[ CAS No. 434-75-3 ] {[proInfo.proName]}

Name: 434-75-3|2-Chloro-6-fluorobenzoic acid|98%
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SKU: A762937
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Quality Control of [ 434-75-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 434-75-3 ]

Product Details of [ 434-75-3 ]

CAS No. :	434-75-3	MDL No. :	MFCD00002417
Formula :	C₇H₄ClFO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XNTIGDVFBDJLTQ-UHFFFAOYSA-N
M.W :	174.56	Pubchem ID :	67947
Synonyms :

Calculated chemistry of [ 434-75-3 ] Expand+

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	38.37
TPSA :	37.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.87 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.29
Log Po/w (XLOGP3) :	2.11
Log Po/w (WLOGP) :	2.6
Log Po/w (MLOGP) :	2.63
Log Po/w (SILICOS-IT) :	2.28
Consensus Log Po/w :	2.18

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.59
Solubility :	0.45 mg/ml ; 0.00258 mol/l
Class :	Soluble
Log S (Ali) :	-2.52
Solubility :	0.522 mg/ml ; 0.00299 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.66
Solubility :	0.379 mg/ml ; 0.00217 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.4

Safety of [ 434-75-3 ]

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

Application In Synthesis of [ 434-75-3 ]

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

Upstream synthesis route of [ 434-75-3 ]
Downstream synthetic route of [ 434-75-3 ]

[ 434-75-3 ] Synthesis Path-Upstream 1~8

1
[ 387-45-1 ]
[ 434-75-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium chlorite; sodium dihydrogenphosphate; dihydrogen peroxide In tetrahydrofuran; water at 20℃; for 3 h;	To the solution of 2-chloro-6-fluorobenzaidehyde {1 ,0 g, 6.31 mmoi) in 25 mL of THF and 10 ml of H2O was added 8H2PO4 (454 rng, 3.78 mmoi). The reaction was stirred 10 min at room temperature before introduction of NaCiC (1.88 g, 20.8_.1 mmoi) and 1 ,4 mL of H₂O₂ (30percentwt ._.in H2O), The reaction was stirred at room temperature 3h, Upon completion, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with an aqueous solution of NaOH 1 .. The combined aqueous layers were acidified to pH-1 ^'with an aqueous solution of HG 1 and wer extracted with EtOAc. The combined organic layers were washed with brine and dried over >SQ . Filtration and removal of the solven in. vacuo provided 1.10 g (99percent) of the title compound as a colorless solid which was used without further purification; ^{FontWeight="Bold" FontSize="10"}H NMR (400 MHz, CDC ) δ - 7.44 - 7.37 (m, 1 H), 7.31 - 7.27 (m, 1 H), 7.1 - 7,07 (m, 1 H},

Reference： [1] ChemMedChem, 2016, vol. 11, # 23, p. 2607 - 2620
[2] Patent: WO2018/52903, 2018, A1, . Location in patent: Page/Page column 47-48
[3] Tetrahedron Letters, 1988, vol. 29, # 16, p. 1967 - 1970
[4] Chemische Berichte, 1936, vol. 69, p. 2253,2255
[5] Tetrahedron Letters, 1988, vol. 29, # 16, p. 1967 - 1970

2
[ 668-45-1 ]
[ 434-75-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	at 60 - 65℃; for 2.5 h; Green chemistry	General procedure: Aromatic or aliphatic nitriles (2 mmol) were dissolved in 5 ml of [bmim]HSO₄ and the reaction mixture was heated at 60-65 °C for 1-3 h. The progress of reaction was monitored by TLC. After completion of reaction, as checked by TLC, the reaction mixture was poured into water containing crushed ice. The product was precipitated out, filtered and dried. The yield of the final product was high (>90percent) in all cases. All final products obtained were found sufficiently pure so it didn’t need further purification.The filtrate was concentrated under vacuum, washed with diethylether twice and concentrated under high vacuum. After proper drying under reduced pressure, approximately 95percent ionic liquid was recovered from the reaction and compared with the original ionic liquid to check its authenticity. The efficiency of recovered ionic liquid in conversion of nitriles to acids was found unchanged in comparison to the original one and we reused it up to 5-6 cycles without any significant loss of its activity.

Reference： [1] Tetrahedron Letters, 2014, vol. 55, # 28, p. 3802 - 3804

3
[ 443-33-4 ]
[ 434-75-3 ]

Reference： [1] Synthetic Communications, 2001, vol. 31, # 20, p. 3151 - 3159

4
[ 443-83-4 ]
[ 434-75-3 ]

Reference： [1] Journal of the Indian Chemical Society, 1944, vol. 21, p. 112,114
[2] Chemical and Pharmaceutical Bulletin, 1979, vol. 27, # 6, p. 1287 - 1298
[3] Chemische Berichte, 1936, vol. 69, p. 2253,2255

5
[ 124-38-9 ]
[ 625-98-9 ]
[ 434-75-3 ]

Reference： [1] Tetrahedron Letters, 1996, vol. 37, # 36, p. 6551 - 6554

6
[ 95-52-3 ]
[ 434-75-3 ]

Reference： [1] Journal of the Indian Chemical Society, 1944, vol. 21, p. 112,114

7
[ 434-75-3 ]
[ 363-51-9 ]

Reference： [1] Journal of Organic Chemistry, 1955, vol. 20, p. 1577,1589
[2] Patent: US4032639, 1977, A,

8
[ 434-75-3 ]
[ 56961-31-0 ]

Reference： [1] Dalton Transactions, 2018, vol. 47, # 12, p. 4341 - 4351

[ 434-75-3 ] Synthesis Path-Downstream 1~109

1
[ 443-83-4 ]
[ 434-75-3 ]

Reference： [1]Journal of the Indian Chemical Society,1944,vol. 21,p. 112,114
[2]Chemical and Pharmaceutical Bulletin,1979,vol. 27,p. 1287 - 1298
[3]Chemische Berichte,1936,vol. 69,p. 2253,2255

2
[ 387-45-1 ]
[ 434-75-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium chlorite; sodium dihydrogenphosphate; dihydrogen peroxide; In tetrahydrofuran; water; at 20℃; for 3h;	To the solution of 2-chloro-6-fluorobenzaidehyde {1 ,0 g, 6.31 mmoi) in 25 mL of THF and 10 ml of H2O was added 8H2PO4 (454 rng, 3.78 mmoi). The reaction was stirred 10 min at room temperature before introduction of NaCiC (1.88 g, 20.8.1 mmoi) and 1 ,4 mL of H2O2 (30%wt ..in H2O), The reaction was stirred at room temperature 3h, Upon completion, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with an aqueous solution of NaOH 1 .. The combined aqueous layers were acidified to pH-1 'with an aqueous solution of HG 1 and wer extracted with EtOAc. The combined organic layers were washed with brine and dried over >SQ . Filtration and removal of the solven in. vacuo provided 1.10 g (99%) of the title compound as a colorless solid which was used without further purification; FontWeight="Bold" FontSize="10" H NMR (400 MHz, CDC ) delta - 7.44 - 7.37 (m, 1 H), 7.31 - 7.27 (m, 1 H), 7.1 - 7,07 (m, 1 H},

Reference： [1]ChemMedChem,2016,vol. 11,p. 2607 - 2620
[2]Patent: WO2018/52903,2018,A1 .Location in patent: Page/Page column 47-48
[3]Tetrahedron Letters,1988,vol. 29,p. 1967 - 1970
[4]Chemische Berichte,1936,vol. 69,p. 2253,2255
[5]Tetrahedron Letters,1988,vol. 29,p. 1967 - 1970

3
[ 90-05-1 ]
[ 434-75-3 ]
[ 57317-67-6 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2357 - 2362

4
[ 124-38-9 ]
[ 625-98-9 ]
[ 434-75-3 ]

Reference： [1]Tetrahedron Letters,1996,vol. 37,p. 6551 - 6554

5
[ 959992-18-8 ]
[ 434-75-3 ]
C₂₆H₂₅ClFN₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; at 20℃; for 30h;	Example 28.1; N-(2-chloro-6-fluorobenzovn-0-[2-(3,4-dihvdro-2H-pyrido[3.2-bU1.41oxazin-6- vDethvU -L-tyrosine; To a solution of 2-chloro-5-fluorobenzoic acid (65 mg, 0.37 mmol) in DMF (1 ml) were added TBTU (141 mg, 0.37 mmol) and methyl O-[2-(3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-6-yl)ethyl]-L-tyrosinate (120 mg, 0.34 mmol). The mixture was stirred at room temperature for 30 hours. LiOH (62 mg, 1.34 mol) and H2O (0.2 ml) were then added. After stirring for 12 hours, the resulting mixture was purified by Cl 8 reverse phase chromatography (basic conditions) to give the title compound (125 mg, 74%); Mass Spectrum [M+H]+ = 500; 1H NMR Spectrum: (DMSO-d6) 2.87 (t, 2H), 2.89 (dd, IH), 3.06 (dd, IH), 3.34-3.38 (m, 2H), 4.07 (t, 2H), 4.17 (t, 2H), 4.41 (dd, IH), 6.41 (d, IH), 6.65

Reference： [1]Patent: WO2007/141473,2007,A1 .Location in patent: Page/Page column 245-246

6
[ 137-07-5 ]
[ 434-75-3 ]
2-(2-chloro-6-fluorophenyl)benzo[d]thiazole [ No CAS ]

