ 338795-16-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 115 - 120 °C / 30-60 min 2: Dowtherm A / 1 h / 250 °C

Reference： [1]Podanyi, Benjamin; Kereszturi, Geza; Vasvari-Debreczy, Lelle; Chinoin, Istvan Hermecz; Toth, Gabor [Magnetic Resonance in Chemistry, 1996, vol. 34, # 11, p. 972 - 978]

11
[ 57946-56-2 ]
[ 141337-26-0 ]

Yield	Reaction Conditions	Operation in experiment
73%		Compound 53. 2-fluoro-4-chloroaniline (22.90 g, 151 mmol) was dissolved in 120 mL of AcOH and 80 mL of concentrated HCl was added with stirring. The reaction mixture was cooled to 0 C. and a solution of NaNO2 (27.2 g, 0.4 mol) dissolved in 40 mL of H2O was added over 10 min. The reaction mixture was stirred for 30 min at 0 C. In a separate flask, 500 mg of CuCl was dissolved in 200 mL of AcOH. The flask was cooled to 0 C. and SO2 gas was bubbled into the solution for 40 minutes. The contents of the ?aniline? flask were added to the contents of the second flask over 20 minutes causing a vigorous evolution of gas. After the addition was complete, the ice bath was removed, and the reaction mixture was allowed to warm to rt. The reaction mixture was poured into 500 g of chipped ice and the resulting solids were collected, washed and dried to give 26.1 g (73%) of compound 53.

Reference： [1]Patent: US2003/232859,2003,A1 .Location in patent: Page 56
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9539 - 9553

12
[ 205448-66-4 ]
[ 57946-56-2 ]
[ 205447-81-0 ]

Yield	Reaction Conditions	Operation in experiment
28%	In cyclohexanol; at 130 - 160℃; for 4h;	EXAMPLE 55 <strong>[205448-66-4]4-Chloro-7-methoxy-6-methoxycarbonylquinoline</strong> (1.4 g, 5.5 mmol) was dissolved in cyclohexanol (30 ml) and 4-chloro-2-fluoroaniline (0.786 g, 5.8 mmol) was added.. The mixture was heated at 130 C. for 1 hour then at 160 C. for 3hours.. The solvent was removed by evaporation and the residue was purified by flash chromatography eluding with methylene chloride/ethylacetate (100/0 increasing to 50/50).. The solvent was removed by evaporation and the solid was triturated with ether/isohexanes.. The solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-methoxy-6-methoxycarbonylquinoline (570 mg, 28%). 1H NMR Spectrum: (DMSOd6) 3.85 (s, 3H); 3.95 (s, 3H); 6.30 (m, 1H); 7.35 (br s, 2H); 7.45 (m, 1H); 7.60 (d, 1H); 8.40 (br s, 1H); 8.75 (s, 11H); 9.15 (br s, 1H); MS-ESI: 361 [MH]30 ;

Reference： [1]Patent: US6809097,2004,B1 .Location in patent: Page column 66; 67

13
[ 205448-71-1 ]
[ 57946-56-2 ]
[ 205447-84-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	With hydrogenchloride; In diethyl ether; isopropyl alcohol; for 2h;Heating / reflux;	EXAMPLE 58 A suspension of 7-benzyloxy-4-chloro-6-cyanoquinoline (2 g, 6.8mmol), <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (1.1 g, 7.5 mmol) in isopropanol (50 ml) containing 1M ethereal hydrogen chloride (8 ml) was heated at reflux for 2 hours.. After cooling to ambient temperature ether was added.. The precipitate was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-cyanoquinoline hydrochloride (2.41 g, 81%). 1H NMR Spectrum: (DMSOd6) 5.45 (s, 2H); 6.60 (dd, 1H);7.50 (m, 8H); 7.75 (s, 1H); 7.80 (dd, 1H); 8.55 (d, 1H); 9.45 (s, 1H); MS-ESI: 404 [MH]+;

Reference： [1]Patent: US6809097,2004,B1 .Location in patent: Page column 69

14
[ 205448-74-4 ]
[ 57946-56-2 ]
[ 205448-75-5 ]

Yield	Reaction Conditions	Operation in experiment
25%	With hydrogenchloride; In diethyl ether; cyclohexanol; at 155℃; for 18h;	A solution of 4-chloro-6-hydroxy-7-methoxyquinoline (3.0 g, 14 mmol) and <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (3.5 g, 23 mmol) in cyclohexanol (100 ml) containing 1M ethereal hydrogen chloride (16 ml) was heated at 155 C. for 18 hours.. After cooling the mixture was diluted with ether and isohexanes and the precipitate was collected by filtration.. The crude product was dissolved in a mixture of methylene chloride/methanol/ammonia (100/10/1) and silica (10 g) was added.. The solvent was removed by evaporation and the resulting powder was purified by flash chromatography eluding with methylene chloride/methanol/ammonia (95/5/1 increasing to 80/20/1) to give 4-(4-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinoline (1.12 g, 25%). 1H NMR Spectrum: (DMSOd6) 3.95 (s, 3H); 6.30 (m, 1H); 7.25 (s, 1H);7.35 (m, 2H); 7.55 (m, 2H); 8.20 (d, 1H); MS (ESI): 319 [MH]+.

Reference： [1]Patent: US6809097,2004,B1 .Location in patent: Page column 72

15
[ 57946-56-2 ]
[ 199328-31-9 ]
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (4-chloro-2-fluoro-phenyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With pyridine; In tetrahydrofuran; at 20℃; for 24h;	To a mixture of 5-chlorosulfonyl-2-oxindoel (5 g, 21.6 mmol) and <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (2.9 mL, 26 mmol) in tetrahydrofuran (30 mL) was added pyridine (3.4 g, 43 mmol). The mixture was stirred at room temperature for 1 day. The precipitate was collected by vacuum filtration, washed with water in methanol (20%), dried, washed with 60 mL of hot ethanol and dried to give 6.3 g (85%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid (4-chloro-2-fluoro-phenyl)-amide as a light pink-colored solid. 1H-NMR (300 MHz, dimethylsulfoxide-d6) delta 10.79 (br s, 1H, NH), 10.12 (br s, 1H, NH), 7.54 (m, 2H), 7.39 (dd, 1H), 7.17-7.27 (m, 2H), 6.90 (d, 1H), 3.54 (s, 2H, CH2). MS m/z 340 [M+].
85%	With pyridine; In tetrahydrofuran; at 20℃; for 24h;	[0295] To a mixture of 5-chlorosulfonyl-2-oxindoel (5 g, 21.6 mmol) and <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (2.9 mL, 26 mmol) in tetrahydrofuran (30 mL) was added pyridine (3.4 g, 43 mmol). The mixture was stirred at room temperature for 1 day. The precipitate was collected by vacuum filtration, washed with water in methanol (20%), dried, washed with 60 mL of hot ethanol and dried to give 6.3 g (85%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid (4-chloro-2-fluoro-phenyl)-amide as a light pink-colored solid. 1H-NMR (300 MHz, dimethylsulfoxide-d6) delta 10.79 (br s, 1H, NH), 10.12 (br s, 1H, NH), 7.54 (m, 2H), 7.39 (dd, 1H), 7.17-7.27 (m, 2H), 6.90 (d, 1H), 3.54 (s, 2H, CH2). MS m/z 340 [M+].

Reference： [1]Patent: US2004/204407,2004,A1 .Location in patent: Page/Page column 28
[2]Patent: US2004/266843,2004,A1 .Location in patent: Page 23; 24

16
[ 401811-89-0 ]
[ 57946-56-2 ]
[ 338992-08-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogenchloride; In 1,4-dioxane; isopropyl alcohol; for 4h;Heating / reflux;	tert-Butyl 4- [(4-CHLORO-6-METHOXYQUINAZOLIN-7-YL) OXY3METHYL} PIPERIDINE-1- carboxylate (L. OG, 2. 45MMOL), (prepared as described for the starting material in Example 1), and <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (0. 33ML, 2. 94MMOL) were stirred in 2-propanol (30ml) and hydrogen chloride (0. 74ML of a 4M solution in dioxane, 2. 94mmol) was added. The mixture was heated at reflux for 4 hours, cooled and filtered. The solid was dissolved in methanol, placed on an ISOLUTE0 SCX column, washed with methanol and then eluted with 7N ammonia in methanol to give 4- (4-CHLORO-2-FLUOROANILINO)-6-METHOXY-7- (PIPERIDIN-4- ylmethoxy) quinazoline (L. OG, 98%) as a white solid. LC-MS (ESI) 417.1 and 419. 1 [MH] + 1H NMR (spectrum): (DMSOd6) 1.47 (m, 2H); 1.93 (d, 2H); 2.13 (m, 1H); 2. 78 (t, 2H); 3.20 (d, 2H); 4.06 (m, 5H); 7.31 (s, 1H); 7.45 (m, 1H); 7.67 (m, 2H); 7.95 (s, 1H); 8.46 (s, 1H); 9.73 (br s, 1H)

Reference： [1]Patent: WO2005/13998,2005,A1 .Location in patent: Page/Page column 63-64

17
[ 401811-91-4 ]
[ 57946-56-2 ]
[ 844511-01-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With hydrogenchloride; In 1,4-dioxane; isopropyl alcohol; for 1.5h;Heating / reflux;	tert-Butyl {2- [ (4-chloro-6-methoxyquinazolin-7-yl) oxy] ETHYL} PIPERIDINE-1-CARBOXYLATE (0.4g, 0.95mmol) and <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (126, L, 1. 14MMOL) were stirred in 2-propanol (15ML) and hydrogen chloride (1. 2ML of a 4M solution in dioxane, 4. 75MMOL) was added. The mixture was heated at reflux for 1.5 hours, cooled and concentrated under reduced pressure. Column chromatography of the residue (10% 7N ammonia in methanol/dichloromethane) GAVE 4- (4-CHLORO-2-FLUOROANILINO)-6-METHOXY-7- [2- (PIPERIDIN-4- yl) ethoxy] quinazoline (320mg, 75%) as a white solid. LC-MS (ESI) 431.0 and 433.0 [MH] + 1H NMR (spectrum): (DMSOd6) 1.09 (m, 2H); 1.57 (m, 1H); 1.69 (m, 4H); 2.45 (dt, 2H); 2.92 (br d, 2H); 3.95 (s, 3H); 4.18 (t, 2H); 7.20 (s, 1H); 7.34 (m, 1H); 7.54 (dd, 1H); 7.59 (t, 1H); 7.79 (s, 1H); 8.35 (s, 1H); 9.52 (br s, 1H)

Reference： [1]Patent: WO2005/13998,2005,A1 .Location in patent: Page/Page column 70-71

18
[ 280110-69-2 ]
[ 57946-56-2 ]
4-[4-(4-chloro-2-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidine ditrifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In toluene; at 110℃; for 72h;	A mixture of the compound of preparation 1 (900 mg, 3.4 mmol), 4-chloro-2-fluoroaniline (109.1 mg, 0.75 mmol) and trifluoroacetic acid (288 muL, 3.74 mmol) in toluene (8 mL) was stirred at 110 C. for 72 hours. The cooled mixture was concentrated under reduced pressure, 0.88 ammonia added and the mixture was concentrated under reduced pressure. The residue was azeotroped with toluene and the crude product was purified by column chromatography on silica gel using an elution gradeint of dichloromethane:methanol:0.88 ammonia (90:10:1 to 80:20:3) to afford the title compound as an off-white foam, 985 mg. 1H NMR (400 MHz, CDCl3): delta2.02-2.30 (m, 7H), 2.80 (m, 1H), 3.10 (m, 2H), 3.59 (m, 2H), 3.86 (m, 1H), 7.26 (m, 1H), 7.40 (m, 2H), 9.34 (br s, 1H), 10.10 (br s, 1H); LCMS: m/z APCl+295 [MH]+

Reference： [1]Patent: US2005/154024,2005,A1 .Location in patent: Page/Page column 49-50

19
[ 57946-56-2 ]
[ 216393-67-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With silver(II) sulfate; iodine; In ethanol; at 20℃; for 2h;	Step 1: synthesis of 4-chloro-2-fluoro-6-iodoaniline To a solution of 4-chloro-2-fluoroaniline (1.15 g, 7.9 mmol) in 125 mL of ethanol added silversulphate (1.7 g, 8.3 mmol), then followed by addition of ?2 (2.1 g, 8.3 mmol) in portions. Afterthe addition was completed, the mixture was stirred at RT for 2 hours. The mixture was filtered through celite and the filtration was evaporated to give dark oil which was dissolved in 125 mL of DCM. The solution was washed with 2M sodium hydroxide (40 mL x 2), saturated Na25203 (40 mL x 2) and water (40 mL x 2). The resulting solution was dried over Mg504 and thenevaporated to give the crude 4-chloro-2-fluoro-6-iodoaniline as dark oil (2.1 g, yield: 98%).
87%	With iodine; silver sulfate; In ethanol; at 20℃; for 1.5h;	4-Chloro-2-fluoroaniline (2.9 g, 20 mmol) was dissolved in ethanol (200 mL). Silver sulphate (6.22 g, 20 mmol) was added and then iodine (5.08 g, 20 mmol) was added in small portions. After the addition was complete the reaction mixture was stirred at ambient temperature for 90min. The reaction mixture was filtered through Celite and evaporated to leave a dark oil which was taken up in DCM (200 mL). and washed with 2M sodium hydroxide (2 x 50 mL), saturated sodium thiosulphate (2x50 mL) and water (2x50 mL). The solution was dried (MgSO4) and evaporated to leave the title compound as a dark oil (4.73g, 87%).1H NMR (400 MHz, DMSO-d6) delta 5.30 (2H, s), 7.25 - 7.29 (IH, m), 7.47 (IH, t)
40%	With iodine; silver sulfate; In ethanol; at 20℃; for 2h;	To a solution of 4-chloro-2-fluoroaniline (2 g, 14 mmol) in EtOH (40 mL) was added Ag2S04 (12.9 g, 42 mmol), followed by the addition of I2 (10.5 g, 42 mmol). The reaction mixture was stirred at RT for 2 h and then filtered through Celite. The filtrate was evaporated to give a dark oil. The residue was dissolved in DCM (70 mL), washed with 2M NaOH (40 mL x 2), Na2S203 (40 mL x 2) and water (40 mL x 2). The resulting solution was dried over MgS04, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE/EA = 5/1) to give 4-chloro-2-fluoro-6-iodoaniline (1.5 g, 40% yield) as a dark oil. 1H NMR (400 MHz, DMSO-i): d 7.47-7.46 (m, 1H), 7.28-7.25 (m, 1H), 5.31 (brs, 2H).

