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[ CAS No. 85118-01-0 ]

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

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

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Chemical Structure| 85118-01-0

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Product Details of [ 85118-01-0 ]

CAS No. :	85118-01-0	MDL No. :	MFCD00009889
Formula :	C₇H₅BrF₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JJIFTOPVKWDHJI-UHFFFAOYSA-N
M.W :	207.02	Pubchem ID :	581436
Synonyms :

Calculated chemistry of [ 85118-01-0 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	39.19
TPSA :	0.0 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.66 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.2
Log Po/w (XLOGP3) :	2.68
Log Po/w (WLOGP) :	3.55
Log Po/w (MLOGP) :	3.95
Log Po/w (SILICOS-IT) :	3.67
Consensus Log Po/w :	3.21

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.19
Solubility :	0.134 mg/ml ; 0.000646 mol/l
Class :	Soluble
Log S (Ali) :	-2.33
Solubility :	0.963 mg/ml ; 0.00465 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.22
Solubility :	0.0125 mg/ml ; 0.0000604 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.66

Safety of [ 85118-01-0 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P261-P280-P305+P351+P338-P310	UN#:	3265
Hazard Statements:	H227-H314-H335	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 85118-01-0 ]

* 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 [ 85118-01-0 ]
Downstream synthetic route of [ 85118-01-0 ]

[ 85118-01-0 ] Synthesis Path-Upstream 1~4

1
[ 85118-01-0 ]
[ 31105-90-5 ]

Reference： [1] Tetrahedron Letters, 2000, vol. 41, # 6, p. 923 - 927

2
[ 85118-01-0 ]
[ 198474-90-7 ]

Reference： [1] Tetrahedron Letters, 2000, vol. 41, # 6, p. 923 - 927

3
[ 609-71-2 ]
[ 85118-01-0 ]
[ 1001413-01-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 2 h; Inert atmosphere Stage #2: at 50℃; for 16 h;	A stirred suspension of NaH 60percent dispersion in mineral oil (206 mg, 5.14 mmol), washed twice with distilled n-hexane and once with Et20 in 2 mL of anhydrous DMF under N2 atmosphere was treated dropwise with a solution containing the 2-hydroxynicotinic acid (600 mg, 4.31 mmol) in 5 mL of anhydrous DMF. The mixture was left under stirring at room temperature for 2h and then 3,4-difluoro-benzylbromide (1.06 g, 5.14 mmol) was added and the mixture stirred and heated at 50°C for 1 6h. After the mixture was concentrated under reduced pressure and the residue was treated with water to give a solid, which was collected by vacuum filtration. Next the solid was refluxed for 4h in aq. 10percent NaOH (10 mL) and the resulting mixture was cooled and made acid with 1 N aq.HCI. The white solid formed was collected by filtration and washed with nhexane and Et20, giving the derivative 3.9 as white solid (857 mg, 3.23 mmol, 75percent yield).1HNMR (400 MHz, DMSO-d6): 65.30 (5, 2H, CH2); 6.78 (t, 1H, J = 6.9 Hz, Ar);7.22-7.24 (m, 1H, Ar); 7.41 -7.53 (m, 2H, Ar); 8.41 (d, 2H, J = 6.9 Hz, Ar) ppm.Anal. Calcd for C13H9NO3F2: C, 58,87percent; H, 3.42percent; N, 5.28percent; Found: C, 58,99percent; H, 3.47percent; N, 5.43percent
75%	Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 2 h; Inert atmosphere Stage #2: at 50℃; for 16 h; Inert atmosphere Stage #3: for 4 h; Reflux	1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (5). A stirred suspension of NaH 60percent dispersion in mineral oil (206 mg, 5.14 mmol), washed twice with distilled n-hexane and once with Et20 under N2 atmosphere, was treated dropwise with a solution containing the 2-hydroxynicotinic acid (600 mg, 4.31 mmol) in 5 mL of anhydrous DMF. The mixture was left under stirring at rt for 2h and then 3,4-difluoro-benzylbromide (1 .06 g, 5.14 mmol) was added and the mixture stirred and heated at 50°C for 1 6h. After, the mixture was concentrated under reduced pressure and the residue was treated with water to give a solid, which was collected by vacuum filtration. Next the solid was refluxed for 4h in aq. 10percent NaOH (10 mL) and the resulting mixture was cooled and made acid with 1 N aq. HCI. The white solid formed was collected by filtration and washed with n-hexane and Et20, giving 5 as white solid (857 mg, 3.23 mmol, 75percent yield). H-NMR (400 MHz, DMSO-de): δ 5.30 (s, 2H, CH2); 6.78 (t, 1 H, J = 6.9 Hz, Ar); 7.22-7.24 (m, 1 H, Ar); 7.41 -7.53 (m, 2H, Ar); 8.41 (d, 2H, J = 6.9 Hz, Ar) ppm. Anal. Calcd for C13H9NO3F2: C, 58.87percent; H, 3.42percent; N, (0126) 3percent.

Reference： [1] Patent: WO2016/198597, 2016, A1, . Location in patent: Page/Page column 18; 19
[2] Patent: WO2017/211946, 2017, A1, . Location in patent: Page/Page column 21

4
[ 609-71-2 ]
[ 85118-01-0 ]
[ 1001413-01-9 ]

Reference： [1] European Journal of Medicinal Chemistry, 2016, vol. 118, p. 47 - 63

[ 85118-01-0 ] Synthesis Path-Downstream 1~68

1
[ 2927-34-6 ]
[ 85118-01-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide;zirconium(IV) chloride; In dichloromethane; at 0℃; for 6h;Conversion of starting material;	The reaction of NBS and toluene in the presence of 5 mole % ZrCI4 did not give the ring substituted product, but rather benzyl bromide almost exclusively. Table 5 shows some additional examples. The reaction also proceeds smoothly in the presence of FeCk or AICI3 with almost the same reactivity as that of ZrCU. Without wishing to be bound by any theory of interpretation, it is believed that this reaction may proceed by a radical mechanism. In fact, the reaction does not proceed at all in the presence of a radical inhibitor. EPO <DP n="30"/>Table 5 ZrCI4 Catalyzed Radical Bromination of Aromatic Compound by NBSa(5 mol %), CH2CI2 (4 c See spectroscopic data for characterization.

Reference： [1]Journal of medicinal chemistry,1967,vol. 10,p. 64 - 66
[2]Phosphorus, Sulfur and Silicon and the Related Elements,1990,vol. 53,p. 43 - 67
[3]Synlett,2005,p. 2837 - 2842
[4]Patent: WO2007/27917,2007,A2 .Location in patent: Page/Page column 28-29

2
[ 85118-01-0 ]
[ 485-71-2 ]
(1S,2S,4S,5R)-1-(3,4-Difluoro-benzyl)-2-((R)-hydroxy-quinolin-4-yl-methyl)-5-vinyl-1-azonia-bicyclo[2.2.2]octane; bromide [ No CAS ]

Reference： [1]Organic letters,2002,vol. 4,p. 4245 - 4248

3
[ 61204-01-1 ]
[ 85118-01-0 ]
1,2-Difluoro-4-{2-[4-(4-pentyl-cyclohexyl)-phenyl]-ethyl}-benzene [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals,2004,vol. 411,p. 49/[1091]-56/[1098]

4
[ 24279-39-8 ]
[ 140-89-6 ]
[ 85118-01-0 ]
4-chloro-2-(3,4-difluoro-benzylsulfanyl)-6-trifluoromethyl-benzothiazole [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 8280 - 8285

5
[ 16001-93-7 ]
[ 85118-01-0 ]
[2-(3,4-difluoro-phenyl)-1-(dimethoxy-phosphoryl)-ethyl]-phosphonic acid dimethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 5804 - 5814

6
[ 85118-01-0 ]
[ 31105-90-5 ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 923 - 927

7
[ 85118-01-0 ]
[ 198474-90-7 ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 923 - 927

8
[ 85118-01-0 ]
[ 31737-09-4 ]
C₁₂H₉ClF₂N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h;	Scheme 85 represents an alternative method of synthesizing compounds of formula [I-EII.] Briefly, compound IX, which is prepared as described in [KAZIMIERCZUK,] et al., Intermediates in the synthesis of purines and [PTERIDINES] : N- methylated 6-chlorouracils, Acta Biochim. Pol. (1970), 17 (4), 325-9; Pfleider, et al. , Liebigs Ann. Chem, 612,158, (1958); and Hirota, et al. , Pyrimidines. 65. Synthesis of 6-substituted thieno [2,3-d] pyrimidine-2,4 (1H, 3H)-diones, J. Heterocycl. Chem. (1990), 27 (3), 717-21; each of which are incorporated herein by reference, is reacted with 3,4-di-fluorobenzyl bromide (1.1 equiv. ) in DMF at room temperature for 18 hours in the presence of cesium carbonate 1.5 equiv. ) to give product X. Reaction of X (1.0 equiv. ) with thiogylcolic acid ethyl ester (1.0 equiv. ) in room temperature ethanol in the presence of triethyl amine (1.0 equiv. ) for 1.5 hour provided [[1- (3,] 4-Difluoro-benzyl) -3-methyl-2, 6-oxo-1, 2,3, 6-tetrahydro- [PYRIMIDIN-4-YLSULFANYL]-ACETIC] acid ethyl ester, compound XI. This material is treated with POC13 (1.2 equiv. ) and DMF (1.1 equiv. ) in methylene chloride at [0 XB0;C] to reflux under Vilsmeier-Haack conditions to provide [FORMYLATED] product XII. Heating this material in the presence of sodium carbonate (1.5 equiv. ) in ethanol at-reflux for 18 hours provides the cyclized product [3- (3,] 4-difluoro- [BENZYL)-1-METHYL-2,] 4-dioxo-1,2, 3,4-tetrahydro-thieno [2,3-d] pyrimidine-6- carboxylic acid ethyl ester XIII. Saponification of XIII with sodium hydroxide sodium hydroxide (1.2 equiv) in methanol/water (1: 1) mixture at room temperature for 18 hours gives XIV. EDAC HCl (1.3 equiv. ) coupling of XIV in DMF with [3- (OR 4-)- (Z-L)-BENZYLAMINE] (1.3 equiv. ), and HOBT (1.3 equiv. ) for 18 hours at room temperature provided [Z-L- {3- (3, 4-DIFLUORO-BENZYL)-1-METHYL-] 2, 4-oxo-1, 2,3, 4-tetrahydro-thieno [2,3-d] pyrimidine-6-carboxylic acid [BENZYLAMIDE}] XV.

Reference： [1]Patent: WO2004/14384,2004,A2 .Location in patent: Page/Page column 251-253

Yield	Reaction Conditions	Operation in experiment
	With piperidine; Carbonyldiimidazole; tin-2-ethylhexanoate dihydrate; potassium tert-butylate; water; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; diisopropyl-carbodiimide; dibromotriphenylphosphorane; In DMF (N,N-dimethyl-formamide); dichloromethane; N,N-dimethyl acetamide; 1,2-dichloro-ethane;Combinatorial reaction / High throughput screening (HTS);	EXAMPLE 1 [0213] This example shows the synthesis of a combinatorial library of thioquinazolinone derivatives. [0214] Step 1a: Preparation of Wang Bromide Resin [0215] 40 tea bags containing 2 g each of Wang resin (80 g, 120 mmol) was taken in a 5 L PP container. A solution of triphenylphosphine dibromide (152 g, 0.15 M, 3 eq., 360 mmol) in 2000 ml DCM was added and the solution was shaken at room temperature overnight. The resin was sequentially washed with DCM (4×, 1.5 L each) and diethylether (6×, 1.5 L each) and dried under vacuum, to give the bromo wang resin. [0216] Step 1b: Loading of the Nitrophenol on Bromo Wang [0217] 20 g of the Bromo wang resin (1.5 meq/g) was taken in a 2 L wide-mouthed glass container and 1000 mL DMA was addded to it followed by the addition of the nitro phenol (10 eq., 0.3M, 300 mmol). Potasium t-butoxide (33.46 g, 10 eq., 300 mmol) was then added to it and the bottles were heated at 50 C. overnight. The bags were washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The tea bags were then dried overnight in air. The following nitrophenols were used: [0218] 2-METHYL-5-NITROPHENOL [0219] 5-HYDROXY-2-NITROBENZOTRIFLUORIDE [0220] 3-METHYL-4-NITROPHENOL [0221] 2-METHOXY-5-NITROPHENOL [0222] M-NITROPHENOL [0223] Step 1c: Reduction of the Nitro Group to Amine [0224] A 2.0 M solution of tin-2-ethylhexanoate dihydrate was prepared in DMF containing 0.5% H2O. The tea bags were added and the solution is heated at 50 C. for 40 hours. After cooling the bags are washed with DMF/10% HOAc (3×), DMF (3×), 5% DIEA/DCM (2×), DCM (2×) and MeOH (2×) and dried in air overnight. [0225] Step 1d: Coupling N-FMOC Protected Amino Acid to Wang Resin. [0226] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL plastic bottle. DMF (300 mL), DCM (300 mL), FMOC-Cyclohexyl alanine (70.82 g, 6 eq., 0.3M, 180 mmol), DIC (22.71 g, 6 eq., 180 mmol), HOBt (24.32 g, 6 eq., 180 mmol) were added sequentially. After shaking for 12 hours, the packet was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried overnight in air. The tea bags containing the amino acids were then treated with 20% piperidine/DMF for 2 h at room temperature to deblock the FMOC group. The following amino acids were used: [0227] FMOC-GLY-OH [0228] FMOC-ALA-OH [0229] FMOC-L-ISOLEUCINE [0230] FMOC-L-PHENYLALANINE [0231] FMOC-D-NLE-OH [0232] FMOC-CHA-OH [0233] FMOC-L-TRYPTOPHAN [0234] Step 1e: Coupling of the Diamines to Wang Resin [0235] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL Nalgene bottle. 600 mL of DCM was added followed by the addition of the carbonyl diimidazole (29.9 g, 6 eq., 0.3M, 180 mmol) and the flasks were shaken at room temperature for 3 hours after which they were decanted and washed with DCM (2×, 600 mL). To these Nalgene bottles were added the diamines (6 eq., 0.4M, 180 mmol) in 450 mL of DCM (0.4M) and they were shaken at room temperature overnight. The diamines used were as follows: [0236] 2,2-DIMETHYL-1,3-PROPANEDIAMINE [0237] 1,3-CYCLOHEXANEDIAMINE [0238] (1R,2R)-(-)-1,2-DIAMINOCYCLOHEXANE [0239] TRANS-1,4-DIAMINOCYCLOHEXANE [0240] P-XYLYLENEDIAMINE [0241] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE [0242] ETHYLENEDIAMINE [0243] 1,3-DIAMINOPROPANE [0244] 1,8-DIAMINO-3,6-DIOXAOCTANE [0245] 1,4-DIAMINOBUTANE [0246] 1,5-DIAMINOPENTANE [0247] 1,6-HEXANEDIAMINE [0248] N,N-BIS(3-AMINOPROPYL)METHYLAMINE [0249] 2,2'-THIOBIS(ETHYLAMINE) [0250] 2,5-DIMETHYL-1,4-PHENYLENEDIAMINE [0251] After shaking overnight, the packets was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried in air. [0252] Step 2: Formation of the Isothiocyanate [0253] The o-amino benzoate ester (136 g, 10 eq., 900 mmol) was taken in a 5 L wide-mouthed glass bottle and 2.7 L of dichloroethane was added to it (0.3M). The following esters were used: [0254] METHYL ANTHRANILATE [0255] METHYL 2-AMINO-4-CHLOROBENZOATE [0256] 2-AMINO-4,5-DIMETHOXYBENZOIC ACID [0257] METHYL ESTER [0258] METHYL 3,4,5-TRIMETHOXYANTHRANILATE [0259] DIMETHYL AMINOTEREPHTHALATE [0260] METHYL 2-AMINO-5-BROMOBENZOATE [0261] METHYL 3-AMINOTHIOPHENE-2-CARBOXYLATE [0262] METHYL 3-AMINO-5-PHENYLTHIOPHENE-2-CARBOXYLATE [0263] Thiocarbonyl diimidazole (160 g, 10 eq., 900 mmol) was added to it and the solution was heated at 55 C. overnight to form the isothiocyanate. [0264] Step 3: Formation of the Thioquinazolinone [0265] The next day the tea bags containing the amino acids, diamines and the amino phenols on wang resin (90 mmol) was added to the isothiocyanate solution from reaction 2 and the glass bottles were heated at 55 C. overnight. After cooling the bags was washed alternatively with DMF (2000 mL) and DCM (2000 mL) 3 cycles followed by 6 cycles of MeOH...