Reference： [1]Magnetic Resonance in Chemistry,2006,vol. 44,p. 102 - 105

7
[ 696-62-8 ]
[ 434-75-3 ]
2-chloro-6-fluoro-4'-methoxybiphenyl [ No CAS ]

Reference： [1]Organic Letters,2007,vol. 9,p. 1781 - 1783
[2]Tetrahedron,2009,vol. 65,p. 4635 - 4638

8
[ 96-50-4 ]
[ 434-75-3 ]
6-fluoro-5H-[1,3]-thiazolo[2,3-b]quinazolin-5-one [ No CAS ]

Reference： [1]Synthetic Communications,2007,vol. 37,p. 1853 - 1864
[2]Magnetic Resonance in Chemistry,2009,vol. 47,p. 174 - 178

9
[ 7305-71-7 ]
[ 434-75-3 ]
6-fluoro-2-methyl-5H-[1,3]-thiazolo[2,3-b]quinazolin-5-one [ No CAS ]

Reference： [1]Synthetic Communications,2007,vol. 37,p. 1853 - 1864
[2]Magnetic Resonance in Chemistry,2009,vol. 47,p. 174 - 178

10
[ 434-75-3 ]
benzoic acid N'-tert-butyl-N'-(2-chloro-6-fluoro-benzoyl)-hydrazide [ No CAS ]

Reference： [1]Pesticide Science,1994,vol. 41,p. 139 - 148

11
[ 434-75-3 ]
[ 213208-10-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,1998,vol. 35,p. 675 - 686

12
[ 434-75-3 ]
5-{2-[4-(4-Diethylamino-butyl)-phenyl]-acetyl}-1-fluoro-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,1998,vol. 35,p. 675 - 686

13
[ 434-75-3 ]
5-{2-[4-(4-Diisopropylamino-butyl)-phenyl]-acetyl}-1-fluoro-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,1998,vol. 35,p. 675 - 686

14
[ 434-75-3 ]
[ 57317-25-6 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2357 - 2362

15
[ 434-75-3 ]
[ 57317-80-3 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2357 - 2362

16
[ 434-75-3 ]
[ 57317-73-4 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2357 - 2362

17
[ 95-52-3 ]
[ 434-75-3 ]

Reference： [1]Journal of the Indian Chemical Society,1944,vol. 21,p. 112,114

18
[ 544704-12-3 ]
[ 434-75-3 ]
C₂₇H₃₂ClF₄N₃O [ No CAS ]

Reference： [1]Patent: US6391865,2002,B1 .Location in patent: Page column 38

19
[ 554418-82-5 ]
[ 434-75-3 ]
[ 554418-86-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 30℃; for 24h;	1-hydroxybenzotriazol monohydrate (37 mg), <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (42 mg), triethylamine (34 mul), dichloromethane (2 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46 mg) were added to the compound obtained as a synthetic intermediate in Process 4 of Example 1, that is, a crude material of methyl (2S)-2-amino-3-[4-(1-methyl-2-oxo-1,2-dihydro-3-quinolinyl) phenyl] propionate hydrochloride (30 mg). After stirring the mixture at 30C for 24 hours, the reaction solution was concentrated. After adding ethyl acetate, the mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate to remove the solvent. The residue was purified with a silica gel chromatography (hexane - ethyl acetate) to obtain the objective compound (40 mg). MS (ESI MH+) : 493 CHNO : C27H22ClFN204

Reference： [1]Patent: EP1454898,2004,A1 .Location in patent: Page 30

20
[ 1056618-50-8 ]
[ 434-75-3 ]
C₂₇H₃₃ClFN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium hydrogencarbonate; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃;	To a solution of 36b (3.5 g, 10.0 mmol) in DMF (100 ml) at RT was added <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (1.75g, 10.0 mmol). To the resulting solution were added sequentially EDCI (2.0 g, 10.0 mmol), HOBt (1.35 g, 10.0 mmol) and NaHC03 (3.4g, 40.0 mmol) and the mixture was stirred overnight at RT. The solvent was evaporated under reduced pressure and the residue was dissolved in DCM (100 ml). The organics were washed with 2% HCI, water, saturated. NaHC03 solution, dried (Na2S04) and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (3.5% MeOH/DCM) to afford 3.3 g (66%) of37a: MS (ES+) m/z 502 (M + H) +.

Reference： [1]Patent: WO2005/121145,2005,A2 .Location in patent: Page/Page column 130-131

21
(E)-2-amino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester [ No CAS ]
[ 434-75-3 ]
(E)-2-(2-chloro-6-fluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 28h;	Example 64 (E)-2-(2-Chloro-6-fluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester [Show Image] Under an argon atmosphere, EDC hydrochloride (39 mg) and HOBT (3 mg) were added to a solution of 2-amino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (51 mg) and <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> in dichloromethane (1.5 ml), and the resulting mixture was stirred at room temperature for 28 hours. To the reaction solution, 1N hydrochloric acid was added, and the resulting mixture was extracted with ethyl acetate. Organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by thin layer chromatography (silica gel, developing solvent: hexane/ethyl acetate = 1/2) to obtain (E)-2-(2-chloro-6-fluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (39 mg).
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 28h;	Example 64 (E)-2-(2-Chloro-6-fluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester [Show Image] Under an argon atmosphere, EDC hydrochloride (39 mg) and HOBT (3 mg) were added to a solution of 2-amino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (51 mg) and <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> in dichloromethane (1.5 ml), and the resulting mixture was stirred at room temperature for 28 hours. To the reaction solution, 1N hydrochloric acid was added, and the resulting mixture was extracted with ethyl acetate. Organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by thin layer chromatography (silica gel, mobile phase: hexane/ethyl acetate = 1/2) to obtain (E)-2-(2-chloro-6-fluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (39 mg).

Reference： [1]Patent: WO2006/68213,2006,A1 .Location in patent: Page/Page column 101-102; 127
[2]Patent: EP2033637,2009,A1 .Location in patent: Page/Page column 70; 71
[3]Patent: EP2042171,2009,A1 .Location in patent: Page/Page column 70

22
[ 902152-86-7 ]
[ 434-75-3 ]
4-(2-chloro-6-fluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (1-methanesulphonyl-piperidin-4-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3h;	4B. 4-(2-Chloro-6-fluoro-benzoylamino)-1H-pyrazole-3-carboxyric acid (1- niethanesulphonyl-piperidin-4-yl)-amideA solution of 4-amino-1H-pyrazole-3-carboxylic acid (1-methanesulphonyl- piperidin-4-yl) amide (150 mg, 5.23 mmoles), <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (91 mg, 0.523 mmoles), HOBt (85 mg, 0.627 mmoles) and EDC (120 mg, 0.627 mmoles) in DMF (10 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was partitioned between EtOAc and a saturated solution of sodium hydrogen carbonate. The organic portion was washed with water (x2), brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography (Biotage SP4, 25S, flow rate 25ml/min, gradient EtOAc/Petrol (1 :1) to EtOAc) to give 4-(2-chloro-6-fluoro-benzoylamino)-1H-pyrazole-3- carboxylic acid (l-methanesulphonyl-piperidin-4-yl)-amide as a white solid (25 mg, 11%). (LC/MS: Rt 2.57, [M+H]+ 444.22)

Reference： [1]Patent: WO2006/77414,2006,A1 .Location in patent: Page/Page column 165

23
[ 60-29-7 ]
[ 434-75-3 ]
methyl 2-chloro-6-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In methanol;	a Esterification of 2-Chloro-6-fluorobenzoic Acid A 50-mL round-bottom flask was equipped with a magnetic stir bar, reflux condenser, thermometer, nitrogen inlet, and a heating mantle attached to a temperature controller. The flask was charged with <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (8.30 g, 47.55 mmol), methanol (15 g), and concentrated sulfuric acid (1 g). The reaction mixture was heated to 60 C. for seven days, then cooled to room temperature. Ethyl ether (50 mL) was added; the reaction mixture was transferred to a separatory funnel and washed with 1M sodium hydroxide solution (3*40 mL), then with water (40 mL). The organic layer was dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was dried under vacuum to give 5.34 g of methyl 2-chloro-6-fluorobenzoate as a yellow oil.
	With sulfuric acid; In methanol;	a) Preparation of Methyl 2-Chloro-6-fluorobenzoate from 2-Chloro-6-fluorobenzoic Acid Esterification of 2-Chloro-6-fluorobenzoic Acid A 50-mL round-bottom flask was equipped with a magnetic stir bar, reflux condenser, thermometer, nitrogen inlet, and a heating mantle attached to a temperature controller. The flask was charged with <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (8.30 g, 47.55 mmol), methanol (15 g), and concentrated sulfuric acid (1 g). The reaction mixture was heated to 60 C for seven days, then cooled to room temperature. Ethyl ether (50 mL) was added; the reaction mixture was transferred to a separatory funnel and washed with 1 M sodium hydroxide solution (3 x 40 mL), then with water (40 mL). The organic layer was dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was dried under vacuum to give 5.34 g of methyl 2-chloro-6-fluorobenzoate as a yellow oil.