	With iodine; silver sulfate; In ethanol; at 20℃; for 2h;	Step 1: synthesis of 4-chloro-2-fluoro-6-iodoaniline To a solution of 4-chloro-2-fluoroaniline (1.15 g, 7.9 mmol) in 125 mL of ethanol added silver sulphate (1.7 g, 8.3 mmol), then followed by addition of I2 (2.1 g, 8.3 mmol) in portions. After the addition was completed, the mixture was stirred at RT for 2 hours. The mixture was filtered through celite and the filtration was evaporated to give dark oil which was dissolved in 125 mL of DCM. The solution was washed with 2M sodium hydroxide (40 mL2), saturated Na2S2O3 (40 mL2) and water (40 mL*2). The resulting solution was dried over MgSO4 and then evaporated to give the crude 4-chloro-2-fluoro-6-iodoaniline as dark oil (2.1 g, yield: 98%).
	With iodine; silver sulfate; In ethanol; at 20℃; for 2h;	To a solution of 4-chloro-2-fluoroaniline (1.15 g, 7.9 mmol) in 125 mL of ethanol added silver sulphate (1.7 g, 8.3 mmol), then followed by addition of I2 (2.1 g, 8.3 mmol) in portions. After the addition was completed, the mixture was stirred at RT for 2 hours. The mixture was filtered through celite and the filtration was evaporated to give dark oil which was dissolved in 125 mL of DCM. The solution was washed with 2M sodium hydroxide (40 mL×2), saturated Na2S2O3 (40 mL×2) and water (40 mL×2). The resulting solution was dried over MgSO4 and then evaporated to give the crude 4-chloro-2-fluoro-6-iodoaniline as dark oil (2.1 g, yield: 98%).

Reference： [1]Patent: WO2014/9302,2014,A1 .Location in patent: Page/Page column 119
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 5088 - 5109
[3]Patent: WO2006/82400,2006,A1 .Location in patent: Page/Page column 56
[4]Patent: WO2019/152883,2019,A1 .Location in patent: Paragraph 00135
[5]Patent: US2015/158879,2015,A1 .Location in patent: Paragraph 0581; 0582
[6]Patent: US2016/200741,2016,A1 .Location in patent: Paragraph 0582-0583

20
[ 57946-56-2 ]
[ 364793-57-7 ]
7-Bromo-4-(4-chloro-2-fluoroanilino)-3-quinolinecarbonitlile [ No CAS ]
7-bromo-4-(4-chloro-2-fluoroanilino)-3-quinolinecarbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.0 g (43%)	With pyridine hydrochloride; In diethyl ether; 1-ethoxyethanol;	REFERENCE EXAMPLE 7 7-Bromo-4-(4-chloro-2-fluoroanilino)-3-quinolinecarbonitlile A mixture of <strong>[364793-57-7]7-bromo-4-chloro-3-quinolinecarbonitrile</strong> (5.0 g, 18.69 mmole), 4-chloro-2-fluoroaniline (3.27 g, 22.43 mmol) and pyridine hydrochloride (2.2 g, 18.69 mmol) in 150 mL of ethoxyethanol was heated at reflux for 4 hours. After cooling, the solvent was removed in vacuo and the residue was diluted with ice water, basified (pH 9) with ammonium hydroxide, and extracted into ethyl acetate. The extracts were washed with saturated sodium chloride, dried over sodium sulfate and concentrated. The residue was treated with diethyl ether, and the yellow solid was collected by filtration. The filtrate was concentrated and purified by flash silica gel chromatography eluding with methylene chloride: diethyl ether: methanol (9:1:0.1) to provide 3.0 g (43%) of 7-bromo-4-(4-chloro-2-fluoroanilino)-3-quinolinecarbonitrile as a light brown solid; H NMR (DMSO-d6) delta 7.38 d, J=9 Hz, 1H), 7.47-7.53 (m, 1H), 7.62 (dd, J=3, 9 Hz, 1H), 7.84 (d, J=9 Hz, 1H), 8.13 (s, 1H), 8.44 (d, J=9 Hz, 1H), 8.62 (s, 1H); MS (ES) m/z 377.7 (M+1). Analysis for C16H8 BrClFN3: Calcd: C, 51.03;H, 2.14; N, 11.16. Found: C, 50.67;H, 2.20; N, 11.02.

Reference： [1]Patent: US2002/26052,2002,A1

21
[ 7518-70-9 ]
[ 57946-56-2 ]
[ 214470-55-0 ]
[ 214485-81-1 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine hydrochloride; sodium carbonate; In water;	EXAMPLE 86 4-(4-Chloro-2-fluoro-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile A mixture of 2.0 g of <strong>[214470-55-0]4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile</strong>, 1.46 g of 4-chloro-2-fluoroaniline, 0.925 g of pyridine hydrochloride, and 125 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 1 h. The mixture was cooled and added to 1000 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 2.61 g of 4-(4-chloro-2-fluoro-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 139-141 C.; mass spectrum (electrospray, m/e): M+H 357.9.
	With pyridine hydrochloride; sodium carbonate; In water;	EXAMPLE 228 4-(4-Chloro-2-fluoro-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile A mixture of 2.0 g of <strong>[214470-55-0]4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile</strong>, 1.46 g of 4-chloro-2-fluoroaniline, 0.925 g of pyridine hydrochloride, and 125 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 1 h. The mixture was cooled and added to 1000 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 2.61 g of 4-(4-chloro-2-fluoro-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 139-141 C.; mass spectrum (electrospray, m/e): M+H 357.9.
	With pyridine hydrochloride; sodium carbonate; In water;	Example 228 4-(4-Chloro-2-fluoro-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile A mixture of 2.0 g of <strong>[214470-55-0]4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile</strong>, 1.46 g of 4-chloro-2-fluoroaniline, 0.925 g of pyridine hydrochloride, and 125 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 1 h. The mixture was cooled and added to 1000 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 2.61 g of 4-(4-chloro-2-fluoro-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 139-141C; mass spectrum (electrospray, m/e): M+H 357.9.

Reference： [1]Patent: US6297258,2001,B1
[2]Patent: US6002008,1999,A
[3]Patent: EP1263503,2005,B1

22
[ 57946-56-2 ]
[ 214470-68-5 ]
[ 214484-54-5 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine hydrochloride; In 2-ethoxy-ethanol;	EXAMPLE 76 4-(4-Chloro-2-fluoro-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile A mixture of 3.1 g (9.96 mmol) of <strong>[214470-68-5]7-(3-Chloro-propoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile</strong>, 1.6 g (10.96 mmol) of 4-chloro-2-fluoro-aniline, and 1.2 g (10 mmol) of pyridine hydrochloride in 31 ml of 2-ethoxyethanol was stirred at reflux for 1.5 hr. The mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution was dried and solvent was removed. The residue was purified on a silica gel column eluding with chloroform-ether mixtures to give 2.88 g of the title compound as an off-white solid powder: mass spectrum (electrospray, m/e) M+H 419.7.
	With pyridine hydrochloride; In 2-ethoxy-ethanol;	Example 76 4-(4-Chloro-2-fluoro-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile A mixture of 3.1 g (9.96 mmol) of <strong>[214470-68-5]7-(3-Chloro-propoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile</strong>, 1.6 g (10.96 mmol) of 4-chloro-2-fluoro-aniline, and 1.2 g (10 mmol) of pyridine hydrochloride in 31 ml of 2-ethoxyethanol was stirred at reflux for 1.5 hr. The mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution was dried and solvent was removed. The residue was purified on a silica gel column eluding with chloroform-ether mixtures to give 2.88 g of the title compound as an off-white solid powder: mass spectrum (electrospray, m/e) M+H 419.7.

Reference： [1]Patent: US6002008,1999,A
[2]Patent: EP1263503,2005,B1

23
[ 57946-56-2 ]
[ 214476-78-5 ]
4-(4-chloro-2-fluoro-phenylamino)-8-methoxy-quinoline-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine hydrochloride; In 2-ethoxy-ethanol;	EXAMPLE 275 4-(4-Chloro-2-fluoro-phenylamino)-8-methoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 274. A reaction mixture of 328.0 mg (1.5 mmol) of <strong>[214476-78-5]4-chloro-8-methoxy-3-quinolinecarbonitrile</strong>, 173.3 mg (1.5 mmol) of pyridine hydrochloride and 240.0 mg (1.7 mmol) of 2-fluoro-4-chloro-aniline in 15 mL of 2-ethoxyethanol was heated at 100 C. for 2 hr. After the work up, 431.3 mg (87.9%) of the product was obtained as an off white solid, m.p. 127 C. (dec.), mass spectrum (electrospray, m/e): M+H 327.8, 329.9.
	With pyridine hydrochloride; In 2-ethoxy-ethanol;	EXAMPLE 275 4-(4-Chloro-2-fluoro-phenylamino)-8-methoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 274. A reaction mixture of 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 173.3 mg (1.5 mmol) of pyridine hydrochloride and 240.0 mg (1.7 mmol) of 2-fluoro-4-chloroaniline in 15 mL of 2-ethoxyethanol was heated at 100 C. for 2 hr. After the work up, 431.3 mg (87.9%) of the product was obtained as an off white solid, m.p. 127 C. (dec.), mass spectrum (electrospray, m/e): M+H 327.8, 329.9.
	With pyridine hydrochloride; In 2-ethoxy-ethanol;	Example 275 4-(4-Chloro-2-fluoro-phenylamino)-8-methoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 274. A reaction mixture of 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 173.3 mg (1.5 mmol) of pyridine hydrochloride and 240.0 mg (1.7 mmol) of 2-fluoro-4-chloro-aniline in 15 mL of 2-ethoxyethanol was heated at 100 C for 2 hr. After the work up, 431.3 mg (87.9%) of the product was obtained as an off white solid, m.p. 127 C (dec.), mass spectrum (electrospray, m/e): M+H 327.8, 329.9.

Reference： [1]Patent: US6384051,2002,B1
[2]Patent: US6002008,1999,A
[3]Patent: EP1263503,2005,B1

24
[ 57946-56-2 ]
[ 162364-72-9 ]
7-benzyloxy-4-(4-chloro-2-fluorophenylamino)-6-methoxyquinazoline hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With hydrogenchloride; In isopropyl alcohol; for 2h;Reflux;	Hydrogen chloride (6.5 M, 2.54 mL) was added to a mixture of compound 1 (4.51 g, 15.0 mmol) and <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (2.40 g, 16.5 mmol) in 2-propanol (160 mL), then the mixture was heated at reflux for 2 h. The mixture was cooled and solid was filtered. The solid was then washed with 2-propanol, followed by Et2O, and dried under vacuum overnight to give 2a (7.9 g, 94%) as a white solid.
64%	In isopropyl alcohol;	The starting material was prepared as follows: A solution of 7-benzyloxy-4chloro-6-methoxyquinazoline (1.2 g, 4 mmol), (prepared as described for the starting material in Example 1), and <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (4441 mul, 4 mmol) in 2-propanol (40 ml) was refluxed for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with 2-propanol then ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (1.13 g, 64%). m.p. 239-242 C. 1H NMR Spectrum: (DMSOd6) 4.0(s, 3H); 5.36(s, 2H); 7.39-7.52(m, 9H); 8.1(s, 1H); 8.75(s, 1H); MS-ESI: 410 [MH]+; Elemental analysis: Found C, 59.2; H, 4.3; N, 9.4; C22H17N3O2ClF 1 HCl Requires C, 59.2; H, 4.1; N, 9.41%.
64%	In isopropyl alcohol; for 1.5h;Heating / reflux;	A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline (1.2 g, 4 mmol), (prepared for example as described in WO 00/47212 Example 1), and <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (444 [mu]l, 4 mmol) in 2-propanol (40 ml) was refluxed for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with 2-propanol then ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluorophenylamino)-6-methoxyquinazoline hydrochloride (1.13 g, 64%). [0514] m.p. 239-242[deg.] C. [0515] <1>H NMR Spectrum: (DMSO-d6) 4.0 (s, 3H); 5.36 (s, 2H); 7.39-7.52 (m, 9H); 8.1 (s, 1H); 8.75 (s, 1H) [0516] MS-ESI: 410 [MH]<+><tb><sep>Elemental analysis:<sep>Found<sep>C 59.2<sep>H 4.3<sep>N 9.4<tb><sep>C22H17N3O2ClF 1 HCl<sep>Requires<sep>C 59.2<sep>H 4.1<sep>N 9.41%

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3222 - 3226
[2]Patent: US6414148,2002,B1
[3]Patent: US2003/191308,2003,A1 .Location in patent: Page/Page column 26

25
[ 3056-18-6 ]
[ 57946-56-2 ]
[ 534-17-8 ]
[ 166330-10-5 ]
[ 253127-10-5 ]

Yield	Reaction Conditions	Operation in experiment
	palladium diacetate; In toluene;	(2R,3R,4R,5R)4-(acetyloxy)-2-[(acetyloxy)methyl]-5-[2-chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3-yl acetate To a stirred solution of 2,6-dichloro-9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-9H-purine 2(1.09) in toluene (25 ml) was added palladium acetate (50 mg), 4-chloro-2-fluoroaniline (0.5 ml) and bis[2-(diphenylphosphino)phenyl] ether 3(120 mg) and the reaction stirred at 20 C. for 15 min. Caesium carbonate (872 mg) was added and the mixture heated at 90 C. for 16 hours. The reaction mixture was cooled to 20 C. and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with brine (100 ml), dried with magnesium sulphate and the solvent removed in vacuo. Purification by flash chromatography on silica gel, eluding with ethyl acetate:cyclohexane (1:1) gave the title compound (400 mg). 2.M. J. Robins and B. Uznanski Canad. J. Chem., 1981, 59(17), 2608 3.J. P. Sadighi, M. C. Harris and S. L. Buchwald Tett. Lett. 1998, 5327-5330 Mass Spectrum m/z 556 [MH+]

Reference： [1]Patent: US6492348,2002,B1

26
[ 57946-56-2 ]
[ 86988-02-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	With nitric acid; In sulfuric acid;	EXAMPLE 1 Preparation of 4-chloro-2-fluoro-5-nitroaniline A solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (10.0 g, 69 mmol) in concentrated sulfuric acid is cooled to -20 C., treated dropwise with 90% nitric acid (5.0 mL, 107 mmol) over ten minutes, stirred at -15 C. for 90 minutes, and poured onto ice. The resultant aqueous mixture is extracted with diethyl ether, neutralized with 50% sodium hydroxide solution, and extracted again with diethyl ether. The organic extracts are combined, washed sequentially with dilute sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a brown solid (11.3 g, 86% yield, mp 82-83.5 C.) which is identified by 1H, 19F and 13C NMR spectral analyses.
86%	With nitric acid; In sulfuric acid;	EXAMPLE 1 Preparation of 4-Chloro-2-fluoro-5-nitroaniline A solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (10.0 g, 69 mmol) in concentrated sulfuric acid is cooled to -20C, treated dropwise with 90% nitric acid (5.0 mL, 107 mmol) over ten minutes, stirred at -15C for 90 minutes, and poured onto ice. The resultant aqueous mixture is extracted with diethyl ether, neutralized with 50% sodium hydroxide solution, and extracted again with diethyl ether. The organic extracts are combined, washed sequentially with dilute sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a brown solid (11.3 g, 86% yield, mp 82-83.5C) which is identified by 1H, 19F and 13C NMR spectral analyses.
	With nitric acid; In sulfuric acid;	EXAMPLE 9 Production of the nitroaniline (XI): 4-Chloro-2-fluoroaniline (23 g) was dissolved in conc. sulfuric acid (120 ml), and the resultant mixture was cooled to -20 C., followed by dropwise addition of fuming nitric acid (15 g). The reaction mixture was stirred at -20 to -15 C. for 1.5 hours, poured into ice-water and then extracted with ether. The ether extract was washed with water and a saturated sodium bicarbonate solution, dried and concentrated. The residue was crystallized from a mixture of toluene and hexane (2:1) to obtain 20 g of 4-chloro-2-fluoro-5-nitroaniline. m.p., 83-84.5 C.