Reference： [1]Patent: US2004/102629,2004,A1 .Location in patent: Page 16-18

10
[ 85118-01-0 ]
[ 16353-27-8 ]
[ 515869-49-5 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In <i>N</i>-methyl-acetamide; water; ethyl acetate	11.2 Step 2 Step 2 3-(3,4-Difluoro-benzyl)-6-iodo-1-methyl-1H-quinazoline-2,4-Dione 0.5 g (1.6 mmol) of 6-Iodo-1H-quinazoline-2,4-dione from the preceding stage is dissolved in 10 ml of dimethylformamide and 1.0 g (3.2 mmol) of cesium carbonate is added. The mixture is stirred 10 minutes before adding 3,4-di-fluorobenzyl bromide 0.38 g (1.8 mmol). Stirring is continued overnight at room temperature. Water (30 ml) is added and the product is filtered. Slurried solid product in hot ethyl acetate and filtered to obtain: Weight: 0.49 g Yield: 68% MS: m/z (APCI, AP+) 429.0 [M.]+

Reference： [1]Current Patent Assignee: PFIZER INC - US2003/130278, 2003, A1

11
[ 85118-01-0 ]
[ 885225-87-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 7-bromo-5-fluoro-3-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide at -10 - 20℃; for 0.5h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide at -10 - 20℃; for 1.04167h; Stage #3: With hydrogenchloride In diethyl ether; water; N,N-dimethyl-formamide	12 Synthesis of 7-Bromo- 1 -(3 ,4-difluoro-benzyl)-5-fluoro-3-methyl- lH-indole, 1-15. To a suspension of NaH (60% in mineral oil, 263 mg, 10.5 mmol, 1.5 equiv.) in DMF (20 niL) was added 7-bromo-5-fluoro-3-methyl-lH-indole, 1-10 (1 g, 4.38 mmol, 1 equiv.) at -10 °C. The reaction mixture was allowed to warm to rt and stir for 30 min. 3,4-Difluorobenzyl bromide (0.95 g, 4.6 mmol, 1.05 equiv.) was added over 2.5 min at -10 0C. The reaction mixture was allowed to warm to rt and stir for 1 h. The reaction mixture was added to stirring solution of 10 % aqueous HCl/water/ether (1:1:2, 40 mL). The layers were separated and the aqueous layer was extracted with ether (2 x 20 mL). The combined organic layers were washed with water (3 x 75 mL), brine (25 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford crude product as a brown oil. The crude product was purified via column chromatography, eluting with ethyl acetate/hexanes (2.5%) to afford 1.4 g of 1-15 in 90% yield. 1H-NMR (500 MHz, CDCl3) confirmed the structure.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2006/44405, 2006, A1 Location in patent: Page/Page column 64

12
[ 73874-95-0 ]
[ 85118-01-0 ]
[ 160358-08-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: tert‐butyl piperidin‐4‐ylcarbamate; alpha-bromo-3,4-difluorotoluene With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; Stage #2: With trifluoroacetic acid In dichloromethane for 2h; Stage #3: With sodium carbonate In dichloromethane; water	7 A mixture of piperidin-4-ylcarbamic acid tert-butyl ester (5 g, 25.0 mmol), 3,4- difluorobenzyl bromide (4.7 g, 22.7 mmol) and diisoproylethylamine (5.9 ml, 34.0 mmol) in dichloromethane (50 ml) was stirred at room temperature for 2 h. After this period, trifluoroacetic acid (31 ml) was added and the reaction was stirred for a further 2 h. The solvent was evaporated in vacuo and a saturated solution of sodium carbonate was added. The mixture was extracted with dichloromethane and the separated organic layers were dried (Na2SO4), filtered, and the solvent evaporated in vacuo to yield D7 (5.2 g, 93%) as a solid. Ci2Hi6F2N2 requires 226; Found 227 (MH+).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2008/128996, 2008, A1 Location in patent: Page/Page column 24

13
[ 1073635-64-9 ]
[ 85118-01-0 ]
[ 1073635-36-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 0.0833333h; Microwave irradiation;	5 A mixture of piperidin-4-yl-(5-trifluoromethyl-[l,3,4]thiadiazol-2-yl)-amine (D4) (0.040 g, 0.16 mmol), 3,4-difiuorobenzyl bromide (0.024 ml, 0.19 mmol) and diisopropylethylamine (0.042 ml, 0.24 mmol) in acetonitrile (3 ml) was stirred at 100° C for 5 min., under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and extracted with a 10 % solution of ammonium chloride (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 0-3 % ammonia in methanol (7M) / dichloromethane) to yield E5 (0.048 g, 80 %) as a solid. Ci5Hi5F5N4S requires 378; Found 379 (MH+).1H NMR (400 MHz, CHLOROFORM-J) δ ppm 1.61 - 1.76 (m, 2 H) 2.06 - 2.14 (m, 2 H) 2.19 (t, J=I 1.09 Hz, 2 H) 2.78 - 2.87 (m, 2 H) 3.37 - 3.46 (m, 1 H) 3.47 (s, 2 H) 6.66 (d, J=5.18 Hz, 1 H) 6.98 - 7.04 (m, 1 H) 7.05 - 7.13 (m, 1 H) 7.17 (ddd, J=I 1.20, 7.88, 2.07 Hz, 1 H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2008/128996, 2008, A1 Location in patent: Page/Page column 28

14
[ 1104394-29-7 ]
[ 85118-01-0 ]
[ 1104621-37-5 ]

Yield	Reaction Conditions	Operation in experiment
61%	Stage #1: N-benzo[b]thiophen-2-yl-benzenesulfonamide With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide at 0 - 20℃;	1 7V-Benzo[Z>]thiophen-2-yWV-(3,4-difluoro-benzyl)-benzenesulfonamide.; Sodium hydride (60% in oil, 100 mg, 2.48 mmol) was added to a solution of compound 1-D (655 mg, 2.26 mmol) in DMF (8 mL) at 0 C and the resultant mixture was stirred at 0 C for 15 min. 3,4-Difluorobenzylbromide (0.318 mL, 2.48 mmol) was added to the reaction mixture, and the resultant solution was stirred at ambient temperature overnight. Water was added to the solution, and the product was extracted into ethyl acetate. The organic layer was washed with water (3X), brine, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo. The residue was purified on silica gel by flash column chromatography eluting with a gradient of ethyl acetate (0-40%) in heptane, to afford compound 1 as a colorless solid (570 mg, 61%). 1H-NMR (DMSO- d6): δ 4.74 (s, 2H), 7.00-7.10 (s superimposed on m, 3H), 7.15-7.21 (m, IH), 7.26-7.36 (m, 2H), 7.49-7.54 (m, 2H), 7.62-7.67 (m, 3H), 7.73-7.78 (m, 2H); MS: m/z 416.1 (MH+).
61%	Stage #1: N-benzo[b]thiophen-2-yl-benzenesulfonamide With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide; mineral oil at 20℃;	1 Compound 1 N-benzo[b]thiophen-2-yl-N-(3,4-difluoro-benzyl)-benzenesulfonamide. Sodium hydride (60% in oil, 100 mg, 2.48 mmol) was added to a solution of compound 1-D (655 mg, 2.26 mmol) in DMF (8 mL) at 0° C. and the resultant mixture was stirred at 0° C. for 15 min. 3,4-difluorobenzylbromide (0.318 mL, 2.48 mmol) was added to the reaction mixture, and the resultant solution was stirred at ambient temperature overnight. Water was added to the solution, and the product was extracted into ethyl acetate. The organic layer was washed with water (3*), brine, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo. The residue was purified on silica gel by flash column chromatography eluting with a gradient of ethyl acetate (0-40%) in heptane, to afford compound 1 as a colorless solid (570 mg, 61%). 1H-NMR (DMSO-d6): δ 4.74 (s, 2H), 7.00-7.10 (s superimposed on m, 3H), 7.15-7.21 (m, 1H), 7.26-7.36 (m, 2H), 7.49-7.54 (m, 2H), 7.62-7.67 (m, 3H), 7.73-7.78 (m, 2H); MS: m/z 416.1 (MH+).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2009/12430, 2009, A1 Location in patent: Page/Page column 180-181
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2012/190674, 2012, A1 Location in patent: Page/Page column 73

15
[ 1104395-30-3 ]
[ 85118-01-0 ]
[ 1104630-85-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: (3-methyl-benzo[b]thiophen-2-yl)-carbamic acid tert-butyl ester With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide at 0 - 20℃; for 2h;	4 (3,4-Difluoro-benzyl)-(3-methyl-benzo[Z>]thiophen-2-yl)-carbamic acid tert- butyl ester (125-C); Sodium hydride (60%, 0.37 g, 9.19 mmol) was added to a solution of compound 125-B (2.2 g, 8.35 mmol) in DMF (30 mL), at 0 °C and the resultant mixture was stirred for 15 minutes. 3,4-Difluorobenzylbromide (1.18 mL, 9.2 mmol) was added, and the solution was stirred at ambient temperature for 2 h. The reaction mixture was diluted with water, extracted with ethyl acetate, the organic extract washed with water (3X), brine, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo. The crude residue was purified by flash column chromatography, eluting with an ethyl acetate-heptane gradient, to afford compound 125-C as an oil (2.73 g, 84%). 1H-NMR (CDCl3): δ 1.40 (s, 9H), 1.97 (s, 3H), 4.72 (s, 2H), 6.93-7.19 (m, 3H), 7.28-7.39 (m, 2H), 7.61 (d, IH), 7.70 (d, IH).
84%	Stage #1: (3-methyl-benzo[b]thiophen-2-yl)-carbamic acid tert-butyl ester With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide; mineral oil at 20℃; for 2h;	4 (3,4-difluoro-benzyl)-(3-methyl-benzo[b]thiophen-2-yl)-carbamic acid tert-butyl ester (125-C) Sodium hydride (60%, 0.37 g, 9.19 mmol) was added to a solution of compound 125-B (2.2 g, 8.35 mmol) in DMF (30 mL), at 0° C. and the resultant mixture was stirred for 15 minutes. 3,4-difluorobenzylbromide (1.18 mL, 9.2 mmol) was added, and the solution was stirred at ambient temperature for 2 h. The reaction mixture was diluted with water, extracted with ethyl acetate, the organic extract washed with water (3×), brine, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo. The crude residue was purified by flash column chromatography, eluting with an ethyl acetate-heptane gradient, to afford compound 125-C as an oil (2.73 g, 84%). 1H-NMR (CDCl3): δ 1.40 (s, 9H), 1.97 (s, 3H), 4.72 (s, 2H), 6.93-7.19 (m, 3H), 7.28-7.39 (m, 2H), 7.61 (d, 1H), 7.70 (d, 1H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2009/12430, 2009, A1 Location in patent: Page/Page column 206-207
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2012/190674, 2012, A1 Location in patent: Page/Page column 84

16
[ 1104630-90-1 ]
[ 85118-01-0 ]
[ 1104630-91-2 ]

Yield	Reaction Conditions	Operation in experiment
66%	Stage #1: N-(6-methoxy-benzo[b]thiophen-2-yl)-pyridin-3-yl-sulfonamide With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.5h; Stage #2: alpha-bromo-3,4-difluorotoluene In tetrahydrofuran at 20℃; for 18h;	6 iV-(3.4-Difluoro-benzyl)-iV-(6-methoxy-benzo[Z>]thiophen-2-yl)-pyridin-3-yl- sulfonamide (141-G).; To a solution of compound 141-F (0.488 g; 1.52 mmol) in THF (15 mL) was added IM potassium tert-butoxide (2.28 mL; 2.28 mmol) and the reaction mixture was stirred at ambient temperature for 30 min. 3,4-Difluorobenzyl bromide (0.409 g; 1.97 mmol), dissolved in THF (1.0 mL), was added drop-wise, and the reaction was stirred at ambient temperature for 18 h. The reaction was diluted with EtOAc, washed with 2N HCl, water, brine, dried over Na2SO4, filtered, the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford an oily semisolid, which was further purified by reverse-phase semi-prep HPLC (Gemini, C- 18 column; 100 x 30 mm LD. ; 5 μ) eluting with a 55% to 75% MeCN-H2O gradient to afford compound 141-G as a white solid (0.447 g, 66%). 1H-NMR (DMSO-fe): δ 3.76 (s, 3H), 4.89 (s, 2H), 6.93-6.96 (m, IH), 7.11 (s, IH), 7.19-7.20 (m, IH), 7.34-7.43 (m, 3H), 7.60-7.62 (d, IH), 7.70-7.73 (m, IH), 8.21-8.24 (m, IH), 8.93-8.96 (m, 2H); MS: m/z 447.0 (MH+).
66%	Stage #1: N-(6-methoxy-benzo[b]thiophen-2-yl)-pyridin-3-yl-sulfonamide With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.5h; Stage #2: alpha-bromo-3,4-difluorotoluene In tetrahydrofuran at 20℃; for 18h;	6 N-(3.4-difluoro-benzyl)-N-(6-methoxy-benzo[b]thiophen-2-yl)-pyridin-3-yl-sulfonamide (141-G). To a solution of compound 141-F (0.488 g; 1.52 mmol) in THF (15 mL) was added 1M potassium tert-butoxide (2.28 mL; 2.28 mmol) and the reaction mixture was stirred at ambient temperature for 30 min. 3,4-difluorobenzyl bromide (0.409 g; 1.97 mmol), dissolved in THF (1.0 mL), was added drop-wise, and the reaction was stirred at ambient temperature for 18 h. The reaction was diluted with EtOAc, washed with 2N HCl, water, brine, dried over Na2SO4, filtered, the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford an oily semi-solid, which was further purified by reverse-phase semi-prep HPLC (Gemini, C-18 column; 100*30 mm I.D.; 5μ) eluting with a 55% to 75% MeCN-H2O gradient to afford compound 141-G as a white solid (0.447 g, 66%). 1H-NMR (DMSO-d6): δ 3.76 (s, 3H), 4.89 (s, 2H), 6.93-6.96 (m, 1H), 7.11 (s, 1H), 7.19-7.20 (m, 1H), 7.34-7.43 (m, 3H), 7.60-7.62 (d, 1H), 7.70-7.73 (m, 1H), 8.21-8.24 (m, 1H), 8.93-8.96 (m, 2H); MS: m/z 447.0 (MH+).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2009/12430, 2009, A1 Location in patent: Page/Page column 211; 213
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2012/190674, 2012, A1 Location in patent: Page/Page column 87

