[ CAS No. 63069-50-1 ] {[proInfo.proName]}

Name: 63069-50-1|4-Amino-3-fluorobenzonitrile|97%
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SKU: A237657
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2D 3D

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Quality Control of [ 63069-50-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 63069-50-1 ]

SDS Specification

Alternatived Products of [ 63069-50-1 ]

Product Details of [ 63069-50-1 ]

CAS No. :	63069-50-1	MDL No. :	MFCD00055559
Formula :	C₇H₅FN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RLMBRRQWBTWGMB-UHFFFAOYSA-N
M.W :	136.13	Pubchem ID :	2756431
Synonyms :

Calculated chemistry of [ 63069-50-1 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	35.52
TPSA :	49.81 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 :	Yes
Log Kp (skin permeation) :	-6.31 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.24
Log Po/w (XLOGP3) :	1.16
Log Po/w (WLOGP) :	1.71
Log Po/w (MLOGP) :	1.22
Log Po/w (SILICOS-IT) :	1.5
Consensus Log Po/w :	1.37

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.86
Solubility :	1.88 mg/ml ; 0.0138 mol/l
Class :	Very soluble
Log S (Ali) :	-1.8
Solubility :	2.15 mg/ml ; 0.0158 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.37
Solubility :	0.578 mg/ml ; 0.00425 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.45

Safety of [ 63069-50-1 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P301+P312-P302+P352-P304+P340-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 63069-50-1 ]

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

Upstream synthesis route of [ 63069-50-1 ]
Downstream synthetic route of [ 63069-50-1 ]

[ 63069-50-1 ] Synthesis Path-Upstream 1~16

1
[ 367-24-8 ]
[ 63069-50-1 ]

Yield	Reaction Conditions	Operation in experiment
74.76%	at 200℃; Sealed tube	Step 1: Synthesis of 4-amino-3-fluorobenzonitrile To a solution of 4-bromo-2-fluorobenzenamine (3 g, 15.789 mmol) in NMP (6 mL) was added copper cyanide (2.8 g, 31.578 mmol) and heated overnight at 200° C. in a sealed tube. Progress of reaction was monitored by TLC. After reaction completion 1, 2-diaminoethane (3 mL) and reaction mixture was poured into water. Product was extracted with ethyl acetate and washed with 10percent 1, 2-diaminoethane solution in water and then with water. Organic layer was dried over sodium sulphate, concentrated under reduced pressure. Crude was purified by silica (100-200) column chromatography using 15percent ethyl acetate in hexane as eluent to give 4-amino-3-fluorobenzonitrile (1.6 g, 74.76percent) as white solid. MS: 137.1 [M+1]

Reference： [1] Patent: US2017/291894, 2017, A1, . Location in patent: Paragraph 0533-0535
[2] Patent: US4111681, 1978, A,
[3] Patent: US4120693, 1978, A,

2
[ 29632-74-4 ]
[ 544-92-3 ]
[ 63069-50-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	at 130℃; for 8 h;	Example 20: 2-[4-(fe/t-butyl)-phenoxy]-/V-(3-cyano-5-fluoro-4- methanesulfonylamino)benzylacetamideStep 1 : 4-Amino~3-fluorobenzenecarbonitrile; 2-Fluoro-2-iodoaniiine (2.Og, 8.4mmol) and coppercyanide (982mg, 11.0mmol, 1.5eq) were added into DMF (30ml). And the reaction mixture was heated to 130°C, stirred for 8hrs. The reaction mixture was diluted with ethyl acetate. A diluted solution was washed with H₂O (2 times) and brine, and then dried with MgSO₄. The resulting residue was purified with column chromatography (n-Hexane: EtOAc =3 : 1) to yield solid (914mg, 84percent). <n="84"/>¹H NMR (300 MHz, CDCI₃): 7.21-7.26 (m, 2H), 6.74 (t, 1H, J = 8.3 Hz), 4.20 (bs, 2H); Example 43: 2-[4-(fert-butyl)phenoxy]-/V-(3-cyano-5-fluoro-4- methylsulfonylaminobenzyl)-thioacetamidestep 1 : 4-amino-3-fluorobenzenecarbonitrile2-Fluoro-2-iodoaniline (2.Og, 8.4mmol) and coppercyanide(982mg, H .Ommol, 1.5eq) were added to DMF(30ml). A reaction mixture was heated to 13O⁰C, stirred for 8hrs. The reaction mixture was diluted with ethyl acetate. A diluted solution was washed with H₂O (2 times) and brine, and then dried with MgSO₄. A residue was purified with column chromatography (n-Hexane: EtOAc =3 : 1) to yield solid (914mg, 84percent). ¹H NMR(300MHz, CDCI₃): 7.21-7.26 (m, 2H), 6.74 (t, 1 H, J = 8.3 Hz), 4.20 (bs, 2H)

Reference： [1] Patent: WO2007/120012, 2007, A1, . Location in patent: Page/Page column 82-83; 129
[2] Patent: WO2006/63113, 2006, A2, . Location in patent: Page/Page column 68-69

3
[ 218632-01-0 ]
[ 63069-50-1 ]

Yield	Reaction Conditions	Operation in experiment
4.5 g	With hydrogenchloride; water; iron In methanol at 22 - 26℃; for 2 h;	To a solution of 3-fluoro-4-nitrobenzonitrile (5.0 g, 0.030 mmol) in MeOH (50 mL) were added iron powder (5 g) and conc.HC1 (20 mL). The reaction mass was stirred at RT for 2 h. The reaction mass was filtered. The filtrate was concentrated and then diluted with water, extracted with EtOAc and basified with 10percent NaHCO3 solution. The organic portion wasdried over Na2504 and concentrated to afford 4.5 g of the title product.’H NMR (300 MHz,DMSO-d6): 7.52-7.48 (d, J= 11.7 Hz, 1H), 7.31-7.29 (d, J= 8.1 Hz, 1H), 6.82.-6.76 (d, J=8.7 Hz, 1H), 6.24 (s, 2H).

Reference： [1] Patent: WO2016/55947, 2016, A1, . Location in patent: Page/Page column 56; 57

4
[ 29632-74-4 ]
[ 557-21-1 ]
[ 63069-50-1 ]

Reference： [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 18, p. 5823 - 5836

5
[ 367-24-8 ]
[ 63069-50-1 ]

Reference： [1] Patent: US5200110, 1993, A,
[2] Patent: US5238599, 1993, A,

6
[ 364082-48-4 ]
[ 63069-50-1 ]

Reference： [1] Patent: US2003/176480, 2003, A1,

7
[ 367-24-8 ]
[ 105-56-6 ]
[ 63069-50-1 ]

Reference： [1] Organic Letters, 2012, vol. 14, # 14, p. 3644 - 3647

8
[ 29632-74-4 ]
[ 63069-50-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 10, p. 3557 - 3567
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 24, p. 8149 - 8160

9
[ 75-09-2 ]
[ 3556-52-3 ]
[ 7439-89-6 ]
[ 121-44-8 ]
[ 63069-50-1 ]

Reference： [1] Patent: US5998424, 1999, A,

10
[ 63069-50-1 ]
[ 133059-44-6 ]

Yield	Reaction Conditions	Operation in experiment
34.7%	Stage #1: at 5 - 20℃; for 1 h; Stage #2: With hydrogen bromide; copper(I) bromide In water at 10 - 20℃;	Step 2: Synthesis of 4-bromo-3-fluorobenzonitrile To conc. sulphuric acid (6 mL) was added sodium nitrite (0.97 g, 14.117 mmol) portion wise at 5° C. and stirred for 30 min at RT. Mixture was cooled to 0° C. and acetic acid (9.8 mL) was added dropwise, stirred for 5 min and then 4-amino-3-fluorobenzonitrile (1.6 g, 11.764 mmol) was added in small portions. Mixture was stirred for 1 h at RT. Solution of copper (I) bromide (2.5 g, 17.647 mmol) in aq. HBr (6 mL) was then added at 10° C. The resulting mixture was stirred overnight at RT. Progress of reaction was monitored by TLC. After reaction completion water was added and extracted with diethyl ether. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. Crude was purified by silica (100-200) column chromatography using 2percent ethyl acetate in hexane as eluent to give 4-bromo-3-fluorobenzonitrile (0.8 g, 34.7percent) as white solid. MS: 201.1 [M+1]

Reference： [1] Patent: US2017/291894, 2017, A1, . Location in patent: Paragraph 0536-0538

11
[ 63069-50-1 ]
[ 7787-70-4 ]
[ 133059-44-6 ]

Reference： [1] Patent: US5200110, 1993, A,

12
[ 63069-50-1 ]
[ 140-89-6 ]
[ 315228-79-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	at 120 - 130℃; Inert atmosphere	General procedure: A round-bottomed flask was charged with 2-bromoaniline or 2-fluoro-aniline (>3 g, 1.0 equiv) and potassium O-ethyl carbonodithioate(1.5–1.7 equiv). The mixture was dissolved in DMF (10 volumes) andheated to 120–130 °C until the aniline was fully consumed (3–14 h).The reaction mixture was cooled to r.t. and filtered. The filtrate wasdiluted with H 2 O (50 volumes) and the pH was adjusted to 1–2 usingaqueous 2 M HCl. The solid precipitate was collected, washed withH 2 O and dried to yield the pure product.

Reference： [1] Synthesis (Germany), 2018, vol. 50, # 10, p. 2027 - 2032

13
[ 63069-50-1 ]
[ 80945-83-1 ]

Reference： [1] Synthesis (Germany), 2018, vol. 50, # 10, p. 2027 - 2032

14
[ 63069-50-1 ]
[ 887266-99-1 ]

Yield	Reaction Conditions	Operation in experiment
4.0 g	Stage #1: With toluene-4-sulfonic acid In acetonitrile at 22 - 26℃; for 4 h; Stage #2: With potassium iodide; sodium nitrite In water; acetonitrile at 0℃; for 1 h;	A mixture of 4-amino-3-fluorobenzonitrile (5.0 g, 36.76 mmol) and p-toluenesulfonic acid (20.0 g, 105.2 mmol) in acetonitrile (50 mL) was stirred at RT for 4 h. Then aq. solution of NaNO2 (3.8 g, 55.07 mmol) and KI (9.15 g, 55.07 mmol) were added at 0°C and stirred further for lh. After the reaction completion, the reaction mixture was quenched with water, washed with an aqueous solution of NaHSO3 and extracted with EtOAc. The organic layerwas washed with water, brine, dried over Na2SO4 and concentrated to afford 4.0 g of the title product. ‘H NMR (300 MHz, CDC13): 7.94-7.89 (t, J = 8.4 Hz, 1H), 7.34-7.32 (d, J = 7.5 Hz, 1H), 7.21-7.19 (d, J= 8.1 Hz, 1H).

Reference： [1] Patent: WO2016/55947, 2016, A1, . Location in patent: Page/Page column 57
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 23-24, p. 3766 - 3773

15
[ 63069-50-1 ]
[ 1147558-43-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-chloro-succinimide In acetonitrile at 85℃; for 5 h;	4-Amino-3-chloro-5-fluorobenzonitrile A mixture of 4-amino-3-fluorobenzonitrile (1 equiv.) and N-chlorosuccinimide (1.5 equiv.) in acetonitrile (0.24 M) was stirred at 85° C. for 5 h. The solvent was removed by concentration and the residue was partitioned between ethyl acetate and 5percent NaOH. The organic phase was washed with 5percent NaOH and brine. Then the organic phase was dried over MgSO₄ and dried in vacuum to afford 4-amino-3-chloro-5-fluorobenzonitrile (88percent) as a beige solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.41 (t, J=6 Hz, 1H), 7.24 (dd, J=1.8, 10.2 Hz, 1H), 4.66 (s, 2H).