Reference： [1]Patent: US5886210,1999,A
[2]Patent: EP825173,1998,A1

24
[ 50541-93-0 ]
copper(II) oxide [ No CAS ]
[ 434-75-3 ]
2-(1-benzyl-4-piperidinylamino)-6-fluorobenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N-methyl-acetamide;	Reference Example 34 Potassium carbonate (8.9 g), 4-amino-1-benzylpiperidine (18.5 g), cupric oxide (0.6 g) and dimethylformamide (25 ml) are added to <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (11.3 g) and the mixture is reacted with heating at 140 C. for 6 hours. After the reaction, the solvent is concentrated and to the resulting residue are added water (200 ml) and active carbon (1 g). The mixture is refluxed for 30 minutes. After filtration, the filtrate is cooled and then adjusted to pH 8.0 with diluted hydrochloric acid. The precipitated crystal is collected by filtration and washed successively with water and methanol to give 2-(1-benzyl-4-piperidinylamino)-6-fluorobenzoic acid (7.6 g) as white powders, m.p.: 233-236 C.

Reference： [1]Patent: US5356904,1994,A

25
[ 108-98-5 ]
[ 434-75-3 ]
6-fluoro-2-phenylthiobenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(I) iodide; potassium carbonate; In ethanol; water; nitrobenzene;	The following thiaxanthydrol starting materials were prepared by reduction of the corresponding thiaxanthones in an analogous manner to that described above. 2-methylthiaxanthydrol, m.p. 93C. (from ethanol) 2-hydroxythiaxanthydrol, m.p. 124-126C. 2-chlorothiaxanthydrol, m.p. 126.5C. (from ethanol) 2-methoxythiaxanthydrol, m.p. 103-104C. (from ethanol). The starting material 1-fluorothiaxanthydrol was prepared in the following way. To a stirred mixture of <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (52.4 g.) and nitrobenzene (225 ml.) at 80C. were added anhydrous potassium carbonate (45.6 g.), cuprous iodide (1.5 g.), copper bronze (1.5 g.) and thiophenol (34 ml.). The mixture was stirred at 160-166C. for 6 hours, cooled to room temperature, and shaken with a mixture of ether (1200 ml.) and water (2100 ml.). The aqueous phase was separated, washed with ether, filtered with charcoal and acidified with 5N sulphuric acid to give 6-fluoro-2-phenylthiobenzoic acid, m.p. 152-156C.

Reference： [1]Patent: US3948947,1976,A

26
ethylene dichloride hydrochloride [ No CAS ]
(E)-2-amino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester [ No CAS ]
[ 434-75-3 ]
(E)-2-(2-chloro-6-fluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; benzotriazol-1-ol; In dichloromethane;	Example 64 (E)-2-(2-Chloro-6-fluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester Under an argon atmosphere, EDC hydrochloride (39 mg) and HOBT (3 mg) were added to a solution of 2-amino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (51 mg) and <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> in dichloromethane (1.5 ml), and the resulting mixture was stirred at room temperature for 28 hours. To the reaction solution, 1N hydrochloric acid was added, and the resulting mixture was extracted with ethyl acetate. Organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by thin layer chromatography (silica gel, mobile phase: hexane/ethyl acetate = 1/2) to obtain (E)-2-(2-chloro-6-fluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (39 mg).

Reference： [1]Patent: EP1840121,2007,A1

27
[ 54-96-6 ]
[ 434-75-3 ]
[ 1467869-46-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5111 - 5114

28
[ 1600-27-7 ]
[ 434-75-3 ]
mercury(II) 2-chloro-6-fluorobenzoate [ No CAS ]

Reference： [1]Zeitschrift fur Anorganische und Allgemeine Chemie,
Zeitschrift fuer Anorganische und Allgemeine Chemie,1994,vol. 620,p. 993 - 998

29
[ 894401-36-6 ]
[ 434-75-3 ]
(E)-2-(2-chloro-6-fluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 28h;	Under an argon atmosphere, EDC hydrochloride (39 mg) and HOBT (3 mg) were added to a solution of 2-amino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (51 mg) and <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> in dichloromethane (1.5 ml), and the resulting mixture was stirred at room temperature for 28 hours. To the reaction solution, 1N hydrochloric acid was added, and the resulting mixture was extracted with ethyl acetate. Organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by thin layer chromatography (silica gel, developing solvent: hexane/ethyl acetate = 1/2) to obtain (E)-2-(2-chloro-6-fluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (39 mg).

Reference： [1]Patent: EP2039687,2009,A1 .Location in patent: Page/Page column 69-70

30
[ 844443-81-8 ]
[ 434-75-3 ]
[ 1048675-61-1 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4986 - 4999

31
copper(II) chloride monohydrate [ No CAS ]
[ 434-75-3 ]
tetrakis(μ-2-chloro-6-fluorobenzoato-k(2)O,O')bis[aquacopper(II)] [ No CAS ]

Reference： [1]Polyhedron,2009,vol. 28,p. 1320 - 1330

32
[ 434-75-3 ]
[ 206884-30-2 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sulfuric acid; nitric acid; at 0 - 20℃; for 1h;	[00185] Step A: 2-Chloro-6-fluorobenzoic acid (2.00 g, 11.5 mmol) was dissolved in sulfuric acid (20 mL) and cooled to 0C. Nitric acid (0.529 mL, 12.6 mmol) was added, and the reaction mixture was warmed to room temperature for one hour. The reaction mixture was diluted with water, and the aqueous portion was extracted with DCM (3 X), dried over Na2SO4, concentrated to a solid, 2-chloro-6-fluoro-3-nitrobenzoic acid (97%), which was used directly in the next step without further purification.
97%	With sulfuric acid; nitric acid; at 0 - 20℃; for 1h;	2-Chloro-6-fluorobenzoic acid (2.00 g, 11.5 mmol) was dissolved in sulfuric acid (20 mL) and cooled to 0C. Nitric acid (0.529 mL, 12.6 mmol) was added, and the reaction mixture was warmed to room temperature for one hour. The reaction mixture was diluted with water, and the aqueous portion was extracted with DCM (3 X), dried over Na2SO4, concentrated to a solid, 2-chloro-6-fluoro-3-nitrobenzoic acid (97%), which was used directly in the next step without further purification.
97%	With sulfuric acid; nitric acid; at 0 - 20℃; for 1h;	Step A: 2-Chloro-6-fluorobenzoic acid (2.00 g, 11.5 mmol) was dissolved in sulfuric acid (20 mL) and cooled to 0C. Nitric acid (0.529 mL, 12.6 mmol) was added, and the reaction mixture was warmed to room temperature for one hour. The reaction mixture was diluted with water, and the aqueous portion was extracted with DCM (3 X), dried over Na2SO4, concentrated to a solid, 2-chloro-6-fluoro-3-nitrobenzoic acid (97%), which was used directly in the next step without further purification.

97%	With sulfuric acid; nitric acid; at 0 - 20℃; for 1h;	2-Chloro-6-fluorobenzoic acid (2.00 g, 11.5 mmol) was dissolved in sulfuric acid (20 mL) and cooled to 0C. Nitric acid (0.529 mL, 12.6 mmol) was added, and the reaction mixture was warmed to room temperature for one hour. The reaction mixture was diluted with water, and the aqueous portion was extracted with DCM (3 X), dried over Na2SO4, concentrated to a solid, 2-chloro-6-fluoro-3-nitrobenzoic acid (97%), which was used directly in the next step without further purification.
90%	With sulfuric acid; nitric acid; at 20℃; for 30h;	The 2-chloro-6-fluoro benzoic acid (5.0g, 28 . 6mmol) dissolved in concentrated sulfuric acid (15.0 ml) in, under the condition in the ice water bath is added dropwise fuming nitric acid (1.3 ml, 35 . 3mmol), under conditions such that the stirring 10 minutes, removed ice-water bath, stirring at room temperature for 30 minutes. To the reaction liquid is poured into ice water, stirring 10 minutes, ethyl acetate (50 ml * 3) extraction, liquid, organic phase with saturated salt water, dried with anhydrous sodium sulfate and concentrated in vacuo to obtain the target product (5.7g, 90%).
82.2%		Stepl. 2-Chloro-6-fluoro-3-nitrobenzoic acid. To a 50 mL single-neck round- bottom flask <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong>(3.0 g, 17.1 mmol, l.Oeq) was added to H2SO4 (30 g) at 0 C under an atmosphere of nitrogen and stirred for 1 hour. Then HNO3 (1.90 g, 20.6 mmol, 1.2 eq) was added dropwise to the reaction mixture. The resulting mixture was stirred for 1 hour. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtrated and concentrated to give 2-chloro-6-fluoro-3-nitrobenzoic acid (3.1 g) as a solid. Yield: 82.2%.