17
[ 3964-57-6 ]
[ 85118-01-0 ]
[ 1135439-44-9 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In acetonitrile; at 20℃; for 18h;	Preparation 10Methyl-3-chloro-4-[(3,4-difluorobenzyl)oxy1benzoateTo a stirred solution of <strong>[3964-57-6]methyl 3-chloro-4-hydroxybenzoate</strong> (comm, 6.48 g, 34.73 mmol) in acetonitrile was added cesium carbonate (28.29 g, 86.82 mmol) followed by 4- (bromomethyl)-1 ,2-difluorobenzene (comm, 10.78 g, 52.09 mmol). The reaction mixture was stirred at room temperature for 18 hours. A sodium hydroxide solution (0.5 M, 210 ml_) was then added and the resulting white solid was collected by filtration to yield the title compound, which was used in the next step without further purification.1H NMR (400 MHz, d6-DMSO): delta 3.77 (s, 3H), 5.22 (s, 2H), 7.16 (d, 1H), 7.26-7.32 (m, 1H), 7.39-7.53 (m, 2H), 7.77 (dd, 1H), 7.85 (d, 1H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 665 - 669
[2]Patent: WO2012/7868,2012,A2 .Location in patent: Page/Page column 76-77

18
[ 27825-20-3 ]
[ 85118-01-0 ]
[ 1204400-32-7 ]

Yield	Reaction Conditions	Operation in experiment
43%	Stage #1: methyl 3-oxo-3,4-dihydropyrazine-2-carboxylate With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.75h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide at 20℃; for 24h;	A.38 Sodium hydride (60 %; 61 mg, 1 .5 mmol) is placed in DMF (1 .2 mL), combined with carboxylic acid ester A.a.4 (212 mg, 1 .4 mmol) and stirred for 45 min at 20°C. Then benzyl bromide A.b.1 (0.18 mL, 1 .4 mmol) is metered in and the mixture is stirred for a further 24 h at 20°C. The reaction mixture is combined with HCI (5 mL, 1 M) and DCM (5 mL), the organic phase is separated off and extracted with HCI (2 x 5 mL, 1 N). Then the organic phase is dried on Na2S04, filtered off, the solvent is eliminated in vacuo and carboxylic acid ester A*.38 (166 mg, 43 %; HPLC-MS: MS(M+H)+ = 281 ; tRet = 1 .63 min; method FECS) is obtained.
43%	Stage #1: methyl 3-oxo-3,4-dihydropyrazine-2-carboxylate With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.75h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide at 20℃; for 24h;	A.45 Sodium hydride (60 %; 61 mg, 1.5 mmol) is placed in DMF (1.2 mL), combined with carboxylic acid ester A.a.4 (212 mg, 1.4 mmol) and stirred for 45 min at 20°C. Then benzyl bromide A.b.1 (0.18 mL, 1.4 mmol) is metered in and the mixture is stirred for a further 24 h at 20°C. The reaction mixture is combined with HCI (5 mL, 1 M) and DCM (5 mL), the organic phase is separated off and extracted with HCI (2 x 5 mL, 1 N). Then the organic phase is d ried on N a2S04, filtered off, the solvent is eliminated in vacuo and carboxylic acid ester A*.45 (166 mg, 43 %; HPLC-MS: MS(M+H)+ = 281 ; tRet.= 1 .63 min; method FECS) is obtained.
43%	Stage #1: methyl 3-oxo-3,4-dihydropyrazine-2-carboxylate With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.75h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide at 20℃; for 24h;	a.A.38 Method of Synthesising A.38Carboxylic acid ED.2 (300 mg, 2.20 mmol) is placed in conc. H2SO4 (1.3 mL), cooled to 0° C., a mixture of NaNO2 (149 mg, 2.20 mmol) in conc. H2SO4 (1.6 mL) is added dropwise and the mixture is stirred for 1 h. Then the reaction mixture is added dropwise to an ice-water mixture with vigorous stirring, the precipitate formed is filtered off and pyrazinonic acid Z.2 (200 mg, 66%; MS (M-H)-=139; tRet.=0.00 min; method LCMSBAS1) is obtained.Pyrazinonic acid Z.2 (200 mg, 1.4 mmol) is placed in MeOH (10 mL), combined with HCl (0.1 mL, 4 M in dioxane) and stirred for 12 h at 20° C. Then the solvent is removed and carboxylic acid ester A.a.4 (212 mg, 96%; HPLC-MS: MS (M-H)-=153; tRet.=0.00 min; method LCMSBAS1) is obtained.Sodium hydride (60%; 61 mg, 1.5 mmol) is placed in DMF (1.2 mL), combined with carboxylic acid ester A.a.4 (212 mg, 1.4 mmol) and stirred for 45 min at 20° C. Then benzyl bromide A.b.1 (0.18 mL, 1.4 mmol) is metered in and the mixture is stirred for a further 24 h at 20° C. The reaction mixture is combined with HCl (5 mL, 1 M) and DCM (5 mL), the organic phase is separated off and extracted with HCl (2×5 mL, 1 N). Then the organic phase is dried on Na2SO4, filtered off, the solvent is eliminated in vacuo and carboxylic acid ester A.38 (166 mg, 43%; HPLC-MS: MS (M+H)+=281; tRet.=1.63 min; method FECS) is obtained.Carboxylic acid ester A.38 (166 mg, 0.60 mmol) is taken up in MeOH (4.0 mL) and combined with NaOH (0.71 mL, 1 M). After 5 h at 20° C. the mixture is diluted with water and extracted with DCM. The organic phase is discarded, the aqueous phase is acidified with HCl (5 mL, 1 M) and extracted with DCM. The organic phase is dried on Na2SO4, filtered off, the solvent is eliminated in vacuo and the free carboxylic acid A. 38 (150 mg, 95%; HPLC-MS: MS (M+H)+=267; tRet.=1.59 min; method FECS) is obtained.

Stage #1: methyl 3-oxo-3,4-dihydropyrazine-2-carboxylate With sodium hydride In 1,4-dioxane at 20℃; for 0.25h; Stage #2: alpha-bromo-3,4-difluorotoluene In 1,4-dioxane at 50℃; for 5h;

a Methyl carboxylate B.l-le (2.7 g, 17.4 mmol) is taken up in dioxane (30 mL), combined with NaH (1.4 g, 34.9 mmol) and stirred for 15 min at RT. Then 3,4-difluorobenzyl bromide B.2a (2.26 rnL, 17.4 mmol) is added and the reaction mixture is heated for 5 h to 500C. The reaction is quenched with NaHCO3, acidified with HCl (2 M), and methyl carboxylate A.l*e (HPLC-MS: tRet. = 0 min; MS(M+H)+ = 281; method LCMSBASl) is obtained.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2011/131741, 2011, A1 Location in patent: Page/Page column 65
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2011/144622, 2011, A1 Location in patent: Page/Page column 58-59
[3]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2012/94976, 2012, A1 Location in patent: Page/Page column 35-36
[4]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2010/7114, 2010, A2 Location in patent: Page/Page column 105-106

19
[ 4774-35-0 ]
[ 85118-01-0 ]
[ 1204400-22-5 ]

Yield	Reaction Conditions	Operation in experiment
89%		Method of svnthesising A.25Sodium hydride (60 %; 1.40 g, 36.0 mmol) is placed in DMF (70 mL), mixed with carboxylic acid ester A.a.1 (5.00 g, 32.0 mmol) and stirred for 45 min at 20C. Then benzylbromide A.b.1 (4.10 mL, 32.0 mmol) is metered in and the mixture is stirred for a further 3 h at 20C. The reaction mixture is combined with HCI (50 mL, 1 N) and DCM (50 mL), the organic phase is separated off and extracted again with HCI (2 x 30 mL). Then the organic phase is dried, the solvent is eliminated in vacuo and carboxylic acid ester A*.25 (10.0 g, 89 %; HPLC-MS: MS(M+H)+ = 281 ; tRel = 1 .57 min; method FEC3) is obtained.
89%		Sodium hydride (60 %; 1.40 g, 36.0 mmol) is placed in DMF (70 mL), carboxylic acid ester A.a.1 (5.00 g, 32.0 mmol) is added and the mixture is stirred for 45 min at 20C. Then benzylbromide A.b.1 (4.10 mL, 32.0 mmol) is metered in and the mixture is stirred for a further 3 h at 20C. The reaction mixture is combined with HCI (50 mL, 1 N) and DCM (50 mL), the organic phase is separated off and extracted again with HCI (2 x 30 mL). Then the organic phase is dried, the solvent is eliminated in vacuo and carboxylic acid ester A*.32 (10.0 g, 89 %; HPLC-MS: MS(M+H)+ = 281 ; = 1.57 min; method FEC3) is obtained.
89%		Method of Synthesising A.25Sodium hydride (60%; 1.40 g, 36.0 mmol) is placed in DMF (70 mL), mixed with carboxylic acid ester A.a.1 (5.00 g, 32.0 mmol) and stirred for 45 min at 20 C. Then benzylbromide A.b.1 (4.10 mL, 32.0 mmol) is metered in and the mixture is stirred for a further 3 h at 20 C. The reaction mixture is combined with HCl (50 mL, 1 N) and DCM (50 mL), the organic phase is separated off and extracted again with HCl (2×30 mL). Then the organic phase is dried, the solvent is eliminated in vacuo and carboxylic acid ester A.25 (10.0 g, 89%; HPLC-MS: MS (M+H)+=281; tRet.=1.57 min; method FEC3) is obtained.Carboxylic acid ester A.25 (1.9 g, 5.6 mmol) is taken up in MeOH (7.3 mL) and mixed with NaOH (6.2 mL, 1 M). After 16 h at 20 C. the mixture is diluted with water and extracted with DCM. The organic phase is discarded, the aqueous phase is acidified and extracted with DCM. The organic phase is dried on Na2SO4, filtered, the solvent is eliminated in vacuo and the free carboxylic acid A.25 (694 mg, 47%; HPLC-MS: MS (M+H)+=267; tRet.=0.29 min; method FECB4) is obtained.

a) Synthesis of free cyclic carboxylic acids A.1; Method for svnthesising A. Ia; Sodium hydride (60 %; 28.6 mg, 0.714 mmol) is suspended in 1.5 rnL DMF, combined with carboxylic acid ester B.l-la (100 mg, 0.649 mmol) and stirred for 45 min at 20C. Benzyl bromide B.2a (134 mg, 0.649 mmol) is metered into the suspension and it is stirred for a further 3 h at 200C. The reaction mixture is combined with 1 N hydrochloric acid and DCM, the organic phase is separated off and extracted 2 x with 1 N hydrochloric acid. Then the organic phase is dried, the solvent is eliminated in vacuo and carboxylic acid ester A.l*a (HPLC-MS: tRet. = 1.50 min; MS(M+H)+ = 281; method FECB3) is obtained.

Reference： [1]Patent: WO2011/131741,2011,A1 .Location in patent: Page/Page column 59-60
[2]Patent: WO2011/144622,2011,A1 .Location in patent: Page/Page column 52
[3]Patent: US2012/94976,2012,A1 .Location in patent: Page/Page column 30-31
[4]Patent: WO2010/7114,2010,A2 .Location in patent: Page/Page column 101

20
[ 85118-01-0 ]
[ 27825-20-3 ]
[ 1204400-32-7 ]

Yield	Reaction Conditions	Operation in experiment
		Methyl 2-hydroxy-3-pyrazinecarboxylate (103 mg, 0.67 mmoi) (obtained fromFulcrum Scientific Ltd.) was placed in a 25-mL RBF and placed under a nitrogen atmosphere. DMF (3 mL) was added, followed by NaH (33 mg, 0.83 mmol) and the reaction was allowed to stir for twenty minutes at room temperature. 3,4-Difluorobenzyl bromide (0.094 mL, 0.735 mmol) was added, and the reaction was allowed to stir at room temperature overnight, and the reaction was found to be complete by LC-MS. The reaction was added to a separatory funnel containing ethyl acetate (125 mL) and dilute aqueous NaHCO3 (75 mL); the phases were separated and the organic layer was washed with brine and dried over anhydrous Na2SO4, then concentrated in vacuo. The crude product was purified by silica gel chromatography using 10- 100% EtOAc in n-heptane to afford methyl 4-(3,4-difluorobenzyI)-3-oxo-3,4-dihydropyrazine-2- carboxylate as a yellow solid. .H NMR (500 MHz, C2D6SO) delta 8.08 (d, IH), 7.49 (t, IH), 7.44 (d, IH), 7.42 (t, IH), 7.23 (m, IH), 5.09 (s, 2H), 3.80 (s, 3H). LRMS (ESI) calc'd for (C13HnF2N2O3) [M+H]+, 281.1; found 281.1

Reference： [1]Patent: WO2010/65384,2010,A1 .Location in patent: Page/Page column 35

21
[ 15015-57-3 ]
[ 85118-01-0 ]
[ 1309876-40-1 ]

Reference： [1]Synthetic Communications,2011,vol. 41,p. 1805 - 1808

22
[ 24922-01-8 ]
[ 85118-01-0 ]
[ 1335027-52-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine; lithium chloride; In tetrahydrofuran; at 80℃; for 18h;	Method IVEthyl 3-cyclobutyl-2-[(3,4-difluorophenyl)methyl]-3-oxo-propanoateN-Ethyl-N-isopropylpropan-2-amine (3.07 mL, 17.63 mmol) was added to lithium chloride (0.374 g, 8.81 mmol), <strong>[24922-01-8]ethyl 3-cyclobutyl-3-oxopropanoate</strong> (1.5g, 8.81 mmol) and 4- (bromomethyl)-l,2-difluorobenzene (1.128 mL, 8.81 mmol) in THF (12 mL) at 20C. The resulting mixture was stirred at 80 C for 18 hours. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (20 mL), saturated brine (20 mL). The organic layer was dried over MgS04, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 15% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (2.400 g, 92 %) as a colourless oil.1H NMR (400.13 MHz, CDC13) delta 1.15-1.23 (3H, m), 1.74-1.81 (1H, m), 1.87-1.96 (1H, m), 2.01-2.10 (1H, m), 2.02-2.10 (2H, m), 2.23-2.32 (1H, m), 3.01-3.15 (2H, m), 3.36 (1H, t), 3.68 (1H, t), 4.09-4.18 (2H, m), 6.88-6.92 (1H, m), 6.96-6.99 (1H, m), 7.01-7.07 (1H, m); m/z (ES) (M-H) = 295.