Reference： [1] Patent: US2016/96841, 2016, A1, . Location in patent: Paragraph 0281
[2] Patent: WO2012/174342, 2012, A1, . Location in patent: Page/Page column 45
[3] Patent: WO2013/12500, 2013, A1, . Location in patent: Page/Page column 61
[4] Patent: US2015/203455, 2015, A1, . Location in patent: Paragraph 0457-0458
[5] Patent: WO2015/110378, 2015, A1, . Location in patent: Paragraph 00260; 00312
[6] Patent: US9440929, 2016, B2, . Location in patent: Page/Page column 59
[7] Patent: WO2017/12647, 2017, A1, . Location in patent: Paragraph 0688

16
[ 63069-50-1 ]
[ 1310918-28-5 ]

Reference： [1] Patent: WO2012/174342, 2012, A1,

[ 63069-50-1 ] Synthesis Path-Downstream 1~79

1
[ 63069-50-1 ]
[ 162364-72-9 ]
[ 413599-60-7 ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 1300 - 1312

2
[ 29632-74-4 ]
[ 557-21-1 ]
[ 63069-50-1 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 5823 - 5836

3
[ 63069-50-1 ]
[ 849353-46-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	With Iodine monochloride; In dichloromethane; for 20h;	Step 2: 4-Amino-3-fluoro-5-iodobenzenecarbonitrile; 4~Amino~3-fluorobenzenecarbonitrile (4.06g, 29.9mmol) and ICI(LOM in methylene chloride, 40.0 ml, 40.0mmol) were added into methylene chloride (100ml). And the reaction mixture was stirred for 20 hrs. The reaction was quenched by adding sodium thiosulfate solution, and the aqueous solution was extracted with MC. The combined organic solution was washed with H2O and brine, dried with Na2SO4, and then concentrated in vacuo. A residue was purified with column chromatography (n-Hexane: EtOAc = 5: 1) to yield solid (4.8Og, 91 %). 1H-NMR (300MHz, CDCI3): delta 7.69 (t, 1 H, J = 1.5 Hz), 7.23 (del, 1 H, J = 10.0, 1.7 Hz), 4.68 (bs, 2H); step 2: 4-amino-3-fluoro-5-iodobenzenecarbonitrile <n="131"/><strong>[63069-50-1]4-amino-3-fluorobenzenecarbonitrile</strong> (4.06g, 29.9mmol) and ICI (1.0M in methylene chloride, 40.0 ml, 40.0mmol) were added to methylene chloride (100ml). A reaction mixture was stirred for 20hrs. A reaction was quenched by adding sodium thiosulfate solution. An aqueous solution was extracted with MC. A combined organic solution was washed with H2O and brine, dried with Na2SOzJ, concentrated in vacuo. The residue was purified with column chromatography (n-Hexane: EtOAc = 5: 1) to yield solid (4.8Og, 91%). 1H-NMR (300MHz, CDCI3): 57.69 (t, 1 H1 J = 1.5 Hz), 7.23 (dd, 1 H, J = 10.0, 1.7 Hz), 4.68 (bs, 2H)
54%	With Iodine monochloride; In dichloromethane; at 20℃;	To a solution of reagent 1 (13 g, 0.096 mol) in 200 mL of CH2CI2 was added ICI (20 g, 0.12 mol) at room temperature. The mixture was stirred at room temperature overnight. The mix- ture was evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 50:1 ) gave reagent 2 (13.6 g, 54%). 1H NMR (CDCI3) delta 7.72 (t, 1 H), 7.24-7.27 (m, 1 H), 4.70 (br s, 2 H).
	With iodine; silver sulfate; In ethanol; at 20℃; for 1.5h;	General procedure: 1.4.2. Illustrative example of method A1: synthesis of 4-Amino-3-fluoro-5-iodo-benzonitrile (Int.4) A mixture of <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (147 mmol), I2 (147 mmol) and Ag2SO4 (147 mmol) in EtOH (700 mL) was stirred at room temperature for 1.5 h. The mixture was filtered and concentrated. The residue was dissolved in EtOAc and washed (sat. Na2S2O3*3). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (SiO2, 95:5 to 70:30 cyclohexane/EtOAc) to yield the desired product.

	With iodine; silver sulfate; In ethanol; at 20℃; for 1.5h;	General procedure: 1.4.1. MethodAlj00243j A mixture of the amino aromatic or heteroaromatic starting material (1 eq), Ag2SO4 (1 eq) and 12 (1 eq) in EtOH is stirred at temperatures ranging from room temperature to 50C for a period which can vary from 1 h to approximately 16 h. The mixture is filtered, concentrated and diluted in an organic solvent. The organic mixture undergoes aqueous work up. The solvent is removed under reduced pressure and the residue is purified by flash column chromatography to yield the desired product.1.4.2. Illustrative example ofmethodAl: synthesis of 4-Amino-3-fluoro-5-iodo-benzonitrile (Int.4).N NH2 NI H2j00244j A mixture of <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (147 mmol), 12 (147 mmol) and Ag2SO4 (147 mmol) in EtOH (700 mL) was stirred at room temperature for 1.5 h. The mixture was filtered and concentrated. The residue was dissolved in EtOAc and washed (sat. Na2S2O3 x 3). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (Si02, 95:5 to 70:3 0 cyclohexane/EtOAc) to yield the desired product.
	With iodine; silver sulfate; In ethanol; at 20℃; for 1.5h;	General procedure: A mixture of <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (147 mmol), 12(147 mmol) and Ag2504 (147 mmol) in EtOH (700 mE) wasstirred at room temperature for 1 .5 h. The mixture was filtered and concentrated. The residue was dissolved in EtOAc and washed (sat. Na25203x3). The organic layer was dried (Na2504) and concentrated. The residue was purifiedby flash colunm chromatography (SiO2, 95:5 to 70:30 cyclohexane/EtOAc) to yield the desired product.
	With iodine; silver sulfate; In ethanol; at 20℃;	1.6.1. Step i): 2,4-Difluoro-6-iodoaniline Iodine (1 eq, 19.7 g) is dissolved in EtOH (350 mL) at room temperature, and 2,4-difluoroaniline (1 eq, 8 mL) and silver sulfate (1 eq, 24.1 g) are added. The suspension is stirred at room temperature overnight. After completion of the reaction as seen by LC-MS, the silver salts are filtered off and the filtrate is concentrated in vacuo. The residue is dissolved in DCM and washed with sat. Na2S203 (3 x 100 mL). The organic layer is washed with sat. brine, dried over anhydrous sodium sulfate, and purified by column chromatography (silica, petroleum ether/EtOAc; 100:0 to 95:5) to give the desired product.
	With N-iodo-succinimide; trifluoroacetic acid; In tetrahydrofuran; at 20℃; for 24h;	To a solution of 4-Amino-3-fluoro-benzonitrile (4.00 g, 29.4 mmol, 1.0 eq) and NIS (6.64 g, 29.4 mmol, 1.0 eq) in dry THF (90 mL) was added TFA (680 jiL, 8.84 mmol, 0.3 eq). Reaction mixture was stirred at room temperature for 24h. It was then quenched with saturated NaHCO3 solution followed by extraction with DCM. Resulting organic layer washed with brine, dried over Na2SO4 and concentrated to dryness to afford the desired product. This was used as such in the next step. LCMS: m/z = 263 [M+H].

Reference： [1]Patent: WO2007/120012,2007,A1 .Location in patent: Page/Page column 83; 129-130
[2]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 3557 - 3567
[3]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 8149 - 8160
[4]Patent: WO2014/49133,2014,A1 .Location in patent: Page/Page column 40
[5]Patent: US2015/203455,2015,A1 .Location in patent: Paragraph 0430-0433
[6]Patent: WO2015/110378,2015,A1 .Location in patent: Paragraph 00243; 00244; 00312
[7]Patent: US9440929,2016,B2 .Location in patent: Page/Page column 54
[8]Patent: WO2017/12647,2017,A1 .Location in patent: Paragraph 0240
[9]Patent: WO2019/76716,2019,A1 .Location in patent: Paragraph 0280

4
[ 849345-19-3 ]
[ 63069-50-1 ]
(4S)-4-({4-[(4-cyano-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N,N,1-trimethyl-D-prolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; acetonitrile; at 65℃; for 3h;	Example 4 HCl in Dioxan (4. 0M, 0. 4ml) was added to a stirred solution of (13) (200 mg) 4- amino-3-fluorobenzonitrile (83 mg) in acetonitrile (10 RRA) and the reaction mixture was heated at 65C for 3 hours. The resulting precipitate was filtered, washed with acetonitrile then diethyl ether and dried under vacuum to give the title compound as a beige powder solid HCl salt, (210 MG). LH NMR Spectrum : (DMSO D6 + CD3CO2D) 2.55-2. 69 (M, 1H), 2.75-2. 88 (M, 1H), 2.92 (s, 3H), 2.95 (s, 3H), 2.98 (s, 3H), 3.50-3. 57 (M, 1H), 4.01 (s, 3H), 4.29 (dd, 1H), 4.94 (dd, 1H), 5.47 (M, 1H), 7.47 (s, 1H), 7.74-7. 86 (M, 2H), 8.04 (d, 1H), 8.66 (M, 1H), 8.86 (s, 1H) Mass Spectrum : (M+H) +465. The starting material L-PYRROLIDINECARBOXYLIC acid, 2-[(DIMETHYLAMINO) CARBONYL]-4- hydroxy-, 1, 1-dimethylethyl ester, (2R, 4R)- (9) was prepared as follows : 1- [3- (DIMETHYLAMINO) PROPYL]-3-ETHYLCARBODIIMIDE HYDROCHLORIDE (25.53 g) was added to a stirred suspension of BOC-D-CIS-HYP-OH, 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-1- (1, 1-dimethylethyl) ester, (2R, 4R) (1) (22.0 g), DIMETHYLAMINOPYRIDINE (58. 11 g) and DIMETHYLAMINE hydrochloride (15.3 g) in methylene chloride (600 ML) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with citric acid (1.0 M), saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulphate and filtered. The organic phase was then purified by column chromatography on silica eluting with increasingly polar mixtures OF METHANOL/METHYLENE chloride (1/99-5/95). The desired product fractions were combined and evaporated to give (9) as a white crystalline solid, (16.95 G). LH NMR Spectrum : (DMSO D6) 1.30 + 1.38 (2s, 9H), 1.50-1. 61 (M, 1H), 2. 31-2. 42 (m, 1H), 2.83 + 3.02 (2M, 6H), 3.08-3. 15 (M, 1H), 3.46- 3.58 (M, 1H), 4.09-4. 18 (M, 1H), 4.53-4. 61 (M, 1H), 5.15-5. 22 (M, 1H). Starting material Boc-D-cis-hyp-OH (1), 1, 2-PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy- 1- (1, 1-DIMETHYLETHYL) ester, (2R, 4R) is commercially available The starting material (10) was prepared as follows: TFA (20 ML) was added to a stirred solution of L-PYRROLIDINECARBOXYLIC acid, 2- [ (DIMETHYLAMINO) CARBONYL] -4-HYDROXY-, 1, 1-DIMETHYLETHYL ESTER, (2R, 4R)- (9) (SG) IN METHYLENE chloride (20 ML) at 25C under an atmosphere of nitrogen and the reaction mixture was stirred for 1.5 hours. The reaction mixture was then reduced in vacuo and triturated with diethyl ether to give the TFA salt of (4R)-4-HYDROXY-N, N-DIMETHYL-D-PROLINAMIDE (10) as a white solid. (4.83 G) 1H NMR Spectrum : (DMSO D6) 1.68-1. 77 (M, 1H), 2.56-2. 67 (M, 1H), 2.90 (s, 3H), 2.95 (s, 3H), 3.16-3. 20 (m, 2H), 4.37 (M, 1H), 4.52-4. 58 (M, 1H), 5.32 (M, 1H). The starting material (4R)-4-HYDROXY-N, N, L-TRIMETHYL-D-PROLINAMIDE (4) was prepared as follows: Platinum oxide was added to a solution of (4R)-4-HYDROXY-N, N-DIMETHYL-D- prolinamide (10) (4.83g) in formaldehyde (37 wt % solution in water) (3g), water (16 ML) and acetic acid (30 ML) under an atmosphere of nitrogen. The reaction was then purged with hydrogen and stirred vigorously for 16 hours. The reaction mixture was filtered through celite and reduced in vacuo. The residue was dissolved in methylene chloride and dried over magnesium sulphate. Potassium carbonate (7g) was added and the mixture stirred for one hour. The crudes were filtered and purified by column chromatography on silica eluting with increasingly polar mixtures of methanol (saturated with AMMONIA)/METHYLENE chloride (5/95- 15/85). The fractions containing the desired product were combined and reduced in vacuo to give (4R)-4-hydroxy-N, N, l-trimethyl-D-prolinamide (11) as a colourless oil. (2. 57G). 1H NMR Spectrum : (DMSO D6) 1. 51-1. 60 (M, 1H), 2.17 (s, 3H), 2.28-2. 39 (m, 2H), 2.79-2. 86 (M, 4H), 3.06 (s, 3H), 3.17 (t, 1H), 4.10-4. 19 (M, 1H), 4.80 (d, 1H). The starting material (45)-4- [ (4-CHLORO-7-METHOXYQUINAZOLIN-6-YL) OXY]-N, N, 1- trimethyl-D-prolinamide (13) was prepared as follows: Di-ethyl azodicarboxylate (1.38g) was added slowly to a stirred suspension of (4R)-4- hydroxy-N, N, L-TRIMETHYL-D-PROLINAMIDE (11) (1. OG), 4-CHLORO-7-METHOXYQUINAZOLIN-6-OL (3) (1. 1 LG) AND TRIPHENYLPHOSPHINE (2.07g) IN METHYLENE CHLORIDE (60 ML) AT 25C under an atmosphere of nitrogen and the reaction mixture was stirred for 2 hours. The reaction mixture was then reduced in vacuo to 1/2 volume, applied to a silica flash column and eluted with increasingly polar mixtures OF METHANOL/METHYLENE chloride (5/95-10/90). The fractions containing the desired product were combined and evaporated to give (4S)-4-[(4-CHLORO-7- METHOXYQUINAZOLIN-6-YL) oxy]-N, N, L-TRIMETHYL-D-PROLINAMIDE (13) as a colourless foam. (1.6g). H NMR Spectrum : (DMSO d6) 2.09-2. 20 (M, 1H), 2.25 (s, 3H), 2.28-2. 40 (M, 1H), 2.60 (M, 1H), 2.81 (s, 3H), 3.02 (s, 3H), 3.52 (M, 1H), 3.74 (m, 1H), 3.98 (s, 3H), 5.12-5. 20 (M, 1H), 7.28 (s, 1H), 7.41 (s, 1H), 8.83 (s, 1H) ; Mass SPECTRUM : (M+H) + 365.