Reference： [1]Patent: WO2011/25951,2011,A1 .Location in patent: Page/Page column 34
[2]Patent: WO2009/111277,2009,A1 .Location in patent: Page/Page column 42
[3]Patent: WO2009/111280,2009,A1 .Location in patent: Page/Page column 41
[4]Patent: WO2009/111279,2009,A1 .Location in patent: Page/Page column 69
[5]Patent: CN103102349,2017,B .Location in patent: Paragraph 0297-0299
[6]Patent: WO2012/138809,2012,A1 .Location in patent: Page/Page column 15

33
C₆₄H₆₉F₂N₈O₁₅P [ No CAS ]
[ 434-75-3 ]
C₇₁H₇₁ClF₃N₈O₁₆P [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2009,vol. 131,p. 13072 - 13079

34
[ 136-95-8 ]
[ 434-75-3 ]
[ 1120366-09-7 ]

Reference： [1]Magnetic Resonance in Chemistry,2009,vol. 47,p. 174 - 178

35
[ 434-75-3 ]
[ 1206164-19-3 ]

Reference： [1]Angewandte Chemie - International Edition,2009,vol. 48,p. 9350 - 9354
[2]Organic Letters,2010,vol. 12,p. 1000 - 1003

36
[ 3581-91-7 ]
[ 434-75-3 ]
[ 1218780-38-1 ]

Reference： [1]Organic Letters,2010,vol. 12,p. 1564 - 1567

37
[ 95-16-9 ]
[ 434-75-3 ]
2-(2-chloro-6-fluorophenyl)benzo[d]thiazole [ No CAS ]

Reference： [1]Organic Letters,2017,vol. 19,p. 5589 - 5592
[2]Organic Letters,2010,vol. 12,p. 1564 - 1567

38
[ 5404-86-4 ]
[ 434-75-3 ]
[ 1233081-06-5 ]

Yield	Reaction Conditions	Operation in experiment
12%		-chloro-6-fluoro-LambdaT-(9H-purin-6-yl)benzohydrazideTo a solution of <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (0.52 g, 3.0 mmol) in anhydrous Lambda/,Lambda/-dimethyl-formamide (20 ml_) was added O-benzotriazole- Lambda/,Lambda/,Lambda/',Lambda/'-tetramethyl uronium hexafluoro-phosphate (HBTU, 1.14 g, 3.0 mmol). The solution was stirred at room temperature for 10 minutes then diisopropylethylamine (0.77 g, 6.0 mmol) and 6-hydrazinyl-9H-purine (0.45 g, 3.0 mmol) were added to the reaction mixture. The reaction was flushed with argon and stirred at 75C for 18 hours overnight. The reaction was transferred to a separatory funnel containing water (100 ml_) and diluted with ethyl acetate (75 ml_). The layers were shaken and separated, and the aqueous layer was concentrated in vacuo to give a dark brown solid. The crude solid was recrystallized in hot ethanol to give a beige powder (110 mg, 12%). 1H- NMR (400 MHz, d6-DMSO) delta 13.11 (s, 1 H), 10.69 (s, 1H), 9.87 (s, 1 H), 8.30- 8.20 (m, 2H), 7.58-7.49 (m, 1H), 7.44-7.38 (m, 1 H), 7.34 (t, J = 8.40 Hz, 1 H); Mass spectrum (ESI +ve) m/z 307.0 (MH+, 35CI), 309.0 (MH+, 37CI).

Reference： [1]Patent: WO2010/74746,2010,A1 .Location in patent: Page/Page column 89-90

39
[ 913570-34-0 ]
[ 434-75-3 ]
[ 1253188-10-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16.1667h;	Example 180: 2-Chloro-Lambda/-H -(( 5-chloro-2-r(phenylmethyl)oxy1phenyl)methyl)- 1H-pyrazol-3-yll-6-fluorobenzamide; To a solution of <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (18 mg, 0.1 mmol, Aldrich) in DMF (0.1 ml) was added a solution of HATU (38 mg, 0.1 mmol) in DMF (0.2 ml). After 5 min, DIPEA (0.050 ml, 0.27 mmol) was added to the mixture. To the mixture was added a solution of 1-({5-chloro-2-[(phenylmethyl)oxy]phenyl}methyl)-1 H-pyrazol-3-amine (for a preparation see Intermediate 55)(0.1 mmol) in DMF (0.1 ml). After shaking for 10 min, the resulting solution was allowed to stand for 16 h at ambient temperature. The solvent was removed using a genevac. The sample was dissolved in 1 :1 MeOH:DMSO (0.6 ml) and purified by MDAP on a C18 column using Acetonitrile- Water with a TFA modifier (Method D). The solvent was evaporated in vacuo using the Genevac to give the title compound; LCMS (System 3) MH+ = 470/472, tRET = 1.32 min.

Reference： [1]Patent: WO2010/122089,2010,A1 .Location in patent: Page/Page column 143

40
[ 925252-73-9 ]
[ 434-75-3 ]
3-butyl-8-chloro-1-{4-[5-(2-chloro-6-fluorophenyl)-1,2,4-oxadiazol-3-yl]-butyl}-3,7-dihydro-1H-purine-2,6-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5%		Example 140: 3-Butyl-8<:hloro-144-r5-(2-chloro-6-fluorophenyl)-1.2.4-oxadiazol-3- v?butyl>-3.7-dihvdro-1H-purine-2.6-dione2-Chloro-6-fluorobenzoic acid (44mg, 0.25mmol) and CDI (45mg, 0.28mmol) were stirred in anhydrous DMSO (0.9ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo- 2,3,6,7-tetrahydro-1/-/-purin-1-yl)-Lambda/-hydroxypentanimidamide (100mg, 0.28mmol) was added and the mixture was stirred at 9O0C for 16h. The mixture was purified by MDAP.The product fraction was combined and concentrated to give the title compound as a white solid (6.4mg, 5%).LC/MS: m/z 495 [MH]+, RT 3.58min.

Reference： [1]Patent: WO2007/17261,2007,A1 .Location in patent: Page/Page column 101

41
[ 434-75-3 ]
[ 1186194-01-3 ]

Reference： [1]Patent: WO2011/25951,2011,A1
[2]Patent: CN103102349,2017,B
[3]Patent: WO2009/111277,2009,A1
[4]Patent: WO2009/111280,2009,A1

42
[ 434-75-3 ]
[ 1294494-80-6 ]

Reference： [1]Patent: WO2011/48004,2011,A1
[2]Patent: US2011/263556,2011,A1

43
[ 434-75-3 ]
[ 1294552-10-5 ]

Reference： [1]Patent: WO2011/48004,2011,A1
[2]Patent: US2011/263556,2011,A1

44
[ 50667-69-1 ]
[ 434-75-3 ]
[ 1294496-80-2 ]

Yield	Reaction Conditions	Operation in experiment
23%	With sulfuric acid; at 20℃;Cooling with ice;	(a) 2-Chlor-6-flour-3-(trifluormethylcarbonylamino)methyl-benzoic acidN-(Hydroxymethyl)trifluoracetamide (0,82 g; 5,73 mmol) was added to a mixture of 10 mL cone. H2S04 and 2-chlor-6-fluorbenzoic acid (1 g; 5,73 mmol) under ice bath cooling and stirred at rt overnight. The mixture was poured into ice, DCM was added, the resulting precipitate was filtered, washed with DCM and water and dried. The residue was purified by HPLC.Yield: 400 mg (23%; Purity: 95%) MS: [M-H]" = 298
23%	With sulfuric acid; at 20℃;	N-(Hydroxymethyl)trifluoracetamide (0.82 g; 5.73 mmol) was added to a mixture of 10 mL conc. H2SO4 and <strong>[434-75-3]2-chlor-6-fluorobenzoic acid</strong> (1 g; 5.73 mmol) under ice bath cooling and stirred at rt overnight. The mixture was poured into ice, DCM was added, the resulting precipitate was filtered, washed with DCM and water and dried. The residue was purified by HPLC.Yield: 400 mg (23%; Purity: 95%) MS: [M-H]-=298

Reference： [1]Patent: WO2011/48004,2011,A1 .Location in patent: Page/Page column 92
[2]Patent: US2011/263556,2011,A1 .Location in patent: Page/Page column 44

45
[ 434-75-3 ]
[ 1094457-24-5 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 2594 - 2596

46
[ 434-75-3 ]
(2-chloro-6-fluorophenyl)(phenyl)methanone [ No CAS ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 2594 - 2596
[2]Angewandte Chemie - International Edition,2019,vol. 58,p. 5085 - 5089
Angew. Chem.,2019,vol. 131,p. 5139 - 5143,5

47
[ 552-16-9 ]
[ 434-75-3 ]
[ 2436-96-6 ]
[ 1352638-60-8 ]
[ 1352638-63-1 ]

Reference： [1]European Journal of Organic Chemistry,2011,p. 5787 - 5790

48
[ 3113-72-2 ]
[ 434-75-3 ]
[ 1352638-63-1 ]
[ 1352638-62-0 ]
[ 114324-70-8 ]

Reference： [1]European Journal of Organic Chemistry,2011,p. 5787 - 5790

49
[ 2516-95-2 ]
[ 434-75-3 ]
[ 1352638-63-1 ]
[ 1352638-61-9 ]
[ 19036-42-1 ]

Reference： [1]European Journal of Organic Chemistry,2011,p. 5787 - 5790

50
[ 494769-44-7 ]
[ 434-75-3 ]
[ 1363397-35-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 8h;	General procedure: The intermediate (3) (0.5 g, 0.00217 mol), EDCl (0.622 g, 0.00325 mol), DMAP (0.345 g, 0.0028 mol) were stirred in dichloromethane (6 mL) at 0 C, and the substituted acid (0.00217 mol) were dissolved in (4 mL) of dichloromethane and charged to the reaction mixture and stirred at room temperature for 8 h. The reaction completion was monitored by TLC. Reaction was completed. The reaction mixture was diluted with (10 mL) of dichloromethane, and was washed with 10% NaHCO3 (10 mL). Separated the organic layer and was washed with saturated brine solution (10 mL). The organic layer was dried over sodium sulfate and concentrated the organic layer under reduced pressure to afford compounds 4a-t. The spectral data of compounds 4(a-t) are given below.

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 49,p. 172 - 182

51
[ 434-75-3 ]
[ 935984-69-3 ]

Reference： [1]Journal of Fluorine Chemistry,2012,vol. 135,p. 240 - 245

52
[ 434-75-3 ]
[ 1363189-03-0 ]

Reference： [1]Journal of Fluorine Chemistry,2012,vol. 135,p. 240 - 245

53
[ 434-75-3 ]
[ 1363189-44-9 ]

Reference： [1]Journal of Fluorine Chemistry,2012,vol. 135,p. 240 - 245

54
[ 434-75-3 ]
[ 1363189-63-2 ]

Reference： [1]Journal of Fluorine Chemistry,2012,vol. 135,p. 240 - 245

55
[ 434-75-3 ]
[ 1363189-23-4 ]

Reference： [1]Journal of Fluorine Chemistry,2012,vol. 135,p. 240 - 245

56
[ 1374298-77-7 ]
[ 434-75-3 ]
[ 1374298-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; for 18h;	Step 2 -Preparation of methyl 2-(2-chloro-6-fluorobenzamido)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate To a solution of methyl 2-amino-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (1.00 g, 3.81 mmol) in THF (25 mL) was added EDCI.HCl (1.4 g, 7.62 mmol), HOBT (1.00 g, 7.62 mmol), <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (1.32 g 7.62 mmol) and TEA (3 mL). The reaction mass was stirred for 18 h. The reaction mass was quenched in water extracted with 10% DCM: methanol. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on basic alumina eluting with 0.7% DCM: MeOH to afford 0.700 g of the desired product. 1HNMR (DMSO-d6): delta 1.43 (s, 6H), 3.02 (s, 2H), 3.58 (s, 3H), 6.08 (bs, 1H), 7.59-7.69 (m, 2H), 7.83 (q, J=6.6 Hz, 1H), 8.14 (bs, 2H); MS [M+H]+: 418.05.

Reference： [1]Patent: US2012/108583,2012,A1 .Location in patent: Page/Page column 39

57
[ 434-75-3 ]
[ 1254566-97-6 ]

Reference： [1]Patent: WO2012/138809,2012,A1

58
[ 434-75-3 ]
[ 1402558-52-4 ]

Reference： [1]Patent: WO2012/138809,2012,A1

59
[ 434-75-3 ]
[ 1402558-54-6 ]

Reference： [1]Patent: WO2012/138809,2012,A1

60
[ 434-75-3 ]
[ 1402558-56-8 ]

Reference： [1]Patent: WO2012/138809,2012,A1

61
[ 434-75-3 ]
[ 1402558-62-6 ]

Reference： [1]Patent: WO2012/138809,2012,A1

62
[ 434-75-3 ]
[ 1402558-60-4 ]

Reference： [1]Patent: WO2012/138809,2012,A1

63
[ 1400745-80-3 ]
[ 434-75-3 ]
[ 1400745-13-2 ]

Yield	Reaction Conditions	Operation in experiment
56%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	General procedure: Compound 3 (1 mmol) and amine compounds (1.2 mmol) and HATU (1.2 mmol) or EDCI (1.2 mmol) and HOBt (1.2 mmol) were added to DCM (10 mL) containing Et3N (0.5 mmol); the mixture was then stirred at room temperature for 6-12 h. After the reaction was completed, the mixture was poured onto 100 mL of distilled water and partitioned with ethyl acetate (3 × 50 mL). The target compounds were purified on a flash column with chloroform/methanol (20:1, v/v) to yield compounds 4a-4w. The structures were confirmed by IR, ESI-MS, 1H NMR and 13C NMR (see Supporting information).

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 58,p. 128 - 135

64
[ 271-34-1 ]
[ 434-75-3 ]
[ 1415125-05-1 ]

Yield	Reaction Conditions	Operation in experiment
39.5%		Step a: (2-chloro-6-fluorophenyl)( 1H-pyrrolo[3,2-c]pyridin-1 -yl)methanoneTo a stirred solution of <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (2.5 g, 14.32 mmol) in dichloromethane (20 ml_), oxalyl chloride (3.029 ml, 28.64 mmol) was added at 0 C. After stirring at the same temperature for 15 min, dimethylfromamide (2-3 drops) was added, and the reaction was allowed to stir at room temperature for 1 .5 hours. The reaction mixture was cooled and concentrated on rotary evaporator. The residue was taken up in dichloromethane (20 ml_) and treated with 5-azaindole (1 .72 g, 14.51 mmol) and triethylamine (6.1 ml_, 43.52 mmol). The resulting reaction mixture was allowed to stir at room temperature for 20 hours. The reaction mixture was concentrated under vacuum, diluted with water (50 ml_) and extracted with ethyl acetate (2 x 100 ml_). The combined organic layer was washed with saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under rotary evaporator. The product was isolated by silica gel column chromatography using ethyl acetate (25%) in hexanes as eluent to yield (2-chloro-6-fluorophenyl)(1 H- pyrrolo[3,2-c]pyridin-1 -yl)methanone (1 .56 g, 39.5%).MS (m/z): 274.68 (M+)
39.5%		To a stirred solution of <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (2.5 g, 14.32 mmol) in dichloromethane (20 mL), oxalyl chloride (3.029 ml, 28.64 mmol) was added at 0 C. After stirring at the same temperature for 15 min, dimethylfromamide (2-3 drops) was added, and the reaction was allowed to stir at room temperature for 1.5 hours. The reaction mixture was cooled and concentrated on rotary evaporator. The residue was taken up in dichloromethane (20 mL) and treated with 5-azaindole (1.72 g, 14.51 mmol) and triethylamine (6.1 mL, 43.52 mmol). The resulting reaction mixture was allowed to stir at room temperature for 20 hours. The reaction mixture was concentrated under vacuum, diluted with water (50 mL) and extracted with ethyl acetate (2*100 mL). The combined organic layer was washed with saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under rotary evaporator. The product was isolated by silica gel column chromatography using ethyl acetate (25%) in hexanes as eluent to yield (2-chloro-6-fluorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (1.56 g, 39.5%). MS (m/z): 274.68 (M+)

Reference： [1]Patent: WO2012/160464,2012,A1 .Location in patent: Page/Page column 124-125
[2]Patent: US2014/155398,2014,A1 .Location in patent: Paragraph 0757

65
[ 1417411-63-2 ]
[ 65407-77-4 ]
[ 434-75-3 ]
[ 1417411-64-3 ]
[ 1417411-65-4 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 19 (I- 19a) and (I- 19b)(1-1 9a) (l-19b)2-Chloro-6-fiuorobenzoic acid (0.698 g, 4 mmol) in DMF (20 mL) and DIPEA(1.072 mL, 6.22 mmol) was treated with HBTU (1.52 g, 4 mmol) and the r.m. was stirred for 15 min at r.t. Then a mixture of intermediates (I-18a) and (I-18b) (0.9 g, 3.56 mmol) in DMF (20 mL) was added and the stirring was prolonged for further 16 h at the same temperature. The r.m. was then poured onto ice/H20 (0.5 L) and the solid thus obtained was collected by filtration. The solid was then diluted with DCM (0.1 L) and treated with 1 M NaOH aq. solution (20 mL). The organic layers were separated, washed with IM HCl (20 mL), then with IM NaOH (20 mL), dried (MgS04), filtered and the solvent concentrated in vacuo. The crude mixture was purified by column chromatography (silica; MeOH in DCM 0: 100 to 5:95) to give an off white solid which was recrystallized from Heptane/EtOAc (~15 mL/~5 mL) yielding finally a mixture of intermediates (I-19a) and (I-19b) as off white solid (0.75 g, 51%). Ci6HiiBrClFN40, LCMS: 5.18 (co-elution of the two peaks), m/z 409 [M + H]+ (method 10)

Reference： [1]Patent: WO2013/924,2013,A1 .Location in patent: Page/Page column 65

66
[ 434-75-3 ]
[ 1427158-58-4 ]

Reference： [1]Patent: WO2013/38308,2013,A1

67
[ 1436502-37-2 ]
[ 434-75-3 ]
[ 1436500-19-4 ]

Yield	Reaction Conditions	Operation in experiment
30 mg		To a solution of <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (441 mg, 2.53 mmol) in CH2C12 (4.0 mL) was added oxalyl chloride (956 mg, 7.58 mmol) and DMF (0.5 mL). The reaction mass was stirred at rt for 2 h before it was concentrated. The residue was dissolved in DMF (1 mL) and was added to a solution of 7-amino-2-(4-bromophenyl)phthalazin-l(2H)-one (Intermediate-2, 100 mg, 0.316 mmol) in DMF (2 mL) and pyridine (1.0 mL) at rt. The reaction mass was stirred at 80-90C for 2-3 h. Then the reaction mass was concentrated and purified by column chromatography to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d6): delta 1 1.44 (s, 1H), 8.76 (s, 1H), 8.55 (s, 1H), 8.15 (d, / = 8.4 Hz, 1H), 8.04 (d, / = 8.7 Hz, 1H), 7.71 (d, / = 8.7 Hz, 2H), 7.56-763 (m, 3H), 7.41 -7.51 (m, 2H), MS [M]+ :474.15.

Reference： [1]Patent: WO2013/72825,2013,A1 .Location in patent: Page/Page column 65

68
[ 434-75-3 ]
[ 1016522-68-1 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 8436 - 8439

69
[ 434-75-3 ]
[ 895700-93-3 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 8436 - 8439

70
[ 434-75-3 ]
[ 1438897-26-7 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 4521 - 4536

71
[ 434-75-3 ]
C₁₂H₇BrClFN₂O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 4521 - 4536

72
[ 30235-26-8 ]
[ 434-75-3 ]
2-[(2-chloro-6-fluorobenzoyl)amino]-4-(pyridin-2-yl)thiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		General procedure: 5.1.3. General procedure C. To the carboxylic acid substrate (0.42 mmol, 1.2 equiv) in DMF (1.5 mL) was added CDI (0.50 mmol, 1.1equiv) and DBU (0.67 mmol, 1.9 equiv). The reaction was stirred for 30 min at 23 C. Next, 2-amino-4-(2-pyridyl)thiazole 20 (0.35 mmol, 1.0 equiv) was added and the reaction mixture was stirred for 16 h at 23 C. A small amount of silica gel was added to the reaction mixture, which was concentrated in vacuo under reduced pressure. The crude product impregnated on the silica gel was purified by silica gel flash chromatography (0-10% MeOH-CH2Cl2) to afford the title compound.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 6385 - 6397

73
[ 434-75-3 ]
[ 1417411-03-0 ]

Reference： [1]Patent: WO2014/1314,2014,A1

74
[ 434-75-3 ]
[ 1417411-66-5 ]

Reference： [1]Patent: WO2014/1314,2014,A1

75
[ 434-75-3 ]
[ 1417409-16-5 ]

Reference： [1]Patent: WO2014/1314,2014,A1

76
[ 600-22-6 ]
[ 1575-37-7 ]
[ 434-75-3 ]
C₁₆H₁₃BrClFN₄O [ No CAS ]
C₁₆H₁₃BrClFN₄O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Intermediates 1-a and 1-b ((I-la) and (I-lb)) Methyl pyruvate (8.69 mL, 96.24 mmol) was added to a solution of 4-bromo-l,2- diaminobenzene (15 g, 80 mmol) dissolved in toluene (120 mL) in a round flask, equipped with a Dean-Stark apparatus. Then the r.m. was heated under reflux for 3 h. When the reaction was finished, the solvent was removed in vacuo and the crude product was washed with diethyl ether to give a mixture of intermediates (I-la) and (I- lb) as a pale gray solid that was used as such in the next step (16 g, 83%). LCMS: Rt 1.07 (first isomer), 1.15 (second isomer), m/z 239 [M + H]+ (method 2). A batch of the regioisomeric mixture was separated by suspending the mixture in methanol and ammonium hydroxide (q.s.), warming up to reflux and cooling down to room temperature. The precipitate that formed was filtered, water was added to the filtrate and the precipitate that formed was also recovered by filtration. Two additional cycles were repeated to obtain a precipitate containing a 94:6 mixture of I-la:I-lb. Intermediates 2-a and 2-b ((I-2a) and (I-2b)) (l-2a) (\|-2b) The mixture of intermediates (I-la) and (I-lb) (16 g, 66.95 mmol) was dissolved in POCI3 (78 mL), and the r.m. was stirred for 2 h at 120C. The solvent was then evaporated and the mixture was cooled down in an ice bath and gently NH4OH was added dropwise until it reached a basic pH. Once the addition was completed, the formed precipitate was filtered off, washed with H20 and then washed several times with DCM. The organic solvent was dried (Na2S04), filtered, and concentrated in vacuo. The crude product was purified by open column chromatography (silica, DCM in heptane 20/80 to 80/20), the desired fractions were collected and concentrated in vacuo to give a mixture of intermediates (I-2a) and (I-2b) as white solid (12 g, 69%). C9H6BrCl 2, LCMS: Rt 2.95 (co-elution of the two peaks), m/z 257 [M + H]+ (method 8). Intermediate 13-a and 13-b (I-13a) and (I-13b) Hydrazine hydrate (60% in H20, 0.52 mL, 9.7 mmol) was added to a mixture of Intermediate (I-2a) and Intermediate (I-2b) (1 g, 3.88 mmol) in MeOH (15 mL) at r.t. The r.m. was then heated at 50 C for 30 min, after that it was diluted with H20 (5 mL) and extracted with DCM (20 mL). The organic layers were separated, dried (MgS04), filtered and concentrated in vacuo to give a mixture of intermediates (I-13a) and (I-13b) (0.92 g, 96%) that was used as such in the next reaction step. LCMS: 4.29 (co-elution of the two peaks), m/z 253 [M + H]+ (method 7). Intermediate 14-a and 14-b (I-14a) and (I-14b) (l-14a) (l-14b) 2-Chloro-6-fiuorobenzoic acid (0.698 g, 4 mmol) in DMF (20 mL) and DIPEA (1.072 mL, 6.22 mmol) was treated with HBTU (1.52 g, 4 mmol) and the r.m. was stirred for 15 min at r.t. Then a mixture of intermediates (I-13a) and (I-13b) (0.9 g, 3.56 mmol) in DMF (20 mL) was added and the stirring was prolonged for further 16 h at the same temperature. The r.m. was then poured onto ice/H20 (0.5 L) and the solid thus obtained was collected by filtration. The solid was then diluted with DCM (0.1 L) and treated with 1 M NaOH aq. solution (20 mL). The organic layers were separated, washed with 1M HC1 (20 mL), then with 1M NaOH (20 mL), dried (MgS04), filtered and the solvent concentrated in vacuo. The crude mixture was purified by column chromatography (silica; MeOH in DCM 0: 100 to 5:95) to give an off white solid which was recrystallized from Heptane/EtOAc (~15 mL/~5 mL) yielding finally a mixture of intermediates (I-14a) and (I-14b) as off white solid (0.75 g, 51%). Ci6HiiBrClFN40, LCMS: 5.18 (co-elution of the two peaks), m/z 409 [M + H]+ (method 7).

Reference： [1]Patent: WO2014/1314,2014,A1 .Location in patent: Page/Page column 50-51; 56

77
[ 600-22-6 ]
[ 1575-37-7 ]
[ 434-75-3 ]
[ 1417411-02-9 ]
[ 1417411-45-0 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediates 1-a and 1-b ((I-la) and (I-lb)) Methyl pyruvate (8.69 mL, 96.24 mmol) was added to a solution of 4-bromo-l,2- diaminobenzene (15 g, 80 mmol) dissolved in toluene (120 mL) in a round flask, equipped with a Dean-Stark apparatus. Then the r.m. was heated under reflux for 3 h. When the reaction was finished, the solvent was removed in vacuo and the crude product was washed with diethyl ether to give a mixture of intermediates (I-la) and (I- lb) as a pale gray solid that was used as such in the next step (16 g, 83%). LCMS: Rt 1.07 (first isomer), 1.15 (second isomer), m/z 239 [M + H]+ (method 2). A batch of the regioisomeric mixture was separated by suspending the mixture in methanol and ammonium hydroxide (q.s.), warming up to reflux and cooling down to room temperature. The precipitate that formed was filtered, water was added to the filtrate and the precipitate that formed was also recovered by filtration. Two additional cycles were repeated to obtain a precipitate containing a 94:6 mixture of I-la:I-lb. Intermediates 2-a and 2-b ((I-2a) and (I-2b)) (l-2a) (\|-2b) The mixture of intermediates (I-la) and (I-lb) (16 g, 66.95 mmol) was dissolved in POCI3 (78 mL), and the r.m. was stirred for 2 h at 120C. The solvent was then evaporated and the mixture was cooled down in an ice bath and gently NH4OH was added dropwise until it reached a basic pH. Once the addition was completed, the formed precipitate was filtered off, washed with H20 and then washed several times with DCM. The organic solvent was dried (Na2S04), filtered, and concentrated in vacuo. The crude product was purified by open column chromatography (silica, DCM in heptane 20/80 to 80/20), the desired fractions were collected and concentrated in vacuo to give a mixture of intermediates (I-2a) and (I-2b) as white solid (12 g, 69%). C9H6BrCl 2, LCMS: Rt 2.95 (co-elution of the two peaks), m/z 257 [M + H]+ (method 8). Intermediate 13-a and 13-b (I-13a) and (I-13b) Hydrazine hydrate (60% in H20, 0.52 mL, 9.7 mmol) was added to a mixture of Intermediate (I-2a) and Intermediate (I-2b) (1 g, 3.88 mmol) in MeOH (15 mL) at r.t. The r.m. was then heated at 50 C for 30 min, after that it was diluted with H20 (5 mL) and extracted with DCM (20 mL). The organic layers were separated, dried (MgS04), filtered and concentrated in vacuo to give a mixture of intermediates (I-13a) and (I-13b) (0.92 g, 96%) that was used as such in the next reaction step. LCMS: 4.29 (co-elution of the two peaks), m/z 253 [M + H]+ (method 7). Intermediate 14-a and 14-b (I-14a) and (I-14b) (l-14a) (l-14b) 2-Chloro-6-fiuorobenzoic acid (0.698 g, 4 mmol) in DMF (20 mL) and DIPEA (1.072 mL, 6.22 mmol) was treated with HBTU (1.52 g, 4 mmol) and the r.m. was stirred for 15 min at r.t. Then a mixture of intermediates (I-13a) and (I-13b) (0.9 g, 3.56 mmol) in DMF (20 mL) was added and the stirring was prolonged for further 16 h at the same temperature. The r.m. was then poured onto ice/H20 (0.5 L) and the solid thus obtained was collected by filtration. The solid was then diluted with DCM (0.1 L) and treated with 1 M NaOH aq. solution (20 mL). The organic layers were separated, washed with 1M HC1 (20 mL), then with 1M NaOH (20 mL), dried (MgS04), filtered and the solvent concentrated in vacuo. The crude mixture was purified by column chromatography (silica; MeOH in DCM 0: 100 to 5:95) to give an off white solid which was recrystallized from Heptane/EtOAc (~15 mL/~5 mL) yielding finally a mixture of intermediates (I-14a) and (I-14b) as off white solid (0.75 g, 51%). Ci6HiiBrClFN40, LCMS: 5.18 (co-elution of the two peaks), m/z 409 [M + H]+ (method 7). Intermediate 15-a and 15b (I- 15a) and (I- 15b) 8-Bromo- l-(2-chloro-6-fluor ophenyl)-4-methyl [ 1 ,2,4] triazolo [4,3-a] quinoxaline A mixture of intermediates (I-14a) and (I-14b) (1 g, 2.44 mmol) in DCE (20 mL) was treated with POCI3 (0.6 mL, 6.5 mmol) and the r.m. was heated at 70 C for 16 h. Then, additional POCI3 (0.6 mL, 6.5 mmol) was added and the mixture heated at the same temperature as before further for 5 h. After this time, again more POCI3 (1.2 mL, 13 mmol) was added and the mixture heated as before for further 16 h. The r.m. was cooled and poured onto ice/aq. NH4OH (150 mL/150 mL) and the layers separated. The organic phase was dried (MgS04), filtered and concentrated in vacuo. The crude compound was purified by chromatography (silica; MeOH in DCM 0/100 to 2/98) to give a mixture of intermediate (I-15a) together with its regioisomer (I-15b) (0.7 g, 75%). A batch of the regioisomeric mixture was separated by column chromatography (silica, EtOAC in CH2CI2, 0/100 to 25/75) to give intermediate (I-15a) as pure isomer. Ci6H9BrClFN4, LCMS: 2.58, m/z 391 [M + H]+ (method 3).

Reference： [1]Patent: WO2014/1314,2014,A1 .Location in patent: Page/Page column 50-51; 56-57

78
[ 874473-14-0 ]
[ 434-75-3 ]
[ 1572516-34-7 ]
[ 1572516-37-0 ]

Yield	Reaction Conditions	Operation in experiment
		Synthesis of 6-chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid and 2- chloro-6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (2 g, 11.46 mmol) was treated with chlorosulfonic acid (10 mL, 150.44 mmol) and this was heated to 100C and stirred for 5 hours. The resulting mixture was cooled to room temperature and added dropwise to ice-water (1 liter). This was then extracted using dichloromethane (2 x 500 mL). The combined organics were dried on Na2S04, filtered and concentrated in vacuo yielding an isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fluoro-benzoic acid and 6-chloro-3- chlorosulfonyl-2-fluoro-benzoic acid (3.1 gram) as a slightly yellow powder which was used as such.Method F, Rt: 0.47 min and 0.49 min. m/z : 270.9 (M-H)- Exact mass: 271.9. Sodium carbonate (1.21 g, 11.4 mmol) was dissolved in distilled water (22 mL). To this was added 3-methyl-3-oxetanamine (1.19 g, 13.68 mmol) at once followed by THF (20 mL). The obtained solution was stirred and cooled in an ice bath. An isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fluoro-benzoic acid and 6-chloro-3- chlorosulfonyl-2-fluoro-benzoic acid (3.1 g, 11.4 mmol) was dissolved in THF (30 mL) and this was added drop wise to the stirring solution. The resulting mixture was stirred for 30 minutes while cooling was continued. Then, the mixture was stirred for 3 hours at room temperature.The mixture was concentrated in vacuo untill only water remained. Then water (20 mL) was added and the mixture was acidified with HC1 (46 mL, 1M / aq). This was extracted using Me-THF (3 X 50 mL). The combined organics were dried on Na2S04, filtered and concentrated in vacuo. The residue was purified, and isomers were separated using preparative HPLC (Stationary phase: Uptisphere CI 8 ODB - IotaOmicronmuetaiota, 200g, 5cm), Mobile phase: 0.25% NH4HC03 solution in water, MeOH) , yielding 6-chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid as a white powder. Method G, Rt: 0.40 min. m/z : 322.0 (M-H)" Exact mass: 323.0. 1H NMR (400 MHz, DMSO-d ) ppm 1.42 (s, 3 H), 4.15 (d, J=6.6 Hz, 2 H), 4.61 (d, J=5.9 Hz, 13 H), 7.29 (dd, J=8.5, 0.8 Hz, 1 H), 7.36 - 7.73 (m, 5 H). and 2-chloro-6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid as a white powder. Method G, Rt: 0.34 min. m/z : 321.9 (M-H)" Exact mass: 323.0
		Synthesis of 6-chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid and 2- chloro-6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (2 g, 11.46 mmol) was treated with chlorosulfonic acid (10 mL, 150.44 mmol) and this was heated to 100C and stirred for 5 hours. The resulting mixture was cooled to room temperature and added dropwise to ice-water (1 liter). This was then extracted using dichloromethane (2 x 500 mL). The combined organics were dried on Na2S04, filtered and concentrated in vacuo yielding an isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fluoro-benzoic acid and 6-chloro-3- chlorosulfonyl-2-fluoro-benzoic acid (3.1 gram) as a slightly yellow powder which was used as such.Method F, Rt: 0.47 min and 0.49 min. m/z : 270.9 (M-H)- Exact mass: 271.9. Sodium carbonate (1.21 g, 11.4 mmol) was dissolved in distilled water (22 mL). To this was added 3-methyl-3-oxetanamine (1.19 g, 13.68 mmol) at once followed by THF (20 mL). The obtained solution was stirred and cooled in an ice bath. An isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fluoro-benzoic acid and 6-chloro-3- chlorosulfonyl-2-fluoro-benzoic acid (3.1 g, 11.4 mmol) was dissolved in THF (30 mL) and this was added drop wise to the stirring solution. The resulting mixture was stirred for 30 minutes while cooling was continued. Then, the mixture was stirred for 3 hours at room temperature.The mixture was concentrated in vacuo untill only water remained. Then water (20 mL) was added and the mixture was acidified with HC1 (46 mL, 1M / aq). This was extracted using Me-THF (3 X 50 mL). The combined organics were dried on Na2S04, filtered and concentrated in vacuo. The residue was purified, and isomers were separated using preparative HPLC (Stationary phase: Uptisphere CI 8 ODB - IotaOmicronmuetaiota, 200g, 5cm), Mobile phase: 0.25% NH4HC03 solution in water, MeOH) , yielding 6-chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid as a white powder. Method G, Rt: 0.40 min. m/z : 322.0 (M-H)" Exact mass: 323.0. 1H NMR (400 MHz, DMSO-d ) ppm 1.42 (s, 3 H), 4.15 (d, J=6.6 Hz, 2 H), 4.61 (d, J=5.9 Hz, 13 H), 7.29 (dd, J=8.5, 0.8 Hz, 1 H), 7.36 - 7.73 (m, 5 H). and 2-chloro-6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid as a white powder. Method G, Rt: 0.34 min. m/z : 321.9 (M-H)" Exact mass: 323.0

Reference： [1]Patent: WO2014/33170,2014,A1 .Location in patent: Page/Page column 111; 112
[2]Patent: WO2014/33176,2014,A1 .Location in patent: Page/Page column 111-112

79
[ 434-75-3 ]
[ 1572516-30-3 ]
[ 1572516-32-5 ]