	With nitric acid; In sulfuric acid;	EXAMPLE 11 Production of the nitroaniline (XIII): 4-Chloro-2-fluoroaniline (23 g) was dissolved in conc. sulfuric acid (120 ml), and the resultant mixture was cooled to -20 C., followed by dropwise addition of fuming nitric acid (15 g). The reaction mixture was stirred at -20 to -15 C. for 1.5 hours, poured into ice-water and then extracted with ether. The ether extract was washed with water and a saturated sodium bicarbonate solution, dried and concentrated. The residue was crystallized from a mixture of toluene and hexane (2:1) to obtain 20 g of 4-chloro-2-fluoro-5-nitroaniline. m.p., 83-84.5 C.
	With sulfuric acid; nitric acid;	Example 3 Production of the nitroaniline (XIII):- 4-Chloro-2-fluoroaniline (23 g) was dissolved in conc, sulfuric acid (120 ml), and the resultant mixture was cooled to -20C, followed by dropwise addition of fuming nitric acid (15 g). The reaction mixture was stirred at -20 to -15C for 1.5 hours, poured into ice-water and then extracted with ether. The ether extract was washed with water and a saturated sodium bicarbonate solution, dried and concentrated. The residue was crystallized from a mixture of toluene and hexane (2: 1) to obtain 20 g of 4-chloro-2-fluoro-5-nitroaniline. M.P., 83 - 84.5C.

Reference： [1]Patent: US6303783,2001,B1
[2]Patent: EP985670,2000,A1
[3]Patent: US4624699,1986,A
[4]Patent: US4670043,1987,A
[5]Patent: EP208374,1991,B1

27
[ 2426-02-0 ]
[ 57946-56-2 ]
[ 61330-03-8 ]

Yield	Reaction Conditions	Operation in experiment
69%	In acetic acid; ethyl acetate;	EXAMPLE 5 Preparation of N-(4-chloro-2-fluorophenyl)-1-cyclohexene-1,2-dicarboximide A solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (19.0 g, 130.6 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (19.85 g, 130.6 mmol) in acetic acid is refluxed for 2 hours, treated with additional <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (3.0 g), refluxed for 90 minutes, stirred at room temperature overnight and poured into water. The resultant aqueous mixture is extracted with ethyl acetate. The organic extract is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a purple oil. Flash column chromatography of the oil using silica gel and 15 to 20% ethyl acetate in hexanes solutions gives the title product as an off-white solid (25.3 g, 69% yield, mp 81-82 C.) which is identified by 1H, 13C and 19F NMR spectral analyses.
69%	In acetic acid; ethyl acetate;	EXAMPLE 5 Preparation of N-(4-chloro-2-fluorophenyl)-1-cyclohexene-1,2-dicarboximide A solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (19.0 g, 130.6 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (19.85 g, 130.6 mmol) in acetic acid is refluxed for 2 hours, treated with additional <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (3.0 g), refluxed for 90 minutes, stirred at room temperature overnight and poured into water. The resultant aqueous mixture is extracted with ethyl acetate. The organic extract is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuoto obtain a purple oil. Flash column chromatography of the oil using silica gel and 15 to 20% ethyl acetate in hexanes solutions gives the title product as an off-white solid (25.3 g, 69% yield, mp 81-82C) which is identified by 1H, 13C and 19F NMR spectral analyses.
	In acetic acid; ethyl acetate;	EXAMPLE 35 Preparation of N-(4-Chloro-2-fluorophenyl)-1-cyclohexene-1,2-dicarboximide STR115 A mixture of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (19.0 g, 130.6 mmol), and 3,4,5,6-tetrahydrophthalic anhydride (19.85 g, 130.6 mmol) in acetic acid (150 mL) is refluxed for 2 hours, treated with additional <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (3.0 g), refluxed for 90 minutes, stirred at room temperature overnight and poured into a water/ethyl acetate mixture. The organic phase is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a purple oil. Flash column chromatography of the oil using silica gel and 15% to 20% ethyl acetate in hexanes solutions gives the title product as an off-white solid (25.3 g, mp 81-82 C.).

	In acetic acid; ethyl acetate;	EXAMPLE 35 Preparation of N-(4-Chloro-2-fluorophenyl)-1-cyclohexene-1,2-dicarboximide STR114 A mixture of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (19.0 g, 130.6 mmol), and 3,4,5,6-tetrahydrophthalic anhydride (19.85 g, 130.6 mmol) in acetic acid (150 mL) is refluxed for 2 hours, treated with additional <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (3.0 g), refluxed for 90 minutes, stirred at room temperature overnight and poured into a water/ethyl acetate mixture. The organic phase is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a purple oil. Flash column chromatography of the oil using silica gel and 15% to 20% ethyl acetate in hexanes solutions gives the title product as an off-white solid (25.3 g, mp 81-82 C.).
	In acetic acid; ethyl acetate;	EXAMPLE 35 Preparation of N-(4-Chloro-2-fluorophenyl)-1-cyclohexene-1,2-dicarboximide STR121 A mixture of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (19.0 g, 130.6 mmol), and 3,4,5,6-tetrahydrophthalic anhydride (19.85 g, 130.6 mmol) in acetic acid (150 mL) is refluxed for 2 hours, treated with additional <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (3.0 g), refluxed for 90 minutes, stirred at room temperature overnight and poured into a water/ethyl acetate mixture. The organic phase is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a purple oil. Flash column chromatography of the oil using silica gel and 15% to 20% ethyl acetate in hexanes solutions gives the title product as an off-white solid (25.3 g, mp 81-82 C.).

Reference： [1]Patent: US6303783,2001,B1
[2]Patent: EP985670,2000,A1
[3]Patent: US5610120,1997,A
[4]Patent: US5679791,1997,A
[5]Patent: US5726126,1998,A

28
cuprous (I) chloride [ No CAS ]
[ 57946-56-2 ]
[ 141337-26-0 ]

Yield	Reaction Conditions	Operation in experiment
87.1%	With hydrogenchloride; acetic acid; sodium nitrite; In water;	a 4-Chloro-2-fluorobenzenesulfonyl chloride In a mixture, maintained at -10 C., of 75 ml HCl 10N and 22 ml acetic acid, 32.5 g (223 mmoles) of commercial 4-chloro-2-fluoroaniline, and 16.7 g (241 mmoles) of sodium nitrite in solution in 26 ml water are added. This reaction mixture is added by fractions to a solution maintained at 10 C. of 220 ml acetic acid saturated with SO2 and containing 5.5 g (56.3 mmoles) of cuprous (I) chloride (I). Stirring is continued 1/2 hour at room temperature, before pouring over a ice-water mixture and extracting with ether. The organic phase is washed with a solution saturated with NaHCO3, dried over Na2 SO4 and concentrated. After distillation, there is obtained 44.5 g (yield=87.1%) of a pale yellow liquid which crystallizes. b.p.0.1 =81 C. M.P.=36-8 C. I.R. (film): nu (SO2)=1375 cm-1; (SO2)=1175 cm-1. N.M.R. (CDCl3): delta=7.1-7.5 (2H,m); 7.7-8.1 (1H,m).

Reference： [1]Patent: US5387709,1995,A

29
[ 57946-56-2 ]
[ 75-36-5 ]
[ 59280-70-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; ethanol;	EXAMPLE 28 Preparation of 4'-Chloro-2'-fluoroacetanilide STR108 Acetyl chloride (24.2 mL, 0.34 mol) is added slowly to a solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (49.4 g, 0.34 mol), and triethylamine (47 mL, 0.34 mol) in tetrahydrofuran while maintaining the reaction mixture temperature below 20 C. After the addition is complete, the reaction mixture is stirred overnight at room temperature, and poured into ethyl acetate. The organic solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an off-white solid. A mixture of the solid in ethanol is stirred for several minutes, and filtered to give the title product as a white solid.
	With triethylamine; In tetrahydrofuran; ethanol;	EXAMPLE 28 Preparation of 4'--Chloro-2'-fluoroacetanilide STR114 Acetyl chloride (24.2 mL, 0.34 mol) is added slowly to a solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (49.4 g, 0.34 mol), and triethylamine (47 mL, 0.34 mol) in tetrahydrofuran while maintaining the reaction mixture temperature below 20 C. After the addition is complete, the reaction mixture is stirred overnight at room temperature, and poured into ethyl acetate. The organic solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an off-white solid. A mixture of the solid in ethanol is stirred for several minutes, and filtered to give the title product as a white solid.
	With triethylamine; In tetrahydrofuran; ethanol;	EXAMPLE 28 Preparation of 4'-Chloro-2'-fluoroacetanilide STR107 Acetyl chloride (24.2 mL, 0.34 mol) is added slowly to a solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (49.4 g, 0.34 mol), and triethylamine (47 mL, 0.34 mol) in tetrahydrofuran while maintaining the reaction mixture temperature below 20 C. After the addition is complete, the reaction mixture is stirred overnight at room temperature, and poured into ethyl acetate. The organic solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an off-white solid. A mixture of the solid in ethanol is stirred for several minutes, and filtered to give the title product as a white solid.

With triethylamine; In dichloromethane; at 20 - 25℃; for 16h;

Step (i): N-(4-Chloro-2-fluorophenyl)acetamide To the solution of [57946-56-2]4-chloro-2-fluoroaniline (25.0 g, 172.41 mmol) in dichloromethane (500 ml) was added triethylamine (34.82 g, 344.82 mmol) and acetyl chloride (14.79 g, 189.65 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mass was quenched with water and the aqueous layer was extracted into dichloromethane. The organic layer was dried (sodium sulphate) and evaporated in vacuo to afford the crude product which was triturated from diethyl ether and used without further purification.1H NMR (DMSO-d6) delta ppm 2.09 (s, 3 H) 7.35-7.37 (m, 1 H), 7.47-7.50 (m, 1 H), 7.92 - 7.96 (m, 1 H), 9.84 (br. s, 1 H)MS ES+: 188

Reference： [1]Patent: US5610120,1997,A
[2]Patent: US5726126,1998,A
[3]Patent: US5679791,1997,A
[4]Patent: WO2015/55994,2015,A1 .Location in patent: Page/Page column 65; 66

30
[ 328-38-1 ]
[ 57946-56-2 ]
[ 75-24-1 ]
[ 158174-69-7 ]

Yield	Reaction Conditions	Operation in experiment
55%	In hexane; dichloromethane	17 Preparation of R-2-amino-N-(4-chloro-2-fluorophenyl)-4-methylpentanamide EXAMPLE 17 Preparation of R-2-amino-N-(4-chloro-2-fluorophenyl)-4-methylpentanamide The title compound of Example 16 was also prepared in the following manner. To a mixture of 4-chloro-2-fluoroaniline(5.21 g, 35.83 mmol) and D-leucine (4.10 g, 35.83 mmol) in methylene chloride (100 mL), was added trimethylaluminum (35.8 mL of a 2M solution in hexane, 71.66 mmol) dropwise at 0° C. under nitrogen. The resultant brown solution was stirred at room temperature for 2 days. A similar workup as in Example 16 yielded the title compound (4.04 g, 55%) as a whim solid, mp 75°-77° C. Spectral data matched that of the compound prepared in Example 16. By the general procedures described herein, or obvious modifications thereof, the compounds of Index Tables K-P can be prepared. In the Tables, the α-amino amide product, when chiral, is indicated by a wedge or hash bond at the chiral carbon, if not so indicated, the product is racemic. In Index Tables K-N, the designations R, R', R" and R"' are used to indicate the substituents on the aromatic ring as previously defined for R43.
	With hydrogenchloride; sodium hydroxide In hexane; dichloromethane; water; ethyl acetate	16 Preparation of R-2-amino-N-(4-chloro-2-fluorophenyl)-4-methylpentanamide EXAMPLE 16 Preparation of R-2-amino-N-(4-chloro-2-fluorophenyl)-4-methylpentanamide A solution of trimethylaluminum (35.8 mL of a 2M solution in hexane, 71.66 mmol) was added dropwise to a stirred suspension of D-leucine (4.70 g, 35.83 mmol, Aldrich Chemical; Milwaukee, Wis.) in 100 mL of methylene chloride under nitrogen, at 0° C. (ice-water bath). The resulting clear solution was stirred at room temperature overnight. To the solution was added 4-chloro-2-fluoroaniline (5.21 g, 35.83 mmol) portionwise via solid addition funnel and the mixture was stirred at room temperature for 2 days. To the reaction mixture 6N HCl (200 mL) was added until foaming stopped. Methylene chloride(400 mL) and water (200 mL) were added. The aqueous layer was separated and basicified with 50% NaOH to pH 10. Methylene chloride (400 mL) was added. The organic layer was separated, dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The dried residue was chromatographed on silica gel using 30% ethyl acetate in hexane as eluding solvent. The desired fractions were collected and evaporated under reduced pressure to yield (3.61 g, 48%) of the title compound as a white solid, mp 75°-77° C. IR (Nujol, cm-1), N--H (3382, 3251), C=O, (1680). 1 H NMR (400 MHz, CDCl3): δ9.99 (br,1H), 8.40-8.36 (t,1H), 7.13-7.10 (m,2H), 3.58-3.92 (m,1H), 1.85-1.73 (m,2H), 1.56 (br,2H), 1.48-1.44 (t,1H), 1.01-0.97 (m,6H).