Reference： [1]Patent: WO2005/30757,2005,A1 .Location in patent: Page/Page column 110-112

5
[ 63069-50-1 ]
[ 28920-43-6 ]
[ 871681-48-0 ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium hydrogencarbonate; In acetonitrile; at 0 - 20℃; for 16h;	A mixture of 2.05 g (15.06 mmol) <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> and 2 g (23.8 mmol) sodium bicarbonate in 30 mL acetonitrile was cooled in an ice-bath and 4.4 g (17.0 mmol) FMOC-Cl were added. Mixture was allowed to warm to room temperature. After 16 h, mixture was concentrated and extracted with 1M HCl and ethyl acetate. Combined organic phases were dried over magnesium sulfate, filtered, and concentrated. Crystallization out of ethyl acetate/hexane gave (4-cyano-2-fluoro- phenyl) -carbamic acid 9H-fluoren-9-ylmethyl ester as a white solid (2.68 g, 50%). ¹HNMR (CDCl3, 400 MHz) d 4.21-4.24 (t, 1H), 4.50-4.54 (d, 2H), 6.99 (s br, 1H), 7.19-7.32 (m, 6H), 7.48-7.58 (m, 2H), 7.67-7.74 (m, 2H), 8.16 (s br, 1H). Exact mass calculated for C22H15FN202 3 5 8.11, found 3 5 8.9 (MH+).

Reference： [1]Patent: WO2005/121121,2005,A2 .Location in patent: Page/Page column 140-141

6
[ 29632-74-4 ]
[ 544-92-3 ]
[ 63069-50-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	In N,N-dimethyl-formamide; at 130℃; for 8h;	Example 20: 2-[4-(fe/t-butyl)-phenoxy]-/V-(3-cyano-5-fluoro-4- methanesulfonylamino)benzylacetamideStep 1 : 4-Amino~3-fluorobenzenecarbonitrile; 2-Fluoro-2-iodoaniiine (2.Og, 8.4mmol) and coppercyanide (982mg, 11.0mmol, 1.5eq) were added into DMF (30ml). And the reaction mixture was heated to 130C, stirred for 8hrs. The reaction mixture was diluted with ethyl acetate. A diluted solution was washed with H2O (2 times) and brine, and then dried with MgSO4. The resulting residue was purified with column chromatography (n-Hexane: EtOAc =3 : 1) to yield solid (914mg, 84%). <n="84"/>1H NMR (300 MHz, CDCI3): 7.21-7.26 (m, 2H), 6.74 (t, 1H, J = 8.3 Hz), 4.20 (bs, 2H); Example 43: 2-[4-(fert-butyl)phenoxy]-/V-(3-cyano-5-fluoro-4- methylsulfonylaminobenzyl)-thioacetamidestep 1 : 4-amino-3-fluorobenzenecarbonitrile2-Fluoro-2-iodoaniline (2.Og, 8.4mmol) and coppercyanide(982mg, H .Ommol, 1.5eq) were added to DMF(30ml). A reaction mixture was heated to 13O0C, stirred for 8hrs. The reaction mixture was diluted with ethyl acetate. A diluted solution was washed with H2O (2 times) and brine, and then dried with MgSO4. A residue was purified with column chromatography (n-Hexane: EtOAc =3 : 1) to yield solid (914mg, 84%). 1H NMR(300MHz, CDCI3): 7.21-7.26 (m, 2H), 6.74 (t, 1 H, J = 8.3 Hz), 4.20 (bs, 2H)
	In N,N-dimethyl-formamide; for 5h;Heating / reflux;	EXAMPLE 33; N-[4-(dimethylaminoimino)-2-fluoroplienyl]-2-plienyl-2-(4- chlorophenylaminocarbonylamino)-acetamide; A. 4-amino-3-fluoro-benzonitrile; [0346] A mixture of 2-fluoro-4-iodoaniline (10.0 g, 42.2 mmol) and CuCN (7.56 g, 84.4 mmol) in DMF (40 mL) was heated at reflux for 5h. After being cooled down, EtOAc and IN HCl were added. The mixture was filtered through celite. The organic phase was separated, washed sequentially with IN HCl and brine. It was then dried over MgSO4, concentrated in vacuo to give a brown solid (5.69 g), which was pure enough for the next step. MS 137.1 (M+H).

Reference： [1]Patent: WO2007/120012,2007,A1 .Location in patent: Page/Page column 82-83; 129
[2]Patent: WO2006/63113,2006,A2 .Location in patent: Page/Page column 68-69

7
[ 63069-50-1 ]
[ 2835-06-5 ]
C₁₅H₁₂FN₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; trichlorophosphate; at 0℃; for 3h;	B. N-[4-(dimethylaminoimino)-2-fluorophenyl]-2-phenyl-2-(4- chlorophenylaminocarbonylamino)-acetamide; [0347] To a solution of DL-phenylglycine (2.51 g, 10.0 mmol) and 4-amino-3-fluoro- benzonitrile (1.36 g, 10.0 mmol) in pyridine (25 mL) cooled in an ice-bath, POCl3 (2.30 mL, 25.0 mmol) was added. The mixture was stirred for 3h. EtOAc and H2O were added. The organic layer was separated, washed with brine, dried over MgSO4, concentrated in vacuo to give a solid (3.15 g), which was pure enough for the next step.[0348] To a solution of the solid (1.50 g, 4.06 mmol) in CH2Cl2 (10 mL), TFA (6 mL) was added. After it was stirred for 30 min, it was then concentrated in vacuo. The residue was dissolved in THF (15 mL). To the solution, TEA (1.09 mL, 7.84 mmol) was added, followed by addition of 4-chlorophenylisocyanate (0.626 g, 4.07 mmol). After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by HPLC to give a powder (0.842 g). MS 423.1 (M+H) and 445.1 (M+Na).[0349] To a solution of the powder (0.842 g, 1.99 mmol) in pyridine (10 mL) and TEA (1.0 mL), H2S gas was bubbled until saturation was reached. The solution was then stirred at room temperature overnight. It was concentrated in vacuo. The residue was dissolved in acetone (10 mL). Iodomethane (0.620 mL, 9.95 mmol) was added. It was heated at reflux for 30 min, EPO <DP n="70"/>then concentrated in vacuo. The residue was dissolved in MeOH (28 mL).To a seventh of the solution (4 mL, 0.284 mmol), a pre-mixed dimethylamine (2M in THF, 0.713 niL, 1.42 mmol) and HOAc (0.122 mL, 2.14 mmol) were added. The mixture was then stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give white powder (15 mg). MS 468.2 and 470.1 (M+H, Cl pattern).

Reference： [1]Patent: WO2006/63113,2006,A2 .Location in patent: Page/Page column 68-69

8
[ 63069-50-1 ]
[ 873009-47-3 ]

Yield	Reaction Conditions	Operation in experiment
79%		EXAMPLE 320; N-(( 1 -(4-(N,N-Dimethylcarbamimidoyl)-2-fluorophenyl)- 1 H- 1 ,2,3-triazol-4-yl)methyl)-5- chlorothiophene-2-carboxamide (59); SCHEME 10; Step 1:; [0853] To a solution of <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (56, 1.0 g, 7.35 mmol) in 5 mL TFA at O0C was added NaNO2 (558 mg, 8.09 mmol) in small portions. The reaction mixture was stirred at O0C for 0.5 hr. Then a solution OfNaN3 (478 mg, 7.35 mmol) in 4 mL water was added. The resulting mixture was stirred at 00C for 2 hr. The reaction solution was concentrated in avcuo and then neutralized to pH = 7 with the aqueous saturated NaHCO3 solution and extracted with DCM three times. The combined organic phase was washed with water and brine, dried over Na2SO4 and evaporated in vacuo to give compound 57 (0.94g, 79%).

Reference： [1]Patent: WO2006/2099,2006,A2 .Location in patent: Page/Page column 200

9
[ 364082-44-0 ]
[ 63069-50-1 ]
4'-Cyano-2'-fluoro-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	trimethylaluminum; In hexane;	(3) In the same manner as that described in Example 3(4), a reaction was carried out using <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (129 mg, 0.95 mmol), obtained in Example 25(2), trimethylaluminium (0.89 ml, 1.07M n-hexane solution, 0.95 mmol) and methyl 4-[(trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (120 mg, 0.24 mmol), obtained in Example 12 (1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (134 mg, yield 92%) as a white solid which was recrystallized from ethyl acetate-hexane to give white powdery crystals. Melting point: 136 C. NMR spectrum (500 MHz, CDCl3) delta ppm: 1.22 (3H, d, J=7 Hz), 3.36 (1H, q, J=7 Hz), 3.4-3.6 (1H, m), 3.76 (1H, t, J=11 Hz), 3.79 (1H, t, J=11 Hz), 4.42 (1H, ddd, J=11, 5, 2 Hz), 4.55 (1H, ddd, J=11, 5, 2 Hz), 4.85 (1H, d, J=14 Hz), 5.05 (1H, d, J=14 Hz), 5.05 (1H, s), 5.55 (1H, s), 6.7-6.8 (2H, m), 7.3-7.4 (1H, m), 7.45 (1H, d, J=12 Hz), 7.53 (1H, d, J=8 Hz), 7.66 (2H, d, J=8 Hz), 7.79 (2H, s), 7.91 (2H, d, J=8 Hz), 8.22 (1H, bd, J=4 Hz), 8.73 (1H, t, J=8 Hz). IR spectrum: nu max (KBr) cm-1: 3435, 2232, 1686, 1520, 1139. Mass spectrum m/z (FAB): 610 (M++1).

Reference： [1]Patent: US2003/176480,2003,A1

10
[ 364082-48-4 ]
[ 63069-50-1 ]

Yield	Reaction Conditions	Operation in experiment
47%	With trifluoroacetic acid;	(2) Trifluoroacetic acid (1 ml) was added dropwise to a solution of 3-fluoro-4-[(4-methoxybenzyl)amino]benzonitrile (1.0 g, 3.9 mmol), obtained in Example 25(1), in anhydrous dichloromethane (20 ml) cooled to 0 C. with stirring. The resulting mixture was stirred at room temperature overnight. At the end of this time, the reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution at 0 C. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual oil was chromatographed on a silica gel column using ethyl acetate-hexane (1:6) as the eluant to afford 4-amino-3-fluorobenzonitrile (252 mg, yield 47%) as a pale orange solid which was recrystallized from ethyl acetate-hexane to give white powdery crystals. Melting point: 84 C. NMR spectrum (400 MHz, CDCl3) delta ppm 4.23 (2H, bs), 6.76 (1H, t, J=9 Hz), 7.2-7.3 (2H, m). IR spectrum nu max (KBr) cm1: 3449, 3353, 2224, 1641. Mass spectrum m/z (EI): 136 (M+, 100%).

Reference： [1]Patent: US2003/176480,2003,A1

11
[ 63069-50-1 ]
[ 7787-70-4 ]
[ 133059-44-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; hydrogen bromide; acetic acid; sodium nitrite;	Step 8 30.8 g (0.45 mol) of sodium nitrite was added slowly to 244 cm3 of concentrated sulfuric acid while stirring. After the addition was complete, the solution was heated to a temperature of 50 C. to dissolve the crystals. The solution was added drop-wise to 406 cm3 of acetic acid while cooling on an ice water bath and stirring. 55 g (0.40 mol) of 4-amino-3-fluorobenzonitrile was added slowly to maintain the temperature below 25 C. and the mixture was stirred at 25 C. for one hour to dissolve the crystals and form the corresponding diazonium salt. While cooling with ice water and stirring, the diazonium salt was added drop-wise to a solution of 87.4 g (0.61 mol) of copper (I) bromide and 244 cm3 of hydrobromic acid (47%) and allowed to remain overnight at room temperature. The crystals deposited were filtered out, washed with water and recrystallized from hexane to yield 61.7 g (0.31 mol) of 4-bromo-3-fluorobenzonitrile.

Reference： [1]Patent: US5200110,1993,A

12
[ 367-24-8 ]
[ 63069-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	In 1-methyl-pyrrolidin-2-one; water; ethylenediamine;	Step 7 100 g (0.53 mol) of 4-bromo-fluoroaniline (manufactured by Aldorich Co.) and 70.8 g (0.79 mol) of copper (I) cyanide was refluxed in N-methyl-2-pyrrolidinone for three hours while stirring. The solution was cooled and a solution of 130 cm3 of ethylene diamine and 130 cm3 of water was added drop-wise while stirring. The solution was extracted three times with 200 cm3 of chloroform and sufficiently washed with water. The chloroform was distilled off and the residue was distilled under reduced pressure (150 C./9 mmHg) to yield 55 g (0.40 mol) of 4-amino-3-fluorobenzonitrile.
	CuCN; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate;	Step 4 50 g (0.26 mol) of 4-bromo-2-fluoroaniline and 30 g (0.34 mol) of CuCN were dissolved in 130 cm3 of NMP and the solution was refluxed with a mantle heater for 2 hours. The reaction solution was cooled to room temperature. 42 cm3 of EDA was added to the cooled solution and the solution was poured into 300 cm3 of ice water. The resulting mixture was extracted with chloroform and washed with an aqueous EDA solution and water. The chloroform was distilled off the washed mixture. The distillation residue was dissolved in ether and washed with water to remove the NMP. The residue was distilled in a vacuum (b.p. 165 C./23 mmHg) to yield 28 g (0.21 mol) of 4-amino-3-fluorobenzonitrile. It was necessary to perform the distillation under an elevated degree of vacuum since the product was extremely sublimable and the crystals adhered to the output of the distillation tube and clogged the tube.

Reference： [1]Patent: US5200110,1993,A
[2]Patent: US5238599,1993,A

13
[ 367-24-8 ]
copper(l) cyanide [ No CAS ]
[ 63069-50-1 ]

Yield	Reaction Conditions	Operation in experiment
74.76%	In 1-methyl-pyrrolidin-2-one; at 200℃;Sealed tube;	Step 1: Synthesis of 4-amino-3-fluorobenzonitrile To a solution of 4-bromo-2-fluorobenzenamine (3 g, 15.789 mmol) in NMP (6 mL) was added copper cyanide (2.8 g, 31.578 mmol) and heated overnight at 200 C. in a sealed tube. Progress of reaction was monitored by TLC. After reaction completion 1, 2-diaminoethane (3 mL) and reaction mixture was poured into water. Product was extracted with ethyl acetate and washed with 10% 1, 2-diaminoethane solution in water and then with water. Organic layer was dried over sodium sulphate, concentrated under reduced pressure. Crude was purified by silica (100-200) column chromatography using 15% ethyl acetate in hexane as eluent to give 4-amino-3-fluorobenzonitrile (1.6 g, 74.76%) as white solid. MS: 137.1 [M+1]
	In 1-methyl-pyrrolidin-2-one; water;	EXAMPLE 6 Preparation of 4-amino-3-fluorobenzonitrile 6.8 Parts of 4-bromo-2-fluoroaniline were dissolved in 75 parts of N-methylpyrrolidone. This solution was treated with 4.2 parts of cuprous cyanide. The reaction mixture was heated to 190 for 2 hours. The reaction mass was poured onto a mixture of 200 parts of ice and 15 parts of sodium cyanide. This mixture was then heated on a steam bath for 2 hours at 60-70. This aqueous solution was then extracted with four 100 ml portions of toluene. The toluene extracts were combined and washed with four 300 ml portions of water followed by 100 ml of saturated aqueous NaCl solution. The toluene solution of the product was dried over sodium sulfate and stripped to give 2.6 parts of the desired product, m.p. 71-73.
	In 1-methyl-pyrrolidin-2-one; water;	Preparation of 4-Amino-3-fluorobenzonitrile 6.8 Parts of 4-bromo-2-fluoroaniline were dissolved in 75 parts of N-methylpyrrolidone. This solution was treated with 4.2 parts of cuprous cyanide. The reaction mixture was heated to 190 for 2 hours. The reaction mass was poured into a mixture of 200 parts of ice and 15 parts of sodium cyanide. This mixture was then heated on a steam bath for 2 hours at 60-70. This aqueous solution was then extracted with four 100-part portions of toluene. The toluene extracts were combined and washed with four 300-part portions of water followed by 100-parts of saturated aqueous NaCl. The toluene solution of the product was dried over sodium sulfate and evaporated at a reduced pressure of 50 mm.Hg to give 2.6 parts of 4-amino-3-fluorobenzonitrile, m.p. 71-73.

Reference： [1]Patent: US2017/291894,2017,A1 .Location in patent: Paragraph 0533-0535
[2]Patent: US4111681,1978,A
[3]Patent: US4120693,1978,A

14
[ 63069-50-1 ]
[ 124-63-0 ]
C₉H₉FN₂O₄S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 10 - 24℃; for 16.5h;	Example 1; Production of N-(2-fluoro-4-cyanophenyl) methanesulfonamide; To 244g (1.79 mol ) <strong>[63069-50-1]3-fluoro-4-aminobenzonitrile</strong> in 1.8 I (22.3 mol) pyridine, 348 ml (4.49 mol) methanesulfonylchloride is added dropwise at a temperature of between 10 CC and 24 0C.The mixture is stirred for 30 min at 10 0C and then for further 16 hours without cooling. 3.3 I water is then added for hydrolysis of the dimesyl compound. The mixture is held under reflux for 1.5 hours, then cooled down to 0 0C and finally crystallized by stirring for 1 h at 0 0C. The product is subsequently washed with each 300 ml water, 1 M hydrochloric acid and acetone and then dried for 12 hours at 50 0C in vacuo. EPO <DP n="26"/>Yield: 355.4 g = 92.6 % of th. Purity: HPLC: 99.9 %Identity determination:MS: M+1 and fragmentation corresponds to expected structureNMR: 1 H and 13C signals can be interpreted according to the expected structureMelting point: 202.2 0C

Reference： [1]Patent: WO2007/9798,2007,A2 .Location in patent: Page/Page column 24-25

15
[ 63069-50-1 ]
[ 103321-53-5 ]
[ 947183-93-9 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; dmap; In dichloromethane; at 0 - 20℃;	EXAMPLE 181; (S)-N-(4-Cyano-2-fluoro-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-methyl-butyramide; Prepared by the same method as described in example 43 except that step 1 was performed as described below.Step 1: To a solution of (S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl-butyric acid (2.5 g, 7.37 mmol) and a few drops of N,N-dimethylformamide in dichloromethane (20 mL) was slowly added oxalyl chloride (1.3 mL, 14.74 mmol) at 0 C. under an atmosphere of dry nitrogen. The mixture was stirred for 15 minutes at 0 C. and 2 hours at room temperature. After removal of the solvent, the residue was dissolved in dichloromethane (20 mL) and to the resulting solution was added <strong>[63069-50-1]4-amino-3-fluoro-benzonitrile</strong> (840 mg, 6.14 mmol), 4-dimethylaminopyridine (150 mg, 1.2 mmol) and pyridine (0.78 mL, 9.21 mmol) at 0 C. The mixture was stirred for 2 hrs at 0 C. and overnight at room temperature. The reaction was quenched with 1 M aqueous citric acid solution and then extracted with dichloromethane (three times). The combined organic extracts were washed with 1 M aqueous citric acid solution, brine, saturated aqueous sodium carbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted from 100% dichloromethane up to 10% methanol/90% dichloromethane over 30 minutes. Concentration of the product containing fractions gave [(S)-1-(4-cyano-2-fluoro-phenylcarbamoyl)-2-methyl-propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a white solid (2.15 mg, 77%).LC-MS: Obs Mass (M+H+), 458; Calcd. Mass, 548 for C27H25FN3O3+.
	With pyridine; dmap; In dichloromethane; at 0 - 20℃;	To a solution of (S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl-butyric acid (2.5 g, 7.37 mmol) and a few drops of N,N-dimethylformamide in dichloromethane (20 mL) was slowly added oxalyl chloride (1.3 mL, 14.74 mmol) at 0 C. under an atmosphere of dry nitrogen. The mixture was stirred for 15 minutes at 0 C. and 2 hours at room temperature. After removal of the solvent, the residue was dissolved in dichloromethane (20 mL) and to the resulting solution was added <strong>[63069-50-1]4-amino-3-fluoro-benzonitrile</strong> (840 mg, 6.14 mmol), 4-dimethylaminopyridine (150 mg, 1.2 mmol) and pyridine (0.78 mL, 9.21 mmol) at 0 C. The mixture was stirred for 2 hrs at 0 C. and overnight at room temperature. The reaction was quenched with 1 M aqueous citric acid solution and then extracted with dichloromethane (three times). The combined organic extracts were washed with 1 M aqueous citric acid solution, brine, saturated aqueous sodium carbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted from 100% dichloromethane up to 10% methanol/90% dichloromethane over 30 minutes. Concentration of the product containing fractions gave [(S)-1-(4-cyano-2-fluoro-phenylcarbamoyl)-2-methyl-propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a white solid (2.15 mg, 77%). LC-MS: Obs Mass (M+H+), 458; Calcd. Mass, 548 for C27H25FN3O3+.LC-MS: Obs Mass (M+H+), 455; Calcd. Mass, 455 for C23H24FN4O5+.

Reference： [1]Patent: US2007/197617,2007,A1 .Location in patent: Page/Page column 57
[2]Patent: US2008/207563,2008,A1 .Location in patent: Page/Page column 54

16
isopropyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate [ No CAS ]
[ 63069-50-1 ]
[ 1079051-57-2 ]

Yield	Reaction Conditions	Operation in experiment
59%	With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In toluene; at 110℃; for 0.5h;Microwave irradiation;	Example 20.[00169] A mixture of Example 2OA (62 mg, 0.18 mmol), 4-amino-3- fluorobenzonitrile (25 mg, 0.18 mmol), Pd(dppf)Cl2 (5.3 mg, 0.0073 mmol), BINAP (6.7 mg, 0.011 mmol) and t-BuONa ( 17.5 mg, 0.18 mmol) in toluene (1.5 mL) was degassed and heated in a sealed vial in the microwave at 110 0C for 30 min. After this time, the reaction mixture was purified by flash chromatography on silica gel (elution with 0-100% EtOAc/hexane) to afford 47 mg (59%) of Example 20 as an off- white solid. 1H NMR (400 MHz, CDCl3): delta 1.48 (s, 9H), 1.60-1.72 (m, 4H), 2.88 (broad s, 2H), 3.05 (s, 3H), 3.47 (t, 2H, J= 4.4 Hz), 4.28 (t, 4H, J= 4.4 Hz), 4.84 (m, IH), 7.23 (d, IH, J= 4.4 Hz), 7.65 (dd, IH, J= 2.2,10.4 Hz), 7.70 (dd, IH, J= 2.2, 8.2 Hz), 8.09 (s, IH), 8.90 (dd, IH, J= 7.9, 8.6 Hz). LRMS (ESI): 441.1 [M + H]+.