Yield	Reaction Conditions	Operation in experiment
	With chlorosulfonic acid; at 100℃; for 5h;	Synthesis of 6-chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid and 2- chloro-6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (2 g, 11.46 mmol) was treated with chlorosulfonic acid (10 mL, 150.44 mmol) and this was heated to 100C and stirred for 5 hours. The resulting mixture was cooled to room temperature and added dropwise to ice-water (1 liter). This was then extracted using dichloromethane (2 x 500 mL). The combined organics were dried on Na2S04, filtered and concentrated in vacuo yielding an isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fluoro-benzoic acid and 6-chloro-3- chlorosulfonyl-2-fluoro-benzoic acid (3.1 gram) as a slightly yellow powder which was used as such.Method F, Rt: 0.47 min and 0.49 min. m/z : 270.9 (M-H)- Exact mass: 271.9. Sodium carbonate (1.21 g, 11.4 mmol) was dissolved in distilled water (22 mL). To this was added 3-methyl-3-oxetanamine (1.19 g, 13.68 mmol) at once followed by THF (20 mL). The obtained solution was stirred and cooled in an ice bath. An isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fluoro-benzoic acid and 6-chloro-3- chlorosulfonyl-2-fluoro-benzoic acid (3.1 g, 11.4 mmol) was dissolved in THF (30 mL) and this was added drop wise to the stirring solution. The resulting mixture was stirred for 30 minutes while cooling was continued. Then, the mixture was stirred for 3 hours at room temperature.The mixture was concentrated in vacuo untill only water remained. Then water (20 mL) was added and the mixture was acidified with HC1 (46 mL, 1M / aq). This was extracted using Me-THF (3 X 50 mL). The combined organics were dried on Na2S04, filtered and concentrated in vacuo. The residue was purified, and isomers were separated using preparative HPLC (Stationary phase: Uptisphere CI 8 ODB - IotaOmicronmuetaiota, 200g, 5cm), Mobile phase: 0.25% NH4HC03 solution in water, MeOH) , yielding 6-chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid as a white powder. Method G, Rt: 0.40 min. m/z : 322.0 (M-H)" Exact mass: 323.0. 1H NMR (400 MHz, DMSO-d ) ppm 1.42 (s, 3 H), 4.15 (d, J=6.6 Hz, 2 H), 4.61 (d, J=5.9 Hz, 13 H), 7.29 (dd, J=8.5, 0.8 Hz, 1 H), 7.36 - 7.73 (m, 5 H). and 2-chloro-6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid as a white powder. Method G, Rt: 0.34 min. m/z : 321.9 (M-H)" Exact mass: 323.0
	With chlorosulfonic acid; at 100℃; for 5h;	Synthesis of 6-chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid and 2- chloro-6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (2 g, 11.46 mmol) was treated with chlorosulfonic acid (10 mL, 150.44 mmol) and this was heated to 100C and stirred for 5 hours. The resulting mixture was cooled to room temperature and added dropwise to ice-water (1 liter). This was then extracted using dichloromethane (2 x 500 mL). The combined organics were dried on Na2S04, filtered and concentrated in vacuo yielding an isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fluoro-benzoic acid and 6-chloro-3- chlorosulfonyl-2-fluoro-benzoic acid (3.1 gram) as a slightly yellow powder which was used as such.Method F, Rt: 0.47 min and 0.49 min. m/z : 270.9 (M-H)- Exact mass: 271.9. Sodium carbonate (1.21 g, 11.4 mmol) was dissolved in distilled water (22 mL). To this was added 3-methyl-3-oxetanamine (1.19 g, 13.68 mmol) at once followed by THF (20 mL). The obtained solution was stirred and cooled in an ice bath. An isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fluoro-benzoic acid and 6-chloro-3- chlorosulfonyl-2-fluoro-benzoic acid (3.1 g, 11.4 mmol) was dissolved in THF (30 mL) and this was added drop wise to the stirring solution. The resulting mixture was stirred for 30 minutes while cooling was continued. Then, the mixture was stirred for 3 hours at room temperature.The mixture was concentrated in vacuo untill only water remained. Then water (20 mL) was added and the mixture was acidified with HC1 (46 mL, 1M / aq). This was extracted using Me-THF (3 X 50 mL). The combined organics were dried on Na2S04, filtered and concentrated in vacuo. The residue was purified, and isomers were separated using preparative HPLC (Stationary phase: Uptisphere CI 8 ODB - IotaOmicronmuetaiota, 200g, 5cm), Mobile phase: 0.25% NH4HC03 solution in water, MeOH) , yielding 6-chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid as a white powder. Method G, Rt: 0.40 min. m/z : 322.0 (M-H)" Exact mass: 323.0. 1H NMR (400 MHz, DMSO-d ) ppm 1.42 (s, 3 H), 4.15 (d, J=6.6 Hz, 2 H), 4.61 (d, J=5.9 Hz, 13 H), 7.29 (dd, J=8.5, 0.8 Hz, 1 H), 7.36 - 7.73 (m, 5 H). and 2-chloro-6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid as a white powder. Method G, Rt: 0.34 min. m/z : 321.9 (M-H)" Exact mass: 323.0

Reference： [1]Patent: WO2014/33170,2014,A1 .Location in patent: Page/Page column 111; 112
[2]Patent: WO2014/33176,2014,A1 .Location in patent: Page/Page column 111-112

80
[ 668-45-1 ]
[ 434-75-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With 1-butyl-3-methylimidazolium hydrogen sulfate; water; at 60 - 65℃; for 2.5h;Green chemistry;	General procedure: Aromatic or aliphatic nitriles (2 mmol) were dissolved in 5 ml of [bmim]HSO4 and the reaction mixture was heated at 60-65 C for 1-3 h. The progress of reaction was monitored by TLC. After completion of reaction, as checked by TLC, the reaction mixture was poured into water containing crushed ice. The product was precipitated out, filtered and dried. The yield of the final product was high (>90%) in all cases. All final products obtained were found sufficiently pure so it didn?t need further purification.The filtrate was concentrated under vacuum, washed with diethylether twice and concentrated under high vacuum. After proper drying under reduced pressure, approximately 95% ionic liquid was recovered from the reaction and compared with the original ionic liquid to check its authenticity. The efficiency of recovered ionic liquid in conversion of nitriles to acids was found unchanged in comparison to the original one and we reused it up to 5-6 cycles without any significant loss of its activity.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 3802 - 3804

81
[ 19335-11-6 ]
[ 434-75-3 ]
2-chloro-6-fluoro-N-(1H-indazol-5-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	General procedure: To a solution of 1H-indazol-5-amine (1, 1.0 equiv), dihalo-substituted benzoic or 2-(3,4-dichlorophenyl)acetic acid (2a, 2b, 2c, or 3, 1.4 equiv) in DMF (6.0-8.0mL/mmol; extra dry over molecular sieves, 99.8%, Acros) were added EDC-HCl (1.2 eqiv) and DIPEA (1.2 equiv). The mixture was stirred at room temperature until completed conversion (TLC control: CH2Cl2/MeOH 9/1 v/v). Then, the solvent was removed in vacuo and the residue washed with water (20mL/mmol) and dried at 70C. The crude product was purified by column chromatography on silica gel (eluent: CH2Cl2/MeOH 9/1 v/v) following by recrystallization from methanol.

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6679 - 6703
[2]European Journal of Medicinal Chemistry,2019,vol. 162,p. 793 - 809

82
[ 67-56-1 ]
[ 434-75-3 ]
methyl 2-chloro-6-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With sulfuric acid; at 110℃; for 3h;Microwave irradiation;	PREPARATION 7 Methyl 2-chloro-6-fluorobenzoate A mixture of 2-chloro-6-fluorolbenzoic acid (1.0 g, 5.7 mmol) in methanol (10 mL) and a few drops of concentrated sulfuric acid were added. The reactions took place in 3h under microwave irradiation at 110C. After cooling to room temperature, methanol was evaporated, and the residue was dissolved in ethyl acetate. The solution was extracted with saturated NaHCO3 .The organic layer was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 0.64 g (3.39 mmol, 59%) of methyl 2-chloro-6-fluorolbenzoate. The product was used without further purification.

Reference： [1]Patent: EP2848615,2015,A1 .Location in patent: Paragraph 0093

83
[ 434-75-3 ]
3-(2-chloro-6-fluorophenyl)-3-oxopropanenitrile [ No CAS ]

Reference： [1]Patent: EP2848615,2015,A1

84
[ 434-75-3 ]
5-(2-chloro-6-fluorophenyl)-1H-pyrazol-3-amine [ No CAS ]

Reference： [1]Patent: EP2848615,2015,A1

85
[ 273-53-0 ]
[ 434-75-3 ]
C₁₃H₇ClFNO [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2014,vol. 2014,p. 7586 - 7589

86
C₃₆H₅₈N₂O₃ [ No CAS ]
[ 434-75-3 ]
C₄₃H₆₀ClFN₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	General procedure: Compound 2a (1 mmol) and K2CO3 (2 mmol) were added to DMF (15 mL) and stirred at room temperature for 10 min, and then piperazine (5 mmol) was dripped into the mixture, which was stirred at 80 C for 5 h. After cooling to room temperature, the reaction mixture was poured onto 100 mL of distilled water and partitioned with DCM (3 x 20 mL). The organic layer was washed with saturated sodium chloride, dried over Na2SO4 and purified via silica gel column chromatography with CHCl3/MeOH (10:1, v/v) to obtain compound 4. Compound 4 (1 mmol), amine compounds (1.2 mmol), EDCI (1.2 mmol) and HOBt (1.2 mmol) were added to DCM (25 mL) containing Et3N (0.5 mmol); the mixture was then stirred at room temperature for 6-12 h. After the reaction was completed, the mixture was poured onto 100 mL of distilled water and partitioned with ethyl acetate (3 x 50 mL). The target compounds were purified on a flash column with chloroform/methanol (20:1, v/v) to yield compounds 5a-5i.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 96,p. 58 - 65

87
[ 107-85-7 ]
[ 434-75-3 ]
C₁₂H₁₆FNO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(I) oxide; copper; potassium carbonate; In 1,2-dimethoxyethane; at 100℃; for 1.5h;	A mixture of 3-methylbutylamine (1 .33 mL, 11 .46 mmol, Aldrich), 2-chloro-6-methylbenzoic acid (1 .0 g, 5.73 mmol, Aldrich), potassium carbonate (791 .8 mg, 5.73 mmol), copper powder (36.4 mg, 0.573 mmol) and copper(l) oxide (41.0 mg, 0.286 mmol) in DME (20 mL) is heated to 100C for 1 .5 hours. The mixture is cooled to RT, and water is added. The mixture is neutralized with HCI 1 N until slightly acidic (pH 5-6) and then extracted with EtOAc (3x). The organic layers are combined, washed with water (2x), NH4CI saturated (2x) and brine, dried over Mg504, filtered and concentrated. The residue is purified by Combif lash (Hex/EtOAc 100:0 to 70:30) to afford 42a.

Reference： [1]Patent: WO2015/65336,2015,A1 .Location in patent: Page/Page column 58; 59

88
[ 434-75-3 ]
C₁₂H₁₇FN₂O [ No CAS ]