Reference： [1]Patent: WO2011/114148,2011,A1 .Location in patent: Page/Page column 81-82

23
[ 89581-64-6 ]
[ 85118-01-0 ]
[ 1204400-37-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: methyl 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylate With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.75h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide at 20℃; for 2h;	A.34 Sodium hydride (60 %; 93 mg, 2.3 mmol) is placed in DMF (1 .5 mL), combined with carboxylic acid ester A.a.3 (397 mg, 2.10 mmol) and stirred for 45 min at 20°C. Then benzyl bromide A.b.1 (0.27 mL, 2.1 mmol) is metered in and the mixture is stirred for a further 2 h at 20°C. The reaction mixture is combined with HCI (5 mL, 1 N) and DCM (5 mL), the organic phase is separated off and extracted again with HCI (2 x 5 mL). Then the organic phase is dried on MgS04, filtered off, the solvent is eliminated in vacuo and carboxylic acid ester A*.34 (922 mg, 98 %; H PLC-MS: MS(M+H)+ = 31 5; tRet = 2.2 min; method AFEC) is obtained.
98%	Stage #1: methyl 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylate With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.75h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide at 20℃; for 2h;	A.41 Sodium hydride (60 %; 93 mg, 2.3 mmol) is placed in DMF (1.5 mL), combined with carboxylic acid ester A.a.3 (397 mg, 2.10 mmol) and stirred for 45 min at 20°C. Then benzyl bromide A.b.1 (0.27 mL, 2.1 mmol) is metered in and the mixture is stirred for a further 2 h at 20°C. The reaction mixture is combined with HCI (5 mL, 1 N) and DCM (5 mL), the organic phase is separated off and extracted again with HCI (2 x 5 mL). Then the organic phase is dried on MgS04, filtered off, the solvent is eliminated in vacuo and carboxylic acid ester A*.41 (922 mg, 98 %; HPLC-MS: MS(M+H)+ = 315; tRet.= 2.2 min; method AFEC) is obtained.
98%	Stage #1: methyl 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylate With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.75h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide at 20℃; for 2h;	a.A.34 Method of Synthesising A.34Carboxylic acid ester ED.1 (2.00 g, 10.4 mmol) is placed in dioxane (9.0 mL), combined with HCl (10.4 mL, 1 M) and stirred for 20 h at 90° C. Then the reaction mixture is cooled to 0° C., the precipitate is filtered off, washed with water and pyridazinonic acid Z.1 (955 mg, 53%; HPLC-MS: MS (M-H)-=173; tRet.=0.00 min; method LCMSBAS1) is obtained.Pyridazinonic acid Z.1 (955 mg, 5.4 mmol) is placed in MeOH (6.0 mL), combined with HCl (6.0 mL, 4M in dioxane) and stirred for 20 h at 50° C. The reaction mixture is combined with H2O and DCM, the organic phase is separated off and extracted with H2O (2×10 mL). Then the organic phase is dried on MgSO4, filtered off, the solvent is eliminated in vacuo and carboxylic acid ester A.a.3 (890 mg, 86%; HPLC-MS: MS (M+H)+=189; tRet.=1.47 min; method AFEC) is obtained.Sodium hydride (60%; 93 mg, 2.3 mmol) is placed in DMF (1.5 mL), combined with carboxylic acid ester A.a.3 (397 mg, 2.10 mmol) and stirred for 45 min at 20° C. Then benzyl bromide A.b.1 (0.27 mL, 2.1 mmol) is metered in and the mixture is stirred for a further 2 h at 20° C. The reaction mixture is combined with HCl (5 mL, 1 N) and DCM (5 mL), the organic phase is separated off and extracted again with HCl (2×5 mL). Then the organic phase is dried on MgSO4, filtered off, the solvent is eliminated in vacuo and carboxylic acid ester A.34 (922 mg, 98%; HPLC-MS: MS (M+H)+=315; tRet.=2.2 min; method AFEC) is obtained.Carboxylic acid ester A.34 (470 mg, 1.00 mmol) is taken up in MeOH (3.0 mL) and combined with 1 N NaOH (1.3 mL). After 5 h at 20° C. the mixture is diluted with water and extracted with DCM. The organic phase is discarded, the aqueous phase is acidified with HCl (5 mL, 1 M) and extracted with DCM (3×5 mL). The organic phase is dried, the solvent is eliminated in vacuo and the free carboxylic acid A. 34 (149 mg, 48%; HPLC-MS: MS (M-H)-=299; tRet.=0.76 min; method LCMSBAS1) is obtained.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2011/131741, 2011, A1 Location in patent: Page/Page column 62-63
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2011/144622, 2011, A1 Location in patent: Page/Page column 55-56
[3]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2012/94976, 2012, A1 Location in patent: Page/Page column 33-34

24
6-methyl-3-oxo-2,3-dihydro-pyridazine-4-carboxylic acid methyl ester [ No CAS ]
[ 85118-01-0 ]
[ 1345443-19-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	Stage #1: 6-methyl-3-oxo-2,3-dihydro-pyridazine-4-carboxylic acid methyl ester With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.75h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide at 20℃; for 48h;	A.26 Method of synthesising A.26Sodium hydride (60 %; 105 mg, 2.60 mmol) is placed in DMF (1 .50 mL), mixed with carboxylic acid ester A.a.2 (400 mg, 2.40 mmol) and stirred for 45 min at 20°C. Then benzyl bromide A.b.1 (0.31 mL, 2.4 mmol) is metered in and the mixture is stirred for a further 48 h at 20°C. The reaction mixture is combined with HCI (50 mL, 1 N) and DCM (50 mL), the organic phase is separated off and extracted again with HCI (2 x 30 mL). Then the organic phase is dried, the solvent is eliminated in vacuo and carboxylic acid ester A*.26 (487 mg, 69 %; HPLC-MS: MS(M+H)+ = 295; tRel = 2.09 min; method AFEC) is obtained.
69%	Stage #1: 6-methyl-3-oxo-2,3-dihydro-pyridazine-4-carboxylic acid methyl ester With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.75h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide at 20℃; for 48h;	A.33 Method for synthesising A.33Sodium hydride (60 %; 105 mg, 2.60 mmol) is placed in DMF (1.50 mL), combined with carboxylic acid ester A.a.2 (400 mg, 2.40 mmol) and stirred for 45 min at 20°C. Then benzylbromide A.b.1 (0.31 mL, 2.4 mmol) is metered in and the mixture is stirred for a further 48 h at 20°C. The reaction mixture is combined with HCI (50 mL, 1 N) and DCM (50 mL), the organic phase is separated off and extracted again with HCI (2 x 30 mL). Then the organic phase is dried, the solvent is eliminated in vacuo and carboxylic acid ester A*.33 (487 mg, 69 %; HPLC-MS: MS(M+H)+ = 295; tRe,= 2.09 min; method AFEC) is obtained.
69%	Stage #1: 6-methyl-3-oxo-2,3-dihydro-pyridazine-4-carboxylic acid methyl ester With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.75h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide at 20℃; for 48h;	a.A.26 Method of Synthesising A.26Sodium hydride (60%; 105 mg, 2.60 mmol) is placed in DMF (1.50 mL), mixed with carboxylic acid ester A.a.2 (400 mg, 2.40 mmol) and stirred for 45 min at 20° C. Then benzyl bromide A.b.1 (0.31 mL, 2.4 mmol) is metered in and the mixture is stirred for a further 48 h at 20° C. The reaction mixture is combined with HCl (50 mL, 1 N) and DCM (50 mL), the organic phase is separated off and extracted again with HCl (2×30 mL). Then the organic phase is dried, the solvent is eliminated in vacuo and carboxylic acid ester A.26 (487 mg, 69%; HPLC-MS: MS (M+H)+=295; tRet.=2.09 min; method AFEC) is obtained.Carboxylic acid ester A.26 (487 mg, 1.71 mmol) is taken up in MeOH (4.0 mL) and mixed with NaOH (2.0 mL, 1 N). After 2 h at 20° C. the mixture is diluted with water and extracted with DCM. The organic phase is discarded, the aqueous phase is acidified and extracted with DCM. The organic phase is dried on Na2SO4, the solvent is eliminated in vacuo and the free carboxylic acid A.26 (HPLC-MS: MS (M-H)-=279; tRet.=0.00 min; method LCMSBAS1) is obtained.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2011/131741, 2011, A1 Location in patent: Page/Page column 60
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2011/144622, 2011, A1 Location in patent: Page/Page column 52-53
[3]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2012/94976, 2012, A1 Location in patent: Page/Page column 31

25
[ 3731-16-6 ]
[ 85118-01-0 ]
[ 1363145-38-3 ]

Yield	Reaction Conditions	Operation in experiment
		ethyl 3-(3,4-difluorobenzyl)-2-oxopiperidine-3-carboxylateUnder a nitrogen atmosphere, to a mixture of ethyl 2-oxopiperidine-3-carboxylate (2.0 g) in DMF (20 mL) was added sodium hydride (60%, 0.47 g) at 0 C., and the mixture was stirred at 0 C. for 30 min. 4-(Bromomethyl)-1,2-difluorobenzene (1.50 mL) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.82 g).1H NMR (300 MHz, CDCl3) delta 1.30 (3H, t, J=7.1 Hz), 1.54-1.66 (1H, m), 1.69-1.92 (2H, m), 2.11 (1H, dd, J=11.4, 3.7 Hz), 2.99 (1H, d, J=13.7 Hz), 3.03-3.11 (1H, m), 3.21-3.32 (1H, m), 3.55 (1H, d, J=13.5 Hz), 4.11-4.34 (2H, m), 6.12 (1H, brs), 6.88-7.18 (3H, m).

Reference： [1]Patent: US2012/59030,2012,A1 .Location in patent: Page/Page column 53-54

26
[ 1363144-58-4 ]
[ 85118-01-0 ]
[ 1363135-45-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: alpha-bromo-3,4-difluorotoluene In N,N-dimethyl-formamide; mineral oil at 0℃; for 1h;	16 5.16 Ethyl 8-(3,4-difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (34) To a suspension of NaH (60% in oil, 0.34g, 8.5mmol) in DMF (5mL) was added 33 (3.0g, 7.8mmol) at 0°C. After the mixture was stirred for 30 min at 0°C, 3,4-difluorobenzyl bromide (1.5g, 9.4mmol) was added at 0°C. After being stirred for 1h at 0°C, the reaction mixture was diluted with EtOAc, washed with satd NH4Cl aq and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/EtOAc) to give 34 (3.5g, 87%) as a colorless amorphous. 1H NMR (CDCl3) δ: 1.37 (3H, t, J=7.0Hz), 2.16-2.30 (1H, m), 2.34-2.60 (5H, m), 2.70-2.83 (1H, m), 3.97-4.16 (4H, m), 4.19-4.31 (1H, m), 4.39 (2H, q, J=7.0Hz), 7.21-7.28 (1H, m), 7.46 (1H, d, J=1.4Hz), 7.50 (1H, s), 7.83 (1H, d, J=8.2Hz). MS m/z: 509.2 (M+H)+.
	With sodium hydride In N,N-dimethyl-formamide; mineral oil for 1.5h; Cooling with ice;	47.B ethyl 8-(3,4-difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylateEthyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (3.00 g) was added to a suspension of sodium hydride (60%, 340 mg) in DMF (5 mL) under ice-cooling. The reaction mixture was stirred for 30 min under ice-cooling, 3,4-difluorobenzyl bromide (1.53 g) was added under ice-cooling, and the mixture was stirred for 1 hr under ice-cooling. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (3.47 g).

Reference： [1]Takai, Takafumi; Koike, Tatsuki; Nakamura, Minoru; Kajita, Yuichi; Yamashita, Toshiro; Taya, Naohiro; Tsukamoto, Tetsuya; Watanabe, Tomomichi; Murakami, Koji; Igari, Tomoko; Kamata, Makoto [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 14, p. 3192 - 3206]
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2012/59030, 2012, A1 Location in patent: Page/Page column 48

27
[ 957059-39-1 ]
[ 85118-01-0 ]
[ 957056-06-3 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: (3-methylbenzo[b]thiophen-2-ylmethyl)phosphonic acid diethyl ester With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 0.5h; Stage #2: alpha-bromo-3,4-difluorotoluene In tetrahydrofuran; hexane at -70 - 20℃; for 0.5h;	[2-(4-Fluoro-phenyl)-1-(3-methyl-benzo[b]thiophene-2-yl)-ethyl]-phosphonic acid diethyl ester, 9l General procedure: To a solution of compound 8 (2.5 g; 8.38 mmol) in THF (20 mL) cooled to -70 °C, was added a 2.5 M solution of n-butyllithium in hexanes (4.4 mL; 11.0 mmol), dropwise. The reaction mixture was allowed to stir at -70 °C for 30 min, to which was then added a solution of 3,4-difluorobenzyl bromide (2.08 g; 10.0 mmol) in THF (5 mL), dropwise. The reaction mixture was allowed to slowly warm to ambient temperature, and stirred for an additional 30 min before quenching with a solution of saturated aqueous NH4Cl (5.0 mL). The mixture was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel) eluting with a heptane-ethyl acetate gradient to afford 2.71 g (76%) of compound 9l as an oil. 1H-NMR 1H-NMR (300 MHz, CDCl3): 7.76-7.78 (m, 1H), 7.54-7.56 (m, 1H), 7.28-7.35 (m, 2H), 6.86-6.93 (m, 2H), 6.73-6.76 (m, 1H), 4.03-4.18 (m, 3H), 3.89-4.01 (m, 1H), 3.74-3.88 (m, 1H), 3.45-3.51 (m, 1H), 3.08-3.16 (m, 1H), 2.07 (s, 3H), 1.30-1.33 (t, 3H), 1.18-1.22 (t, 3H); LC/MS: C21H23F2O3PS: m/z 424.8 (M+).