Reference： [1]Patent: WO2008/137435,2008,A1 .Location in patent: Page/Page column 80

17
[ 1159997-16-6 ]
[ 63069-50-1 ]
[ 1159997-17-7 ]

Yield	Reaction Conditions	Operation in experiment
		Example 89:(R)-N-(4-Cyano-2-fluorophenyl)-l-(4-(trifluoromethyl)phenyl)-3,4-dihydro- isoquinoline-2(lH)-carboxamide; A solution of (R)-4-nitrophenyl l-(4-(trifluoromethyl)phenyl)-3,4-dihydroiso- quinoline-2(lH)-carboxylate (50 mg, 113 mumol, example 88) and 4-amino-3- fluorobenzonitrile (17 mg, 124 mumol) in MeCN (0.7 mL) was subjected to a microwave irradiation at 120 C for 15 min and at 150 0C for 15 min. Then, NaH <n="118"/>(60% dispersion in mineral oil, 20 mg) was added and the mixture was then stirred at RT for overnight. Then, H2O (1.0 mL) was added and the mixture was extracted with EtOAc (2 x 1.5 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was then dissolved in a solution of DMSO and MeOH (1 : 1 , 0.1 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give a desired product, which was then dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP-resin and the resin was washed with MeOH (2 x 0.5 mL). The combined washings were concentrated and dried under vacuum to give the title compound as a colorless solid. MS (ESI, positive ion) m/z: 440 (M+H).

Reference： [1]Patent: WO2009/73203,2009,A1 .Location in patent: Page/Page column 116-117

18
[ 63069-50-1 ]
[ 74-88-4 ]
[ 160658-69-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In tetrahydrofuran; at 20℃;	EXAMPLES 11-28Synthesis of Examples 11-28 were prepared following General Procedures l-lll. <n="53"/> General Procedure I. Preparation of Dimethylamino Compounds 2a-iTo mixture of 1a-i (1 mmol) and NaH (2.6 mmol) in anhydrous THF (4 ml.) was added CH3I (2.6 mmol). The reaction mixture was stirred at room temperature for 3-12 hours, monitoring by TLC. The reaction was quenched by adding small amount of CH3OH, then H2O, the mixture was then concentrated and extracted three times with EtOAc. The combined extracts were washed with H2O, then dried over Na2SO4. Separation and purification (hexane/EtOAc = 10:1 or 10:2) gave the following compounds. 4-Dimethylamino-3-fluoro-benzonitrile, MS: m/z 165 (M + H)

Reference： [1]Patent: WO2009/120826,2009,A1 .Location in patent: Page/Page column 50; 51

19
[ 491864-74-5 ]
[ 63069-50-1 ]
[ 1075253-61-0 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 7273 - 7286

20
[ 108-77-0 ]
[ 63069-50-1 ]
4-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]-3-fluorobenzonitrile [ No CAS ]

Reference： [1]Chemistry and biodiversity,2009,vol. 6,p. 561 - 568

21
[ 1219496-67-9 ]
[ 63069-50-1 ]
[ 1219496-68-0 ]

Yield	Reaction Conditions	Operation in experiment
42%		58.2 [rac]-2-[2-(4-Chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-N-(4-cyano-2-fluoro-phenyl)-2-cyclohexyl-acetamide To a stirred solution of [rac]-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid methyl ester (250 mg, 0.64 mmol) in dry THF was added LiHMDS (1.0 M solution in THF; 4.5 ml, 4.5 mmol) at -30 C. and stirring continued for another 30 min at that temperature. 4-Amino-3-fluoro-benzonitrile (90.64 mg, 0.768 mmol; CAS Reg. No. 115661-37-5) in THF (1 ml) was then added at that temperature and slowly brought to room temperature. Reaction mixture was then stirred at room temperature for 13 h. TLC shows formation of a new spot. LC-MS of the crude material shows formation of desired product. Reaction mixture was quenched with saturated NH4Cl and the aqueous layer was extracted with EtOAc (3*5 ml). Combined organic layers were washed with brine and concentrated under reduced pressure to give crude material (260 mg); which was then purified by column chromatography [SiO2 (230-400 mesh), EtOAc:hexane 30:70] to give the title compound (130 mg, 42%) as light yellow solid.

Reference： [1]Patent: US2010/76027,2010,A1 .Location in patent: Page/Page column 44-45

22
[ 63069-50-1 ]
[ 1258399-08-4 ]
[ 1258400-24-6 ]

Yield	Reaction Conditions	Operation in experiment
48%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 105℃; for 16h;Inert atmosphere;	Reference Example 71 methyl { (3S) -6-[{ (3S) -7- [ (4-cyano-2-fluorophenyl) amino] -2, 3- dihydro-1-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate; [ 0403 ]A suspension of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate (0.300 g, 0.6 mmol) , 4-amino-3- fluorobenzonitrile (0.098 g, 0.72 mmol), tris (dibenzylideneacetone) dipalladium (0) (22 mg, 0.024 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (27.8 mg, 0.048 mmol) and cesium carbonate (391 mg, 1.2 mmol) in toluene(8 mL) was stirred under an argon atmosphere at 1050C for 16 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give the title compound (0.160 g, yield 48%) as a solid. MS m/z 556 (M + H)+.

Reference： [1]Patent: WO2010/143733,2010,A1 .Location in patent: Page/Page column 163-164

23
[ 32315-10-9 ]
[ 63069-50-1 ]
[ 1228022-48-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With triethylamine; In toluene; at 70℃;Cooling with ice;	Preparation 35 3-Fluoro-4-isocyanatobenzonitrile Cool a solution of triphosgene (1.09 g, 3.67 mmol) in toluene (20 mL) in an ice-water bath. Treat with a solution of a <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (1.36 g, 10.0 mmol) and triethylamine (2.8 mL, 20.0 mmol) in toluene (30 mL) dropwise. Heat the resulting mixture at 70 C. for 5 h. Cool the reaction mixture to ambient temperature and filter off the solid. Concentrate the filtrate under reduced pressure to give a white solid (1.44 g, 84%) which is used without further purification. GC/MS m/z 162 (M+).

Reference： [1]Patent: US2011/190304,2011,A1 .Location in patent: Page/Page column 11

24
[ 367-24-8 ]
[ 105-56-6 ]
[ 63069-50-1 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 3644 - 3647

25
[ 63069-50-1 ]
[ 874880-58-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	With N-Bromosuccinimide; In dichloromethane; at 20℃; for 15h;Inert atmosphere;	Step 1: To a stirred mixture of <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (5 g, 37 mmol) in anhydrous CH2Cl2 (40 mL) underAr at rt was added dropwise N-bromosuccinimide (6.5 g, 37 mmol). After 15 h, the mixture was concentrated underreduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanesto 50% EtOAc in hexanes to afford 4-amino-3-bromo-5-fluorobenzonitrile (6.4 g, 81%) as a tan solid. 1H NMR (500 MHz,DMSO-d6) delta 7.76 (s, 1H), 7.62 (dd, J = 1.5, 11.1 Hz, 1H), 6.44 (s, 2H); LCMS (ESI) m/z 214, 216 (M+H)+.
	With bromine; In acetic acid; at 20℃;	3-bromo-5-fluoro-4-nitrobenzonitrile Step 1 : 4-amino-3-bromo-5-fluorobenzonitrile To a solution of <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (15.0 g, 1 10 mmol) in acetic acid (200 mL) was added a solution of bromine (5.68 mL, 1 10 mmol) in 15 mL of acetic acid. The reaction was stirred at rt overnight. The mixture was concentrated and repeatedly diluted with hexanes and concentrated to azeotropically remove the trace acetic acid. The crude product was suspended in saturated sodium thiosulfate solution and 2 N NaOH. The mixture was stirred for 10 min. The product was then extracted into EtOAc. The combined organics were dried over Na2S04, filtered, and concentrated to provide the crude title comound (19.8 g, 83 % crude yield) as a yellow solid. MS (m/z) 215.0, 217.0 (M+H+).

Reference： [1]Patent: EP2766359,2016,B1 .Location in patent: Paragraph 0906
[2]Patent: WO2012/174342,2012,A1 .Location in patent: Page/Page column 77

26
[ 63069-50-1 ]
[ 1310918-28-5 ]

Reference： [1]Patent: WO2012/174342,2012,A1

27
[ 63069-50-1 ]
[ 1147558-43-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-chloro-succinimide; In acetonitrile; at 85℃; for 5.0h;	4-Amino-3-chloro-5-fluorobenzonitrile A mixture of 4-amino-3-fluorobenzonitrile (1 equiv.) and N-chlorosuccinimide (1.5 equiv.) in acetonitrile (0.24 M) was stirred at 85 C. for 5 h. The solvent was removed by concentration and the residue was partitioned between ethyl acetate and 5% NaOH. The organic phase was washed with 5% NaOH and brine. Then the organic phase was dried over MgSO4 and dried in vacuum to afford 4-amino-3-chloro-5-fluorobenzonitrile (88%) as a beige solid. 1H NMR (400 MHz, CDCl3) delta ppm: 7.41 (t, J=6 Hz, 1H), 7.24 (dd, J=1.8, 10.2 Hz, 1H), 4.66 (s, 2H).
	With N-chloro-succinimide; In acetonitrile; at 86℃; for 6.0h;	INTERMEDIATE 74-Amino-3-chloro-5-fluorobenzonitrile A solution of 4-amino-3-fluorobenzonitrile (25.13 g, 185 mmol) and NCS (24.65 g, 185 mmol) in acetonitrile (500 mL) was stirred at 86 C (reflux) for 5 h. LCMS showed -17% of starting material remained. Additional NCS (0.2 eq) was added and the reaction was stirred for 1 h. The reaction was partly concentrated and the residue was partitioned between 5% NaOH (100 mL) and EtOAc. The aqueous layer was back extracted with EtOAc. The organic extracts were dried over Na2S04 and concentrated to a pink solid. The NMR spectrum showed some of the succinimate side product still remained. The crude product was washed with H20 and air dried to give the desired product as a beige solid. This product was used in the next step without any futher purification. MS (m/z) 171.1 (M+H+).
	With N-chloro-succinimide; In acetonitrile; at 86℃; for 6.0h;	4-Amino-3-chloro-5-fluorobenzonitrileA solution of 4-amino-3-fluorobenzonitrile (25.13 g, 185 mmol) and NCS (24.65 g, 185 mmol) in acetonitrile (500 mL) was stirred at 86 C (reflux) for 5 h. LCMS showed -17% of starting material remained. Additional NCS (0.2 eq) was added and the reaction was stirred for 1 h. The reaction was partly concentrated and the residue was partitioned between 5% NaOH (100 mL) and EtOAc. The aqueous layer was back extracted with EtOAc. The organic extracts were dried over Na2S04 and concentrated to a pink solid. The NMR spectrum showed some of the succinimate side product still remained. The crude product was washed with H20 and air dried to give the desired product as a beige solid. This product was used in the next step without any futher purification. MS (m/z) 171.1 (M+H+).

	With N-chloro-succinimide; acetic acid; at 70℃; for 16.0h;	1.13. Synthesis of 4-amino-3-chloro-5-fluoro-benzonitrile (Int.21) A mixture of 4-amino-3-fluorobenzonitrile (184 mmol) and NCS (276 mmol) in AcOH (300 mL) was stirred at 70 C. for approximately 16 h. The mixture was concentrated. H2O was added to the residue and the solid product was filtered off and washed (sat. NaHCO3 and H2O). To eliminate H2O, THF was added and removed under reduced pressure to yield the desired product.
	With N-chloro-succinimide; acetic acid; at 70℃; for 16.0h;	1.13. Synthesis of 4-amino-3-chloro-5-fluoro-benzonitrile (mt. 21) j00260j A mixture of 4-amino-3-fluorobenzonitrile (184 mmol) and NCS (276 mmol) in AcOH (300 mL) was stirred at 70C for approximately 16 h. The mixture was concentrated. H20 was added to the residue and the solid product was filtered off and washed (sat. NaHCO3 and H20). To eliminate H20, THF was added and removed under reduced pressure to yield the desired product.
	With N-chloro-succinimide; acetic acid; at 70℃; for 0.16h;	A mixture of 4-amino-3-fluorobenzonitrile (184 mmol) and NCS (276 mmol) in AcOH (300 mE) was stirred at 70 C. for approximately 16 h. The mixture was concentrated. H20 was added to the residue and the solid product was filtered oil and washed (sat. NaHCO3 and H20). To eliminate H20, THF was added and removed under reduced pressure to yield the desired product.
	With N-chloro-succinimide; In acetic acid; at 70℃; for 16.0h;	3.123. Compound 111: (lR,2R)-N-[6-(2-chloro-4-cyano-6-fluoro-N-methyl-anilino)-l-methyl- 3.123.1. Step i): 4-amino-3-chloro-5-fluoro-benzonitrile A mixture of 4-amino-3-fluorobenzonitrile (184 mmol) and NCS (276 mmol) in AcOH (300 mL) is stirred at 70C for approximately 16 h. The mixture is concentrated. H20 is added to the residue and the solid product is filtered off and washed (sat. NaHCC>3 and H20). To eliminate H20, THF is added and removed under reduced pressure to yield the desired product (Int. 21). 3.123.2. Step ii): 4-[[6-[bis[(4-methoxyphenyl)methyl]amino]-4-(methylamino)-5-nitro-2- pyridyl]amino]-3-chloro-5-fluoro-benzonitrtte

Reference： [1]Patent: US2016/96841,2016,A1 .Location in patent: Paragraph 0281
[2]Patent: WO2012/174342,2012,A1 .Location in patent: Page/Page column 45
[3]Patent: WO2013/12500,2013,A1 .Location in patent: Page/Page column 61
[4]Patent: US2015/203455,2015,A1 .Location in patent: Paragraph 0457-0458
[5]Patent: WO2015/110378,2015,A1 .Location in patent: Paragraph 00260; 00312
[6]Patent: US9440929,2016,B2 .Location in patent: Page/Page column 59
[7]Patent: WO2017/12647,2017,A1 .Location in patent: Paragraph 0688

28
[ 63069-50-1 ]
[ 1273585-10-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-chloro-succinimide / acetonitrile / 6 h / 86 °C 2: acetic acid; sodium perborate / 71 h / 20 - 80 °C
	Multi-step reaction with 2 steps 1: N-chloro-succinimide / acetonitrile / 6 h / 86 °C 2: sodium perborate tetrahydrate; acetic acid / 71 h / 20 - 80 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/174342, 2012, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2013/12500, 2013, A1

29
[ 63069-50-1 ]
[ 909912-12-5 ]
[ 1360628-98-3 ]

Yield	Reaction Conditions	Operation in experiment
6.69 g	With acetic acid; at 50℃; for 18h;	6-Benzyloxy-4-chloro-7-methoxy-3-nitroquinoline (6.75 g, 19.58 mmol) and <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (2.46 g, 18.1 mmol) were dissolved in glacial acetic acid (106 ml) and stirred at 50 C. for 18 h overnight. The suspension obtained was subsequently added to water (1 l) and stirred for a further 30 min. The precipitate formed was filtered off with suction, rinsed with water and dried in vacuo, giving 4-(6-benzyloxy-7-methoxy-3-nitro-quinolin-4-ylamino)-3-fluorobenzonitrile (6.69 g, 15.06 mmol) as solid. MS: 445.1 (M+H+), TLC (HPTLC): Rf=0.31 (cyclohexane/ethyl acetate 2:1, parts by volume).

Reference： [1]Patent: US2013/172337,2013,A1 .Location in patent: Paragraph 0184

30
[ 63069-50-1 ]
(±)-(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid trifluoroacetic acid salt [ No CAS ]
rac-(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluoro-phenyl)-2'-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid (4-cyano-2-fluoro-phenyl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Step (A): To a solution of racemic (2?S,3?R,4?S,5?R)-6-chloro-4?-(3-chloro-2-fluoro-phenyl)-2?-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3?-pyrrolidine]-5?-carboxylic acid trifluoroacetic acid salt 17 (R3 = H, R1 = CH2C(CH3)3, Ref. 29) (0.2 g, 0.36 mmol) in dichloromethane (10 mL) was added diisopropylethylamine (0.18 g, 1.4 mmol), diphenylphosphinic chloride (Aldrich) (0.25 g, 1.1 mmol), respectively. The mixture was stirred at room temperature for 0.5 h, then methyl 4-amino-2-methoxybenzoate (Acros) (0.077 g, 0.43 mmol) or methyl 4-amino-3-methoxy-benzoate (Ark Pharm) (0.16 g, 0.9 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over Na2SO4, then concentrated. The residue was purified by chromatography (3-20% of EtOAc in CH2Cl2) to give a white solid (yield 0.12 g, 54%).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 4001 - 4009

31
[ 63069-50-1 ]
4-amino-3-fluoro-N'-hydroxybenzenecarboxyimidamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydroxylamine; In water; isopropyl alcohol; at 70℃; for 5h;	A 50% aqueous solution of Hydroxylamine (2.18 mL, 33.1 mmol) was added to a 2-propanol (44 mL) solution of <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (3.00 g, 22.0 mmol) at room temperature, and the mixture was stirred at 70C for 5 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was washed with a hexane-ethyl acetate (4:1, v/v) mixture to give the title compound (3.67 g, yield: 98%). 1H-NMR (500 MHz, DMSO-d6) delta ppm: 9.35 (1H, s), 7.27 (1H, dd, J = 13, 2 Hz), 7.21 (1H, dd, J = 8, 2 Hz), 6.71 (1H, dd, J = 9, 8 Hz), 5.63 (2H, s), 5.33 (2H, s).
	With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 100℃; for 5h;	To a solution of <strong>[63069-50-1]4-amino-3-fluoro-benzonitrile</strong> (5.0 g, 36.7 mmol) in ethanol (61 mL) was added a hydroxylamine hydrochloride solution (5.16 g, 73.5 mmol) in 50 mL of water followed by potassium carbonate (8.12 g, 58.8 mmol) in 75 mL of water. To the cloudy solution was then introduced quinolin15 8-01 (0.07 g, 0.48 mmol). The reaction mixture was stirred for 5 hours at 100C. The reaction mixturewas then cooled to 25C, the ethanol was removed under reduced pressure, and the resulting mixture was then extracted with ethyl acetate. The total combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5.83 g of 4-amino-3- fluoro-N-hydroxy-benzamidine as a yellow solid. The crude residue was used in the following stepwithout further purification. LC/MS (Method A) retention time = 0.20 mm; 166 [M+H].(brs, 2H).1H NMR (400 MHz, CDCI3) oe ppm: 9.30 (s, 1H), 7.25 (m, 2H), 6.70 (t, 1H), 5.60 (brs, 2H), 5.30

Reference： [1]Patent: EP2805941,2014,A1 .Location in patent: Paragraph 0181
[2]Patent: WO2018/15458,2018,A1 .Location in patent: Page/Page column 49

32
[ 63069-50-1 ]
[ 79-08-3 ]
C₉H₇FN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In water; at 100℃; for 8h;	Compound 1 (50mmol) and 2 (75mmol) were dissolved in H2O (150mL) and heated to reflux for 8h. Then the reaction mixture was cooled to room temperature and filtered, washed with CH3CH2OH (20mL) and dried to obtain compound 3 as a white solid. Yield: 80-85%.
	In water; at 100℃;	General procedure: Compound 1 (50 mmol) and compound 2 (60 mmol) were dissolvedin H2O (150 mL) and stirred at 100 C for 8 h. After the completion,the reaction mixture was cooled under ice-bath withstrong agitation. The precipitation was filtered and dried to getcompound 3, yield: 80%.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 126,p. 799 - 809
[2]Archiv der Pharmazie,2015,vol. 348,p. 353 - 365
[3]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 2739 - 2753
[4]European Journal of Pharmaceutical Sciences,2019,vol. 137

33
[ 63069-50-1 ]
[ 53484-16-5 ]
3-fluoro-4-[methyl-(3-methylbenzimidazol-5-yl)amino]benzonitrile [ No CAS ]

Reference： [1]Patent: US2015/203455,2015,A1
[2]Patent: WO2015/110378,2015,A1
[3]Patent: US9440929,2016,B2

34
[ 63069-50-1 ]
[ 53484-16-5 ]
3-fluoro-4-[(3-methylbenzimidazol-5-yl)amino]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; caesium carbonate; XPhos; In toluene; at 110℃; for 16h;	Step i: 3-fluoro-4-[(3-methylbenzimidazol-5-yl)amino]benzonitrile A mixture containing <strong>[53484-16-5]6-bromo-1-methyl-benzimidazole</strong> (2.38 mmol), 4-amino-3-fluoro-benzonitrile (3.57 mmol), XPhos (0.95 mmol), Cs2CO3 (7.14 mmol) and Pd(OAc)2 (0.71 mmol) in dry toluene (8 mL) was stirred at 110° C. for approximately 16 h. The mixture was diluted (EtOAc), washed (H2O), dried (Na2SO4) and concentrated to yield the desired product 3-fluoro-4-[(3-methylbenzimidazol-5-yl)amino]benzonitrile.
	With palladium diacetate; caesium carbonate; XPhos; In toluene; at 110℃; for 16h;	3.3.1. Step i. 3-fluoro-4-[(3-methylbenzimidazol-5-yl)amino]benzonitrilej00319j A mixture containing <strong>[53484-16-5]6-bromo-1-methyl-benzimidazole</strong> (2.38 mmol), 4-amino-3-fluoro- benzonitrile (3.57 mmol), XPhos (0.95 mmol), Cs2CO3 (7.14 mmol) and Pd(OAc)2 (0.71 mmol) in dry toluene (8 mL) was stirred at 110°C for approximately 16 h. The mixture was diluted (EtOAc), washed (H20), dried (Na2SO4) and concentrated to yield the desired product 3-fluoro-4-[(3-methylbenzimidazol- 5-yl)amino]benzonitrile.
	With palladium diacetate; caesium carbonate; XPhos; In toluene; at 110℃; for 0.16h;	A mixture containing 6-bromo-1 -methyl-benzimidazole (2.38 mmol), 4-amino-3-fluoro-benzonitrile (3.57 mmol),XPhos (0.95 mmol), Cs2CO3 (7.14 mmol) and Pd(OAc)2 (0.71 mmol) in dry toluene (8 mE) was stirred at 1100 C. forapproximately 16 h. The mixture was diluted (EtOAc), washed (H20), dried (Na2SO4) and concentrated to yield thedesired product 3-fluoro-4-[(3-methylbenzimidazol-5-yl)amino]benzonitrile.

Reference： [1]Patent: US2015/203455,2015,A1 .Location in patent: Paragraph 0544-0545
[2]Patent: WO2015/110378,2015,A1 .Location in patent: Paragraph 00319
[3]Patent: US9440929,2016,B2 .Location in patent: Page/Page column 124

35
[ 63069-50-1 ]
[ 887266-99-1 ]

Yield	Reaction Conditions	Operation in experiment
4.0 g		A mixture of <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (5.0 g, 36.76 mmol) and p-toluenesulfonic acid (20.0 g, 105.2 mmol) in acetonitrile (50 mL) was stirred at RT for 4 h. Then aq. solution of NaNO2 (3.8 g, 55.07 mmol) and KI (9.15 g, 55.07 mmol) were added at 0C and stirred further for lh. After the reaction completion, the reaction mixture was quenched with water, washed with an aqueous solution of NaHSO3 and extracted with EtOAc. The organic layerwas washed with water, brine, dried over Na2SO4 and concentrated to afford 4.0 g of the title product. ?H NMR (300 MHz, CDC13): 7.94-7.89 (t, J = 8.4 Hz, 1H), 7.34-7.32 (d, J = 7.5 Hz, 1H), 7.21-7.19 (d, J= 8.1 Hz, 1H).