Reference： [1]Current Patent Assignee: DUPONT DE NEMOURS INC - US5643855, 1997, A
[2]Current Patent Assignee: DUPONT DE NEMOURS INC - US5643855, 1997, A

31
[ 59280-70-5 ]
[ 57946-56-2 ]

Yield	Reaction Conditions	Operation in experiment
95.6%	With sodium hydroxide; water In ethanol for 3h; Reflux;
	With sodium hydroxide In ethanol; water	C Step C: Step C: Synthesis of 4-Chloro-2-fluoroaniline as an Intermediate To a stirred solution of 155 g (0.83 mole) of 4-chloro-2-fluoroacetanilide in 400 ml of ethanol was added dropwise a solution of 72.0 g (1.8 moles) of sodium hydroxide in 100 ml of water. Upon completion of addition the reaction mixture was heated under reflux for three hours. The reaction mixture was cooled to ambient temperature and extracted with diethyl ether. The combined extracts were concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure to yield 81.0 g of 4-chloro-2-fluoroaniline; b.p. 83-85/12 mm.
	With sodium hydroxide In ethanol; water	C Synthesis of 4-Chloro-2-fluoroaniline as an Intermediate Step C Synthesis of 4-Chloro-2-fluoroaniline as an Intermediate To a stirred solution of 155 g (0.83 mole) of 4-chloro-2-fluoroacetanilide in 400 ml of ethanol was added dropwise a solution of 72.0 g (1.8 moles) of sodium hydroxide in 100 ml of water. Upon completion of addition the reaction mixture was heated under reflux for three hours. The reaction mixture was cooled to ambient temperature and extracted with diethyl ether. The combined extracts were concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure to yield 81.0 g of 4-chloro-2-fluoroaniline; b.p. 83-85/12 mm.

Reference： [1]Location in patent: experimental part Zhang, Chuan-Yu; Wang, Bao-Lei; Liu, Xing-Hai; Li, Yong-Hong; Wang, Su-Hua; Li, Zheng-Ming [Heterocyclic Communications, 2008, vol. 14, # 6, p. 397 - 404]
[2]Current Patent Assignee: FMC CORP - US5041155, 1991, A
[3]Current Patent Assignee: FMC CORP - US4818275, 1989, A

32
CH₃ NO₂ [ No CAS ]
[ 446-30-0 ]
[ 57946-56-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; PPA;	A mixture of <strong>[446-30-0]2-fluoro-4-chlorobenzoic acid</strong> (6.05 g), polyphosphoric acid (62.51 g) and CH3 NO2 (5.1 g) is heated at 130. After about 2.5 hr, the reaction mixture is poured onto ice and made basic by addition of dilute sodium hydroxide. The reaction is then worked up by extracting with ether. The combined ether extracts are washed with water and brine, dried over sodium sulfate, filtered and evaporated to yield 2-fluoro-4-chloroaniline.

Reference： [1]Patent: US4243819,1981,A

33
[ 766-39-2 ]
[ 57946-56-2 ]
[ 115087-24-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	With hydrogenchloride; dmap; sodium hydroxide; In o-xylene; ethyl acetate;	EXAMPLE 9 Preparation of N-(2-fluoro-4-chlorophenyl)-2,3-dimethylmaleic acid imide STR19 A mixture of 126 g (1.0 mol) of dimethylmaleic anhydride, 145.5 g (1.0 mol) of <strong>[57946-56-2]2-fluoro-4-chloroaniline</strong> and 2 g of 4-dimethylaminopyridine is heated under reflux in 800 ml of o-xylene for 16 hours using a water separator. The whole is then evaporated to dryness in vacuo and the residue is dissolved in a 1:1 mixture of ethyl acetate:ether and washed with each of 1N hydrochloric acid, 1N sodium hydroxide solution and water. Afer drying over sodium sulphate and evaporating off the solvent, the residue (227.5 g) is recrystallized from methanol. In this manner there are obtained 211.1 g (84% of the theoretical yield) of the title product in the form of colourless crystals which melt at 96-97.

Reference： [1]Patent: US4804400,1989,A

34
cis-1,2-cyclohexanedicarboxylic anhydride [ No CAS ]
[ 54416-81-8 ]
[ 57946-56-2 ]
[ 59280-70-5 ]
[ 61330-03-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In methanol; sodium hydroxide; ethanol; dichloromethane; acetic acid	1 Preparation of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione A mixture of 119 parts of 4'-chloro-2'-fluoroacetanilide in 475 parts of ethanol and 200 parts of 37% hydrochloric acid was refluxed for 17 hours and the solvent removed under a reduced pressure of 300 mm.Hg. to yield the moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline. The moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline was cooled to 10° C in an ice-acetone bath and 50% aqueous sodium hydroxide was added dropwise, with stirring, until pH 11 was obtained. The resulting two-phase mixture was extracted four times; 500 parts of methylene chloride were used for each extraction. The combined organic extracts were dried with anhydrous sodium sulfate and the solvent removed under reduced pressure of 300 mm Hg. to leave 89 parts of light brown, oily 4-chloro-2-fluoroaniline, nD25 = 1.5541. 9.44 Parts of 4-chloro-2-fluoroaniline were then added to a solution of 10 parts of cyclohexane-1,2-dicarboxylic anhydride in 75 parts of glacial acetic acid. After refluxing for 6 hours, the reaction mixture was poured into 200 parts of ice. The resulting crystals were filtered and recrystallized from 70 parts of methanol at -40° C to yield 12.4 parts of white crystals of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)dione melting at 94°-95.5° C.
	With hydrogenchloride In methanol; sodium hydroxide; ethanol; dichloromethane; acetic acid	1 Preparation of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione A mixture of 119 parts of 4'-chloro-2'-fluoroacetanilide in 475 parts of ethanol and 200 parts of 37% hydrochloric acid was refluxed for 17 hours and the solvent removed at a reduced pressure of 300 mm.Hg to yield the moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline The moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline was cooled to 10° in an ice-acetone bath and 50% aqueous sodium hydroxide was added dropwise, with stirring, until pH 11 was obtained. The resulting two-phase mixture was extracted four times; 500 parts of methylene chloride were used for each extraction. The combined organic extracts were dried with anhyrous sodium sulfate and the solvent removed at a reduced pressure of 300 mm.Hg to leave 89 parts of light brown, oily 4-chloro-2-fluoroaniline, nD25 = 1.5541. 9.44 parts of 4-chloro-2-fluoroaniline were then added to a solution of 10 parts of cyclohexane-1,2-dicarboxylic anhydride in 75 parts of glacial acetic acid. After refluxing for 6 hours, the reaction mixture was poured into 200 parts of ice. The resulting crystals were filtered and recrystallized from 70 parts of methanol at -40° C. to yield 12.4 parts of white crystals of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)dione melting at 94°-95.5°.

Reference： [1]Current Patent Assignee: DUPONT DE NEMOURS INC - US3987057, 1976, A
[2]Current Patent Assignee: DUPONT DE NEMOURS INC - US4120693, 1978, A

35
[ 2426-02-0 ]
[ 57946-56-2 ]
[ 59280-70-5 ]
[ 61714-44-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide In diethyl ether; ethanol; dichloromethane	1 Preparation of 2-(4-chloro-2-fluorophenylaminocarbonyl)-1-cyclohexene-1-carboxylic acid A mixture of 119 parts of 4'-chloro-2'-fluoroacetanilide in 475 parts of ethanol and 200 parts of 37% hydrochloric acid was refluxed for 17 hours and the solvent removed under a reduced pressure of 300 mm Hg. to yield the moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline. The moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline was cooled in an ice-acetone bath, down to 10° C, and 50% aqueous sodium hydroxide was added until pH 11 was reached. The resulting two-phase mixture was extracted four times; 500 parts of methylene chloride were used for each extraction. The combined organic extracts were dried with anhydrous sodium sulfate and the solvent removed under reduced pressure of 300 mm Hg. to leave 89 parts of light brown, oily 4-chloro-2-fluoroaniline, nD25 1.5541. The moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline was cooled in an ice-acetone bath and treated at 10° C with 50% aqueous sodium hydroxide until pH 11 was reached. The resulting two-phase mixture was extracted four times; 500 parts of methylene chloride were used for each extraction. The combined organic extracts were dried with anhydrous sodium sulfate and the solvent removed under reduced pressure of 300 mm Hg. to leave 89 parts of light brown, oily 4-chloro-2-fluoroaniline, nD25 - 1.5541. 4.8 Parts of 4-chloro-2-fluoroaniline were added to a solution of 5 parts of 3,4,5,6-tetrahydrophthalic anhydride in 150 parts of diethyl ether and stirred for 1.5 hours. The solution was divided into two equal portions. One portion was evaporated under reduced pressure of 300 mm Hg. at 25° C to isolate 5.4 parts of 2-(4-chloro-2-fluorophenylaminocarbonyl)-1-cyclohexene-1-carboxylic acid as white crystals melting at 91°-93° C. The other portion was used in Example 3.

Reference： [1]Current Patent Assignee: DUPONT DE NEMOURS INC - US4003926, 1977, A

36
[ 399-31-5 ]
[ 57946-56-2 ]
[ 59280-70-5 ]

Yield	Reaction Conditions	Operation in experiment
	With chlorine In acetic acid	1.a (a) (a) Preparation of 4-chloro-2-fluoroaniline Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during one hour, at 25°-27°, with ice water cooling. While stirring for 4 hours at 25°-27°, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155°.
	With chlorine In acetic acid	1.a (a) (a) Preparation of 4-chloro-2-fluoroaniline Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during one hour, at 25°-27° C, with icewater cooling. While stirring for 4 hours at 25°-27° C, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° C to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155° C.
	With chlorine In acetic acid	1.a a. a. Preparation of 4-Chloro-2-fluoroaniline Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during one hour, at 25°-27°, with icewater cooling. While stirring for 4 hours at 25°-27°, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155°.

	With chlorine In acetic acid	1 Preparation of 4-chloro-2-fluoroaniline EXAMPLE 1 Preparation of 4-chloro-2-fluoroaniline Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during one hour, at 25°-27°C, with icewater cooling. While stirring for 4 hours at 25°-27°C, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45°C to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155°C.
	With chlorine In acetic acid	1.a (a) (a) Preparation of 4-Chloro-2-fluoroaniline Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during one hour, at 25°-27°, with ice-water cooling. While stirring for 4 hours at 25°-27°, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155°.
	With chlorine In acetic acid	1 Preparation of 3-Chloro-2-(4-chloro-2-fluorophenyl)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole STR9 a. Preparation of 4-Chloro-2-fluoroaniline Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during one hour, at 25°-27° C., with ice-water cooling. While stirring for 4 hours at 25°-27° C., 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° C. to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155° C.
	With chlorine In glacial acetid acid	1 Preparation of 4-chloro-2-fluoroaniline EXAMPLE 1 Preparation of 4-chloro-2-fluoroaniline Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetid acid, during one hour, at 25°-27°, with ice-water cooling. While stirring for 4 hours at 25°-27°, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° to yield 199 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155°.

Reference： [1]Current Patent Assignee: DUPONT DE NEMOURS INC - US4111681, 1978, A
[2]Current Patent Assignee: SPX CORP - US4124374, 1978, A
[3]Current Patent Assignee: DUPONT DE NEMOURS INC - US4059434, 1977, A
[4]Current Patent Assignee: DUPONT DE NEMOURS INC - US3958976, 1976, A
[5]Current Patent Assignee: DUPONT DE NEMOURS INC - US4033751, 1977, A
[6]Current Patent Assignee: DUPONT DE NEMOURS INC - US4042373, 1977, A
[7]Current Patent Assignee: DUPONT DE NEMOURS INC - US3992189, 1976, A

37
[ 57946-56-2 ]
[ 144876-59-5 ]
[ 1044501-13-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	In chloroform; at 0 - 20℃; for 8h;	Description 12: Methyl 1 -([(4-chloro-2- fluorophenyl)amino]carbonate; To a solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (2.9Og, 20mmol) in chloroform (30ml) cooled to 00C with ice-water bath was added dropwise methyl 1-isocyanatocyclohexanecarboxylate(4.76g, 26mmol, description 1 1 ). The reaction mixture was stirred to form a clear solution and warmed to room temperature. After an additional 8 hours stirring, methyl 1-([(4- chloro-2-fluorophenyl)amino]carbonyl}amino)cyclohexanecarboxylate (5.0Og, 15mmol) was obtained by filtration and evaporation (yield:75%). Mass Spectrum (ESI, LC/MS) calcd for Ci5H18CIFN2O3328.1 , found 329.1 (MH+ ).

Reference： [1]Patent: WO2008/92878,2008,A1 .Location in patent: Page/Page column 37

38
[ 137640-84-7 ]
[ 57946-56-2 ]
C₁₉H₁₁ClF₄N₂O₂ [ No CAS ]

Reference： [1]Patent: EP1207154,2002,A1 .Location in patent: Example 41

39
[ 57946-56-2 ]
[ 541-41-3 ]
[ 1103234-34-9 ]

Yield	Reaction Conditions	Operation in experiment
72%		4-Chloro-2-fluoroaniline (14, 12 mL) was dissolved in 200 mL of anhydrous tetrahydrofuran under a nitrogen atmosphere in a 1 L 3-neck round bottom flask. The mixture was cooled to -78 0C (dry ice/acetone bath) and n-butyllithium (2.5 M, 45 mL) was slowly added dropwise, maintaining the temperature below -70 0C. The mixture was stirred at -70 0C for 30 minutes. 1,2-Bis(chlorodimethylsilyl)ethane (24.80 g) was dissolved in 80 mL of anhydrous tetrahydrofuran and slowly added dropwise to the reaction mixture while maintaining the temperature below -70 0C. The resulting mixture was stirred at -78 0C for 1 hour, then n-butyllithium (2.5 M, 45 mL) was slowly added dropwise maintaining the temperature below -70 0C. The mixture was then stirred for 30 minutes at -78 0C, then warmed up to 15 0C over 1 hour. The reaction mixture was cooled down to -78 0C and n-butyllithium (2.5 M, 50 mL) was slowly added dropwise maintaining the temperature below -70 0C. The mixture was stirred at -70 0C for 90 minutes, then 13.40 mL of ethylchloroformate <n="81"/>was slowly added drop wise maintaining the temperature below -70 0C. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 64 hours. The reaction was quenched by careful addition of a solution of 50 mL of concentrated hydrochloric acid in 160 mL of water while cooling with an ice/water bath. The mixture was stirred at room temperature for 2 hours, then made basic by addition of potassium carbonate. The mixture was extracted with 3 x 100 mL of ethyl acetate and the combined organic extracts were washed with 50 mL of brine and dried with magnesium sulfate. After removal of the solvent, the residue was purified with silica gel column chromatography eluting with ethyl acetate in hexane to provide the desired compound (15, 17 g, 72 %).
68%		To a solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (1.00 g, 6.87 mmol) in tetrahydrofuran (10 mL) at -78 C was added n-BuLi (2.94 mL of a 2.5M solution in hexanes, 7.35 mmol) and the resulting solution was stirred at this temperature for 20 minutes. After this time a solution of 1 ,2-bis(chlorodimethylsilyl)ethane (1.55 g, 7.21 mmol) in tetrahydrofuran (5 mL) was added dropwise via cannula. After 1 hour at -78 C, further n-BuLi (3.02 mL of a 2.5M solution in hexanes, 7.56 mmol) was added and the resulting mixture was stirred for 20 minutes and then allowed to warm room temperature and stirred for a further 1 hour. The mixture was then cooled to -78 C and further n-BuLi (3.02 mL of a 2.5M solution in hexanes, 7.56 mmol) was added and the resulting mixture was stirred for 1 hour at this temperature. ethylchloroformate (0.90 mL, 8.28 mmol) was then added and the reaction was then allowed to warm to room temperature and stirred for 16 hours. After this time the reaction mixture was diluted with EtOAc and 2M aqueous hydrogen chloride solution. The organic layer was removed, the aqueous layer basified by addition of saturated aqueous sodium hydrogen carbonate, extracted with EtOAc and the organic layer isolated, washed with saturated aqueous sodium chloride solution, dried (MgS04), filtered and concentrated at reduced pressure. The combined organics were purified by Biotage Isolera chromatography (eluting with a gradient of eluents; 100 heptane to 8:2 heptane/ EtOAc) giving the title product (1.30 g, 68% yield) as a brown oil. 1H NMR (250 MHz, DMSO-d6) delta [ppm] 7.06 (dd, J = 8.7, 1 .1 Hz, 1 H), 6.92 - 6.79 (m, 1 H), 5.58 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). LCMS (Analytical Method A) Rt = 1.15min, MS (ESIpos): m/z = 217.85 (M+H)+.
54%		Example 91 Preparation of ethyl 3-amino-6-chloro-2-fluorobenzoate (C320) To a solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (11 g, 76 mmol) in anhydrous tetrahydrofuran (151 mL) cooled to -76 C. was added butyllithium (31.7 mL, 79 mmol) as a 2.5 M solution in hexanes at a rate which maintained the temperature between below -68 C., and the resulting greenish-brown solution was stirred at -75 C. for 45 minutes. The heterogeneous brown reaction mixture was treated with a tetrahydrofuran solution (50 mL) of 1,2-bis(chlorodimethylsilyl)ethane (17.24 g, 80 mmol) at a rate which maintained the temperature between -68 and -75 C. Following the addition, the resulting brown solution was stirred at -75 C. for 75 minutes. The resulting brown solution was treated with butyllithium (31.7 mL, 79 mmol) at a rate which maintained the temperature below -70 C., and the resulting solution was stirred at -74 C. for 30 minutes. The cooling bath was removed and the reaction solution was allowed to slowly warm to 15 C. over approximately a 2-hour period. The solution was cooled to -72 C. and treated dropwise with butyllithium (31.7 mL, 79 mmol) at a rate which maintained the temperature below -70 C. After stirring for 60 minutes at -74 C., the resulting amber-brown solution was treated with ethyl carbonochloridate (10.66 g, 98 mmol) dropwise at a rate which maintained the temperature below -70 C., and the resulting dark solution was allowed to slowly warm to room temperature as the dry ice was consumed. The resulting heterogeneous mixture (tan ppt) was cooled to 0 C. and quenched by the cautious addition of 3 N aqueous hydrogen chloride (140 mL, 0.42 mmol). The ice bath was removed and the resulting dark solution was stirred at room temperature for 60 minutes. The pH was adjusted to ?8 by the careful addition of solid sodium carbonate (?28 g) and the mixture was extracted with ethyl acetate (3150 mL). The combined extracts were washed with brine (3100 mL), dried over sodium sulfate, filtered, and concentrated to a dark oil. The crude oil was purified by automated flash chromatography (silica gel; 0?30% ethyl acetate in hexanes) to give the title compound as a light-orange oil (8.96 g. 54%): 1H NMR (400 MHz, CDCl3) delta 6.97 (dd, J=8.6, 1.5 Hz, 1H), 6.73 (t, J=8.9 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.84 (s, 2H), 1.40 (t, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) delta 163.49, 149.38, 146.94, 133.85, 133.73, 125.36, 125.32, 122.35, 122.18, 119.48, 119.44, 117.95, 117.90, 62.19, 14.14; 19F NMR (376 MHz, CDCl3) delta -134.47; EIMS m/z 217.

Reference： [1]Patent: WO2009/12283,2009,A1 .Location in patent: Page/Page column 79-80
[2]Patent: WO2018/114786,2018,A1 .Location in patent: Page/Page column 207-208
[3]Patent: US2018/98541,2018,A1 .Location in patent: Paragraph 3126

40
[ 1450-14-2 ]
[ 57946-56-2 ]
[ 955372-99-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium fluoride;Pd(dibenzylideneacetone)2 chloroform adduct; dicyclohexylphenylphosphine; In 1,4-dioxane; at 100℃; for 18h;	INTERMEDIATE 1; 2-Fluoro-4-(trimethylsilanyl')phenylamineTo a stirred solution of bis(dibenzylideneacetone)palladium chloroform adduct (190 mg, 0.2 mmol) and dicyclohexylphenylphosphine (430 mg, 1.2 mmol) in 1,4- dioxane (16 mL) was added hexamethyldisilane (5.0 mL, 24.4 mmol), 4-chloro-2- fluoroaniline (1.5 mL, 13.6 mmol), water (0.2 mL, 13.6 mmol) and KF (3.9 g, 68.0 mmol). The reaction mixture was heated in a sealed flask at 1000C for 18 h. DCM (200 mL) was added to the reaction mixture. The solids were filtered off, water was added and the mixture extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by chromatography (silica, 100% hexane) to give the title compound as a yellow oil (2.3 g, 93%). 5H(DMSO-d6) 6.85 (IH, dd, J 11.9, 1.1 Hz), 6.80 (IH, dd, J7.7, 1.3 Hz), 6.59 (IH, dd, J 8.9, 7.9 Hz), 5.01 (2H, s), 0.01 (9H, s).

Reference： [1]Patent: WO2009/93013,2009,A1 .Location in patent: Page/Page column 29

41
[ 13528-93-3 ]
[ 57946-56-2 ]
[ 501-53-1 ]
[ 918523-46-3 ]

Yield	Reaction Conditions	Operation in experiment
78.3%	Stage #1: 2-fluoro-4-chloroaniline With n-butyllithium In tetrahydrofuran; hexane Inert atmosphere; Cooling with acetone-dry ice; Stage #2: 1,2-bis-(chlorodimethylsilyl)ethane In tetrahydrofuran; hexane Stage #3: benzyl chloroformate	3.1 To 4-chloro-2-fluoro-phenylaminc (15, 6 30 mL, 57.0 mmol) in 300 mL of tctrahydrofuran cooled with dry ice'acctone bath under an atmosphere of nitrogen, n-butyllithium (2.50 M in hexane, 24,4 mL) was added slowly. After 20 minutes, l ,2-bis-(chloro-dimelhyl-silanyl)-ethanc (12.9 g, 60.0 mmol) dissolved in tctrahydrofuran (40 0 mL) was added slowly to the reaction. After 1 hour, n-butyllithium (2.50 Vl in hexane, 25 0 mL) was added slowly to the reaction. The reaction was stirred at -78 0C for 20 minutes and then allowed to warm to room temperature over 60 minutes. The reaction was cooled to -78 0C, followed by addition of n-butyl lithium (2.50 M in hexane. 26.0 mL) slowly. After 80 minutes, benzyl chloroformate (2, 10.0 mL, 70.0 mmol) was added to the reaction. The reaction mixture was stirred at -78 DC overnight followed by addition of 80 mL of water and 25 mL of concentrated hydrochloric acid. The18 reaction was allowed to warm to room temperature for 2 hours. The organic layer was separated. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The desired compound was isolated by silica gel column chromatography (ethyl acetate hexane 20%) to give a colorless oil (16, 12.5 g, 78.3%). MS(ESI) [M+HY = 280.0.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - WO2010/104945, 2010, A1 Location in patent: Page/Page column 38-39

42
[ 57946-56-2 ]
[ 127-68-4 ]
[ 52200-53-0 ]

Yield	Reaction Conditions	Operation in experiment
70%		Intermediate 56-Chloro-8-fluoroquinolineA solution of concentrated sulphuric acid (16 ml, 300 mmol) in water (12 ml) was treated with sodium 3-nitro-benzenesulfonate (commercially available, for example, from Aldrich) (11.3 g, 50 mmol) and glycerol (commercially available, for example, from Fisher and/or Aldrich) (12 ml, 160 mmol) to give a suspension. This was heated to 110 C. with stirring, and 4-chloro-2-fluoroaniline (commercially available, for example, from Aldrich) (5.6 ml, 50 mmol) was added. The reaction was heated to 140 C. and stirred overnight. The reaction mixture was cooled and then poured into water (400 ml) and basified to pH 11 with aqueous ammonium hydroxide (0.88 s.g., 60 ml). The brown precipitate that formed was collected by filtration and dried under suction. EtOAc was then added to the sinter funnel, dissolving most of the material to give a brown solution. This filtrate was concentrated in vacuo to give a brown solid (7.7 g). This was purified by chromatography on silica (2×100 g, eluting with 0-50% EtOAc-cyclohexane over 60 min). The relevant fractions were concentrated in vacuo to give the title compound as a yellow solid (6.5 g, 70%) LCMS RT=2.78 min, ES+ve m/z 182/184 [M+H]+.

Reference： [1]Patent: US2009/270355,2009,A1 .Location in patent: Page/Page column 22

43
[ 57946-56-2 ]
[ 501-53-1 ]
[ 918523-46-3 ]

Yield	Reaction Conditions	Operation in experiment
78.3%		To <strong>[57946-56-2]4-chloro-2-fluoro-phenylamine</strong> (11, 6.30 mL, 57.0 mmol) in 300 mL of tetrahydrofuran, cooled with dry ice/acetone bath under an atmosphere of nitrogen, n-butyllithium (24.4 mL, 2.50 M in hexane) was added slowly. After 20 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (12.9 g, 60.0 mmol) dissolved in 40.0 mL of tetrahydrofuran was added slowly to the reaction. After 1 hour, n-butyllithium (25.0 mL, 2.50 M in hexane) was added slowly to the reaction. The reaction was stirred at -78 C. for 20 minutes and then allowed to warm to room temperature over 60 minutes. The reaction was cooled to -78 C., followed by slowly adding n-butyllithium (26.0 mL, 2.50 M in hexane). After 80 minutes, benzyl chloroformate (20, 10.0 mL, 70.0 mmol) was added to the reaction. The reaction mixture was stirred at -78 C. overnight followed by addition of 80 mL of water and 25 mL of concentrated hydrochloric acid. The reaction was allowed to warm to room temperature for 2 hours. The organic layer was separated and the aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluding with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a colorless oil (12, 12.5 g, 78.3%). MS(ESI) [M+H+]+=280.0.
78.3%		To <strong>[57946-56-2]4-chloro-2-fluoro-phenylamine</strong> (47, 6.30 mL, 57.0 mmol) in tetrahydrofuran (300 mL), cooled with dry ice/acetone bath under an atmosphere of nitrogen, was added n-butyllithium (2.500 M in hexane, 24.4 mL) slowly. After 20 minutes, l,2-Bis-(chloro-dimethyl-silanyl)-ethane (12.9 g, 60.0 mmol) dissolved in tetrahydrofuran (40.0 mL) was added to the reaction slowly. After 1 hour, n- butyllithium (2.50 M in hexane, 25.0 mL) was added slowly to the reaction. The reaction was stirred at -78 0C for 20 minutes and allowed to warm to room temperature over 60 minutes. The reaction was cooled to -78 0C, followed by addition of n-butyllithium (2.50 M in hexane, 26.0 mL) slowly. After 80 minutes, benzyl chloroformate (10.0 mL, 70.0 mmol) was added to the reaction. The reaction mixture was stirred at -78 0C overnight followed by addition of water (80 mL) and concentrated hydrochloric acid (25 mL). The reaction was allowed to warm to room temperature for EPO <DP n="79"/>2 hours. The organic layer was separated and the aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (ethyl acetate/hexane 20%) to give a colorless oil (48, 12.5 g, 78.3%). MS(ESI) [M+HY= 280.0.
78.3%		To <strong>[57946-56-2]4-chloro-2-fluoro-phenylamine</strong> (60, 6.30 mL, 57 0 mmol) in tetrahydrofuran (300 mL). cooled with dry ice/acetone bath under an atmosphere of nitrogen, n-butyl lithium (2.50 M in hexane, 24.4 mL) was added slowly After 20 minutes, l,2-Bis-(chloro-dimethyl-silanyl)-ethane (12.9 g, 60.0 mmol) dissolved in tetrahydrofuran (40.0 mL) was added slowly to the reaction. After 1 hour, n- butylhthium (2.50 M in hexane, 25 0 mL) was added slowly to the reaction. The reaction was stirred at -78 0C for 20 minutes and then allowed to warm to room temperature over 60 minutes The reaction was cooled to -78 0C, followed by addition of n-butyllithium (2.50 M in hexane, 26.0 mL) slowly. After 80 minutes, benzyl chloroformate (10.0 mL, 70.0 mmol) was added to the reaction. The reaction mixture was stirred at -78 0C overnight followed by addition of water (80 mL) and concentrated hydrochloric acid (25 mL). The reaction was allowed to warm to room temperature for 2 hours. The organic layer was separated. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography (ethyl acetate/hexane 20%) to give a colorless oil (61, 12.5 g, 78.3%). MS(ESI) [M+HY = 280.0.