Reference： [1]Matthews, Jay M.; Qin, Ning; Colburn, Raymond W.; Dax, Scott L.; Hawkins, Mike; McNally, James J.; Reany, Laura; Youngman, Mark A.; Baker, Judith; Hutchinson, Tasha; Liu, Yi; Lubin, Mary Lou; Neeper, Michael; Brandt, Michael R.; Stone, Dennis J.; Flores, Christopher M. [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2922 - 2926]

28
[ 76003-29-7 ]
[ 85118-01-0 ]
[ 1261279-35-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: 4-(t-butyloxycarbonyl)piperazin-2-one With sodium hydride In 1,4-dioxane at 20℃; Cooling with ice; Stage #2: alpha-bromo-3,4-difluorotoluene In 1,4-dioxane at 20℃; Cooling with ice;	14 Sodium hydride (120 mg, 3.00 mmol) was suspended in 1,4-dioxane and tert-butyl 3-oxopiperazin-1-carboxylate (500 mg, 2.50 mmol) was added under ice-cooling, followed by stirring at room temperature for 30 minutes. After ice-cooling, 4-(bromomethyl)-1,2-difluorobenzene (620 mg, 3.00 mmol) was added, followed by stirring at room temperature for 3 hours. Ethyl acetate (20 ml) and water (10 ml) were added and the mixture was partitioned between an organic layer and an aqueous layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (AcOEt/Hexane:0%-20%) to afford the target compound (815 mg, 98%). LC-MS (Method C): 2.62 min, [M+H] =327.14

Reference： [1]Current Patent Assignee: SHIONOGI & CO., LTD. - EP2455370, 2012, A1 Location in patent: Page/Page column 109

29
[ 109384-19-2 ]
[ 85118-01-0 ]
tert-butyl 4-((3,4-difluorobenzyl)oxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: 1-(tert-Butyloxycarbonyl)-4-piperidinol With sodium hydride In tetrahydrofuran at 0℃; for 5h; Inert atmosphere; Stage #2: 4-bromomethyl-1,2-difluorobenzene at 20℃; for 12h;	13.1 Step 1: tert-Butyl 4-((3, 4-difluorobenzyl) oxy) piperidine-1-carboxylate (2) To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate 1 (500 mg, 2.48 mmol) in dry THF (50 mL) under inert atmosphere were added NaH (89 mg, 3.73 mmol) at 0 °C. The reaction mixture was stirred for 5 mm. Then 4-(bromomethyl)- 1, 2-difluorobenzene (566 mg, 2.73 mmol) was added to the reaction mixture. The reaction mixture was warmed to RT and stirred for 12 h. The reaction progress was monitored by TLC; after reaction completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude material. The crude material was purified through silica gel flash column chromatography using 5% EtOAc/ hexanes to afford compound 2 (517 mg, 63%) as yellow oil. 1H NMR (500 MHz, CDC13): ö 7.19-7.09 (m, 2H), 7.04-7.03 (m, 1H), 4.49 (s, 2H), 3.79-3.74 (m, 2H), 3.57-3.52 (m, 1H), 3.13-3.08 (m, 2H), 1.87-1.84 (m, 2H), 1.62-1.54 (m, 2H), 1.45 (s, 9H); LC-MS: 83.9%; (M-Boc) Found=228.2; (column: X select C-18, 50 x 3.0 mm, 3.5 jim); RT 4.52 mm. 5 mM NH4OAc: ACN; 0.8 mL/min).
46.5%	Stage #1: 1-(tert-Butyloxycarbonyl)-4-piperidinol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: 4-bromomethyl-1,2-difluorobenzene In N,N-dimethyl-formamide at 20℃; for 20h;	General Procedure I General procedure: To a vial with 1-Boc-4-hydroxypiperidine,5, (1 eq.) in DMF, cooled to 0°C, NaH (2 eq.) was slowly added. The mixture was stirred for 1 h and allowed to warm to room temperature. The vial was cooled in an ice bath before adding the substituted benzyl bromide (1.1 eq.). The reaction was allowed to come to room temperature and was stirred for 20 h. The reaction was quenched with water and the product was extracts with EtOAc. The EtOAc layers were collected and washed with brine and dried with sodium sulfate. The product was purified with flash chromatography 0-15% EtOAc:hexanes. Boc deprotection was done using 4N HCl in dioxane. The reaction was stirred for 2 hours before it was concentratedin vacuoyielding7.
46.5%	Stage #1: 1-(tert-Butyloxycarbonyl)-4-piperidinol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: 4-bromomethyl-1,2-difluorobenzene In N,N-dimethyl-formamide at 20℃; for 20h;	General Procedure I General procedure: To a vial with 1-Boc-4-hydroxypiperidine,5, (1 eq.) in DMF, cooled to 0°C, NaH (2 eq.) was slowly added. The mixture was stirred for 1 h and allowed to warm to room temperature. The vial was cooled in an ice bath before adding the substituted benzyl bromide (1.1 eq.). The reaction was allowed to come to room temperature and was stirred for 20 h. The reaction was quenched with water and the product was extracts with EtOAc. The EtOAc layers were collected and washed with brine and dried with sodium sulfate. The product was purified with flash chromatography 0-15% EtOAc:hexanes. Boc deprotection was done using 4N HCl in dioxane. The reaction was stirred for 2 hours before it was concentratedin vacuoyielding7.

Reference： [1]Current Patent Assignee: SABRE THERAPEUTICS LLC - WO2015/48301, 2015, A1 Location in patent: Paragraph 00448
[2]Hopkins, Corey R.; Mashinson, Viktoriya; Tolentino, Kirsten T.; Vadukoot, Anish K. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 61]
[3]Hopkins, Corey R.; Mashinson, Viktoriya; Tolentino, Kirsten T.; Vadukoot, Anish K. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 61]

30
(S)-3-hydroxy-3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazole [ No CAS ]
[ 85118-01-0 ]
(S)-3-(3,4-difluorobenzyloxy)-3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere;	General procedure for the synthesis of (S)-3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazolederivatives (4) General procedure: To a solution of the 3 (2.89 mmol) in anhydrous DMF (12 mL)under argon ware added NaH (60% in mineral oil, 0.145 g,3.63 mmol) followed by BnBr (0.989 g, 5.78 mmol) At 0°C. Thereactionmixturewas stirred at 0°Cfor 30min and roomtemperaturefor overnight. The reaction was diluted with ethyl acetate(50 mL) and washed with satd aqueous NH4C1 (2 × 50 mL)and then the aqueous layer was extracted with ethyl acetate(2 × 40 mL). The combined organic extract was washed withbrine (50 mL) and dried over anhydrous Na2SO4. After filtrationthe solvent was evaporated under reduced pressure, and theresidue was purified on silica gel by flash column chromatography(EtOAc/hexanes, 1: 4) gave the anticipated compounds.

Reference： [1]Gong, Jing-Xu; He, Ya; Cui, Zhen-Lin; Guo, Yue-Wei [Phosphorus, Sulfur and Silicon and the Related Elements, 2016, vol. 191, # 7, p. 1036 - 1041]

31
[ 1592-95-6 ]
[ 85118-01-0 ]
3-bromo-9-(3,4-difluorobenzyl)carbazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 20h; Inert atmosphere;	13.13-1 Into the flask, 3bromocarbazole 2.00g, sodium hydroxide 0.349g and N, was placed in theNdimethylformamide20mL, in the flask was replaced with nitrogen. Thereto was added dropwise 4(bromomethyl) 1,2difluorobenzene1.10 mL, and stirred at room temperature for 3 days. Then, to the stirred deionized water was addeddropwise and the reaction mixture obtained and the resulting slurry was further stirred at room temperature. Finally, the slurrywas filtered and the filtrate was dried to give 3bromo9(3,4difluorobenzyl)carbazole (yield 2.91 g, 96% yield).

Reference： [1]Current Patent Assignee: NISSAN CHEMICAL CORPORATION - JP5790901, 2015, B1 Location in patent: Paragraph 0261

32
[ 609-71-2 ]
[ 85118-01-0 ]
[ 1001413-01-9 ]

Yield	Reaction Conditions	Operation in experiment
		A stirred suspension of NaH 60% dispersion inmineral oil (206 mg, 5.14 mmol), washed twice with distilled n-hexane and once with Et2Oin 2 mL of anhydrous DMF under N2 atmosphere was treated dropwisewith a solution containing the 2-hydroxynicotinic acid (600 mg, 4.31 mmol) in 5mL of anhydrous DMF. The mixture was left under stirring at rt for 2h and then3,4-difluoro-benzylbromide (1.06 g, 5.14 mmol) was added and the mixturestirred and heated at 50C for 16h. After the mixture was concentrated under reducedpressure and the residue was treated with water to give a solid, which wascollected by vacuum filtration. Next the solid was refluxed for 4h in aq. 10% NaOH(10 mL) and the resulting mixture was cooled and made acid with 1N aq. HCl. Thewhite solid formed was collected by filtration and washed with n-hexane and Et2O, givingthe 19 as white solid (857 mg, 3.23 mmol, 75% yield).1H-NMR (400 MHz, DMSO-d6):delta 5.30 (s, 2H, CH2); 6.78 (t, 1H, J = 6.9 Hz, Ar); 7.22-7.24 (m, 1H,Ar); 7.41-7.53 (m, 2H, Ar); 8.41 (d, 2H, J = 6.9 Hz, Ar) ppm. Anal. Calcd for C13H9NO3F2:C, 58.87%; H, 3.42%; N, 5.28%; Found: C, 58.99%; H, 3.47%; N, 5.43%.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 118,p. 47 - 63

33
[ 141-90-2 ]
[ 85118-01-0 ]
S-(3,4-difluorobenzyl)-2-thiouracil [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.22 g	In N,N-dimethyl-formamide; at 20℃;	This compound was prepared by reaction in 5 mL of anhydrous dimethylformamide, reacting 1.28 g (10 mmol) of 2-thiouracil with 2.07 g of alpha-bromo-3,4-difluorotoluene (10 mmol), stirring at ambient temperature overnight. The reaction mixture was quenched by adding it dropwise, with rapid stirring, to 25 mL of 0.5 M aqueous NaHCO3. The product was collected by filtration, washed with a small volume of water and dried under vacuum. Yield was 2.22 g of Compound 5, a white powder, 95.5% pure by HPLC-electrospray MS, which confirmed the molecular weight of 254.

Reference： [1]Patent: US9510593,2016,B2 .Location in patent: Page/Page column 11

34
[ 609-71-2 ]
[ 85118-01-0 ]
[ 1001413-01-9 ]

Yield	Reaction Conditions	Operation in experiment
75%		A stirred suspension of NaH 60% dispersion in mineral oil (206 mg, 5.14 mmol), washed twice with distilled n-hexane and once with Et20 in 2 mL of anhydrous DMF under N2 atmosphere was treated dropwise with a solution containing the 2-hydroxynicotinic acid (600 mg, 4.31 mmol) in 5 mL of anhydrous DMF. The mixture was left under stirring at room temperature for 2h and then 3,4-difluoro-benzylbromide (1.06 g, 5.14 mmol) was added and the mixture stirred and heated at 50C for 1 6h. After the mixture was concentrated under reduced pressure and the residue was treated with water to give a solid, which was collected by vacuum filtration. Next the solid was refluxed for 4h in aq. 10% NaOH (10 mL) and the resulting mixture was cooled and made acid with 1 N aq.HCI. The white solid formed was collected by filtration and washed with nhexane and Et20, giving the derivative 3.9 as white solid (857 mg, 3.23 mmol, 75% yield).1HNMR (400 MHz, DMSO-d6): 65.30 (5, 2H, CH2); 6.78 (t, 1H, J = 6.9 Hz, Ar);7.22-7.24 (m, 1H, Ar); 7.41 -7.53 (m, 2H, Ar); 8.41 (d, 2H, J = 6.9 Hz, Ar) ppm.Anal. Calcd for C13H9NO3F2: C, 58,87%; H, 3.42%; N, 5.28%; Found: C, 58,99%; H, 3.47%; N, 5.43%
75%		1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (5). A stirred suspension of NaH 60% dispersion in mineral oil (206 mg, 5.14 mmol), washed twice with distilled n-hexane and once with Et20 under N2 atmosphere, was treated dropwise with a solution containing the 2-hydroxynicotinic acid (600 mg, 4.31 mmol) in 5 mL of anhydrous DMF. The mixture was left under stirring at rt for 2h and then 3,4-difluoro-benzylbromide (1 .06 g, 5.14 mmol) was added and the mixture stirred and heated at 50C for 1 6h. After, the mixture was concentrated under reduced pressure and the residue was treated with water to give a solid, which was collected by vacuum filtration. Next the solid was refluxed for 4h in aq. 10% NaOH (10 mL) and the resulting mixture was cooled and made acid with 1 N aq. HCI. The white solid formed was collected by filtration and washed with n-hexane and Et20, giving 5 as white solid (857 mg, 3.23 mmol, 75% yield). H-NMR (400 MHz, DMSO-de): delta 5.30 (s, 2H, CH2); 6.78 (t, 1 H, J = 6.9 Hz, Ar); 7.22-7.24 (m, 1 H, Ar); 7.41 -7.53 (m, 2H, Ar); 8.41 (d, 2H, J = 6.9 Hz, Ar) ppm. Anal. Calcd for C13H9NO3F2: C, 58.87%; H, 3.42%; N, (0126) 3%.

Reference： [1]Patent: WO2016/198597,2016,A1 .Location in patent: Page/Page column 18; 19
[2]Patent: WO2017/211946,2017,A1 .Location in patent: Page/Page column 21

35
2-(4-(1-piperazinyl)phenzoyl)-6-diethylaminobenzofuran [ No CAS ]
[ 85118-01-0 ]
C₃₀H₃₁F₂N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With caesium carbonate In dichloromethane at 20℃; for 12h;	General procedure for the preparation of derivatives 8-14, 25 General procedure: To a stirred solution of compound 4(0.5 mmol) and Cs2CO3 (0.5 g) in dried DCM (15 mL), R-X (0.6 mmol) was added, and the reactionmixture was stirred for 12 h at room temperature (r.t.). After completion of the reaction as indicated byTLC, the mixture was filtered off. Then, the organic layer was concentrated in vacuo and purified bycolumn chromatography (1% MeOH/DCM) to afford products.

Reference： [1]Ma, Yulu; Zheng, Xi; Gao, Hui; Wan, Chunping; Rao, Gaoxiong; Mao, Zewei [Molecules, 2016, vol. 21, # 12]

36
[ 81477-94-3 ]
[ 85118-01-0 ]
C₂₆H₂₅F₂NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine In dichloromethane at -78 - -20℃; Inert atmosphere;	A 50-mL round-bottom flask sealed with a rubber septum and charged with 501 mg of 10 in 5 mL of dichloromethane under dry argon gas was treated dropwise via syringe 1.08 mL of 3,4-difluorobenzyl bromide. The contents were cooled to -78° C. and 0.734 mL of 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) was added dropwise via syringe over 10 min. The solution was stirred at -78° C. for 8 h and was then stored at -20° C. overnight. The solution was concentrated to an oil which was chromatographed on silica gel using hexanes to remove the excess benzyl bromide and 95/5 hexanes/ethyl acetate to elute 11d (575 mg, 80%). Imine 11d (572 mg) was heated under reflux in 8 mL of 6N HCl for 6 h and was allowed to cool. The solution was washed with 2×5 mL of diethyl ether (106 mg of an insoluble solid was collected and later identified as the hydrochloride salt of the desired product). The solution was then transferred to a 200-mL rb flask and was concentrated to dryness in vacuo. Approximately 5 mL of boiling ethanol was used to transfer the residue to a 25-mL Erlenmeyer flask as a solution. Upon cooling the solution was treated with 400 uL of propylene oxide and was allowed to stand. The precipitate was collected by filtration and dried in vacuo to afford 104 mg (38%) of 4d.

Reference： [1]Current Patent Assignee: INDIANA UNIVERSITY - US2017/44097, 2017, A1 Location in patent: Paragraph 0094

37
[ 5932-27-4 ]
[ 85118-01-0 ]
ethyl 1-(3,4-difluorobenzyl)-1H-pyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium hydroxide; In tetrahydrofuran; at 70℃; for 12h;	A mixture of <strong>[5932-27-4]ethyl 1H-pyrazole-3-carboxylate</strong> (1.4 g, 9.66 mmol), 4-(bromomethyl)- 1,2-difluorobenzene (1.0 g, 4.83 mmol) and potassium hydroxide (0.27 g, 4.83 mmol) in tetrahydrofuran (100 mL) was stirred at 70 °C for 12H. After cooling to RT, the mixture was filtered and the filtrate was concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100percent) ethyl acetate in petroleum ether) to afford ethyl l -(3,4-difluorobenzyl)-1H-imidazole-4-carboxylate (1.2 g, 93percent yield) as white solid: LCMS (0 to 60percent acetonitrile in water + 0.03percent trifluoroacetic acid over 2 mins) retention timel .25 min, ESI+ found [M+H] = 266.9.