Reference： [1]Patent: WO2016/55947,2016,A1 .Location in patent: Page/Page column 57
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 3766 - 3773

36
[ 218632-01-0 ]
[ 63069-50-1 ]

Yield	Reaction Conditions	Operation in experiment
4.5 g	With hydrogenchloride; water; iron; In methanol; at 22 - 26℃; for 2h;	To a solution of <strong>[218632-01-0]3-fluoro-4-nitrobenzonitrile</strong> (5.0 g, 0.030 mmol) in MeOH (50 mL) were added iron powder (5 g) and conc.HC1 (20 mL). The reaction mass was stirred at RT for 2 h. The reaction mass was filtered. The filtrate was concentrated and then diluted with water, extracted with EtOAc and basified with 10% NaHCO3 solution. The organic portion wasdried over Na2504 and concentrated to afford 4.5 g of the title product.?H NMR (300 MHz,DMSO-d6): 7.52-7.48 (d, J= 11.7 Hz, 1H), 7.31-7.29 (d, J= 8.1 Hz, 1H), 6.82.-6.76 (d, J=8.7 Hz, 1H), 6.24 (s, 2H).

Reference： [1]Patent: WO2016/55947,2016,A1 .Location in patent: Page/Page column 56; 57

37
[ 63069-50-1 ]
[ 135-19-3 ]
(E)-3-fluoro-4-((2-hydroxynaphthalen-1-yl)diazenyl)benzonitrile [ No CAS ]

Reference： [1]Molecules,2016,vol. 21

38
[ 63069-50-1 ]
[ 333-20-0 ]
2-amino-4-fluoro-1,3-benzothiazole-6-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; acetic acid; at 20℃; for 20h;	Step 1 : To a stirred solution of <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (2.0 g, 14.7 mmol) and potassium thiocyanide (5.7 g, 59 mmol) in AcOH (50 mL) was added a solution of bromine (2.3 g, 14.7 mmol) in AcOH (5 mL) over 20 min. The mixture was stirred at rt for 20 h, poured into ice-water (100 mL). Ammonium hydroxide solution (28%) was added to pH 8, stirred for 2 h, filtered, washed with water and dried to afford <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> lnt-6a-1
	With bromine; acetic acid; at 20℃; for 20.3333h;	To a stirred solution of <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (2.0 g, 14.7 mmol) and potassium thiocyanide (5.7 g, 59 mmol) in AcOH (50 mL) was added a solution of bromine (2.3 g, 14.7 mmol) in AcOH (5 mL) over 20 min. The mixture was stirred at rt for 20 h, poured into ice-water (100 mL). Ammonium hydroxide solution (28%) was added to pH 8, the mixture was stirred for 2 h, filtered, washed with water and dried to afford 2-amino-4-fluorobenzo[d]thiazole-6-carbonitrile (1a).

Reference： [1]Patent: WO2016/96115,2016,A1 .Location in patent: Page/Page column 77
[2]Patent: US2017/355694,2017,A1 .Location in patent: Paragraph 0167

39
[ 63069-50-1 ]
endo-tert-butyl 3-(6-chloro-5-nitropyrimidin-4-ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]
endo-tert-butyl 3-(6-(4-cyano-2-fluorophenylamino)-5-nitropyrimidin-4-ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 90℃; for 12h;	General procedure: To the solution of compound 15 (0.2 mmol) and 2-aminobenzonitrile (0.6 mmol) in n-BuOH (3 mL) was added DIPEA (0.6 mmol). After stirred at 90 C for 12 h, the reaction mixture was diluted with EtOAc, washed with brine, dried over MgSO4, and evaporated. The residue was purified by column chromatography to give the product 16 as yellow solid. (22 mg, 25%).

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 254 - 260

40
[ 63069-50-1 ]
silver nitrate [ No CAS ]
C₁₄H₁₀AgF₂N₄⁽¹⁺⁾*NO₃^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	In ethanol; for 120h;Darkness;	An ethanolic solution (5 mL) of <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (L1, 1 mmol, 0.136 g) was added to thesaturated ethanolic solution (5 mL) of AgNO3. The test tube was covered with a perforated foil. Afterkeeping the solution in air for 5 days, light yellow crystals of 1 suitable for structure determination were obtained. Yield 65%, m.p. 120-123 C. Anal. Calcd for C14H10AgF2N5O3: C, 38.03; H, 2.28; N, 15.84%. Found:C, 38.01; H, 2.25; N, 15.82%. IR (KBr, cm-1): 3459 (m), 3339 (s), 3207 (w), 2668 (w), 2359 (s), 2217 (s),1920(w), 1743 (w), 1633 (s), 1524 (s), 1380 (s), 1215 (m), 1127 (w), 1017 (w), 940 (m), 847 (w), 830 (s), 610 (m),467 (w). 1H NMR (400 MHz, DMSO) delta/ppm: 7.50 (dd, J = 11.7, 1.8 Hz, 1H), 7.31 (dd, J = 8.3, 1.7 Hz, 1H),6.80 (t, J = 8.7 Hz, 1H), 6.25 (s, 2H).

Reference： [1]Journal of Coordination Chemistry,2016,vol. 69,p. 3593 - 3602

41
[ 63069-50-1 ]
3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide [ No CAS ]
4-((7-chloro-5-hydroxy-1,1-dioxido-2H-benzo[e][1,2,4]thiadiazin-3-yl)amino)-3-fluorobenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12 mg	With potassium dihydrogenphosphate; In tert-butyl alcohol; at 110℃; for 16h;Inert atmosphere;	Example 57 (2519) 4-((7-Chloro-5-hvdroxy-1 ,1 -dioxido-2H-benzoreiri ,2,41thiadiazin-3-yl)amino)-3- fluorobenzonitrile (2520) To a solution of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) in t-BuOH (5 ml_) were added <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (105 mg) and KH2PO4 (105 mg). The reaction mixture was stirred at 1 10 C for 16 hr under nitrogen. The reaction mixture was allowed to cool to RT and was diluted with cold water. The resulting precipitate was collected by filtration and dried under vacuum to afford the crude product (150 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19x150 mm) using a gradient of 10-55% 0.1 % formic acid/water in acetonitrile. The appropriate fractions were pooled and evaporated under reduced pressure to afford the titled compound (12 mg). LCMS m/z 366.85 (M+H). 1H NMR after D20 exchange (400 MHz, DMSO-c/e) delta ppm 7.12 (d, J=2.19 Hz, 1 H) 7.24 (d, J=2.19 Hz, 1 H) 7.76 (d, J=8.55 Hz, 1 H) 7.92 (dd, J=1 1 .18, 1 .75 Hz, 1 H) 8.43 (t, J=8.33 Hz, 1 H).

Reference： [1]Patent: WO2017/98421,2017,A1 .Location in patent: Page/Page column 199

42
[ 63069-50-1 ]
[ 133059-44-6 ]

Yield	Reaction Conditions	Operation in experiment
34.7%		Step 2: Synthesis of 4-bromo-3-fluorobenzonitrile To conc. sulphuric acid (6 mL) was added sodium nitrite (0.97 g, 14.117 mmol) portion wise at 5 C. and stirred for 30 min at RT. Mixture was cooled to 0 C. and acetic acid (9.8 mL) was added dropwise, stirred for 5 min and then <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (1.6 g, 11.764 mmol) was added in small portions. Mixture was stirred for 1 h at RT. Solution of copper (I) bromide (2.5 g, 17.647 mmol) in aq. HBr (6 mL) was then added at 10 C. The resulting mixture was stirred overnight at RT. Progress of reaction was monitored by TLC. After reaction completion water was added and extracted with diethyl ether. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. Crude was purified by silica (100-200) column chromatography using 2% ethyl acetate in hexane as eluent to give 4-bromo-3-fluorobenzonitrile (0.8 g, 34.7%) as white solid. MS: 201.1 [M+1]

Reference： [1]Patent: US2017/291894,2017,A1 .Location in patent: Paragraph 0536-0538

43
[ 63069-50-1 ]
4-amino-3-fluoro-N-hydroxybenzamidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 100℃; for 5h;	To a solution of <strong>[63069-50-1]4-amino-3-fluoro-benzonitrile</strong> (5.0 g, 36.7 mmol) in ethanol (61 mL) was added 5 a hydroxylamine hydrochloride solution (5.16 g, 73.5 mmol) in 50 mL of water followed by potassiumcarbonate (8.12 g, 58.8 mmol) in 75 mL of water. To the cloudy solution was then introduced quinolin8-01 (0.07 g, 0.48 mmol). The reaction mixture was stirred for 5 hours at 100C. The reaction mixture was then cooled to 25C, the ethanol was removed under reduced pressure, and the resulting mixture was then extracted with ethyl acetate. The total combined organic layer was washed with brine, dried10 over sodium sulfate, filtered and concentrated under reduced pressure to give 5.83 g of 4-amino-3- fluoro-N-hydroxy-benzamidine as a yellow solid. The crude residue was used in the following step without further purification. LC/MS (Method A) retention time = 0.20 mm; 166 [M+H].15 (brs, 2H).1H NMR (400 MHz, CDCI3) 6 ppm: 9.30 (s, 1H), 7.25 (m, 2H), 6.70 (t, 1H), 5.60 (brs, 2H), 5.30

Reference： [1]Patent: WO2018/15449,2018,A1 .Location in patent: Page/Page column 48

44
[ 63069-50-1 ]
[ 540-72-7 ]
2-amino-4-fluoro-1,3-benzothiazole-6-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; acetic acid; at 30℃; for 16h;	To a 250 mL round-bottom flask was added 4-amino-3-Huorobenzonitrile 26a (6505 mg, 4.77 mmoL LO equiv.), AcOH (50 mL), NaSCN (1.548 g, 4.0 equiv), and Bf2 (1.132 g,7.08 mmol, 1.50 equiv) a.nd the resulting mixture was stirred at 30 C for 16 h. 100 mL ofwater -vva<; then added and the pH of the mixture was adjusted to 10 using sodium hydroxide.The solids were collected by filtration and further dried in an oven under reduced pressure togive 600 mg (65(l) of2-amino-4-fluoro-1,3-benzothiazole-6-carbonitrile 26b as a yellow10 solid. The crude product was carried onto the next step without further purification.

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 187

45
[ 63069-50-1 ]
[ 140-89-6 ]
[ 315228-79-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	In N,N-dimethyl-formamide; at 120 - 130℃;Inert atmosphere;	General procedure: A round-bottomed flask was charged with 2-bromoaniline or 2-fluoro-aniline (>3 g, 1.0 equiv) and potassium O-ethyl carbonodithioate(1.5-1.7 equiv). The mixture was dissolved in DMF (10 volumes) andheated to 120-130 C until the aniline was fully consumed (3-14 h).The reaction mixture was cooled to r.t. and filtered. The filtrate wasdiluted with H 2 O (50 volumes) and the pH was adjusted to 1-2 usingaqueous 2 M HCl. The solid precipitate was collected, washed withH 2 O and dried to yield the pure product.

Reference： [1]Synthesis,2018,vol. 50,p. 2027 - 2032

46
[ 63069-50-1 ]
[ 80945-83-1 ]

Reference： [1]Synthesis,2018,vol. 50,p. 2027 - 2032

47
[ 63069-50-1 ]
[ 141-75-3 ]
[ 407-25-0 ]
C₁₃H₁₁F₄N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
130 mg		To a mixture of <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> 150 mg, triethylamine 0.38 mL, and THF 10 mL was added dropwise butyryl chloride 0.19 mL, and the resulting mixture was stilTed at room temperature for 1 hour. The reaction solution was filtered, and then concentrated under reduced pressure. To a mixture of the resulting residues and ethanol 10 mL was added dropwise a 50% aqueous hydroxylamine solution 0.22 mL, and the resulting mixture was stilTed at 80C for 2 hours. The reaction solution was concentrated under reduced pressure. To a mixture of the resulting residues and DMF 10 mL was added dropwise pyridine 0.22 mL at room temperature, and subsequently added dropwise trifluoroacetic anhydride 0.18 mL, and then the resulting mixture was stilTed at 100C for 2 hours. To the reaction solution was added water, and the precipitates were filtered, and the filtered substances were washed with water and hexane, and then dried under reduced pressure to give the Present compound 12 represented by the following formula 130 mg. 1HNMR (CDC13) oe: 8.59 (1H, t), 7.92-7.89 (1H, m), 7.86-7.82 (1H, m), 7.48 (1H, brs), 2.42 (2H, t), 1.83-1.74 (2H, m), 1.02 (3H, t)

Reference： [1]Patent: WO2018/56340,2018,A1 .Location in patent: Paragraph 0049

48
[ 63069-50-1 ]
[ 32980-71-5 ]
3-fluoro-4-((2,6,8-trichloropyrimido[5,4-d]pyrimidin-4-yl)amino)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	In tetrahydrofuran; at 0 - 20℃; for 1h;	A suspension of tetrachloropyrimido[5,4-d]pyrimidine (0.65 g,2.4 mmol) in THF (5 mL) was added <strong>[63069-50-1]2-fluoro-4-cyanoaniline</strong> (0.11 g,0.8 mmol) at 0 C and stirred at ambient temperature for 1 h. The reactiondiluted with EtOAc, washed with brine, dried over MgSO4, andevaporated. The residue was purified by column chromatography(petro ether: EtOAc=5:1) to give compound 19 as yellow solid (0.22 g,74% yield). 1H NMR (600 MHz, CDCl3) delta (ppm): 9.37 (s, 1H), 8.94 (t,J=8.2 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.58 (dd, J=10.4, 1.7 Hz,1H). MS-ESI: [M+H]+ 469.2.