45%		Step A: A flame dried flask equipped with a stir bar and rubber septum was charged with <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (5.00 g, 34.35 mmol) and anhydrous THF (170 mL). This solution was chilled to -78C, and «-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period. This mixture was stirred at -78C for 20 minutes, and then a THF solution (25 mL) of l,2-bis(chlorodimethylsilyl)ethane (7.76 g, 1.05 eq.) was added slowly (over a 10 minute period) to the reaction mixture. This was stirred for 1 hour, and then 2.5M n- BuLi in hexanes (15.11 mL, 1.1 eq.) was added slowly. After allowing the mixture to warm to room temperature for one hour, the mixture was chilled back to -78C. A third allotment of n- BuLi (15.66 mL, 1.14 eq.) was added slowly, and the mixture was stirred at -78C for 75 minutes. Benzyl chloro formate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at -78C for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HCl (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with EtOAc. The extracts were washed twice with a saturated Na2HCO3 solution, once with water, dried over sodium sulfate and concentrated. The resulting residue was flashed on a 65 Biotage (30% ethyl acetate/hexane) to produce benzyl 3-amino-6-chloro-2- fluorobenzoate (4.3 g, 45%) as an oil. 1H NMR (DMSO-d6, 400 MHz) delta 7.37-7.48 (m, 5H), 7.07 (dd, J= 8, 2 Hz, IH), 6.87 (t, J= 8 Hz, IH), 5.61 (br s, 2H), 5.40 (s, 2H).
45%		A flame dried flask equipped with a stir bar and rubber septum was charged with <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (5.00 g, 34.35 mmol) and anhydrous THF (170 mL). This solution was chilled to -78C, and n-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period. This mixture was stirred at -78C for 20 minutes, and then a THF solution (25 mL) of 1 ,2-bis(chlorodimethylsilyl)ethane (7.76 g, 1.05 eq.) was added slowly (over a 10 minute period) to the reaction mixture. This was stirred for 1 hour, and then 2.5M n-BuLi in hexanes (15.11 mL, 1.1 eq.) was added slowly. After allowing the mixture to warm to room temperature for one hour, the mixture was chilled back to -78C. A third allotment of n-BuLi (15.66 mL, 1.14 eq.) was added slowly, and the mixture was stirred at -78C for 75 minutes. Benzyl chloroformate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at -78C for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HCl (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with EtOAc. The extracts were washed twice with a saturated NaHCO3 solution, once with water, dried over sodium sulfate and concentrated. The resulting residue was purified via silica gel column chromatography (30% ethyl acetate/hexane) to produce benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 45%) as an oil. 1H NMR (DMSO- d6, 400 MHz) delta 7.37-7.48 (m, 5H), 7.07 (dd, J= 8 Hz, 2 Hz, IH), 6.87 (t, J= 8 Hz, IH), 5.61 (br s, 2H), 5.40 (s, 2H).
45%		A flame dried flask equipped with a stir bar and rubber septum was charged with <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (5.00 g, 34.35 mmol) and anhydrous THF (170 mL). This solution was chilled to -78C, and n-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period. This mixture was stirred at -78C for 20 minutes, and then a THF solution (25 mL) of l,2-bis(chlorodimethylsilyl)ethane (7.76 g, 1.05 eq.) was added slowly (over a 10 minute period) to the reaction mixture. This was stirred for 1 hour, and then 2.5M n-BuLi in hexanes (15.11 mL, 1.1 eq.) was added slowly. After allowing the mixture to warm to room temperature for one hour, the mixture was chilled back to -78C. A third allotment of n-BuLi (15.66 mL, 1.14 eq.) was added slowly, and the mixture was stirred at - 78C for 75 minutes. Benzyl chloro formate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at -78C for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HCl (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with EtOAc. The extracts were washed twice with a saturated NaHCO3 solution, once with water, dried over sodium sulfate and concentrated. The resulting residue was purified via silica gel column chromatography (30% ethyl acetate/hexane) to produce benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 45%) as an oil. 1H NMR (DMSO- d6, 400 MHz) delta 7.37-7.48 (m, 5H), 7.07 (dd, J= 8 Hz, 2 Hz, IH), 6.87 (t, J= 8 Hz, IH), 5.61 (br s, 2H), 5.40 (s, 2H).
45%		Step A: A flame dried flask equipped with a stir bar and rubber septum was charged with <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (5.00 g, 34.35 mmol) and anhydrous THF (170 mL). This solution was chilled to -780C, and r°-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period. This mixture was stirred at -78C for 20 minutes, and then a THF solution (25 mL) of l,2-bis(chlorodimethylsilyl)ethane (7.76 g, 1.05 eq.) was added slowly (over a 10 minute period) to the reaction mixture. This was stirred for 1 hour, and then 2.5M r°-BuLi in hexanes (15.11 mL, 1.1 eq.) was added slowly. After allowing the mixture to warm to room temperature for one hour, the mixture was chilled back to -78C. A third allotment of «-BuLi (15.66 mL, 1.14 eq.) was added slowly, and the mixture was stirred at - 78C for 75 minutes. Benzyl chloroformate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at -78C for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HCl (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with EtOAc. The extracts were washed twice with a saturated Na2HCO3 solution, once with water, dried over sodium sulfate and concentrated. The resulting residue was flashed on a 65 Biotage (30% ethyl acetate/hexane) to produce benzyl 3-amino-6-chloro-2- fluorobenzoate (4.3 g, 45%) as an oil. 1U NMR (DMSO-d6, 400 MHz) delta 7.37-7.48 (m, 5H), 7.07 (dd, J= 8, 2 Hz, IH), 6.87 (t, J= 8 Hz, IH), 5.61 (br s, 2H), 5.40 (s, 2H).
45%		[00188] Step A: A flame dried flask equipped with a stir bar and rubber septum was charged with <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (5.00 g, 34.35 mmol) and dry THF (170 mL). This solution was chilled to -78C, and n-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period. This mixture was stirred at -78C for 20 minutes, and then a THF solution (25 mL) of l,2-bis(chlorodimethylsilyl)ethane (7.76 g, 1.05 eq.) was added slowly (over a 10 minute period) to the reaction mixture. This was stirred for 1 hour, and then 2.5M n-BuLi in hexanes (15.11 mL, 1.1 eq.) was added slowly. After allowing the mixture to warm to room temperature for one hour, the mixture was chilled back to -78C. A third allotment of n-BuLi (15.66 mL, 1.14 eq.) was added slowly, and the mixture was stirred at - 78C for 75 minutes. Benzyl chloroformate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at -78C for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HCl (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with EtOAc. The extracts were washed twice with a saturated Na2HCO3 solution, once with water, dried over sodium sulfate and concentrated. The resulting residue was flashed on a 65 Biotage (30% ethyl acetate/hexane) to produce benzyl 3-amino-6-chloro-2- fluorobenzoate (4.3 g, 45%) as an oil. 1H NMR ((CD3^SO, 400 MHz) delta 7.37-7.48 (m, 5H),7.07 (dd, IH, J = 8, 2), 6.87 (t, IH, J = 8), 5.61 (br s, 2H), 5.40 (s, 2H).
45%		A flame dried flask equipped with a stir bar and rubber septum was charged with <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (5.00 g, 34.35 mmol) and anhydrous THF (170 mL). This solution was chilled to -78C, and n-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period. This mixture was stirred at -78C for 20 minutes, and then a THF solution (25 mL) of l,2-bis(chlorodimethylsilyl)ethane (7.76 g, 1.05 eq.) was added slowly (over a 10 minute period) to the reaction mixture. This was stirred for 1 hour, and then 2.5M n-BuLi in hexanes (15.11 mL, 1.1 eq.) was added slowly. After allowing the mixture to warm to room temperature for one hour, the mixture was chilled back to -78C. A third allotment of n-BuLi (15.66 mL, 1.14 eq.) was added slowly, and the mixture was stirred at -78C for 75 minutes. Benzyl chloroformate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at -78C for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HC1 (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with EtOAc. The extracts were washed twice with a saturated Na2HC03 solution, once with water, dried over sodium sulfate and concentrated. The resulting residue was flashed on a 65 Biotage (30% ethyl acetate/hexane) to produce benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 45%) as an oil. 1H NMR ((CD3)2SO, 400 MHz) delta 7.37-7.48 (m, 5H), 7.07 (dd, 1H, J = 8, 2), 6.87 (t, 1H, J = 8), 5.61 (br s, 2H), 5.40 (s, 2H).
45%		To a solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (5.0 g, 34.3 mmol) in anhydrous THF (50 mL) was added n-BuLi(2.5 M, 14.7 mL) at -78C under N2 atmosphere. After stirred at -78C for 20 min, l,2-Bio(chlorodimethylsily)ethane (7.8 g, 36.1 mmol) in THF (20 mL) was added drop-wise, followed by n-BuLi(2.5 M, 15.6 mL). The mixture was warmed to room temperature for 1 hrs, then n-BuLi(2.5 M, 15.6 mL) was added again at -78C and continued to stirring at -78C for 1 hrs. Benzyl carbonochloridate (7.4 g, 41.2 mmol) was added and the mixture was warmed to room temperature for 1 hrs. The resulting reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified with column chromatography (petrol ether: EtOAc = 5: 1 to 3: 1) to afford the desired product (4.3 g, 45%).1H NMR (CDC13): ? 7.48-7.37 (5H, m), 7.07 (1H, dd, J = 2.0 Hz, 8.0 Hz), 6.87 (1H, t, J = 8.0 Hz), 5.61 (2H, s), 3.81 (1H, s).
45%		To a solution of <strong>[57946-56-2]2-fluoro-4-chloroaniline</strong> (5.0 g, 34.3 mmol) in anhydrous tetrahydrofenitrile (50.0 mL) at 078 C was added n-butyllithium (2.5 M, 14.7 mL ), The control temperature should not exceed -78 C, stir under this condition for 20 minutes,A solution of 1,2-bis (chloromethylsilyl) ethane (7.8 g, 36.1 mmol) in tetrahydrofuran (20. OmL) was added and stirred for 30 minutes. N-butyllithium (2.5M, 15.6 (2.5 M, 15.6 mL) was added dropwise, and the mixture was stirred at this temperature for 75 minutes. Benzyl chloroformate (7.4 mg) was added dropwise to the mixture at room temperature for 1 hour and then to -78 C. (15 mL), concentrated in vacuo, extracted with ethyl acetate (50 mL * 3), separated, and the organic phase was washed with saturated brine (10 mL) and stirred at room temperature Washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting viscous material was purified by silica gel column chromatography (developing solvent, petroleum ether: ethyl acetate = 3: 1) to give the desired product (4.3 g, 45%).
45%		A flame dried flask equipped with a stir bar and rubber septum was charged with <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (5.00 g, 34.35 mmol) and dry THF (170 mL). This solution was chilled to -78C, and n-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period. This mixture was stirred at -78C for 20 minutes, and then a THF solution (25 mL) of l,2-bis(chlorodimethylsilyl)ethane (7.76 g, 1.05 eq.) was added slowly (over a 10 minute period) to the reaction mixture. This was stirred for 1 hour, and then 2.5M n-BuLi in hexanes (15.11 mL, 1.1 eq.) was added slowly. After allowing the <n="44"/>mixture to warm to room temperature for one hour, the mixture was chilled back to -78C. A third allotment of n-BuLi (15.66 mL, 1.14 eq.) was added slowly, and the mixture was stirred at -78C for 75 minutes. Benzyl chloroformate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at -78C for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HCl (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with EtOAc. The extracts were washed twice with a saturated NaHCO3 solution, once with water, dried over sodium sulfate and concentrated. The resulting residue was flashed on a 65 Biotage (30% ethyl acetate/hexane) to produce benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 45%) as an oil. 1H NMR (DMSO-d6, 400 MHz) delta 7.37-7.48 (m, 5H), 7.07 (dd, IH, J = 8, 2), 6.87 (t, IH, J = 8), 5.61 (br s, 2H), 5.40 (s, 2H).
45%		Step A: A flame dried flask equipped with a stir bar and rubber septum was charged with <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (5.00 g, 34.35 mmol) and dry THF (170 mL). This solution was chilled to -78C, and n-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period. This mixture was stirred at -78C for 20 minutes, and then a THF solution (25 mL) of l,2-bis(chlorodimethylsilyl)ethane (7.76 g, 1.05 eq.) was added slowly (over a 10 minute period) to the reaction mixture. This was stirred for 1 hour, and then 2.5M n-BuLi in hexanes (15.11 mL, 1.1 eq.) was added slowly. After allowing the mixture to warm to room temperature for one hour, the mixture was chilled back to -78C. A third allotment of n-BuLi (15.66 mL, 1.14 eq.) was added slowly, and the mixture was stirred at -78C for 75 minutes. Benzyl chloroformate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at -78C for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HCl (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with ethyl acetate ("EtOAc"). The extracts were washed twice with a saturated Na2HCO3 solution, once with water, dried over sodium sulfate and concentrated. The resulting residue was flashed on a 65 Biotage (30% ethyl acetate/hexane) to produce benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 45%) as an oil. 1H NMR (DMSO-d6, 400 MHz) delta 7.37-7.48 (m, 5H), 7.07 (dd, IH, J = 8, 2), 6.87 (t, IH, J = 8), 5.61 (br s, 2H), 5.40 (s, 2H).
45%		A flame dried flask equipped with a stir bar and rubber septum was charged with <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (5.00 g, 34.35 mmol) and dry THF (170 mL). This solution was chilled to -78C, and n-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period. This mixture was stirred at -78C for 20 minutes, and then a THF solution (25 mL) of l,2-bis(chlorodimethylsilyl)ethane (7.76 g, 1.05 eq.) was added slowly (over a 10 minute period) to the reaction mixture. This was stirred for 1 hour, and then 2.5M n-BuLi in hexanes (15.11 mL, 1.1 eq.) was added slowly. After allowing the mixture to warm to room temperature for one hour, the mixture was chilled back to -78C. A <n="72"/>third allotment of n-BuLi (15.66 mL, 1.14 eq.) was added slowly, and the mixture was stirred at -78C for 75 minutes. Benzyl chloroformate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at -78C for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HCl (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with EtOAc. The extracts were washed twice with a saturated Na2HCO3 solution, once with water, dried over sodium sulfate and concentrated. The resulting residue was flashed on a 65 Biotage (30% ethyl acetate/hexane) to produce benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 45%) as an oil. 1H NMR (DMSO-d6, 400 MHz) delta 7.37-7.48 (m, 5H), 7.07 (dd, IH, J = 8, 2), 6.87 (t, IH, J = 8), 5.61 (br s, 2H), 5.40 (s, 2H).

Reference： [1]Patent: US2009/286783,2009,A1 .Location in patent: Page/Page column 43-44
[2]Patent: WO2007/2325,2007,A1 .Location in patent: Page/Page column 77-78; 131-132
[3]Patent: WO2010/129567,2010,A1 .Location in patent: Page/Page column 82-83
[4]Patent: WO2011/25938,2011,A2 .Location in patent: Page/Page column 55
[5]Patent: WO2011/25940,2011,A1 .Location in patent: Page/Page column 60
[6]Patent: WO2011/25947,2011,A1 .Location in patent: Page/Page column 42-43
[7]Patent: WO2011/25965,2011,A1 .Location in patent: Page/Page column 41
[8]Patent: WO2011/25951,2011,A1 .Location in patent: Page/Page column 35
[9]Journal of Medicinal Chemistry,2012,vol. 55,p. 2869 - 2881
[10]Patent: WO2012/118492,2012,A1 .Location in patent: Page/Page column 50
[11]Patent: WO2013/71865,2013,A1 .Location in patent: Page/Page column 37
[12]Patent: CN103102349,2017,B .Location in patent: Paragraph 0270-0272
[13]Patent: WO2009/111277,2009,A1 .Location in patent: Page/Page column 42-43
[14]Patent: WO2009/111280,2009,A1 .Location in patent: Page/Page column 42
[15]Patent: WO2009/111279,2009,A1 .Location in patent: Page/Page column 69-70

44
[ 13528-93-3 ]
[ 57946-56-2 ]
C₁₂H₁₉ClFNSi₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-fluoro-4-chloroaniline With n-butyllithium In tetrahydrofuran; hexane Inert atmosphere; Cooling with acetone-dry ice; Stage #2: 1,2-bis-(chlorodimethylsilyl)ethane In tetrahydrofuran; hexane Inert atmosphere; Cooling with acetone-dry ice; Stage #3: With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere;	7.1 Example 7; Synthesis of propane-1-sulfonic acid [2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-phenyl]-amide P-0008; Propane-1-sulfonic acid [2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-phenyl]-amide P-0008 was prepared in nine steps from 4-chloro-2-fluoro-phenylamine 11 as shown in Scheme 5.; Step 1-Preparation of 3-Amino-6-chloro-2-fluoro-benzoic acid benzyl ester (12); To 4-chloro-2-fluoro-phenylamine (11, 6.30 mL, 57.0 mmol) in 300 mL of tetrahydrofuran, cooled with dry ice/acetone bath under an atmosphere of nitrogen, n-butyllithium (2.50 M in hexane, 24.4 mL) was added slowly. After 20 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (12.9 g, 60.0 mmol) dissolved in 40.0 mL of tetrahydrofuran was added slowly to the reaction. After 1 hour, n-butyllithium (2.50 M in hexane, 25.0 mL) was added slowly to the reaction. The reaction was stirred at -78° C., for 20 minutes and then allowed to warm to room temperature over 60 minutes. The reaction was cooled to -78° C., followed by slowly adding n-butyllithium (2.50 M in hexane, 26.0 mL). After 80 minutes, benzyl chloroformate (10.0 mL, 70.0 mmol) was added to the reaction. The reaction mixture was stirred at -78° C. overnight followed by addition of 80 mL of water and 25 mL of concentrated hydrochloric acid. The reaction was allowed to warm to room temperature for 2 hours. The organic layer was separated and the aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a colorless oil (12, 12.5 g, 78.3%). MS (ESI) [M+H+]+=280.0.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2009/306087, 2009, A1 Location in patent: Page/Page column 42-43

45
[ 57946-56-2 ]
(4-chloro-2-fluorophenyl)hydrazine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97.2%		General procedure: As shown in FIG. 1, the raw material 1 (acidic liquids of aniline) and raw material 2 (NaNO2 aqueous solution with mass concentration of 20%) were fed to temperature section 1 with constant-flow pump, and the diazotization of aniline completed while the materials flowed past the temperature section 1. The raw material 3 (Na2SO3 aqueous solution with mass concentration of 19%) was fed to temperature section 2 with constant-flow pump for preheating, then mixed with diazonium salt formed through temperature section 1 in temperature section 3, flowed through temperature section 3 until the reaction was completed. The reaction solution from temperature section 3 flowed into temperature section 4 after mixed with raw material 4 (acid), and the reaction completed while flow through temperature section 4. The reaction mixture was collected, crystallization by cooling the temperature, after filtration and drying to get the phenylhydrazine salts product. Reaction parameters and results were as follows:
62%		Stepl; (4-Chloro-2-fluorophenyl)-hydrazine: A flask was charged 4-chloro-2-fluoroanaline (5.09 g, 35.0 mmol), followed by dropwise addition of concentrated HCl solution (30.0 mL) at 0 C. The solution was stirred for 5 min at 0 C, then was added sodium nitrite (2.42 g, 35.1 mmol) in water (10.0 mL). The reaction was allowed to stir at room temperature for 30 min, then was cooled to 0 0C and was added tin (II) chloride dihydrate (15.9 g, 70.0 mmol) in a minimum amount of concentrated HCl solution. The reaction was stirred at 0 C for 30 min, then room temperature for 4 hr. The reaction mixture was filtered and the solids were washed with cold ethanol. The solvent was removed in vacuo. The crude product was used directly in the next step without further purification (5.10 g, 62%). IH NMR CD3OD delta 7.33-7.28 (m, IH), 7.26-7.23 (m, IH), 7.15-7.09 (m, IH); MS (ES, m/z) 161 M+H+.

Reference： [1]Patent: US2019/152896,2019,A1 .Location in patent: Paragraph 0129; 0140
[2]Patent: WO2010/53861,2010,A2 .Location in patent: Page/Page column 44-45

46
[ 31970-04-4 ]
[ 57946-56-2 ]
[ 100-52-7 ]
[ 1061340-05-3 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid In acetonitrile at 5℃; for 1h;	1.a Benzaldehyde (2.1 mmol) and the Z-protected unit (1.5 mmol) are dissolved in acetonitrile and cooled to 5° C. Aniline (2.1 mmol) is dissolved in acetonitrile trifluoroacetic acid (2.1 mmol) is subsequently added, cooled to 5° C. and added to the benzaldehyde solution. After stirring at 5° C. for 1 h, the solvent is removed. The crude product is purified by preparative HPLC (Merck Chromolith C-18 column, 25*100 mm, solvent: acetonitrile/water 0.1% of formic acid, gradient: 40% of acetonitrile/60% of water-100% of acetonitrile in 40 minutes). 2 diastereomers in the ratio 3/1 are obtained. The HPLC solvents are removed.

Reference： [1]Current Patent Assignee: MERCK KGAA - US2010/120818, 2010, A1 Location in patent: Page/Page column 14-15

47
[ 57946-56-2 ]
[ 110-13-4 ]
1-(4-chloro-2-fluorophenyl)-2,5-dimethyl-1H-pyrrole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With toluene-4-sulfonic acid; In toluene; for 2h;Reflux;	Example 1 Preparation of 1-(4-chloro-2-fluorophenyl)-2,5-dimethyl-1H-pyrrole (Formula V) To a 5 L three-necked reaction flask equipped with a water segregator was added <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (598 g, 4.11 mol), 2,5-hexanedione (518 g, 4.54 mol) and toluene (3.0 L), and stirred for 10 minutes until the system was uniformly mixed. A catalytic amount of p-toluenesulfonic acid (1.4 g) was added, and heated under reflux for 2 hours. After cooling to room temperature, the system was washed successively with water (1 L) and saturated brine (1 L), and was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed through concentration in vacuo. The resulting residue was concentrated under reduced pressure to obtain a colourless and clear liquid (850 g, 92% yield). The liquid product was rapidly solidified upon cooling. 1H NMR (CDCl3):delta7.28-7.18 (3H, m), 5.93 (2H, s), 2.00 (6H, s).

Reference： [1]Patent: US2018/346418,2018,A1 .Location in patent: Paragraph 0166-0168
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6739 - 6745

48
[ 57946-56-2 ]
[ 31519-22-9 ]
[ 1387566-92-8 ]

Yield	Reaction Conditions	Operation in experiment
31%	With Novozym 51003; In N,N-dimethyl-formamide; at 40℃; for 48h;pH 6.0;aq. phosphate buffer; Enzymatic reaction;	General procedure: Novozym 51003 (1.0 mL) was added to a mixture containing amine (1.8 mmol, 2 equiv), 1,4-dihydroxy-2-naphthoic acid (0.9 mmol), sodium phosphate buffer (3.0 mL, 0.01 M, pH 6.0) and DMF (1.0 mL) while stirring at 40 C. After heating for 2 h more enzyme (1.0 mL) was added. More enzyme (0.5 mL) was again added after 24 h. After heating for 48 h the reaction mixture was transferred to a separating funnel to which water (25 mL) was added. The mixture was extracted with EtOAc, the solvent evaporated and the residue purified by flash chromatography. The product was then washed with a 25% Et2O/hexane solution.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 4472 - 4481

49
[ 57946-56-2 ]
[ 1655-07-8 ]
[ 1322474-37-2 ]

Yield	Reaction Conditions	Operation in experiment
45%		Example 286-Chloro-8-fluoro-l-(trifluoromethyl)-2,3,4,9-tetrahydro-lH-carbazol-l-oIIntermediate 28a2-(2-(4-Chloro-2-fluorophenyl) hydrazono) cyclohexanoneTo <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (2.7 g, 19.0 mmol) in H20 (12 mL), cooled to 0 C, cone. HCl (4.5 mL) was added and stirred for 10 min. NaN02 (1.3 g, 18.8 mmol), dissolved in water (13 mL), was added slowly to the reaction mixture and stirred at 0 C for an additional 30 min., the solids were filtered to give the diazonium salt. In another set up, to ethyl 2-oxocyclohexanecarboxylate (3 g, 19.3 mmol) in H20 (10 mL), 5N NaOH (5 mL) was added. The reaction mixture was stirred at room temperature for 24 h and washed with EtOAc (15 mL). The aqueous layer was separated, cooled to 0 C and cone. HCl (5 mL) was added dropwise to obtain 2-oxocyclohexanecarboxylic acid (2.7 g, crude). 2- oxocyclohexanecarboxylic acid (2.7 g, 19.0 mmol) and diazonium salt (prepared above) were mixed together at 0 C and the reaction mixture was slowly warmed to room temperature and stirred for 1 h during which time a solid precipitated out which was filtered, washed with hexane (20 mL) and air dried to give the title compound as a yellow solid (2.2 g, 45%). 1H NMR (200 MHz, CDC13, delta in ppm) 13.64 (bs, IH), 7.684 (t, J= 8.8Hz, IH), 7.10 (t, J=10.0 Hz, 2H), 2.74-2.67 (m, 2H), 2.56-2.50 (m, 2H), 1.90-1.83 (m, 4H).

Reference： [1]Patent: WO2011/97496,2011,A1 .Location in patent: Page/Page column 90-91

50
[ 57946-56-2 ]
(E)-N'-(2-cyano-6-methoxybenzofuran-3-yl)-N,N-dimethylformimidamide [ No CAS ]
[ 1422548-56-8 ]

Yield	Reaction Conditions	Operation in experiment
78%	With acetic acid; at 118℃; for 0.666667h;Microwave irradiation;	General procedure: A mixture of (E)-N?-(2-cyano-5-methoxybenzofuran-3-yl)-N,N-dimethylformimidamide (5) (0.1 g, 0.38 mmol) and appropriate aniline (1.0 equiv) in acetic acid (2 mL) was irradiated at 118 C (400 W). On completion (followed by thin-layer chromatography), the reaction was cooled to room temperature and water was added. The solid was filtered off, washed with water and dried. The crude solid was purified by column chromatography over silica gel using a gradient of petroleum ether/ethyl acetate (100:0 to 0:100, v/v) as the eluent to give the desired compounds (1b-z).