Reference： [1]Patent: WO2017/4500,2017,A1 .Location in patent: Page/Page column 150

38
[ 17325-26-7 ]
[ 85118-01-0 ]
methyl 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With potassium hydroxide; In tetrahydrofuran; at 70℃; for 12h;	A mixture of 4-(bromomethyl)- 1,2-difluorobenzene (10.0 g, 48.3 mmol), 1H-imidazole-4-carboxylate (12.2 g, 96.6 mmol) and potassium hydroxide (5.4 g, 96.6 mmol) in tetrahydrofuran (100 mL) was heated at 70 C for 12H. After cooled, the mixture was filtered and the filtrate was concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100%) ethyl acetate in petroleum ether) to afford methyl 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylate (5.0 g, 41% yield) as a white solid: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 mins) retention time 0.70 min, ESI+ found [M+H] = 252.8.

Reference： [1]Patent: WO2017/4500,2017,A1 .Location in patent: Page/Page column 151-152

39
(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one [ No CAS ]
[ 85118-01-0 ]
(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1 ,2-a]pyrazin-8(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With caesium carbonate In acetonitrile at 70℃; for 23h; Inert atmosphere;	Intermediate 35a (S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)- 6,7-dihydroimidazo [ 1 ,2-a] pyrazin-8(5H)-one (5^-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[l ,2- a]pyrazin-8(5H)-one (Intermediate 35b; 1.8 g, 5.85 mmol) and CS2CO3 (2.67 g, 8.19 mmol) were slurried in acetronitrile (20 mL) and heated to 70 °C under nitrogen. 4- (bromomethyl)-l ,2-difluorobenzene (1.48 g, 7.02 mmol) in acetonitrile (3 mL) was added via syringe to the slurry and the reaction was stirred at 70 °C for 23 hours. The volatiles were then removed under reduced pressure and ethyl acetate (30 mL) and then water (20 mL) was added to the residue. The phases were separated the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The organic phases were combined and the volatiles removed under reduced pressure. The resulting solid was suspended in heptane/MTBE (4: 1 , 30 mL) and stirred at 50 °C for 2 hours. The solid was filtered off and dried under reduced pressure to afford (5)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)- 6-(methoxymethyl)-6,7-dihydroimidazo[l ,2-a]pyrazin-8(5H)-one (Intermediate 35a; 2.36 g, 93%) as a solid. lU NMR (400 MHz, CDCI3, 25 °C) δ 2.77 (3H, s), 3.28 (4H, s), 3.38 (1H, dd), 3.81 (1H, m), 4.22 (2H, m), 4.41 (1H, dd), 5.37 (1H, d), 7.10 - 7.26 (3H, m), 7.94 (1H, s), 8.42 (1H, s). m/z (ES+), [M+H]+ = 434

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/80979, 2017, A1 Location in patent: Page/Page column 183; 184

40
(S)-2-(2-chloropyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one [ No CAS ]
[ 85118-01-0 ]
(S)-2-(2-chloropyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a] pyrazin-8(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: (S)-2-(2-chloropyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: alpha-bromo-3,4-difluorotoluene With tetra-(n-butyl)ammonium iodide In N,N-dimethyl-formamide; mineral oil at 20℃; for 18h;	Intermediate 18 (S)-2-(2-Chloropyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7- dihydroimidazo [ 1 ,2-a] pyrazin-8(5H)-one Sodium hydride (60% dispersion) (25.03 mg, 0.63 mmol) was added to (S)-2-(2- chloropyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[l,2-a]pyrazin-8(5H)-one(Intermediate 9; 150 mg, 0.57 mmol) in DMF (12 mL) under nitrogen. The resulting suspension was stirred at 20 °C for 30 minutes. 4-(bromomethyl)-l,2-difluorobenzene (130 mg, 0.63 mmol) was added followed by tetrabutyl ammonium iodide (42.0 mg, 0.11 mmol) and the resulting solution stirred at 20 °C for 18 hours. The reaction mixture was poured into saturated aqueous NH4C1 (25 mL) and extracted with ethyl acetate (75 mL). The organic phases were dried over Na2S04 and concentrated in vacuo to give (5)-2-(2-chloropyrimidin- 4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[l,2-a]pyrazin-8(5H)-one (Intermediate 18; 222 mg, 100%) as a brown gum. H NMR (400 MHz, DMSO, 30°C) δ 1.14 (3H, d), 3.94 - 4.07 (1H, m), 4.27 (1H, dd), 4.36 (1H, d), 4.47 (1H, dd), 5.06 (1H, d), 7.26 (1H, s), 7.37 - 7.51 (2H, m), 7.93 (1H, d), 8.26 (1H, s), 8.74 (1H, d). m/z: ES+ [M+H]+ 390.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/80979, 2017, A1 Location in patent: Page/Page column 101

41
(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazine-8(5H)-one [ No CAS ]
[ 85118-01-0 ]
(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo [1 ,2-a]pyrazin-8(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.75%	With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2.5h;	5.1 Step 1 Synthesis of Compound D-1 Compound B-2 (460 mg, 2.22 mmol) was added to a solution of compound A-1 (456 mg, 1.48 mmol) and NaH (152 mg, 3.82 mmol) in anhydrous DMF (10 mL) at room temperature, and reacted at room temperature for 2.5 h. Water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and concentrated by column chromatography for purification (dichloro). Methane / methanol = 4%) gave 620 mg of a pale yellow solid, yield: 96.75%.
95%	With sodium hydride In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere;	Intermediate 62 (R)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)- 6,7-dihydroimidazo [ 1 ,2-a] pyrazin-8(5H)-one 4- (Bromomethyl)-l ,2-difluorobenzene (6.05 g, 29.25 mmol) was added to (i?)-2-(2-chloro-5- methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[l ,2-a]pyrazin-8(5H)-one (Intermediate 61 ; 6g, 19.50 mmol) and NaH (2 g, 50. mmol) in DMF (80 mL) at 25 °C under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with saturated NaHC03 (400 mL), extracted with EtOAc (3 x 250 mL), the organic layers were washed with brine, dried over Na2S04, filtered and evaporated to afford a yellow residue. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford (i?)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6- (methoxymethyl)-6,7-dihydroimidazo[l ,2-a]pyrazin-8(5H)-one (Intermediate 62; 8.00 g, 95%) as a light yellow solid. H NMR (300 MHz, CDC1 ) δ 2.76 (3H, s), 3.25-3.35 (1H, m), 3.28 (3H, s), 3.35-3.42 (1H, m), 3.78-3.85 (1H, m), 4.18-4.26 (2H, m), 4.42 (1H, d), 5.34 (1H, d), 7.08-7.30 (3H, m), 7.95 (1H, s), 8.43 (1H, s). m/z (ES+), [M+H]+ = 434.
95%	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 25℃; for 2h; Inert atmosphere;

Reference： [1]Current Patent Assignee: SHENZHEN TARGETRX INC - CN110577543, 2019, A Location in patent: Paragraph 0253; 0256-0258
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2017/80979, 2017, A1 Location in patent: Page/Page column 147; 148
[3]Ward, Richard A.; Anderton, Mark J.; Bethel, Paul; Breed, Jason; Cook, Calum; Davies, Emma J.; Dobson, Andrew; Dong, Zhiqiang; Fairley, Gary; Farrington, Paul; Feron, Lyman; Flemington, Vikki; Gibbons, Francis D.; Graham, Mark A.; Greenwood, Ryan; Hanson, Lyndsey; Hopcroft, Philip; Howells, Rachel; Hudson, Julian; James, Michael; Jones, Clifford D.; Jones, Christopher R.; Li, Yongchao; Lamont, Scott; Lewis, Richard; Lindsay, Nicola; McCabe, James; McGuire, Thomas; Rawlins, Philip; Roberts, Karen; Sandin, Linda; Simpson, Iain; Swallow, Steve; Tang, Jia; Tomkinson, Gary; Tonge, Michael; Wang, Zhenhua; Zhai, Baochang [Journal of Medicinal Chemistry, 2019, vol. 62, # 24, p. 11004 - 11018]

42
[ 38116-61-9 ]
[ 85118-01-0 ]
1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40 mg		1-(3 -difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (8) To a solution of 2-hydroxy-nicotinic acid 7 (6.53 mmol, 1 g) in DMF anhydrous (5 ml) under N2 current, CsF (19.59 mmol, 2975.3 mg) was added. The reaction mixture was allowed to stir at r.t. for 1 h. After this period, 3,4-difluoro-benzyl bromide (7.83 mmol, 1 ml) was added and the resulting mixture was heated at 50 C for 1 6 h. The solvent was evaporated under reduced pressure and the residue was triturated in H20 and filtered on a pad. This solid was then refluxed for 4h in a solution of NaOH 10% (10 ml_). The cooled solution was acidified with 1 N HCI and the precipitate was collected by filtration and then crushed with Et20 to provide the pure 8 derivative. C14H11 F2NO3 (Yield: 40%) 1H-NMR (DMSO): 2.45 (s, 3H, CH3); 5.42 (s, 2H, CH2); 6.71 (d, 1 H, J=7.6 Hz, Ar); 7.00-7.03 (m, 1 H, Ar); 7.32-7.44 (m, 2H, Ar); 8.33(d, 1 H, J=7.6 Hz, Ar) ppm

Reference： [1]Patent: WO2017/211946,2017,A1 .Location in patent: Page/Page column 33

43
[ 38116-61-9 ]
[ 85118-01-0 ]
5-bromo-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2017/211946,2017,A1

44
[ 3920-50-1 ]
[ 85118-01-0 ]
[ 321405-33-8 ]
C₁₁H₈F₂N₂O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9769 - 9789

45
[ 15366-34-4 ]
[ 85118-01-0 ]
methyl 1-(3,4-difluorobenzyl)-1H-pyrazole-3-carboxylate [ No CAS ]
C₁₂H₁₀F₂N₂O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9769 - 9789

46
[ 40594-98-7 ]
[ 85118-01-0 ]
ethyl 2-(3,4-difluorobenzyl)-2H-1,2,3-triazole-4-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9769 - 9789

47
[ 15294-81-2 ]
[ 85118-01-0 ]
4,5-dibromo-2-(3,4-difluorobenzyl)-2H-1,2,3-triazole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9769 - 9789

48
(6-(1H-pyrazol-1-yl)pyridin-3-yl) (4-(benzylamino)piperidin-1-yl)methanone [ No CAS ]
[ 85118-01-0 ]
(6-(1H-pyrazol-1-yl)pyridin-3-yl) (4-(benzyl(3,4-difluorobenzyl)amino)piperidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; potassium iodide In acetonitrile at 80℃;	4.1.10 General procedure H. Synthesis of compounds 13b-13e General procedure: Compound 13a, K2CO3 (4 equiv), BTEAC (0.1 equiv) and KI (0.1 equiv) were diluted in acetonitrile (15mL). To that various benzyl derivatives (2 equiv) were added and stirred overnight at 80°C, equipped with chlorcalcium tube. The K2CO3 was removed by filtration, the solvent was evaporated under reduced pressure and the compounds were cleaned by column chromatography.

Reference： [1]Kolarič, Anja; Švajger, Urban; Tomašič, Tihomir; Brox, Regine; Frank, Theresa; Minovski, Nikola; Tschammer, Nuska; Anderluh, Marko [European Journal of Medicinal Chemistry, 2018, vol. 154, p. 68 - 90]

49
[ 3470-50-6 ]
[ 85118-01-0 ]
C₁₇H₁₄F₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.4 g	With potassium carbonate; In acetonitrile; at 20℃; for 16h;	A mixture solution of the 5-hydroxyindanone (1) (288.0 mg, 1.74 mmol), alkyl bromide (90) (0.25 ml, 1.91 mmol) and the K2C03 (483.7 mg, 3.5 mmol) in MeCN (50 mL) was stirred at room temperature for 16 hours. The mixture was concentrated to remove the organic solvent. After that. DCM (10 mL) was added to the mixture and the mixture was filtered to remove K2C03. The filtrate was concentrated without further purification to provide a product as a solid product, Compound 91, and the yield thereof was 0.4 g (1.21 mmol).

Reference： [1]Patent: WO2019/51222,2019,A1 .Location in patent: Paragraph 00194; 00195; 00196

50
methyl-3-(4-((3-(piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)acrylate-2,2,2-trifluoroacetate [ No CAS ]
[ 85118-01-0 ]
methyl-3-(4-((3-(1-(3,4-difluorobenzyl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; potassium iodide In acetonitrile at 20℃; for 4h;	4.4 sybthesis of Methyl-3-(4-((3-(1-(3,4-difluorobenzyl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)acrylate(13) The compound of the formula (2-6) (2.27 mmol), K2CO3 (4.53 mmol) and KI (0.22 mmol) were sequentially added to 10 mL of an acetonitrile solution, and then 3,4-difluorobenzyl bromide (2.49 mmol) was added to the reaction system. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the solvent was evaporated, and ethyl acetate (3×60 mL)The organic phases were combined, dried and purified by silica gel chromatography to give the title compound. White powdery solid, yield 89%.

Reference： [1]Current Patent Assignee: SICHUAN UNIVERSITY - CN109942564, 2019, A Location in patent: Paragraph 0171-0173

51
ethyl-2-(methyl((3-(piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methyl)amino)pyrimidine-5-carboxylate-2,2,2-trifluoroacetate [ No CAS ]
[ 85118-01-0 ]
ethyl-2-(((3-(1-(3,4-difluorobenzyl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate; potassium iodide In acetonitrile at 20℃; for 4h;	4.8 Synthesis of ethyl-2-(((3-(1-(3,4-difluorobenzyl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate (44) The compound of the formula (3-4) (2.27 mmol), K2CO3 (4.53 mmol) and KI (0.22 mmol) were sequentially added to 10 mL of an acetonitrile solution, and then 3,4-difluorobenzyl bromide (2.49 mmol) was added to the reaction system. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the solvent was evaporated, and ethyl acetate (3×60 mL)The organic phases were combined, dried and purified by silica gel chromatography to give the title compound. White powdery solid in 75% yield.