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 4080 - 4087

49
[ 63069-50-1 ]
6-bromo-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride [ No CAS ]
6-bromo-N-(4-cyano-2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4%	With pyridine; at 20℃; for 5h;	General procedure: To a solution of 1H-pyrrolo[3,2-H]quinoline-3-sulfonyl chloride (140 mg, 0.52 mmol) in pyridine (1.5 mL) was added 4-chloro-2,5-difluoroaniline (90 mg, 0.55 mmol). The reaction mixture was stirred at room temperature for 4h and then evaporated to dryness. The residue was triturated in a mixture of water/acetonitrile (8/2) and sonicated. The solid suspension was filtered, rinsed with water, dried under vacuum at 35C, to afford 105 mgof N-(4-chloro-2,5-difluorophenyl)-1 H-pyrrolo[3,2-h]quinoline-3-sulfonamide 1-118, as a beige solid.Yield: 50%.Basic LCMS Method 1 (ES): 394 (M+H), 99 % purity.1H NMR (400 MHz, DMSO-d6) 6 13.26 (s, 1H), 10.51 (s, 1H), 8.93 (dd, J = 4.4, 1.6 Hz,1 H), 8.46 (dd, J = 8.3, 1.6 Hz, 1 H), 8.04 - 7.65 (m, 3H), 7.59 (m, 1 H), 7.51 (dd, J = 9.8,6.8 Hz, 1H), 7.40 (dd, J = 10.4, 7.0 Hz, 1H).

Reference： [1]Patent: WO2018/122232,2018,A1 .Location in patent: Page/Page column 313; 317

50
[ 63069-50-1 ]
1-(benzenesulfonyl)-6-(tetrahydrofuran-2-ylmethoxy)indole-3-sulfonyl chloride [ No CAS ]
C₂₆H₂₂FN₃O₆S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 100℃; for 1h;Inert atmosphere; Sealed tube;	General procedure: In a sealed vial, i-(benzenesulfonyl)-6-chloro-indole-3-sulfonyl chloride XII-19 (i92 mg, 0.49 mmol) was dissolved in pyridine (4 mL) under argon. 2,i,3-benzoxadiazol-5-amine(i35 mg, i mmol) was added and stirred at room temperature overnight. The reaction mixture was evaporated to dryness then the residue was taken into DCM. The organic phase was washed with HCI i N and brine, dried over Mg504 and evaporated. The dark oil residue solidified on standing and was then triturated in ACN/water (8/2), sonicated and filtered, washed with water and dried under vacuum to provide i70 mg of ii(benzenesulfonyl)-N-(2,i ,3-benzoxadiazol-5-yl)-6-chloro-indole-3-sulfonamide 1-201 a as a yellow solid.Yield: 7i%.Basic LCMS Method i (ES-): 487 (M-H)-, iOO % purity.1H NMR (400 MHz, DMSO-d6)oe ii.52(s, iH), 8.99(s, iH), 8.i6-8.iO (m, 2H), 7.98(d, J= i .8 Hz, i H), 7.9i (dd, J = 9.i, 3.2 Hz, 2H), 7.63 (t, J = 7.5 Hz, i H), 7.56 - 7.5i (m, 2H),7.43 - 7.36 (m, 2H), 7.25 (dd, J = 9.6, i .9 Hz, i H).

Reference： [1]Patent: WO2018/122232,2018,A1 .Location in patent: Page/Page column 374; 375; 377

51
[ 63069-50-1 ]
7-bromo-6-chloro-1 H-indole-3-sulfonyle chloride [ No CAS ]
7-bromo-6-chloro-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With pyridine; at 100℃; for 24h;	General procedure: To a solution of 1H-pyrrolo[3,2-H]quinoline-3-sulfonyl chloride (140 mg, 0.52 mmol) in pyridine (1.5 mL) was added 4-chloro-2,5-difluoroaniline (90 mg, 0.55 mmol). The reaction mixture was stirred at room temperature for 4h and then evaporated to dryness. The residue was triturated in a mixture of water/acetonitrile (8/2) and sonicated. The solid suspension was filtered, rinsed with water, dried under vacuum at 35C, to afford 105 mgof N-(4-chloro-2,5-difluorophenyl)-1 H-pyrrolo[3,2-h]quinoline-3-sulfonamide 1-118, as a beige solid.Yield: 50%.Basic LCMS Method 1 (ES): 394 (M+H), 99 % purity.1H NMR (400 MHz, DMSO-d6) 6 13.26 (s, 1H), 10.51 (s, 1H), 8.93 (dd, J = 4.4, 1.6 Hz,1 H), 8.46 (dd, J = 8.3, 1.6 Hz, 1 H), 8.04 - 7.65 (m, 3H), 7.59 (m, 1 H), 7.51 (dd, J = 9.8,6.8 Hz, 1H), 7.40 (dd, J = 10.4, 7.0 Hz, 1H).

Reference： [1]Patent: WO2018/122232,2018,A1 .Location in patent: Page/Page column 313; 321

52
[ 63069-50-1 ]
[ 132745-00-7 ]
6-nitro-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With dmap; at 85℃; for 16h;	General procedure: To a solution of 1H-pyrrolo[3,2-H]quinoline-3-sulfonyl chloride (140 mg, 0.52 mmol) in pyridine (1.5 mL) was added 4-chloro-2,5-difluoroaniline (90 mg, 0.55 mmol). The reaction mixture was stirred at room temperature for 4h and then evaporated to dryness. The residue was triturated in a mixture of water/acetonitrile (8/2) and sonicated. The solid suspension was filtered, rinsed with water, dried under vacuum at 35C, to afford 105 mgof N-(4-chloro-2,5-difluorophenyl)-1 H-pyrrolo[3,2-h]quinoline-3-sulfonamide 1-118, as a beige solid.Yield: 50%.Basic LCMS Method 1 (ES): 394 (M+H), 99 % purity.1H NMR (400 MHz, DMSO-d6) 6 13.26 (s, 1H), 10.51 (s, 1H), 8.93 (dd, J = 4.4, 1.6 Hz,1 H), 8.46 (dd, J = 8.3, 1.6 Hz, 1 H), 8.04 - 7.65 (m, 3H), 7.59 (m, 1 H), 7.51 (dd, J = 9.8,6.8 Hz, 1H), 7.40 (dd, J = 10.4, 7.0 Hz, 1H).

Reference： [1]Patent: WO2018/122232,2018,A1 .Location in patent: Page/Page column 313; 321

53
[ 40801-88-5 ]
[ 63069-50-1 ]
N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%		A solution of indole (33.5 mg, 0.29 mmol), sulfur trioxide-pyridine complex (45.43 mg, 0.29 mmol) and pyridine (1 mL) were refluxed for 1 h at 120 C, then the mixture was cooled to room temperature, followed by evaporation of pyridine under vacuum. The resulting suspension was diluted with water (10 mL) and subsequently washed with diethyl ether (3 x 30 mL). The aqueous phase was then dried under high vacuum (or by lyophilization) to yield a solid residue. To the dry residue, triphenylphosphine (230 mg, 0.86 mmol), trichloroacetonitrile (123 mg, 0.86 mmol), and dichloromethane (1 mL) were added andthe resulting mixture was heated at 70 C for 1 h, followed by the addition of the <strong>[63069-50-1]4-amino-3-fluorobenzonitrile</strong> (46.6 mg, 0.34 mmol) and 4-picoline (239 mg, 2.57 mmol). The resulting mixture was stirred overnight at room temperature. Then the organic phase was diluted with DCM, washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The product was purified by column chromatography usingpetroleum ether (b.p. 60C): ethyl acetate, gradient from 4: 1 to 3: 2 yielding a colorless oil, which on crystallization with acetone and petroleum ether gave 9 mg of N-(4-cyano-2- fluorophenyl)-1H-indole-3-sulfonamide 1-105, as a white powder.Yield: 10%.Neutral LCMS Method 3 (ES): 316.05 (M+H)t 97% purity.1H NMR (600 MHz, DMSO-d6) 6 12.08 (s, 1H), 10.76 (s, 1H), 8.08 (d, J = 3.1 Hz, 1H),7.83 (d, J = 7.9 Hz, 1H), 7.70 (dd, J = 10.7, 1.9 Hz, 1H), 7.61 -7.48 (m, 2H), 7.49-7.42 (m, 1H), 7.16-7.24 (m, 2H).

Reference： [1]Patent: WO2018/122232,2018,A1 .Location in patent: Page/Page column 307; 308

54
[ 1024603-85-7 ]
[ 63069-50-1 ]
4-((2-((4-cyano-2-fluorophenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 12h;Reflux; Inert atmosphere;	General procedure: The compound 4-((2-chlorothieno[3,2-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (1.0 mmol) was weighed.Fluorine or trifluoromethyl substituted p-cyanoaniline (1.2 mmol), palladium acetate (0.02 g, 0.1 mmol),4,5-bis (diphenylphosphino) -9,9-dimethyl xanthene (0.06g, 0.1mmol) and cesium carbonate (0.65g, 2mmol) was added in 15mL of dioxane,The mixture was heated to reflux under nitrogen atmosphere for 12 hours.After the reaction was cooled to room temperature, it was filtered over Celite and evaporated to dryness.Then, the mixture was dissolved in dichloromethane, and brine (3×5 mL) was evaporated.The target compound was isolated by flash column chromatography, and then recrystallized from ethyl acetate- petroleum ether system to give the objective compound A1-A20.

Reference： [1]Patent: CN108440559,2018,A .Location in patent: Paragraph 0070; 0071; 0072; 0073; 0074
[2]Journal of Medicinal Chemistry,2020,vol. 63,p. 1298 - 1312

55
[ 67686-01-5 ]
[ 32315-10-9 ]
[ 63069-50-1 ]
(1-benzylpiperidin-4-yl)methyl (4-cyano-2-fluorophenyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37.1%		4-amino-3-fluorobenzonitrile (7A) (5.00 g, 36.7 mmol) and 51 trichloromethyl carbonate (5.45 g, 18.4 mmol) were added to 49 toluene (30 ml), and heated to 100°C to allow a reaction to proceed for 1 h. After cooling to room temperature, the solvent was removed by concentration under reduced pressure, and then 13 tetrahydrofuran (30 ml), 50 triethylamine (7.43 g, 73.5 mmol) and 117 (N-benzylpiperidin-4-yl)methanol (8.29 g, 40.4 mmol) were added, followed by a reaction at 80°C for 1 hour. After cooling to room temperature, 16 water (100 ml) was added to the reaction solution, which was extracted with methylene chloride (100 mL×3), and the organic phases were combined, washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (the eluent was methylene chloride:methanol (v/v) = 99:1 to 49:1), to obtain 118 (1-benzylpiperidin-4-yl)methyl (4-cyano-2-fluorophenyl)carbamate (7B) as a white solid (5.0 g, yield: 37.1percent). 1H NMR (400 MHz, CDCl3) delta 8.24 (t, 1H), 7.71 - 7.53 (m, 3H), 7.43 (dd, 4H), 7.39 - 7.32 (m, 1H), 4.26 - 4.05 (m, 4H), 3.46 (s, 2H), 2.72 (s, 2H), 2.20 (s, 2H), 1.94 (s, 3H). LCMS m/z =368.1 [M+1].

Reference： [1]Patent: EP3406606,2018,A1 .Location in patent: Paragraph 0142

56
[ 63069-50-1 ]
[ 230955-75-6 ]
C₁₈H₁₃FN₄O₃ [ No CAS ]