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 59,p. 283 - 295

51
[ 57946-56-2 ]
[ 14791-78-7 ]

Reference： [1]Organic Letters,2015,vol. 17,p. 5934 - 5937
[2]Organic Letters,2013,vol. 15,p. 3734 - 3737

52
[ 57946-56-2 ]
[ 69-72-7 ]
[ 1308631-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide

Reference： [1]Liou, Jun-Ting; Huang, Hsu-Shan; Chiang, Meng-Lin; Lin, Chin-Sheng; Yang, Shih-Ping; Ho, Ling-Jun; Lai, Jenn-Haung [European Journal of Pharmacology, 2014, vol. 726, # 1, p. 124 - 132]

53
[ 57946-56-2 ]
[ 64-19-7 ]
[ 59280-70-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	In acetic acid; at 25℃; for 2h;	As presented in the following reaction formula, anhydrous acetic acid (Ac2O; 1.7 mL) was added several times in a divided manner to a mixture of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (2 g, 13.8 mmol) in acetic acid (2 mL) at room temperature (about 25C). The resulting reaction mixture was stirred for 2 hours. After the completion of reaction, the mixture was filtered to obtain a crude product, which was washed with hexane to obtain N-(4-chloro-2-fluorophenyl)acetamide (2.4 g, yield: 94%). [0138] The N-(4-chloro-2-fluorophenyl)acetamide was analyzed through proton nuclear magnetic resonance (NMR) in deuterated chloroform (CDCl3) at 400 MHz and 25C. The obtained proton nuclear magnetic resonance spectrum is presented in FIG. 3.
	With acetic anhydride; at 25℃; for 2h;	As presented in the following reaction formula, anhydrous acetic acid (Ac2O; 1.7 mL) was added several times in a divided manner to a mixture of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (2 g, 13.8 mmol) in acetic acid (2 mL) at room temperature (about 25 C.). The resulting reaction mixture was stirred for 2 hours. After the completion of reaction, the mixture was filtered to obtain a crude product, which was washed with hexane to obtain N-(4-chloro-2-fluorophenyl)acetamide (2.4 g, yield: 94%). The N-(4-chloro-2-fluorophenyl)acetamide was analyzed through proton nuclear magnetic resonance (NMR) in deuterated chloroform (CDCl3) at 400 MHz and 25 C. The obtained proton nuclear magnetic resonance spectrum is presented in FIG. 3.

Reference： [1]Patent: EP2647622,2013,A1 .Location in patent: Paragraph 0137-0138
[2]Patent: US2013/317110,2013,A1 .Location in patent: Paragraph 0152; 0153

54
[ 57946-56-2 ]
[ 22494-42-4 ]
[ 1468402-79-0 ]

Yield	Reaction Conditions	Operation in experiment
30%	Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With thionyl chloride In tetrahydrofuran for 8h; Reflux; Inert atmosphere; Stage #2: 2-fluoro-4-chloroaniline In tetrahydrofuran for 14h;	1 N-(4-chloro-2-fluorophenyl)-2',4'-difluoro-4-hydroxybiphenyl-3-carboxamide (compound 1) Thionyl chloride (1 mL, 14 mmol) was added to disfunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus, which residue was used directly in the next step. Freshly prepared intermediate was directly reacted with 4-chloro-2-fluoroaniline (0.5 mL, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude product was washed and purified by crystallization from hot ethanol to afford compound 1. Yield: 30%. Mp: 245-246° C. (EtOH). 1H-NMR (300 MHz, DMSO-d6): δ ppm 7.12 (d, J=6.0 Hz, 1H, Ar-H5), 7.19 (td, J=9.0, 1.8 Hz, 1H, Ar-H6'), 7.31-7.40 (m, 2H, Ar-H5,6"), 7.55-7.64 (m, 3H, Ar-H6,3',5"), 8.14 (t, J=1.5 Hz, 1H, Ar-H2), 8.24 (t, J=8.7 Hz, 1H, Ar-H3"), 10.77 (s, 1H, NH), 12.19 (s, 1H, OH). HRMS (EI) m/z: calcd [M]+, 377.0430 (C19H11ClF3NO2+). found, 377.33.

Reference： [1]Current Patent Assignee: NATIONAL DEFENSE MEDICAL CENTER - US2013/281444, 2013, A1 Location in patent: Paragraph 0049-0052

55
[ 57946-56-2 ]
[ 1441-87-8 ]
[ 1308631-40-4 ]

Yield	Reaction Conditions	Operation in experiment
46%	In tetrahydrofuran for 12h; Reflux;
	In tetrahydrofuran for 14h;	1 N-(4-chloro-2-fluorophenyl)-2-hydroxybenzamide (compound 1a, NDMC101) To a solution of salicylic acid (1.38 g, 10 mmole) in tetrahydrofuran (40 mL) was added thionyl chloride (2.5 mL, 35 mmole) and refluxed 3 hr. The mixture was steamed (110° C.) by Dean-Stark. The residue was directly reacted with 4-chloro-2-fluorobenzenamine (1.1 mL, 10 mmole) in THF (40 mL) for 14 hr. The reaction mixture was concentrated and extracted with ethyl acetate, dried over anhydrous magnesium sulfate. Recrystallization of desired products from hot dichloromethane afforded the compound. The pure compound was obtained as white powder (yield 46%). Mp 184-185° C. 1H NMR (300 MHz, CDCl3): ppm 6.92-6.98 (m, 1H), 7.05 (dd, J=8.4, 1.2 Hz, 1H), 7.18-7.23 (m, 2H), 7.45-7.50 (m, 1H), 7.52 (dd, J=8.1, 1.5 Hz, 1H), 8.27-8.33 (m, 1H), 8.13 (br, 1H), 11.66 (s, 1H). HRMS (EI) m/z calcd for C13H9ClFNO2+ [M]+: 265.0306. Found: 265.0305.

Reference： [1]Chen, Chun-Liang; Liu, Fei-Lan; Lee, Chia-Chung; Chen, Tsung-Chih; Ahmed Ali, Ahmed Atef; Sytwu, Huey-Kang; Chang, Deh-Ming; Huang, Hsu-Shan [Journal of Medicinal Chemistry, 2014, vol. 57, # 19, p. 8072 - 8085]
[2]Current Patent Assignee: NATIONAL DEFENSE MEDICAL CENTER - US2013/281412, 2013, A1 Location in patent: Paragraph 0050; 0051

56
[ 2516-99-6 ]
[ 57946-56-2 ]
[ 1538626-78-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane;	Step 1: synthesis of N-(4-chloro-2-fluoro-phenyl)-3,3,3-trifluoro-propionamide 4-Chloro-2-fluoroaniline (3 g, 20.7 mmol), 3,3,3-trifluoropropanoic acid (2.6 g, 20.7 mmol) and Et3N (5.8 mL) were dissolved in 50 mL of DCM. To this solution was added HATU (8.6 g, 22.7 mmol) slowly and then stirred overnight. The organic phases was washed with aq. NH4Cl (50 mL), NaHCO3 solution (50 mL) and brine (100 mL). The combined organic phases were evaporated and purified by column chromatography (PE/EA=5/1) to give N-(4-chloro-2-fluorophenyl)-3,3,3-trifluoropropanamide which was pure enough for next step. (4.7 g, yield: 90%) was a yellow solid. MS obsd. (ESI+) [(M+H)+] 256.
90%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane;	4-Chloro-2-fluoroaniline (3 g, 20.7 mmol), 3,3,3-trifluoropropanoic acid (2.6 g, 20.7 mmol) and Et3N (5.8 mL) were dissolved in 50 mL of DCM. To this solution was added HATU (8.6 g, 22.7 mmol) slowly and then stirred overnight. The organic phases was washed with aq. NH4Cl (50 mL), NaHCO3 solution (50 mL) and brine (100 mL). The combined organic phases were evaporated and purified by column chromatography (PE/EA=5/1) to give N-(4-chloro-2-fluorophenyl)-3,3,3-trifluoropropanamide which was pure enough for next step. (4.7 g, yield: 90%) was a yellow solid. MS obsd. (ESI+) [(M+H)+] 256.
	With triethylamine; HATU; In dichloromethane;	Step 1: synthesis of N-(4-chloro-2-fluoro-phenyl)-3 ,3 ,3-trifluoro-propionamide 4-Chloro-2-fluoroaniline (3 g, 20.7 mmol), 3,3,3-trifluoropropanoic acid (2.6 g, 20.7 mmol) and Et3N (5.8 mL) were dissolved in 50 mL of DCM. To this solution was added HATU (8.6 g, 22.7mmol) slowly and then stuffed overnight. The organic phases was washed with aq. NH4C1 (50 mL), NaHCO3 solution (50 mL) and brine (100 mL). The combined organic phases were evaporated and purified by column chromatography (PE/EA = 5/1) to give N-(4-chloro-2- fluorophenyl)-3,3,3-trifluoropropanamide which was pure enough for next step. (4.7 g, yield:90%) was a yellow solid. MS obsd. (ESIj [(M+H)?i 256.

Reference： [1]Patent: US2015/158879,2015,A1 .Location in patent: Paragraph 0512; 0513
[2]Patent: US2016/200741,2016,A1 .Location in patent: Paragraph 0513-0514
[3]Patent: WO2014/9302,2014,A1 .Location in patent: Page/Page column 103; 104

57
[ 22131-92-6 ]
[ 57946-56-2 ]
N-(4-chloro-2-fluorophenyl)thietan-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
500 mg	With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 168h;	To a solution of 4-chloro-2-fluoroaniline (2.0 g, 13.7 mmol, CAS No.: 57946-56-2) in dichloromethane (20 mL) was added <strong>[22131-92-6]thietan-3-one</strong> (2.42 g, 27.4 mmol, CAS No.: 2213 1-92-6), sodium triacetoxyborohydride (5.8 g, 27.4 mmol) and acetic acid (2.47 g, 41.1 mmol). The resulting mixture was stuffed at room temperature for 7 days. The reaction mixture was washed with saturated aqueous solution of sodium bicarbonate (20 mL). The organic layer was dried over sodium sulfate and then concentrated in vacuo. The residue was purified by column chromatography to give 500 mg of N-(4-chloro-2-fluorophenyl)thietan-3-amine.

Reference： [1]Patent: WO2015/22263,2015,A1 .Location in patent: Page/Page column 57; 58

58
[ 57946-56-2 ]
[ 76-05-1 ]
[ 144181-67-9 ]

Yield	Reaction Conditions	Operation in experiment
69%	With Oxone; In 1,4-dioxane; at 90℃;Schlenk technique; Inert atmosphere;	General procedure: A Schlenk tube was charged with Oxone (0.398 g, 0.648mmol) and trifloroacetic acid (0.099 mL, 1.296 mmol) in anhydrous dioxane (2 mL) under argon. To this mixture was added 2-fluoroaniline (0.06 g, 0.54 mmol), and the reaction mixture was heated to 90 C under argon until starting material was consumed. As the reaction progressed, the color turned from lightred to dark red. The mixture was then cooled to room temperature and washed with a saturated aqueous sodium bicarbonate.The mixture was extracted with EtOAc (2 × 20 mL) and the combined organic layers were dried over Na2SO4. After filtering andremoval of the solvent under reduced pressure in vacuo, theresidue was purified by silica gel (100-200 mesh) column chromatography(hexane-EtOAc, 9:1), to afford a pale-brown solid(65%) of 2-hydroxy-N-trifluoroacetanilides from 2-fluoroaniline(2a).

Reference： [1]Synlett,2015,vol. 26,p. 1258 - 1262

59
[ 1074-12-0 ]
[ 57946-56-2 ]
[ 88333-03-3 ]
[ 611-73-4 ]
C₃₀H₂₁ClFN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%		General procedure: General procedures for compounds 10 and 15 are as follows:a solution of aldehyde (0.50 mmol) and amine (0.50 mmol)in MeOH (1 mL) was stirred at room temperature for 10min in a 5 mL microwave vial. Next, acid (0.50 mmol) andisonitrile (0.50 mmol) were added separately. The mixturewas stirred at room temperature overnight. The reaction wasmonitored by TLC and the solvent was removed under nitrogenblowing. The residue was dissolved in AcOH (3 mL)and NH4AcO (2.5 mmol, 193 mg) was added and thentreated in microwave (MW) at 150 C for 10 min. The solventwas removed under reduced pressure and the residuewas diluted with EtOAc (15 mL) and washed with sat. sodiumcarbonate and brine. The organic layer was dried overMgSO4 and concentrated. The residue was purified by silicagel column chromatography using a gradient of ethylacetate/hexane (1%-100%) to afford the relative products 9and 14a-14h.

Reference： [1]Science China Chemistry,2015,vol. 58,p. 1239 - 1242

60
[ 931-53-3 ]
[ 1074-12-0 ]
[ 57946-56-2 ]
[ 611-73-4 ]
C₂₉H₂₅ClFN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%		General procedure: General procedures for compounds 10 and 15 are as follows:a solution of aldehyde (0.50 mmol) and amine (0.50 mmol)in MeOH (1 mL) was stirred at room temperature for 10min in a 5 mL microwave vial. Next, acid (0.50 mmol) andisonitrile (0.50 mmol) were added separately. The mixturewas stirred at room temperature overnight. The reaction wasmonitored by TLC and the solvent was removed under nitrogenblowing. The residue was dissolved in AcOH (3 mL)and NH4AcO (2.5 mmol, 193 mg) was added and thentreated in microwave (MW) at 150 C for 10 min. The solventwas removed under reduced pressure and the residuewas diluted with EtOAc (15 mL) and washed with sat. sodiumcarbonate and brine. The organic layer was dried overMgSO4 and concentrated. The residue was purified by silicagel column chromatography using a gradient of ethylacetate/hexane (1%-100%) to afford the relative products 9and 14a-14h.

Reference： [1]Science China Chemistry,2015,vol. 58,p. 1239 - 1242

61
[ 57946-56-2 ]
C₁₃H₈Cl₂N₃O₄P [ No CAS ]
4-chlorophenyl N-(4-chloro-2-fluorophenyl)-P-(5-nitro-1H-indazol-1-yl)phosphonamidate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With N,N'-dimethylpiperazine; In tetrahydrofuran; at 50℃; for 4h;	General procedure: The mixture of 4-chlorophenyl-5-nitro-1H-indazol-1-ylphosphonochloridate (5)(1 mmol, 372 mg), tryptamine (6b) (1 mmol, 160 mg), and 1,4-dimethyl piperazine(DMPipz) (1.2 mmol, 0.16 mL) as a base in THF (10 mL) was stirred for 4 h at 50C. Theprogress of the reaction was monitored by TLC using chloroform:methanol (4:1). Aftercompletion of the reaction, DMPipz.HCl salt was removed by filtration and the filtratewas evaporated to obtain the crude product, 4-chlorophenyl N-2-(1H-indol-3-yl)ethyl-P-(5-nitro-1H-indazol-1-yl) phosphonamidate (7b). The crude product was purified bycolumn chromatography using chloroform:methanol (9:1) as an eluent and the samesynthetic procedure was adopted for the synthesis of remaining title products as shown inScheme 1.

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,2015,vol. 190,p. 1064 - 1075

62
[ 59-67-6 ]
[ 57946-56-2 ]
N-(4-chloro-2-fluorophenyl)nicotinamide [ No CAS ]