Reference： [1]Current Patent Assignee: SICHUAN UNIVERSITY - CN109942564, 2019, A Location in patent: Paragraph 0268-0270

52
[ 85118-01-0 ]
[ 374538-01-9 ]
(E)-3-(5-(3,4-difluorobenzyl)-2-fluorophenyl)-2-(methylsulfonyl)acrylonitrile [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1148 - 1153

53
[ 85118-01-0 ]
[ 374538-01-9 ]
C₁₄H₉F₃O [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1148 - 1153

54
((1aR,7aS,10aS,10bS,E)-1a-methyl-8-methylene-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2',3':9,10]cyclodeca[1,2-b]furan-5-yl)methyl 2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate [ No CAS ]
[ 85118-01-0 ]
((1aR,7aS,10aS,10bS,E)-1a-methyl-8-methylene-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2',3':9,10]cyclodeca[1,2-b]furan-5-yl)methyl 2-(3-(3,4-difluorobenzyl)-5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 6h; Inert atmosphere;	4.1.8 General procedure for synthesis of compounds 12, 13a, 13b, 14a, 14b, and 15a-15o General procedure: To s stirred solution of compound 6, 8, 11a or 11b (0.05mmol) in DMF (1mL) was added different substituted benzyl bromide (13.7μL, 0.12mmol) and K2CO3 (0.18mmol) at room temperature. After stirring for 6h, the reaction mixture was washed with cold saturated NH4Cl and then water. The extract was dried over Na2SO4, filtered and the filtrate was evaporated in vacuo. The resulting crude product was further purified by column chromatography on silica gel to provide desired compounds.

Reference： [1]Ding, Yahui; Li, Shengzu; Ge, Weizhi; Liu, Zhongquan; Zhang, Xuhai; Wang, Mengmeng; Chen, Tianyang; Chen, Yue; Zhang, Quan [European Journal of Medicinal Chemistry, 2019, vol. 183]

55
[ 957065-99-5 ]
[ 85118-01-0 ]
methyl 5-(3,4-difluorobenzyl)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; acetonitrile at 80℃; for 3h; Inert atmosphere;	87.1 Step 1 : Preparation of methyl 5-(3,4-difluorobenzyl)picolinate To a solution of methyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)picolinate (1 .0 g, 3.8 mmol) in acetonitrile (20 ml_) and water (5 ml_) at room temperature was added potassium carbonate (1 .04 g, 7.6 mmol), 1 ,1 '-b/s(diphenylphosphino)ferrocene palladium(ll)dichloride (0.310 g, 0.38 mmol) and 4-(bromomethyl)-1 ,2-difluorobenzene (0.787 g, 3.8 mmol) under nitrogen. The reaction mixture was stirred at 80 °C for 3 h. The reaction solution was cooled to room temperature and diluted with water (200 ml_). The aqueous layer was extracted with ethyl acetate (80 ml_ c 3). The combined organic layers were washed with brine (1 00 ml_), dried over anhydrous sodium sulfate, filtered and concentrated. The crude sample was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 3/1 ) to give methyl 5-(3,4-difluorobenzyl)picolinate (0.610 g, 2.31 mmol, 61 %) as a yellow solid. LCMS (ESI) m/z: 264.1 [M+H]+.
61%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; acetonitrile at 80℃; for 3h; Inert atmosphere;	87.1 Step 1 : Preparation of methyl 5-(3,4-difluorobenzyl)picolinate To a solution of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (1.0 g, 3.8 mmol) in acetonitrile (20 ml_) and water (5 ml_) at room temperature was added potassium carbonate (1.04 g, 7.6 mmol), 1,T-Jb/s(diphenylphosphino)ferrocene palladium(ll)dichloride (0.310 g, 0.38 mmol) and 4-(bromomethyl)-1,2-difluorobenzene (0.787 g, 3.8 mmol) under nitrogen. The reaction mixture was stirred at 80 °C for 3 h. The reaction solution was cooled to room temperature and diluted with water (200 ml_). The aqueous layer was extracted with ethyl acetate (80 ml_ c 3). The combined organic layers were washed with brine (100 ml_), dried over anhydrous sodium sulfate, filtered and concentrated. The crude sample was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 3/1) to give methyl 5-(3,4-difluorobenzyl)picolinate (0.610 g, 2.31 mmol, 61 %) as a yellow solid. LCMS (ESI) m/z: 264.1 [M+H]+.

Reference： [1]Current Patent Assignee: YUMANITY THERAPEUTICS INC - WO2019/183587, 2019, A1 Location in patent: Page/Page column 195-196
[2]Current Patent Assignee: YUMANITY THERAPEUTICS INC - WO2020/198026, 2020, A1 Location in patent: Page/Page column 202

56
[ 389890-42-0 ]
[ 85118-01-0 ]
tert-butyl (trans-3-((3,4-difluorobenzyl)oxy)cyclobutyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃;	Step 1. tert-butyl (trans-3-((3,4-difluorobenzyl)oxy)cyclobutyl)carbamate Sodium hydride (329 mg, 8.23 mmol) was added to a cooled solution (0 C.) of <strong>[389890-42-0]tert-butyl (trans-3-hydroxycyclobutyl)carbamate</strong> 1.4 g, 7.48 mmol) and 3,4-difluorobenzyl bromide (1.01 g, 7.48 mmol) in DMF (10 ml) and stirred at room temperature. Water was added to the reaction and the resulting white precipitate was collected by vacuum filtration, washed well with water, and dried under vacuum to provide the title product, 2.01 g (89{circumflex( )}% yield). ESMS(M+1)=314.21

Reference： [1]Patent: US2019/322673,2019,A1 .Location in patent: Paragraph 0478; 0906

57
2-(2-chloro-5-methylpyrimidin-4-yl)-6-((methoxy-d3)methyl)-6,7-dihydroimidazo[1,2-a]pyrazine-8(5H)-one [ No CAS ]
[ 85118-01-0 ]
C₂₀H₁₅⁽²⁾H₃ClF₂N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.8%	With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2.5h;	8.1 Step 1 Synthesis of Compound D-3 Compound B-2 (536 mg, 2.59 mmol) was added to a solution of compound A-2 (530 mg, 1.72 mmol) and NaH (172 mg, 4.30 mmol) in anhydrous DMF (10 mL) at room temperature, and reacted at room temperature for 2.5 h. Water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Methyl chloride / methanol = 4%) gave 660 mg of a pale yellow solid, yield: 87.8%

Reference： [1]Current Patent Assignee: SHENZHEN TARGETRX INC - CN110577543, 2019, A Location in patent: Paragraph 0274; 0277-0280

58
[ 15644-90-3 ]
[ 85118-01-0 ]
4-((3,4-difluorobenzyl)oxy)-6-methoxy-2-methylquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 18h;	4.2. General procedure for the synthesis of quinolines 3 and 4 General procedure: The synthesis of 4-hydroxyquinoline (2) was performed in accordance to an already reported procedure [9]. The appropriate alkyl halide (1.2 mmol) was added to a mixture of 4-hydroxyquinoline (1 mmol) and potassium carbonate (K2CO3,3.12 mmol) in DMF (6 mL). The reaction mixturewas stirred at 25 °C for 18 h. Afterwards, the reaction mixture was diluted in water(10 mL) with concomitant precipitation of the product. The solid was separated using a centrifuge (18,000 RPM, 4 C, 10 min),washed with water (3 15 mL), and dried under reduced pressure to afford the products in good purity, which was measured by HPLC experiments. In some cases where the purity of the products was not satisfactory, the solids were washed with ethyl ether or purified by flash chromatography using ethyl acetate and hexane in a ratioof 3:7; 1:1, and, finally, 7:3, respectively.

Reference： [1]Abbadi, Bruno Lopes; Basso, Luiz Augusto; Bizarro, Cristiano Valim; Borsoi, Ana Flávia; Macchi, Fernanda Souza; Machado, Diana; Machado, Pablo; Paz, Josiane Delgado; Pissinate, Kenia; Rambo, Raoní S.; Ramos, Alessandro Silva; Sperotto, Nathalia; Viveiros, Miguel [European Journal of Medicinal Chemistry, 2020, vol. 192]

59
[ 666816-98-4 ]
[ 85118-01-0 ]
8-bromo-7-(but-2-yn-1-yl)-1-(3,4-difluorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate In N,N-dimethyl acetamide at 100℃; for 16h;	Procedure for the synthesis of 8-bromo-7-(but-2-yn-1-yl)-1-(3,4-difluorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (4). To a stirred solution of compound 3, (1.2g, 4.04 mmol) and potassium carbonate (1.40g, 10.10 mmol) in DMA (7.0 mL), 3,4-difluoro benzyl bromide (0.62mL, 4.85 mmol) was added. The reaction mixture was heated to 100 °C and stirred for 16 hours at the same temp. After completion of the reaction, the crude product was cooled to room temperature, diluted with water (15 mL) and ethyl acetate (15 mL). Separated the layers and extracted the compound from the aqueous layer with ethyl acetate and washed with water, brine solution. Later, the product was dried over sodium sulfate, filtered and distilled out under vacuum to get compound 4, yielded (87 %) off-white solid.1H NMR (500 MHz, CDCl3): δ 7.35 (m, 1H), 7.25 (m, 1H), 7.08 (m, 1H), 5.11 (s, 2H), 4.75 (s, 2H), 3.55 (s, 3H), 1.81 (s, 3H).

Reference： [1]Konduri, Srihari; Prashanth, Jyothi; Krishna, Vagolu Siva; Sriram, Dharmarajan; Behera; Siegel, Dionicio; Rao, Koya Prabhakara [Bioorganic and Medicinal Chemistry Letters, 2020, vol. 30, # 22]

60
1-(3-fluoro-4-(piperazine-1-yl)phenyl)butane-1-one [ No CAS ]
[ 85118-01-0 ]
1-(4-(4-(3,4-difluorobenzyl)piperazin-1-yl)-3-fluorophenyl)butane-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate In tetrahydrofuran at 20℃; for 20h; Inert atmosphere; Reflux;	1-16 1- (4- (4- (3,4-difluorobenzyl) piperazin-1-yl) -3-fluorophenyl) butane-1-one (UA36) 50 mL double-necked round-bottom flask and K 2 CO 3 (135 mg, 0.54 mmol)Dry in vacuum for 3 minutes with a heat gunAfter cooling to room temperature, N2 was replenished. In this containerA mixture of 1- (3-fluoro-4- (piperazine-1-yl) phenyl) butane-1-one (110 mg, 0.44 mmol) and 3,4-difluorobenzyl bromide (152 mg, 0.73) was added. Dissolved in THF (3 mL). After refluxing for 20 hours, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4. After filtration, the solvent was removed by evaporation. The obtained residue was purified by MPLC (chloroform / MeOH = chloroform only 4: 1) and 1- (4- (4- (3,4-difluorobenzyl) piperazin-1-yl) -3-fluorophenyl). Butane-1-one was obtained as a yellow oil (129 mg, 78%).

Reference： [1]Current Patent Assignee: TOKAI NATIONAL HIGHER EDUCATION AND RESEARCH SYSTEM - JP2020/147524, 2020, A Location in patent: Paragraph 0147-0149

61
4-((5-(2-(cyclopropanecarboxamido)isonicotinamido)nicotinoamido)methyl)piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
[ 85118-01-0 ]
5-(2-(cyclopropanecarboxamido)isonicotinamido)-N-((1-(3,4-difluorobenzyl) piperidin-4-yl)methyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	Stage #1: 4-((5-(2-(cyclopropanecarboxamido)isonicotinamido)nicotinoamido)methyl)piperidine-1-carboxylic acid tert-butyl ester With trifluoroacetic acid In dichloromethane Stage #2: alpha-bromo-3,4-difluorotoluene With potassium carbonate at 60℃; for 5h;	21 5-(2-(Cyclopropanecarboxamide)isonicotinamide)-N-((1-(3,4-Difluorobenzyl)piperidin-4-yl)methyl)nicotinamide (GAD9) Dissolve compound 12a (2.61g, 5.0mmol) in DCM, add TFA (20mL), concentrate and dissolve in DMF (40mL) after the reaction, then add K2CO3 (2.14g, 15.5mmol), 3,4-difluoro bromide Benzyl (768 μL, 6.0 mmol) was reacted at 60° C. for 5 h. MeOH and DCM were added to dilute the reaction solution, filtered with suction and column chromatography to obtain compound GAD9 with a yield of 61%.
61%	Stage #1: 4-((5-(2-(cyclopropanecarboxamido)isonicotinamido)nicotinoamido)methyl)piperidine-1-carboxylic acid tert-butyl ester With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; Stage #2: alpha-bromo-3,4-difluorotoluene With potassium carbonate In N,N-dimethyl-formamide at 55℃; for 5h; Inert atmosphere;	N-((1-benzylpiperidin-4-yl)methyl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide (9a) General procedure: To a solution of 15 (153mg, 352μmol) in 5mL dry DCM, 2mL of trifluoroacetic acid (TFA) was added at 0°C. The reaction solution was stirred at room temperature for 3h. Subsequently, the reaction solution was concentrated and dissolved in DMF (12mL). K2CO3 (97mg, 0.703mmol) and benzyl bromide (51μL, 0.425mmol) were added. The reaction solution was stirred at 55°C for 5h. The solvent was removed, and the residue was purified by flash chromatography to give 9a. Light yellow solid (59%).

Reference： [1]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN112047928, 2020, A Location in patent: Paragraph 0159-0162
[2]Feng, Feng; Jiang, Xueyang; Li, Yuan; Lin, Tailiang; Liu, Chang; Liu, Wenyuan; Lyu, Weiping; Sun, Haopeng; Xie, Huanfang; Xu, Jian; Zou, Manxing [European Journal of Medicinal Chemistry, 2021, vol. 223]

62
[ 52924-71-7 ]
[ 85118-01-0 ]
C₁₇H₁₂F₂N₄OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium azide; 1,10-Phenanthroline; copper(II) acetate monohydrate; sodium L-ascorbate In ethanol; water at 20℃; for 18h;	General procedure for the synthesis of 2-mercapto benzoxazolecoupled benzyl triazoles (BOTs) (1-19): General procedure: Sodium ascorbate (1.57 mmol) was added to a green coloured suspension of Cu(OAc)2·H2O (0.105 mmol) and 1,10-phenanthroline monohydrate (0.105 mmol) in 4:1 EtOH and H2O (8 mL: 2 mL) and stirred the reaction mixture for 5 min at room temperature, then added 2-(prop-2-yn-1-ylthio)benzo[d]thiazole (2) (1.05 mmol), sodium azide (1.26 mmol) and benzyl bromide derivative (1.15 mmol) and the resulting orange coloured suspension was stirred at room temperature for 18 h. After 18 h, diluted the reaction mixture with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was washed with water (30 mL) followed by brine (30 mL), the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by column chromatography over silica gel (100-200 mesh) with eluent 50% to 70 % EtOAcin pet ether followed by recrystallization with diethyl ether to yield compound.
75%	With sodium azide; 1,10-Phenanthroline; copper(II) acetate monohydrate; sodium L-ascorbate In ethanol; water at 20℃; for 18h;	General procedure for the synthesis of 2-mercapto benzoxazolecoupled benzyl triazoles (BOTs) (1-19): General procedure: Sodium ascorbate (1.57 mmol) was added to a green coloured suspension of Cu(OAc)2·H2O (0.105 mmol) and 1,10-phenanthroline monohydrate (0.105 mmol) in 4:1 EtOH and H2O (8 mL: 2 mL) and stirred the reaction mixture for 5 min at room temperature, then added 2-(prop-2-yn-1-ylthio)benzo[d]thiazole (2) (1.05 mmol), sodium azide (1.26 mmol) and benzyl bromide derivative (1.15 mmol) and the resulting orange coloured suspension was stirred at room temperature for 18 h. After 18 h, diluted the reaction mixture with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was washed with water (30 mL) followed by brine (30 mL), the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by column chromatography over silica gel (100-200 mesh) with eluent 50% to 70 % EtOAcin pet ether followed by recrystallization with diethyl ether to yield compound.

Reference： [1]Praveen Kumar; Prashanthi; Rambabu; Ataur Rahman; Yadav [Asian Journal of Chemistry, 2020, vol. 32, # 12, p. 3209 - 3218]
[2]Praveen Kumar; Prashanthi; Rambabu; Ataur Rahman; Yadav [Asian Journal of Chemistry, 2020, vol. 32, # 12, p. 3209 - 3218]

63
[ 85118-01-0 ]
[ 37675-18-6 ]
ethyl (S)-1-(3,4-difluorobenzyl)piperidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere;	247.a Step a. Ethyl (S)-1-(3,4-difluorobenzyl)piperidine-3-carboxylate. To a solution of ethyl (S)-piperidine-3-carboxylate (6.10 g, 38.80 mmol) in dry DCM (130 mL) cooled at 0 °C, DIPEA (10.13 mL, 58.2 mmol) was added dropwiseunder argonatmosphere, followed by 4-(bromomethyl)-1,2-difluorobenzene (4.96 mL, 38.80 mmol). The reaction mixture was allowed to warm up to r.t. and stirred for 16 h. The organic layer washed with aq sat Na2CC>3 sol and brine. Then it was dried over anh Na2SC>4 and concentrated. The residue was purified by flash chromatography, silica gel, hexane: EtOAc as eluents to give the title compound as a yellow oil (9.65 g, Yield: 83 %).HPLC-MS (Method K (b)): Rt.: 4.58 min;ESI+ MS: m/z 284.0 [M +H]+.
83%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere;	247.a Step a. Ethyl (S)-1-(3,4-difluorobenzyl)piperidine-3-carboxylate. To a solution of ethyl (S)-piperidine-3-carboxylate (6.10 g, 38.80 mmol) in dry DCM (130 mL) cooled at 0 °C, DIPEA (10.13 mL, 58.2 mmol) was added dropwiseunder argonatmosphere, followed by 4-(bromomethyl)-1,2-difluorobenzene (4.96 mL, 38.80 mmol). The reaction mixture was allowed to warm up to r.t. and stirred for 16 h. The organic layer washed with aq sat Na2CC>3 sol and brine. Then it was dried over anh Na2SC>4 and concentrated. The residue was purified by flash chromatography, silica gel, hexane: EtOAc as eluents to give the title compound as a yellow oil (9.65 g, Yield: 83 %).HPLC-MS (Method K (b)): Rt.: 4.58 min;ESI+ MS: m/z 284.0 [M +H]+.

Reference： [1]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - WO2021/239558, 2021, A1 Location in patent: Page/Page column 213-214
[2]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - WO2021/239558, 2021, A1 Location in patent: Page/Page column 213-214

64
[ 85118-01-0 ]
geodin [ No CAS ]
methyl (R)-5,7-dichloro-4-((3,4-difluorobenzyl)oxy)-6'-methoxy-6-methyl-3,4'-dioxo-3H-spiro[benzofuran-2,1'-cyclohexane]-2',5'-diene-2'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.2%	With potassium carbonate In propan-2-one at 40℃;	3.4. General Synthetic Methods for Compounds 2-37 General procedure: A corresponding benzyl bromide reagent (3-5 eq.) and anhydrous K2CO3 (15 mg)were added to a stirred solution of 1 (40 mg, 0.10 mmol) in dry acetone (20 mL). Thereaction mixture was stirred at 40 C for 6-12 h. After the completion of the reaction, waterwas added to the reaction mixture, then the solution was extracted two times with EtOAc(40 mL). The organic layer was combined and dried under vacuum to give a crude residuewhich was purified through normal phase silica gel CC (200-300 mesh) eluting with alinear gradient of PE-EtOAc.
91.2%	With potassium carbonate In propan-2-one at 40℃;	3.4. General Synthetic Methods for Compounds 2-37 General procedure: A corresponding benzyl bromide reagent (3-5 eq.) and anhydrous K2CO3 (15 mg)were added to a stirred solution of 1 (40 mg, 0.10 mmol) in dry acetone (20 mL). Thereaction mixture was stirred at 40 C for 6-12 h. After the completion of the reaction, waterwas added to the reaction mixture, then the solution was extracted two times with EtOAc(40 mL). The organic layer was combined and dried under vacuum to give a crude residuewhich was purified through normal phase silica gel CC (200-300 mesh) eluting with alinear gradient of PE-EtOAc.

Reference： [1]Chao, Rong; Chen, Guang-Ying; Hu, Jie; Qi, Yue-Xuan; Said, Gulab; Shao, Chang-Lun; Wei, Mei-Yan; Zhang, Qun; Zheng, Cai-Juan; Zheng, Ji-Yong [Marine Drugs, 2022, vol. 20, # 2]
[2]Chao, Rong; Chen, Guang-Ying; Hu, Jie; Qi, Yue-Xuan; Said, Gulab; Shao, Chang-Lun; Wei, Mei-Yan; Zhang, Qun; Zheng, Cai-Juan; Zheng, Ji-Yong [Marine Drugs, 2022, vol. 20, # 2]

65
ethyl 4-(2-butyl-4-chloro-1H-imidazole-5-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylate [ No CAS ]
[ 85118-01-0 ]
ethyl 4-(2-butyl-4-chloro-1-(2,4-difluorobenzyl)-1H-imidazole-5-yl)-6-methyl-2- oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58.5%	With potassium carbonate In acetonitrile at 60℃; for 20h;	4.1.2. Synthesis of ethyl 4-(2-butyl-4-chloro-1-(2-morpholino-2-oxoethyl)-1H-imidazole-5-yl)-6- methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2) General procedure: A mixture of compound 1 (0.601 g, 1.76 mmol), 2-chloro-1-morpholinoethan-1-one (0.320 g, 1.94 mmol) and potassium carbonate(0.300 g, 2.11 mmol) in acetonitrile (10 mL) was stirred at60 C for 20 h. After the reaction was completed, solvent wasremoved. The crude product was purified by silica gel columnchromatography (eluent, dichloromethane/methanol, 30/1e10/1,V/V) to afford pure product 2 as white solid (0.361 g). Yield: 44.1%,mp: 224.7e226.7 C; 1H NMR (600 MHz, DMSO-d6) d 9.02 (s, 1H,pyrimidine-1-NH), 7.39 (s, 1H, pyrimidine-3-NH), 5.13 (s, 1H, pyrimidine-4-CH), 4.85 (d, J 7.1 Hz, 2H, imdazole-1-NCH2), 3.95 (dd,J 6.9, 5.0 Hz, 2H, OCH2CH3), 3.64 (bs, 2H, morpholino-CH), 3.57(bs, 4H, morpholino-CH), 3.44 (bs, 2H, morpholino-CH), 2.49e2.42(m, 2H, CH2CH2CH2CH3), 2.20 (s, 3H, pyrimidine-6-CH3), 1.57e1.43(m, 2H, CH2CH2CH2CH3),1.31 (d, J 7.4 Hz, 2H, CH2CH2CH2CH3),1.11(t, J 7.0 Hz, 3H, OCH2CH3), 0.86 (t, J 7.3 Hz, 3H, CH2CH2CH2CH3)ppm; 13C NMR (150 MHz, DMSO-d6) d 165.81,165.10, 152.88, 148.99,148.16,136.75,112.04, 97.71, 66.58, 59.35, 47.65, 45.34, 44.63, 42.54,30.05, 29.66, 26.92, 22.22, 18.21, 14.61, 14.17 ppm; HRMS (ESI) calcdfor C21H30ClN5O5 [MH], 468.2008; found, 468.2011.
58.5%	With potassium carbonate In acetonitrile at 60℃; for 20h;	4.1.2. Synthesis of ethyl 4-(2-butyl-4-chloro-1-(2-morpholino-2-oxoethyl)-1H-imidazole-5-yl)-6- methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2) General procedure: A mixture of compound 1 (0.601 g, 1.76 mmol), 2-chloro-1-morpholinoethan-1-one (0.320 g, 1.94 mmol) and potassium carbonate(0.300 g, 2.11 mmol) in acetonitrile (10 mL) was stirred at60 C for 20 h. After the reaction was completed, solvent wasremoved. The crude product was purified by silica gel columnchromatography (eluent, dichloromethane/methanol, 30/1e10/1,V/V) to afford pure product 2 as white solid (0.361 g). Yield: 44.1%,mp: 224.7e226.7 C; 1H NMR (600 MHz, DMSO-d6) d 9.02 (s, 1H,pyrimidine-1-NH), 7.39 (s, 1H, pyrimidine-3-NH), 5.13 (s, 1H, pyrimidine-4-CH), 4.85 (d, J 7.1 Hz, 2H, imdazole-1-NCH2), 3.95 (dd,J 6.9, 5.0 Hz, 2H, OCH2CH3), 3.64 (bs, 2H, morpholino-CH), 3.57(bs, 4H, morpholino-CH), 3.44 (bs, 2H, morpholino-CH), 2.49e2.42(m, 2H, CH2CH2CH2CH3), 2.20 (s, 3H, pyrimidine-6-CH3), 1.57e1.43(m, 2H, CH2CH2CH2CH3),1.31 (d, J 7.4 Hz, 2H, CH2CH2CH2CH3),1.11(t, J 7.0 Hz, 3H, OCH2CH3), 0.86 (t, J 7.3 Hz, 3H, CH2CH2CH2CH3)ppm; 13C NMR (150 MHz, DMSO-d6) d 165.81,165.10, 152.88, 148.99,148.16,136.75,112.04, 97.71, 66.58, 59.35, 47.65, 45.34, 44.63, 42.54,30.05, 29.66, 26.92, 22.22, 18.21, 14.61, 14.17 ppm; HRMS (ESI) calcdfor C21H30ClN5O5 [MH], 468.2008; found, 468.2011.

Reference： [1]Li, Shuo; Maddili, Swetha Kameswari; Sun, Hang; Yang, Ren-Guo; Yang, Xi; Zhou, Cheng-He [European Journal of Medicinal Chemistry, 2022, vol. 232]
[2]Li, Shuo; Maddili, Swetha Kameswari; Sun, Hang; Yang, Ren-Guo; Yang, Xi; Zhou, Cheng-He [European Journal of Medicinal Chemistry, 2022, vol. 232]

66
[ 85118-01-0 ]
[ 143900-44-1 ]
C₁₇H₂₃F₂NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 4-bromomethyl-1,2-difluorobenzene In N,N-dimethyl-formamide at 60℃; for 48h;	General procedure A General procedure: Totert-butyl (S)-3-hydroxypiperidine-1-carboxylate,4, (213 mg, 1.04 mmol) dissolved in dimethylformamide (DMF) (10 mL) was added sodium hydride (125 mg, 3.00 mmol, 3 eq) at room temperature and stirred for 1h then 4-methylbenzyl bromide (195 mg, 1.03 mmol) was added and the reaction mixture was stirred at 60 C for 48h. The reaction was quenched with distilled water (100 mL), extracted with ethyl acetate (30 mL x 3), organic phase washed with brine (20 mL), dried with magnesium sulfate and concentrated in vacuo. The product,4’, was purified via Biotage in hexane/ethyl acetate (15-17%).
	Stage #1: (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 4-bromomethyl-1,2-difluorobenzene In N,N-dimethyl-formamide at 60℃; for 48h;	General procedure A General procedure: Totert-butyl (S)-3-hydroxypiperidine-1-carboxylate,4, (213 mg, 1.04 mmol) dissolved in dimethylformamide (DMF) (10 mL) was added sodium hydride (125 mg, 3.00 mmol, 3 eq) at room temperature and stirred for 1h then 4-methylbenzyl bromide (195 mg, 1.03 mmol) was added and the reaction mixture was stirred at 60 C for 48h. The reaction was quenched with distilled water (100 mL), extracted with ethyl acetate (30 mL x 3), organic phase washed with brine (20 mL), dried with magnesium sulfate and concentrated in vacuo. The product,4’, was purified via Biotage in hexane/ethyl acetate (15-17%).

Reference： [1]Hopkins, Corey R.; Mashinson, Viktoriya; Tolentino, Kirsten T.; Vadukoot, Anish K. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 61]
[2]Hopkins, Corey R.; Mashinson, Viktoriya; Tolentino, Kirsten T.; Vadukoot, Anish K. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 61]

67
[ 36209-51-5 ]
[ 85118-01-0 ]
3-[(3,4-difluorobenzyl)sulfanyl]-5-(pyridin-4-yl)-4H-1,2,4-triazol-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide In methanol at 20℃; for 2.5h;	General procedure for the synthesis of 5-(pyridin-4-yl)-3-(alkylsulfanyl)-4H-1,2,4-triazol-4-amine derivatives9, 13-15, and 17-18. General procedure: The 4-amino-5-(4-pyridinyl)-4H-1,2,4-triazole-3-thiol (5) (200 mg, 1.03 mmol) and NaOH(41 mg, 1.02 mmol) were dissolved in MeOH (8 mL); after complete dissolution, the suitable alkyl halidederivative (1.03 mmol) was added dropwise. We generally employed alkyl bromide derivatives to preparedesigned compounds, except for desired compound 9 for which we used the suitable alkyl chloride derivative.The reaction mixture was stirred for 2.5 hours at room temperature. Upon completion of the reaction, thesolvent was removed under reduced pressure and the solid residue was re-crystalized from diethylether/ethanol, providing the pure final pyridyl-triazole derivatives as a powder. The registered CAS number forcompound 9 has been already assigned and is available at https://www.cas.org; however, its syntheticprocedure, chemical and structural characterization are not available in literature.

Reference： [1]Adornato, lenia; Cacciola, Anna; De Luca, Laura; Germano, Maria Paola; Gitto, Rosaria; Mirabile, Salvatore; Ricci, Federico [Arkivoc, 2022, vol. 2022, # 2, p. 156 - 166]

68
6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one [ No CAS ]
[ 85118-01-0 ]
2-(3,5-difluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.333333h; Stage #2: 4-bromomethyl-1,2-difluorobenzene In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil at 20℃; for 6h;	32.1 Step 1: 2-(3,5-Difluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-keto 32a 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (1.0 g, 2.83 mmol) was dissolved in tetrahydrofuran (14 mL) The solution was added with sodium hydride (0.17g, 4.25mmol, 60mass% in oil) at 0°C, and after 20 minutes of reaction, 3,5-difluorobenzyl bromide (1.17g, 5.66mmol) and N,N-dimethyl bromide were added dropwise formamide (10 mL), followed by 6 hours at room temperature.The reaction was quenched by adding ice water (30 mL), extracted with ethyl acetate (30 mL×2), the combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) gave 32a as a pale yellow oil (1.26 g, yield 93%).

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN114195764, 2022, A Location in patent: Paragraph 0665; 0666; 0667; 0668

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
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P222	Do not allow contact with air.
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P233	Keep container tightly closed.
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P270	Do not eat, drink or smoke when using this product.
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P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
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Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
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P320
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P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
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P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
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P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
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P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
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P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
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P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
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P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
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P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
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Disposal
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Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere