Name: 144230-52-4|4,4-Difluoropiperidine hydrochloride|97%
Brand: Ambeed
SKU: A331925
Price: 5.0 USD
Availability: InStock
Rating: 92 (22 reviews)

1
[ 155137-18-1 ]
[ 144230-52-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: 1-benzyl-4,4-difluoropiperidine With 2-Chloroethyl chloroformate In dichloromethane at 0 - 55℃; for 2h; Stage #2: With methanol for 4h; Heating / reflux;	40.2 In an argon atmosphere, 1-chloroethyl chloroformate (2.62 mL) was added dropwise to a solution of the above N-benzyl-4,4-difluoropiperidine (4.66 g) in methylene chloride (93 mL) at 0°C, and the mixture was stirred for 2 hours at 55°C and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was dissolved in methanol (93 mL). The solution was refluxed for 4 hours and cooled in air. The reaction solvent was removed under reduced pressure, to thereby give the title compound as a solid product (3.03 g, 87%). MS (FAB) m/z : 122 (M+H)+.
87%	With carbonochloridic acid 1-chloro-ethyl ester In methanol; dichloromethane at 0℃; for 6h; Heating / reflux;	12.2 2) Title Compound In an argon atmosphere, 1-chloroethyl chloroformate (2.62 mL) was added dropwise to the above-obtained 1-benzyl-4,4-difluoropiperidine (4.66 g) in dichloromethane (93 mL) at 0°C. The resultant mixture was refluxed for 2 hours, followed by cooling in air. The reaction solvent was evaporated under reduced pressure, and then the residue was dissolved in methanol (93 mL). The resultant mixture was refluxed for 4 hours, followed by cooling in air. The reaction solvent was evaporated under reduced pressure, to thereby give the title compound as a solid product (3.03 g, 87%). 1H-NMR(400MHz,D2O)δ:2.31-2.41(4H,m), 3.43-3.46(4H,m). FAB-MS m/z:122(M+H)+.
87%	Stage #1: 1-benzyl-4,4-difluoropiperidine With carbonochloridic acid 1-chloro-ethyl ester In dichloromethane at 0℃; for 2h; Heating / reflux; Stage #2: With methanol for 4h; Heating / reflux;	18.2 2) Title compound Under an argon atmosphere, 1-chloroethyl chloroformate (2.62 mL) was added dropwise to a solution of 1-benzyl-4, 4-difluoropiperidine (4.66 g) of the above in dichloromethane (93 mL) at 0°C, and then the resultant mixture was heated to reflux for 2 hours. After air cooling, the reaction solvent was evaporated under reduced pressure, and a solution of the residue thus obtained in methanol (93 mL) was heated to reflux for 4 hours. After air cooling, the reaction solvent was evaporated under reduced pressure, diethyl ether was added to the residue thus obtained, and the precipitated solid was filtered, to obtain the title compound (3.03 g, 87%). 1H-NMR(400MHz, D2O)δ: 2.31-2.41(4H, M), 3. 43-3.46 (4H, m). FAB-MSm/z: 122(M+H)+.

87%	Stage #1: 1-benzyl-4,4-difluoropiperidine With carbonochloridic acid 1-chloro-ethyl ester In dichloromethane at 0 - 55℃; for 2h; Stage #2: With methanol for 4h; Heating / reflux;	4.2 2) Title compound Under an argon atmosphere, 1-chloroethyl chloroformate (2.62 mL) was added dropwise to a solution of the N-benzyl-4,4-difluoropiperidine (4.66 g) in dichloromethane (93 mL) at 0°C, and then the resultant mixture was stirred at 55°C for 2 hours. After air cooling, the reaction solvent was evaporated under reduced pressure, and a solution of a residue thus obtained in methanol (93 mL) was heated to reflux for 4 hours. After air cooling, the reaction solvent was evaporated under reduced pressure, to obtain the title compound (3.03 g, 87%) as a solid. FAB-MSm/z: 122 (M+H)+.
	With methanol; carbonochloridic acid 1-chloro-ethyl ester 1.) CH₂Cl₂, 55 deg C, 2 h, 2.) 75 deg C, 4 h; Yield given. Multistep reaction;
		2 Procedure : Chem. Pharm. Bull. 1993, 41, 11, 1971 NMR (1H, DMSO-d6) :8 9.22 (bs, 2H), 3.20 (m, 4H), 2.25 (m, 4H). MS (mlz) : 122 [MH- HCI]+
	Stage #1: 1-benzyl-4,4-difluoropiperidine With carbonochloridic acid 1-chloro-ethyl ester In 1,2-dichloro-ethane at 0 - 85℃; for 12.5h; Inert atmosphere; Stage #2: With methanol at 85℃; for 2h;	31.2 4,4-Difluoropiperidine hydrochloride 1-Benzyl-4,4-difluoro-piperidine (1.20 g, 5.68 mmol, 1.00 eq) was dissolved in dichloroethane (10.00 mL), 1-chloroethylcarbonyl chloride (1.22 g, 8.52 mmol, 1.50 eq) was added at 0 °C under the nitrogen gas atmosphere. Themixture was stirred at this temperature for 0.5 h, then heated to 85 °C and stirred for 12 hours. The mixture wasconcentrated and the residue was added with methanol (10.00 mL) and the mixture was stirred at 85 °C for an additional2 hours. The mixture was cooled and concentrated under reduced pressure at 60 °C to deliver 4,4-difluoropiperidinehydrochloride (580.00 mg, crude) as a black solid which was used in the next step without further purification.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1621537, 2006, A1 Location in patent: Page/Page column 53
[2]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1762568, 2007, A1 Location in patent: Page/Page column 33-34
[3]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1785418, 2007, A1 Location in patent: Page/Page column 41
[4]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1803719, 2007, A1 Location in patent: Page/Page column 27
[5]Mimura; Hayashida; Nomiyama; Ikegami; Iida; Tamura; Hiyama; Ohishi [Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 11, p. 1971 - 1986]
[6]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2003/89409, 2003, A1 Location in patent: Page/Page column 13
[7]Current Patent Assignee: JUMBO DRUG BANK - EP3252059, 2017, A1 Location in patent: Paragraph 0260; 0263; 0264

2
4,4-difluoropiperidine hydrochloride [ No CAS ]
[ 13831-31-7 ]
[ 950662-26-7 ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine In dichloromethane at 0 - 20℃;	31.1 Step iAcetic acid-2-(4,4-difluoro-piperidin-1 -yl)-2-oxo-ethyl ester4,4-Difluoropiperidine hydrochloride (600mg, 3.8mmol) was stirred in DCM (10ml) with Et3N (11.4mmol, 1.151g, 1.59ml) and this mixture was cooled to O0C. Acetoxy acetyl chloride (5.7mmol, 778mg, 0.612ml) in DCM (5ml) was added drop-wise and the reaction mixture was stirred overnight at RT. The reaction mixture was washed sequentially with saturated NaHCO3 solution (x2) and brine(x2). The organic layer was dried (MgSO4), filtered, and the filtrate solvent was removed in vacuo. The residue was cooled and triturated with hexane to produce the title compound as a colourless oil, (773mg (92%).

Reference： [1]Current Patent Assignee: LIGAND PHARMACEUTICALS INC - WO2007/104944, 2007, A1 Location in patent: Page/Page column 72-73

3
[ 144230-52-4 ]
[ 956320-35-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: (R)-3',5'-dichloro-4'-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 1h; Stage #2: 4,4-difluoropiperidine hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h;	26 Preparation 26; (R)-3-[3,5-Dichloro-4'-(4,4-difluoro-piperidine-l-carbonyl)-biphenyl-4-ylmethyl]-l-(4- triisopropylsilanyloxy-piperidin-l-yl)-pyrrolidin-2-one; Treat a solution of (R)-3',5'-dichloro-4'-[2-oxo-l-(4-triisopropylsilanyloxy- piperidin-l-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (4.0 g, 6.45 mmol) in CH2Cl2 (40 mL) with l,l '-carbonyldiimidazole (2.09 g, 12.91 mmol) and stir for 1 hour at room temperature. Treat the reaction with 4,4-difluoropiperidine hydrochloride (1.53 g, 9.68 mmol) and diisopropylethylamine (1.69 g, 9.68 mmol) and stir for 12 hours at room temperature. Load the mixture on silica gel column and flash with 25% to 35% ethyl acetate in hexanes to afford 3.8 g (81%) of the title compound. MS (m/z): 722 (M+).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2007/127688, 2007, A2 Location in patent: Page/Page column 53

4
[ 281652-10-6 ]
4,4-difluoropiperidine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; In 1,4-dioxane; for 2h;	To a stirred solution of <strong>[281652-10-6]tert-butyl 4,4-difluoropiperidine-1-carboxylate</strong> (step 1, 3.73 g, 16.87 mmol) in dioxane (20 ml), was added 6N HCl in dioxane (30 ml) and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to afford the desired product (2.64 g, yield: 100%). Next reaction was carried out without any further purification.
	With hydrogenchloride; In diethyl ether; ethyl acetate; at 20℃; for 1h;	To a solution of the oil in Et20 (1 OML) was added HCI in EtOAc (4N, 5mL) and stirred for 1 hr at RT. White precipitate in the reaction mixture is collected by filtration to give the pure product ; 1H NMR (DMSO-d6, 8 (ppm)) ; 2. 23-2. 2.36 (m, 4H), 3.17-3. 28 (m, 4H), 9.54 (brs, 2H).
	With hydrogenchloride; In 1,4-dioxane; at 25℃; for 6h;	A mixture of tert-butyl 4,4-difluoropiperidine-1 -carboxylate (5 g, 22.60 mmol, 1.00 equiv) and hydrogen chloride (saturated solution in 150 mL of 1,4-dioxane) was stuffed for 6 h at 25C. The resulting mixture was concentrated under vacuum to afford the title compound (4.2 g, crude) as a yellow solid.

	With hydrogenchloride; In 1,4-dioxane; for 0.2h;	To a stirred solution of tert-butyl 4,4-difluoropiperidine- 1-carboxylate (step 1, 3.73 g, 16.87 mmol) in dioxane (20 ml), was added 6N HCl in dioxane (30 ml) and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to afford the desired product (2.64 g, yield: 100%). Next reaction was carried out without any further purification.
4.2 g	With hydrogenchloride; In 1,4-dioxane; for 2h;	To a tert-butyl 4,4-difluoropiperidine- 1-carboxylate (step 2, 6.0 g, 27.15 mmol, 1.0 eq) was added dioxane hydrochloride (60 ml). The reaction mixture was stirred for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated gave the hydrochloride salt product (4.2 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz): delta 3.22-3.18 (m, 4H) and 2.31-2.18 (m, 4H); Mass: [M+H]+121.85 (100%).

Reference： [1]Patent: US2018/237472,2018,A1 .Location in patent: Paragraph 0180; 0181
[2]Patent: WO2004/69256,2004,A1 .Location in patent: Page/Page column 48
[3]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 01573; 01574
[4]Patent: WO2017/17630,2017,A1 .Location in patent: Page/Page column 53-54
[5]Patent: WO2017/149518,2017,A1 .Location in patent: Page/Page column 28

5
[ 96-32-2 ]
[ 144230-52-4 ]
[ 860343-92-6 ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine In tetrahydrofuran for 4h; Heating / reflux;	To a solution of 4, 4-difluoropiperidine hydrochloride (1 g, 6.3 mmol) in THF (20 mL) was added methylbromoacetate (0.63 mL, 6. 6 mmol) and triethylamine (2.65 mL, 19.0 mmol). The reaction was heated at reflux for 4 h. The reaction was diluted with water (50 mL) and the product extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield (4, 4-difluoropiperidin-1-yl) acetic acid methyl ester as a brown oil (1.17g, 96%). MS 194 (M + H). To a solution of (4, 4-difluoropiperidin-1-yl) acetic acid methyl ester (1.17 g, 6.1 mmol) in THF (15 mL) at 0 °C was added potion wise lithium aluminium hydride (0.46 g, 12.2 mmol). Once the effervescence had ceased the reaction was heated at 60 °C for 1.5 h. The reaction was quenched with water (10 mL) followed by sodium hydroxide solution (2N, 10 mL) then water (10 mL). The reaction was filtered and the filtrate extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield 2- (4, 4-difluoropiperidin-1-yl)-ethanol as a brown oil (0. 99 g, 99%). MS 166 (M + H) +. To a solution of diisopropylazodicarboxylate (0. 36 mL, 1. 82 mmol) in DCM (20 mL) was added polymer supported triphenylphosphine (728 mg, 2. 18 mmol). The reaction was stirred at RT for 10 min. 5-Hydroxybenzofuran-2-carboxylic acid ethyl ester (0. 25 g, 1. 21 mmol) and 2-(4, 4-difluoropiperidin-1-yl)-ethanol (210 mg, 1. 27 mmol) were added and the reaction stirred at RT for 16 h. The reaction was filtered and the filtrate concentrated in vacuo. The product was purified on silica elufing with 50 % ter-butyl methyl ether in n-heptane to yield 5- [2- (4, 4-difluoropiperidin-1- yl) ethoxy] benzofuran-2-carboxylic acid ethyl ester as a yellow solid (375 mg, 88%). MS 354 (M + H) +. To a solution of 5- [2- (4, 4-difluoropiperidin-1-yl) ethoxy] benzofuran-2- carboxylic acid ethyl ester (375 mg, 1.06 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide (34 mg, 2.12 mmol). The reaction was stirred at RT for 16 h. The THF was removed in vacuo and the remaining aqueous solution dried overnight in a freeze dryer to yield the crude title compound as a brown solid. MS 326 (M + H, 5.3 min) and used for coupling onto H2N-Leu-P1 without any further purification.
96%	With triethylamine In tetrahydrofuran for 4h; Heating / reflux;	8.17 To a solution of 4,4-difluoropiperidine hydrochloride (1 g, 6.3 mmol) in THF (20 ml_) was added methylbromoacetate (0.63 ml_, 6.6 mmol) and triethylamine (2.65 ml_, 19.0 mmol). The reaction was heated at reflux for 4 h. The reaction was diluted with water (50 ml_) and the product extracted with ethyl acetate (3 * 20 ml_). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield (4,4-difluoropiperidin-1-yl)acetic acid methyl ester as a brown oil (1.17g, 96%). MS 194 (M + H)+. To a solution of (4,4-difluoropiperidin-1-yl)acetic acid methyl ester (1.17 g, 6.1 mmol) in THF (15 ml_) at 0 "C was added potion wise lithium EPO aluminium hydride (0.46 g, 12.2 mmol). Once the effervescence had ceased the reaction was heated at 60 "C for 1.5 h. The reaction was quenched with water (10 ml_) followed by sodium hydroxide solution (2N, 10 ml_) then water (10 ml_). The reaction was filtered and the filtrate extracted with ethyl acetate (3 * 20 ml_). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield 2-(4,4-difluoropiperidin-1-yl)-ethanol as a brown oil (0.99 g, 99%). MS 166 (M + H)+. To a solution of diisopropylazodicarboxylate (0.36 ml_, 1.82 mmol) in DCM (20 ml_) was added polymer supported triphenylphosphine (728 mg, 2.18 mmol). The reaction was stirred at RT for 10 min. 5-Hydroxybenzofuran-2-carboxylic acid ethyl ester (0.25 g, 1.21 mmol) and 2-(4,4-difluoropiperidin-1-yl)-ethanol (210 mg, 1.27 mmol) were added and the reaction stirred at RT for 16 h. The reaction was filtered and the filtrate concentrated in vacuo. The product was purified on silica eluting with 50 % tert-butyl methyl ether in n-heptane to yield 5-[2-(4,4-difluoropiperidin-1- yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester as a yellow solid (375 mg, 88%). MS 354 (M + H)+. To a solution of 5-[2-(4,4-difluoropiperidin-1-yl)ethoxy]benzofuran-2- carboxylic acid ethyl ester (375 mg, 1.06 mmol) in THF (5 ml_) and water (1 ml_) was added lithium hydroxide (34 mg, 2.12 mmol). The reaction was stirred at RT for 16 h. The THF was removed in vacuo and the remaining aqueous solution dried overnight in a freeze dryer to yield the crude title compound as a brown solid. MS 326 (M + H, 5.3 min) and used for coupling onto H2N-I_eu-P1 without any further purification.
65%	With triethylamine In dichloromethane at 0 - 20℃; for 16h;	33 Preparation 33; (4,4-Difluoro-piperidin-l-yl)-acetic acid methyl ester; Treat a 00C solution of 4,4-difluoropiperidine HCl (17.91 g, 0.113 mol) and (CH3CH2)3N (28.75 g, 0.284 mol) in CH2Cl2 (250 mL) with methyl bromoacetate (17.37 g, 0.113 mol), warm to room temperature, and stir 16 hours at room temperature under N2. Dilute the reaction with saturated NaHCO3 and water and extract twice with 3 : 1 chloroform: isopropanol. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with 0 to 5% methanol in CH2Cl2 to afford 14.22 g (65%) of the titled product. Rf = 0.77 (9/1 CH2Cl2/methanol). ES MS (m/z): 194 (M+).

Reference： [1]Current Patent Assignee: MEDIVIR AB - WO2005/66180, 2005, A1 Location in patent: Page/Page column 67-68
[2]Current Patent Assignee: MEDIVIR AB - WO2007/6714, 2007, A1 Location in patent: Page/Page column 86-87
[3]Current Patent Assignee: ELI LILLY & CO - WO2007/127726, 2007, A2 Location in patent: Page/Page column 47

6
[ 937240-39-6 ]
[ 144230-52-4 ]
[ 937240-38-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.666667h;	9.a Intermediates; a) 5-Benzyloxy-2-(4,4-difluoro-piperidine- l-carbonyl)-pyrrolor2,3-blpyridine- 1- carboxylic acid tert-butyl ester; To the solution of 2.3 g (6.2 mmol) 5-benzylo xy-pyrrolo[2,3-b] pyridine- 1,2- dicarboxylic acid 1-tert-butyl ester (intermediate G), 2.5 g (7.8 mmol) O-(benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium tetraflu or ob orate and 1.2 g (7.8 mmol) 4,4- difluoropiperidine hydrochloride in 30 ml DMF, 6.4 ml (4.8 g, 37.4 mmol) N,N- diisopropylethylamine were added. After 40 min. stirring at room temperature the clear solution was poured on saturated aqueous sodium bicarbonate solution and was extracted three times with ethyl acetate. The combined organic layers were washed three times with water and with brine, dried over magnesium sulfate, filtered and evaporated. The residue was re- crystallized from dichloromethane and n-heptane to give 2.8 g (95%) of the desired compound as a colorless solid.MS (TIC): 472.0 (M+H+)

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2007/57329, 2007, A1 Location in patent: Page/Page column 41

7
[ 943130-92-5 ]
[ 144230-52-4 ]
[ 943130-91-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium t-butanolate In toluene at 100℃; for 1h;	112.b To a solution of 2-(4-iodo-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)- [ 1,3,4] oxadiazo Ie (200 mg, 0.47 mmol) in toluene (2 mL) were added under an atmosphere of nitrogen 2-(dicyclohexylphosphino)biphenyl (15 mg, 0.04 mmol), tris(dibenzylideneacetone)di-palladium(0) chloroform complex (15 mg, 0.01 mmol), sodium tert-butoxide (107 mg, 1.12 mmol) and 4,4-difluoropiperidine hydrochloride (88 mg, 0.56 mmol). The reaction mixture was stirred for 1 h at 100 0C and was extracted with water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine. Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate = 80:20 to 50:50) afforded the title compound ( 138 mg, 70%) as a light yellow solid. MS: m/e = 423.3 [M+H]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2007/71598, 2007, A1 Location in patent: Page/Page column 64

8
[ 1238696-45-1 ]
[ 144230-52-4 ]
[ 1238696-82-6 ]

Yield	Reaction Conditions	Operation in experiment
25%	With sodium t-butanolate In 1,4-dioxane at 90℃; for 3h; Inert atmosphere;	106 Example 1061-[4-(4,4-Difluoropiperidin-1-yl)-2-fluorophenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one A suspension of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (408 mg, 0.8 mmol), 4,4-difluoropiperidine hydrochloride (158 mg, 1.0 mmol), Pd2(dba)3 (36.6 mg, 0.04 mmol), Xantphos (92.6 mg, 0.16 mmol), and NaOtBu (192 mg, 2.0 mmol) in 1,4-dioxane (4 mL) was stirred for 3 h at 90° C. under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/2-0/1) and crystallized from hexane/AcOEt to give the title compound (96.0 mg, 25% yield) as a yellow-green solid: mp 192-194° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.01-2.14 (4H, m), 3.38-3.42 (4H, m), 3.89 (3H, s), 6.31 (1H, t, J=9.0 Hz), 6.47 (1H, dd, J=2.3, 9.0 Hz), 6.61 (1H, dd, J=2.6, 14.3 Hz), 7.25 (1H, d, J=1.9 Hz), 7.34-7.45 (5H, m), 7.73 (1H, d, J=2.3 Hz), 7.77 (1H, d, J=2.3 Hz). LC-MS (ESI) m/z 482 [M+H]+. Anal. Calcd for C25H22F3N5O2: C, 62.36; H, 4.61; N, 14.55. Found: C, 62.13; H, 4.62; N, 14.43.
25%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In 1,4-dioxane at 90℃; for 3h; Inert atmosphere;	22 1-[4-(4,4-Difluoropiperidin-1-yl)-2-fluorophenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one A suspension of 3-fluoro-4- [5-methoxy-4-oxo-3- (1-phenyl- lH-pyrazol-5-yl) pyridazin-1 (4H) -yl]phenyl trifluoromethanesulfonate . (408 mg, 0.8 mmol) , 4,4- difluoropiperidine hydrochloride (158 mg, 1.0 mmol), Pd2(dba)3 (36.6 mg, 0.04 mmol), Xantphos (92.6 mg, 0.16 mmol), and NaO-t- Bu (192 mg, 2.0 mmol) in 1, 4-dioxane . (4 ml) was stirred for 3 hr at 90°C under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgS04, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/2-0/1) and crystallized from hexane/AcOEt to give the title compound (96.0 mg, 25% yield) as a yellow-green solid: mp 192-194°C; XH NMR (300 MHz, CDC13) : δ ppm 2.01-2.14 (4H, m) , 3.38-3.42 (4H, m) , 3.89 (3H, s), 6.31 (1H, t, J = 9.0 Hz), 6.47 (1H, dd, J = 2.3, 9.0 Hz), 6.61 (1H, dd, J = 2.6, 14.3 Hz), 7.25 (1H, d, J = 1.9 Hz), 7.34- 7.45 (5H, m) , 7.73 (1H, d, J = 2.3 Hz), 7.77 (1H, d, J = 2.3 Hz). LC-MS (ESI) m/z 482 [M + H] +. Anal. Calcd for C25H22F3 5O2 : C, 62.36; H, 4.61; N, 14.55. Found: C, 62.13; H, 4.62; N, 14.43.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2010/197651, 2010, A1 Location in patent: Page/Page column 134
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2013/27845, 2013, A1 Location in patent: Paragraph 0330

9
[ 1007878-22-9 ]
[ 144230-52-4 ]
[ 1252603-78-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With tetra-(n-butyl)ammonium iodide; triethylamine In tetrahydrofuran	138.B (S)-1-phenylethyl 2-(4,4-difluoropiperidin-1-yl)-2-phenylacetate Example 138B (S)-1-phenylethyl 2-(4,4-difluoropiperidin-1-yl)-2-phenylacetate To a solution of the product from Example 138A (1.00 g, 3.13 mmol) in tetrahydrofuran (20 mL) at room temperature was added triethylamine (1.75 mL, 12.5 mmol) and tetrabutylammonium iodide (0.46 g, 1.25 mmol). The mixture was stirred for 5 minutes and then 4,4-difluoropiperidine hydrochloride (0.74 g, 4.70 mmol) was added as the free base in THF. The mixture was stirred for 1 hour at room temperature and then heated to 55° C. overnight. The cooled mixture was washed with brine, concentrated, then purified by column chromatography (EtOAc-hexane) to provide the title compound (1.04 g, 92% yield).
92%	Stage #1: (S)-1-phenylethyl 2-bromo-2-phenylacetate With tetra-(n-butyl)ammonium iodide; triethylamine In tetrahydrofuran at 20℃; for 0.0833333h; Stage #2: 4,4-difluoropiperidine hydrochloride In tetrahydrofuran at 20 - 55℃;	138B (S)-1-phenylethyl 2-(4,4-difluoropiperidin-1-yl)-2-phenylacetate To a solution of the product from Example 138A (1.00 g, 3.13 mmol) in tetrahydrofuran (20 mL) at roomtemperature was added triethylamine (1.75 mL, 12.5 mmol) and tetrabutylammonium iodide (0.46 g, 1.25 mmol). Themixture was stirred for 5 minutes and then .4,4-difluoropiperidine hydrochloride (0.74g, 4.70 mmol) was added as thefree base in THF. The mixture was stirred for 1 hour at room temperature and then heated to 55 °C overnight. The cooledmixture was washed with brine, concentrated, then purified by column chromatography (EtOAc-hexane) to provide thetitle compound (1.04 g, 92% yield).

Reference： [1]Current Patent Assignee: ABBVIE INC - US2010/267634, 2010, A1
[2]Current Patent Assignee: ABBVIE INC - EP2419404, 2015, B1 Location in patent: Paragraph 0498

10
[ 1290136-72-9 ]
[ 144230-52-4 ]
[ 1290134-79-0 ]

Yield	Reaction Conditions	Operation in experiment
92%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 17h;	82 Example 82(4,4-Difluoro-piperidin-1-yl)-(2-phenylethynyl-thiazol-5-yl)-methanone; Example 82 was prepared via the process of Scheme 1, step 3, Method-C, supra, as follows:In a small culture tube, 2-phenylethynyl-thiazole-5-carboxylic acid (28 mg, 0.12 mmol) [Intermediate 1], 4,4-difluoropiperidine hydrochloride (23 mg, 0.14 mmol) (Oakwood Products, Inc. (West Columbia, S.C., USA) and dichloromethane (1.5 mL) were added. To the mixture, PyBOP (76 mg, 0.14 mmol) was added, followed by N,N-diisopropylethylamine (63 μL, 0.36 mmol), and the reaction was stirred at room temperature for about 17 hours. Afterwards, the crude reaction mixture was directly purified by Preparative TLC, eluting with 40% EtOAc in hexanes to give 37 mg (92%) of the titled compound, (4,4-difluoro-piperidin-1-yl)-(2-phenylethynyl-thiazol-5-yl)-methanone, as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.66-7.59 (m, 2H), 7.49-7.37 (m, 3H), 3.92-3.82 (m, 4H), 2.18-2.01 (m, 4H). LC/MS (Method 3), RT=1.43 min. Calculated [M+H]+=333; Observed [M+H]+=333.

Reference： [1]Current Patent Assignee: H. LUNDBECK A/S - US2011/92475, 2011, A1 Location in patent: Page/Page column 20

11
[ 144230-52-4 ]
[ 590-17-0 ]
[ 824413-96-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate In acetonitrile at 70℃;	111.1 A mixture of 4,4-difluoropiperidine hydrochloride (500 mg, 3.2 mmol), K2C03 (873 mg,6.3 mmol) and 2-bromoacetonitrile (384 mg, 3.2 mmol) in ACN (8 mL) was heated to 70 °Covernight. After cooling to room temperature, the reaction mixture was concentrated to give aresidue which was diluted with H20, and extracted with EtOAc. The organic extract was driedand concentrated to afford 2-(4,4-difluoropiperidin-1-yl)acetonitrile (480 mg, 93%) which wasused in next step without further purification.
1.23 g	With potassium carbonate In acetonitrile at 60℃;	057.1 2-(4, 4-difluoropiperidin- I -yI)ethanamine Step 1: A mixture of 1 .50 g (9.52 mmo[) 4,4-dif[uoropiperidine hydroch[oride (CASNo. 144230-52-4), 0.698 mL (10.5 mmo[) bromoacetonitri[e and 3.29 g (23.8 mmo[)potassium carbonate in acetonitri[e were stirred at 60°C over night. So[ids were fi[trated off and the fi[trate was concentrated and the residue was purified by f[ash chromatography (Snap cartdrige, hexanes/ethy[acetate 1:1) to give 1.23 g of (4,4- dif[uoropiperidin- 1 -y[)acetonitri[e1H-NMR (400 MHz, CDC[3): 6 [ppm] = 3.58 (s, 2H), 2.77-2.69 (m, 4H), 2.16-2.01 (m,4H).
	With triethylamine In tetrahydrofuran at 60℃;	1.A Step A stoichiometry: 4, 4-difluoropiperidine hydrochloride salt (1.0 g, 6.3 mmol, 1 eq. ) , 2-bromoacetonitrile (761 mg, 6.3mmol, 1 eq. ) , triethylamine (2.2 g, 22.2 mmol, 3.5 eq. ) in THF (30 mL) under heating at 60 overnight. LC-MS: m/z 161.0 (M+H) +.

Reference： [1]Current Patent Assignee: SANOFI - WO2014/182829, 2014, A1 Location in patent: Page/Page column 131
[2]Current Patent Assignee: BAYER AG - WO2015/150449, 2015, A2 Location in patent: Page/Page column 204
[3]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - WO2018/39972, 2018, A1 Location in patent: Page/Page column 178

12
[ 4746-97-8 ]
4,4-difluoropiperidine hydrochloride [ No CAS ]
[ 1373516-35-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: cyclohexanedione monoethylene ketal; 4,4-difluoropiperidine hydrochloride With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; for 20h; Stage #2: With sodium hydroxide In dichloromethane	15 Example 15: Synthesis of 6-(4,4-Difluoro-piperidin-l-yl)-4,5,6,7-tetrahydro-benzothiazol-2- ylamine.Partially dissolve a suspension of 4,4-difluoropiperidine hydrochloride (1.47 g, 9.34 mmol) in 75 mL of CH2CI2 by sonication. Add AcOH (1.01 mL, 17.7 mmol), resulting in a clear solution. Add 1,4-cyclohexadione monoethylene ketal (1.38 g, 8.84 mmol) and solid sodium triacetoxyborohydride (3.00 g, 14.1 mmol). Stir the mixture for 20 h at room temperature.Adjust the pH of the mixture to 12 by the addition of 1M NaOH and extract with CH2CI2. Dry the organic layer with MgS04 and evaporate to give 2.41 g, 100% yield ofl-(l,4-dioxa- spiro[4.5]dec-8-yl)-4,4-difluoro-piperidine.
2 g	With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; for 24h; Inert atmosphere;	67 Synthesis of compound 67.2. [00501] Synthesis of compound 67.2. To a solution of 4,4-difluoropiperidine hydrochloride (1.58 g, 10.0 mmol, 1.00 equiv) in dichloromethane (75 mL) was added 1,4- dioxaspiro[4.5]decan-8-one (1.56 g, 10.0 mmol, 1.0 equiv), acetic acid (0.5 mL, 2.00 equiv) and NaBH(OAc)3 (4.24 g, 20 mmol, 2.0 equiv) at room temperature under nitrogen. The resulting solution was stirred for 24 h at ambient temperature. The pH value of the solution was adjusted to 12 with 1 M aqueous NaOH solution and extracted with 3 x 50 mL of dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with DCM/MeOH (80: 1 to 50:1) to give the desired 67.2 (2.0 g) as a white solid.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2012/54367, 2012, A1 Location in patent: Page/Page column 69-70
[2]Current Patent Assignee: NIMBUS THERAPEUTICS INC - WO2014/194242, 2014, A2 Location in patent: Paragraph 00500-00501

13
[ 4774-14-5 ]
[ 144230-52-4 ]
[ 1401348-38-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 0.583333h; Microwave irradiation;	2 Preparation of compound 2a: 2-chloro-6-(4,4-difluoropiperidin-l-yl)pyrazineA mixture of 4,4-difluoropiperidine hydrochloride (598 mg, 3.79 mmol), Cs2C03 (2471 mg, 7.58 mmol) and 2,6-dichloropyrazine (538 mg, 3.61 mmol) in DMF (5 mL) was heated in a microwave at 100°C for 35 min. The mixture was diluted with EtOAc (50 mL) and washed with 2 X 5 mL of H20. The organic layer was dried, filtered and concentrated. The residue was purified on a silica gel column (eluting with 25-35% EtOAc in Hex) to give 2-chloro-6-(4,4-difluoropiperidin-l-yl)pyrazine (717 mg, 85%) as a brown amorphous solid. MS (ESI, pos. ion) m/z 234.1 (M+l); .H NMR (400 MHz, DMSO-dg) δ ppm 8.39 (s, 1 H), 7.89 (s, 1 H), 3.75 (t, J = 5.7 Hz, 4 H), 2.06 (m, 4 H).

Reference： [1]Current Patent Assignee: AMGEN INC - WO2012/129338, 2012, A1 Location in patent: Page/Page column 70-71

14
[ 1610340-26-5 ]
[ 144230-52-4 ]
[ 2126701-70-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: 4,4-difluoropiperidine hydrochloride With potassium carbonate In acetonitrile for 0.25h; Stage #2: 4-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine In acetonitrile at 20℃;	106.2 Step 2.- Synthesis of 4-(4,4-difluoropiperidin-1 -yl)-1-(2-(piperidin-1-yl)ethyl)-1 H- pyrazolo[3,4-d]pyrimidine Step 2.- Synthesis of 4-(4,4-difluoropiperidin-1 -yl)-1-(2-(piperidin-1-yl)ethyl)-1 H- pyrazolo[3,4-d]pyrimidine A suspension of 4,4-difluoropiperidine hydrochloride (44 mg, 0.28 mmol) and potassium carbonate (78 mg, 0.56 mmol) in acetonitrile (3 mL) was stirred for 15 min. Then, 4-chloro-1 -(2-(piperidin-1 -yl)ethyl)-1 H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.19 mmol) in acetonitrile (2 mL) was added to the mixture and was stirred at room temperature overnight. The mixture was filtered and the solvent was removed under reduced pressure to give 4-(4,4-difluoropiperidin-1 -yl)-1 -(2-(piperidin-1 -yl)ethyl)-1 H- pyrazolo[3,4-d]pyrimidine (65 mg, 0.18 mmol, quantitative) as an oil. 1 H NMR (CDCI3) δ ppm: 8.39 (s, 1 H), 7.95 (s, 1 H), 4.62 (t, J = 7.1 Hz, 2H), 4.1 1 (t, J = 5.9 Hz, 4H), 3.12 - 2.88 (m, 2H), 2.73 - 2.46 (m, 4H), 2.23 - 2.01 (m, 4H), 1 .77 - 1 .52 (m, 4H), 1 .52 - 1 .37 (m, 2H).
100%	With potassium carbonate In acetonitrile at 20℃;

Reference： [1]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - WO2013/10950, 2013, A1 Location in patent: Page/Page column 73
[2]Díaz, José Luis; Corbera, Jordi; Martínez, Daniel; Bordas, Magda; Sicre, Cristina; Pascual, Rosalia; Pretel, M José; Marín, Ana Paz; Montero, Ana; Dordal, Albert; Alvarez, Inés; Almansa, Carmen [MedChemComm, 2017, vol. 8, # 6, p. 1246 - 1254]

15
[ 2032-35-1 ]
[ 144230-52-4 ]
[ 1432664-77-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 24h;	Preparation of 1-(6-chloro-1-1((4,4-difluoropiperidin-1-yl)methyl)-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-3-cyclohexylpropan-1-one (Compound 78) Preparation of 1-(6-chloro-1-1((4,4-difluoropiperidin-1-yl)methyl)-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-3-cyclohexylpropan-1-one (Compound 78) A stirred solution of 4,4-difluoropiperidine hydrochloride (0.53 g, 3.36 mmol) and N,N-diisopropylethyamine (1.2 mL, 6.70 mmol) in 5 mL of acetonitrile was treated with 2-bromo-1,1-diethoxyethane (0.25 mL, 1.7 mmol). The reaction mixture was heated at 100° C. for 24 h. The reaction was allowed to cool to ambient temperature and diluted with aqueous NaHCO3 (100 mL). The aqueous phase was extracted with dichloromethane (2*50 mL) and the combined organic were dried (MgSO4), filtered and concentrated in vacuo to give 1-(2,2-diethoxyethyl)-4,4-difluoropiperidine (0.41 g, 100%) as an amber oil. LCMS (+ESI) 238 (M+).

Reference： [1]Current Patent Assignee: ALCON, INC. - US2013/116219, 2013, A1 Location in patent: Paragraph 0097

16
[ 823-78-9 ]
[ 144230-52-4 ]
[ 1443247-99-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate In acetonitrile at 20℃; for 16h;	12.a 1-(3-bromobenzyl)-4,4-difluoropiperidine (Intermediate 12a) A mixture of 3-bromobenzyl bromide (3.43 g, 13.73 mmol), 4,4- difluoro-piperidine hydrochloride (2.20 g, 13.97 mmol) and potassium carbonate (4.82 g, 34.86 mmol) in acetonitrile (50 mL) was stirred at RT for 16 h. The mixture was filtered and evaporated and the residue partitioned between water (30 mL) and EtOAc (3 x 30 mL). The combined organic extracts were washed with water (2 x 50 mL) and dried (Na2SO4). The solvent was evaporated to give the title compound as a colourless oil (3.96 g, 99%). LCMS (Method 1): Rt 1.89 min, m/z 290 / 292 [MH+].

Reference： [1]Current Patent Assignee: Valline SRL - WO2013/83606, 2013, A1 Location in patent: Page/Page column 102

17
[ 1060801-25-3 ]
[ 144230-52-4 ]
[ 1431655-07-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 60℃; for 16h;	89.2 Synthesis of tert-butyl 6-((4,4-difluoropiperidin-1-yl)methyl)pyridin-2- ylcarbamate: A mixture of tert-butyl 6-(chloromethyl)pyridin-2-ylcarbamate (7.0 g, 28.9 mmol), 4,4-difluoropiperidine hydrochloride (5.2 g, 43.1 mmol), K2CO3 (10.4 g, 75.4 mmol) and potassium iodide (800.0 mg, 4.8 mmol) in DMF (70 mL) was stirred at 60 °C for 16 h. H2O (200 mL) was added and the mixture was extracted with EtOAc then washed with H2O. The crude product was purified by column chromatography eluting with EtOAc/pentane (1:2) to give tert-butyl 6-((4,4-difluoropiperidin-1-yl)methyl)pyridin-2-ylcarbamate (8.0 g, 85 % yield). MS (ESI) calcd for C16H23F2N3O2 (m/z): 327.18
85%	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 60℃; for 16h;	89.2 Synthesis of tert-butyl 6-((4,4-difluoropiperidin-1-yl)methyl)pyridin-2-ylcarbamate A mixture of tert-butyl 6-(chloromethyl)pyridin-2-ylcarbamate (7.0 g, 28.9 mmol), 4,4-difluoropiperidine hydrochloride (5.2 g, 43.1 mmol), K2CO3 (10.4 g, 75.4 mmol) and potassium iodide (800.0 mg, 4.8 mmol) in DMF (70 mL) was stirred at 60 °C for 16 h. H2O (200 mL) was added and the mixture was extracted with EtOAc then washed with H2O. The crude product was purified by column chromatography eluting with EtOAc/pentane (1:2) to give tert-butyl 6-((4,4-difluoropiperidin-1-yl)methyl)pyridin-2-ylcarbamate (8.0 g, 85 % yield). MS (ESI) calcd for C16H23F2N3O2 (m/z): 327.18.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2013/59587, 2013, A1 Location in patent: Page/Page column 179
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - EP2768509, 2017, B1 Location in patent: Paragraph 0688; 0689

18
[ 1193-21-1 ]
[ 144230-52-4 ]
[ 1590398-25-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine In water at 115℃; for 16h;	81 4-Chloro-6-(4,4-difluoropiperidin-1-yl)pyrimidine. 4-Chloro-6-(4,4-difluoropiperidin-1-yl)pyrimidine. A mixture of 4,6-dichloropyrimidine(0.89 g,6.0 mmol, DIPEA (1.55 g, 12 mmol) and 4,4-difluoropiperidine hydrochloride (942 mg, 6.0 mmol) inwater (10 mL) was stirred at 115°C for 16 h. After cooling to room temperature, the precipitate wascollected by filtaration, washed with water. and dried in vacuum to afford the title compound (1.25 g,88%) as a white solid. MS-ESI: [M+H] 233.8

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/49047, 2014, A1 Location in patent: Page/Page column 108

19
[ 144230-52-4 ]
[ 199915-38-3 ]
[ 1696413-35-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine In dichloromethane at 20℃; for 1h;	6.A Step A: (9H-Fluoren-9-yl)methyl (4,4-difluoropiperidine-l -carbonothioyl)carbamate To a solution of 4,4-difluoropiperidine hydrochloride (100 mg, 0.635 mmol) in DCM (3.2 mL) was added TEA (88 μ, 0.635 mmol) and 0-((9H-fiuoren-9-yl)methyl) carbonisothiocyanatidate (196 mg, 0.698 mmol) and the resulting mixture was stirred at RT for 1 hour. Saturated aqueous NaHC03 solution was added to the reaction and the resulting mixture was extracted with DCM (3 x 20 mL). Combined organic phases were washed with brine, dried (MgSC^), filtered, and concentrated to pale yellow oil. The residue was purified by flash chromatography on silica gel with Hexanes/EtOAc (0-25%) giving 244 mg (96%) of the desired product as white solid: MS(ES,m/z): 403.1 (M + 1).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/51479, 2015, A1 Location in patent: Page/Page column 71

20
[ 144230-52-4 ]
[ 540-51-2 ]
[ 276862-11-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate In acetonitrile at 90℃; for 20h;
68%	Stage #1: 2-bromoethanol With potassium carbonate In acetonitrile at 20℃; for 0.5h; Stage #2: 4,4-difluoropiperidine hydrochloride In acetonitrile Reflux;	4.4 Synthesis of 2-(4,4-difluoropiperidin-1-yl)ethan-1-ol To a stirred solution of 2-bromoethan-l-ol (9.5 mL, 133.75 mmol, 5.0 eq) in acetonitrile (42 ml) was added potassium carbonate (11.07 g, 80.25 mmol, 3.0 eq). The reaction mixture was stirred for about 30 minutes at room temperature then added 4,4- difluoropiperidine. HCl salt (step 3, 4.2 g, 26.75 mmol, 1.0 eq) in acetonitrile (20 mL). The reaction mixture was refluxed for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room temperature, and filtered. Filtrate was concentrated to get the crude residue which was purified by column chromatography by using 2% MeOH and DCM as an eluent to obtain the desired product (3.0 g, yield: 68.0%) as a colour less liquid. 1H NMR (DMSO-d6, 300 MHz): δ 4.43 (m, 1H), 3.51-3.46 (m, 2H), 2.53-2.41 (m, 4H), 1.98-1.85 (m, 4H) and 1.98-1.90 (m, 2H); Mass: [M+H]+165.97 (30%).
58%	With potassium carbonate In acetonitrile Reflux;	Compound 97 Preparation of Compound 97, 2-(4,4-difluoropiperidin-1-yl)ethanol Preparation of Compound 97, 2-(4,4-difluoropiperidin-1-yl)ethanol[00118] 2-Bromoethanol (0.164 mL, 2.31 mmol) was added to a suspension of 4,4-difluoropiperidine hydrochloride (0.354 g, 2.25 mmol) and potassium carbonate (0.683 g, 4.94 mmol) in dry acetonitrile (5 mL) and the reaction mixture was as heated at reflux overnight, cooled to rt, filtered, and the filtrate concentrated. Added diethyl ether, extracted with 1 M HCI (2x). The aqueous phase was made basic (pH >12) with solid NaOH, then extracted with DCM (3x). This organic phase was dried over K2C03, filtered and concentrated to afford the title compound (216 mg, 58%) as a colourless oil.1H NMR (500 MHz, CDCl3) δ 3.79 (br t, J = 4.7 Hz, 2H), 2.92 (br s, 4H), 2.82 (br s, 2H), 2.23 (br s, 4H). HRMS (ESI+): calcd for C7H14F2NO (M + H)+, 166.1038; found 166.1041 .

	Stage #1: 4,4-difluoropiperidine hydrochloride With triethylamine In acetonitrile at 0℃; for 0.25h; Stage #2: 2-bromoethanol In acetonitrile at 20℃;	29.b Step b. 2-(4,4-difluoropiperidin-1-yl)ethan-1-ol To a stirred solution of 4,4-Difluoropiperidine hydrochloride (3.0 g, 19 mmol), in acetonitrie (30 mL) triethyiamine (9.6 g, 13.7 mL, 95 mmol) was added at 0°C and allowed to stir for 15 minutes then 2- Bromoethanol (1.9 g, 15 mmol) was added drop wise continued stirring at RT for 5 h. The reaction was monitored by TLC and LCMS. The acetonitrile was evaporated and diluted with (30 mL) ice cold water and extracted with EtOAc (2 X 30 mL), washed with brine (30 mL), dried over anhydrous Na?SO-, concentrated to get 1.9 g (59%) crude of the title compound. No purification was done obtained crude was used as such for next step. (0773) LC-MS (method 23): R, = 0.24 min; m/z = 166.05 (M+H*).
	With potassium carbonate; sodium iodide In acetonitrile at 20℃; for 48h; Sealed tube; Inert atmosphere;	Intermediate 13 (S)-2-(2-methylpiperidin-1-yl)ethan-1-ol General procedure: A mixture of (S)-2-methylpiperidine (100 mg, 1.01 mmol), 2-bromoethanol (78 μL, 139 mg, 1.11 mmol, 1.1 eq.), sodium iodide (151 mg, 1 eq.), potassium carbonate (418 mg, 3 eq.) and acetonitrile (1 mL) in a 4-mL vial was purged with nitrogen, sealed and stirred at room temperature for 2 days. The reaction mixture was partitioned between diethyl ether (15 mL) and water (2 mL). The ether layer was washed with brine (2 mL), acidified with TFA and dried under high vacuum for 2 days. The residue was washed with ether (3 mL), diluted with water (0.5 mL) and basified with 10M NaOH (0.2 mL). The layers were separated and the upper layer was carefully dried over NaOH. The ether solution was evaporated under nitrogen to yield crude (S)-2-(2-methylpiperidin-1-yl)ethan-1-ol (100 mg, 0.698 mmol, 69.24% yield) as colorless oil.

Reference： [1]Charvin, Delphine; Pomel, Vincent; Ortiz, Millan; Frauli, Mélanie; Scheffler, Sophie; Steinberg, Edith; Baron, Luc; Deshons, Laurène; Rudigier, Rachel; Thiarc, Delphine; Morice, Christophe; Manteau, Baptiste; Mayer, Stanislas; Graham, Danielle; Giethlen, Bruno; Brugger, Nadia; Hédou, Gaël; Conquet, François; Schann, Stephan [Journal of Medicinal Chemistry, 2017, vol. 60, # 20, p. 8515 - 8537]
[2]Current Patent Assignee: HETERO DRUGS LIMITED - WO2017/149518, 2017, A1 Location in patent: Page/Page column 28
[3]Current Patent Assignee: CANCER RESEARCH UK - WO2015/49535, 2015, A1 Location in patent: Paragraph 00118
[4]Current Patent Assignee: ORYZON GENOMICS S.A. - WO2018/219478, 2018, A1 Location in patent: Page/Page column 87; 88
[5]Current Patent Assignee: PFIZER INC; MIRATI THERAPEUTICS, INC. - US2019/144444, 2019, A1 Location in patent: Paragraph 0312-0313; 0326

21
[ 4487-56-3 ]
4,4-difluoropiperidine hydrochloride [ No CAS ]
2-chloro-4-(4,4-difluoropiperidin-1-yl)-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In tetrahydrofuran; at 20℃; for 18h;	2-Chloro-4-(4,4-difluoropiperidin-l-yl)-5-nitropyridine. In a 50 mL round-bottom flask vial was added <strong>[4487-56-3]2,4-dichloro-5-nitropyridine</strong> (314 mg, 1.627 mmol) in tetrahydrofuran (8 mL) to give a tan solution. 4,4-Difluoropiperidine hydrochloride (256 mg, 1.63 mmol) was added in one portion, followed by Et3N (0.454 mL, 3.25 mmol). The cloudy yellow mixture was stirred at rt for 18 h. The mixture was partitioned between water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 80percent ethyl acetate/hexane, to afford the desired product (430 mg, 95percent>) as a crystalline yellow solid: 1H NMR (400 MHz, CDC13) delta 8.72 (s, 1H), 6.93 (s, 1H), 3.45 - 3.29 (m, 4H), 2.21 (ddd, J = 19.3, 13.4, 5.9 Hz, 4H); 19F NMR (376 MHz, CDC13) delta -98.47 (s).

Reference： [1]Patent: WO2015/69594,2015,A1 .Location in patent: Page/Page column 108

22
[ 27996-87-8 ]
4,4-difluoropiperidine hydrochloride [ No CAS ]
2-(4,4-difluoropiperidin-1-yl)-5-nitrobenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;Inert atmosphere;	A suspension of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (1 g, 5.91mmol), 4,4-difluoropiperidine hydrochloride (0.932 g,5.91 mmol) and potassium carbonate (1.635 g, 11.83 mmol)in anhydrous DMF (5 mL) was heated to 50 C under a nitrogen atmosphere overnight. The reaction mixture was allowed to cool to room temperature, diluted with water (40 mL) and stirred at room temperature for 15 minutes. The precipitated solid was isolated by filtration, washedwith water, sucked dry and freeze-dried overnight to give the title compound as a yellow solid (1.52 g, 95%) . ?H NMR (300 MHz, CDC13) : 5 10.09 (s, 1H) , 8.65 (d, 1H) , 8.33 (dd, 1H), 7.13 (d, 1H), 3.41 (dd, 4H), 2.17-2.34 (m, 4H) . LCMS (Method C) : = 1.47 mi m/z = 271 [M+H].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 290

23
[ 144230-52-4 ]
[ 2937-50-0 ]
[ 1985607-71-3 ]

Yield	Reaction Conditions	Operation in experiment
97%	With triethylamine In dichloromethane at 0℃; for 1h;	2.1 Compound 13 (8.0g, 50.8mmol) in dichloromethane (120mL) suspension of an ice bath triethylamine (17.6mL, 127mmol) was added, dropwise allyl chloroformate (6.44mL, 60.9mmol) , the mixture was stirred for 1 hour at 0°C. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with 5% aqueous citric acid solution and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give compound 14 (10.1g, 97% yield).
97%	With triethylamine In dichloromethane at 0℃; for 1h;	1-2.1 In the first step To a solution of compound 13 (8.0 g, 50.8 mmol) in dichloromethane(120 mL) under ice bath was added triethylamine(17.6 mL, 127 mmol) was added,Allyl chloroformate (6.44 mL, 60.9 mmol)And the mixture was stirred at 0 ° C. for 1 hour. Water was added to the reaction solution,And extracted with dichloromethane. The organic layer was washed with 5% aqueous citric acid solution and saturatedAfter washing with an aqueous solution of sodium bicarbonate, drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain Compound 14 (10.1 g, yield 97%).
97%	With triethylamine In dichloromethane at 0℃; for 1h; Cooling with ice;	2.1 First Step [0245] To a suspension of Compound 13 (8.0 g, 50.8 mmol) in dichloromethane (120 mL) was added triethylamine (17.6 mL, 127 mmol) under ice-water bath, and allyl chloroformate (6.44 mL, 60.9 mmol) was added dropwise thereto, and the mixture was stirred at 0°C. for 1 hour. To the mixture was added water, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with 5% aqueous solution of citric acid and a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain Compound 14 (10.1 g, 97%). [0246] 1H-NMR (CDCl3) δ: 1.96 (br, 4H), 3.62 (s, 4H), 4.60 (s, 2H), 5.22 (d, J=12.0 Hz, 1H), 5.30 (d, J=16.0 Hz, 1H), 5.86-5.99 (m, 1H)

Reference： [1]Current Patent Assignee: SHIONOGI & CO., LTD. - JP5971830, 2016, B1 Location in patent: Paragraph 0075
[2]Current Patent Assignee: SHIONOGI & CO., LTD. - JP6267397, 2018, B1 Location in patent: Paragraph 0076
[3]Current Patent Assignee: SHIONOGI & CO., LTD. - US2020/261481, 2020, A1 Location in patent: Paragraph 0244-0246

24
[ 15761-39-4 ]
[ 144230-52-4 ]
[ 2009027-40-9 ]

Yield	Reaction Conditions	Operation in experiment
82.24%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 0.12h;	3 Synthesis of tert-butyl (S)-2-(4,4-difluoropiperidine-l-carbonyl)pyrrolidine-l- carboxylate: To a stirred solution of (tert-butoxycarbonyl)-L-proline (Intermediate 13-step 1, 5.42 g, 25.22 mmol) and 4,4-difluoropiperidine hydrochloride (step 2, 2.64 g, 16.81 mmol) and DMAP (1.0 g, 8.4 mmol) in DCM (70 ml), was slowly added DCC (6.92 g, 33.63 mmol) in DCM (40 ml) at 0 °C and allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water, saturated NaHC03solution, brine and dried over Na2S04. The solvent was evaporated and to the resulting solid, was added DCM (30 ml) and stirred for about one hour and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (4.4 g, yield: 82.24%) as a solid. 1H MR (300 MHz, CDC13): δ 4.72-4.67 (m, 1H), 3.93-3.41 (m, 6H), 2.22-1.82 (m, 6H), 1.46 (s, 9H), 1.45-1.28 (m, 2H); ES Mass: 336.28 [M+ H4]+
82.24%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 12h;	3 Step 3: Synthesis of tert-butyl (S)-2-(4,4-difluoropiperidine-1-carbonyl)pyrrolidine-1-carboxylate To a stirred solution of (tert-butoxycarbonyl)-L-proline (5.42 g, 25.22 mmol) and 4,4-difluoropiperidine hydrochloride (step 2, 2.64 g, 16.81 mmol) and DMAP (1.0 g, 8.4 mmol) in DCM (70 ml), was slowly added DCC (6.92 g, 33.63 mmol) in DCM (40 ml) at 0° C. and allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, brine and dried over Na2SO4. The solvent was evaporated and to the resulting solid, was added DCM (30 ml) and stirred for about 1 hour and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (4.4 g, yield: 82.24%) as a solid. 1H NMR (300 MHz, CDCl3): δ 4.72-4.67 (m, 1H), 3.93-3.41 (m, 6H), 2.22-1.82 (m, 6H), 1.46 (s, 9H), 1.45-1.28 (m, 2H); ES Mass: 336.28 [M+NH4]+.

Reference： [1]Current Patent Assignee: HETERO DRUGS LIMITED - WO2017/17630, 2017, A1 Location in patent: Page/Page column 55
[2]Current Patent Assignee: HETERO DRUGS LIMITED - US2018/237472, 2018, A1 Location in patent: Paragraph 0182; 0183

25
[ 2080318-98-3 ]
[ 144230-52-4 ]
[ 2080318-95-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: (S)-isopropyl 2-(6-(bromomethyl)-4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-fluoro-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate; 4,4-difluoropiperidine hydrochloride With triethylamine In ethanol at 20℃; for 16h; Stage #2: With ethanol; sodium hydroxide In water at 80℃; for 4h;	128 (S)-2-(tert-Butoxy)-2-(6-((4, 4-dfluoropiperidin-1-yl)methyl)-4-(4, 4-dime thylpiperidin-]5 yl)-5-(2-(4-fluoro-2-methylbenzyl)-1, 2,3, 4-tetrahydroisoquinolin-6-yl)-2-methylpyridin-3-yl)acetic acid: To a solution of (S)-isopropyl 2-(6-(bromomethyl)-4-(4,4- dimethylpiperidin- l-yl)-5 -(2-(4-fluoro-2-methylbenzyl)- 1,2,3 ,4-tetrahydroi soquinolin-6- yl)-2-methylpyridin-3 -yl)-2-(tert-butoxy)acetate (20 mg, 0.028 mmol) and 4,4- difluoropiperidine, HC1 (21.80 mg, 0.138 mmol) in ethanol (1 mL) was added TEA(0.023 mL, 0.166 mmol) and the resulting mixture was stirred at room temp for 16 h.Mixture was then treated with iON NaOH (0.028 mL, 0.277 mmol) at 80 °C for 4 h.Mixture was then cooled and purified by prep HPLC to afford (S)-2-(tert-butoxy)-2-(6-((4,4-difluoropiperidin- 1 -yl)methyl)-4-(4,4-dimethylpiperidin- 1 -yl)-5-(2-(4-fluoro-2-methylbenzyl)- 1,2,3 ,4-tetrahydroi soquinolin-6-yl)-2-methylpyridin-3 -yl)acetic acid (17.4mg, 0.024 mmol, 87% yield). ‘HNMR (500MHz, DMSO-d6) ö 7.37-7.27 (m, 1H),7.25 -7.16 (m, 1H), 7.13 - 7.02 (m, 2H), 6.99 (t, J=8.4 Hz, 1H), 6.91 - 6.79 (m, 1H), 5.80(br. s., 1H), 3.61 (d, J=4.0 Hz, 4H), 3.23 - 3.10 (m, 2H), 2.87 - 2.79 (m, 3H), 2.68 (br. s.,1H), 2.46 (s, 3H), 2.42-2.26 (m, 8H), 2.11 (br. s., 1H), 1.87- 1.67 (m, 5H), 1.49 (br. s.,1H), 1.25 (d, J=11.0 Hz, 1H), 1.19 (d, J=12.1 Hz, 1H), 1.11 (s, 9H), 1.04 (d, J=6.6 Hz,1H), 0.98 (d, J=9.5 Hz, 1H), 0.85 (br. s., 3H), 0.64 - 0.55 (m, 3H). LCMS (M+H) =721.4.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2017/25915, 2017, A1 Location in patent: Page/Page column 184

26
[ 2068721-29-7 ]
[ 144230-52-4 ]
[ 2068723-60-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 72h;	223 Example 223 (7R)-N-{(2R,4R)-2-[4-(4,4-difluoropiperidine-1-carbonyl)phenyl]-7-methoxy-3,4-dihydro-2H-1-benzopyran-4-yl}-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxamide Example 223 (7R)-N-{(2R,4R)-2-[4-(4,4-difluoropiperidine-1-carbonyl)phenyl]-7-methoxy-3,4-dihydro-2H-1-benzopyran-4-yl}-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxamide The product from Example 50 (0.014 g, 0.026 mmol), 4,4-difluoropiperidine hydrochloride (4.91 mg, 0.031 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (9.45 mg, 0.049 mmol) were stirred in N,N-dimethylformamide (0.2 mL) and pyridine (0.200 mL) for 3 days at room temperature. After this time, the mixture was concentrated in vacuo, and the crude product was purified by silica gel chromatography, eluting with 30 to 70% ethyl acetate-heptanes. The title compound was obtained as a white solid (0.0144 g, 86%). 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=8.7 Hz, 1H), 7.58-7.42 (m, 5H), 7.08-6.95 (m, 2H), 6.60-6.40 (m, 2H), 5.31 (m, 2H), 5.00 (d, J=9.0 Hz, 1H), 4.30 (d, J=9.0 Hz, 1H), 3.67 (s, 3H), 3.65 (m, 2H), 3.26 (m, 1H), 3.14 (m, 1H), 2.12-1.95 (m, 6H), 1.54 (s, 3H). MS (ESI+) m/z 642.9 (M+H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC; GALAPAGOS NV - US2017/15675, 2017, A1 Location in patent: Paragraph 1475

27
[ 2082646-66-8 ]
[ 144230-52-4 ]
[ 2082646-67-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20 - 40℃; for 4h;	1 Synthesis of tert-butyl (5 -(3 -(4,4-difluoropiperidine- 1 -carbonyl)-7-(trifluoromethyl)quinolin-6-yl)furan-2-yl)methylcarbamate (158): Synthesis of tert-butyl (5 -(3 -(4,4-difluoropiperidine- 1 -carbonyl)-7- (trifluoromethyl)quinolin-6-yl)furan-2-yl)methylcarbamate (158): 6-(5 -((Tertbutoxycarbonylamino)methyl)furan-2-yl)-7-(trifluoromethyl)quinoline-3 -carboxylic acid (157; 120 mg, 0.28 mmol) was dissolved in DMF (4 mL). 4,4-Difluoropiperidine hydrochloride (54 mg, 0.34 mmol), EDCI (60 mg, 0.31 mmol), HOBt hydrate (42 mg, 0.31 mmol) were added at room temperature, followed by addition of DIPEA (72 mg, 0.56 mmol)drop wise. After stirring at 40 °C for 4 h, the mixture was poured into water and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with NaHCO3 (aq.), brine and saturated ammonium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 150 mg of tert-butyl (5-(3-(4,4-difluoropiperidine-1- carbonyl)-7-(trifluoromethyl)quinolin-6-yl)furan-2-yl)methylcarbamate 158 as a solid. Yield:87%. LCMS: m/z 540.2 [M+H], , tR= 1.99 min

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2017/31213, 2017, A1 Location in patent: Paragraph 00473

28
[ 2082645-55-2 ]
[ 144230-52-4 ]
[ 2082645-56-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃; for 1h;	1 Synthesis of (6-bromo-5 -chloronaphthalen-2-yl)(4,4-difluoropiperidin- 1-yl)methanone (17): Synthesis of (6-bromo-5 -chloronaphthalen-2-yl)(4,4-difluoropiperidin- 1- yl)methanone (17): 6-Bromo-5-chloro-2-naphthoic acid (16; 150 mg, 0.53 mmol ) was dissolved in DMF (5 mL) and 4,4-difluoropiperidine hydrochloride (85 mg, 0.53 mmol) was added at 0 °C. HATU (201 mg, 0.53 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (140 mg, 1.1 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred further for 1 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (20 mL), brine, dried over anhydrous Na2504, concentrated under reduced pressure to give 180 mg of (6-bromo-5-chloronaphthalen-2- yl)(4,4-difluoropiperidin-1-yl)methanone 17, which was used in next step without further purification (88% yield). LCMS: m/z 388.0 [M+H], tR = 1.79 min

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2017/31213, 2017, A1 Location in patent: Paragraph 00323

29
[ 2098194-70-6 ]
[ 144230-52-4 ]
[ 2098189-96-7 ]

Yield	Reaction Conditions	Operation in experiment
67%	Stage #1: rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.0833333h; Stage #2: 4,4-difluoropiperidine hydrochloride In dichloromethane at 0 - 20℃; for 16h;	113 Synthesis of rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4, 4-difluoropiperidin-1-yl)methanone (3) Example 113 4-((4bS,5R,6S,7S,7aR)-6-((4,4-difluoropiperidin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No. 113F) Synthesis of rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4, 4-difluoropiperidin-1-yl)methanone (3) To a solution of rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylic acid (1, 0.9 g, 1.8 mmol) in dichloromethane (10 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.03 g, 5.41 mmol), 1-hydroxybenzotriazole (0.72 g, 5.41 mmol) and N,N-diisopropylethylamine (1.65 mL, 9.12 mmol) were added at 0° C. and stirred for 5 minutes before 4,4-difluoropiperidine hydrochloride (2, 1.4 g, 9.12 mmol) was added at the same temperature and the mixture was stirred for 16 h at RT. After completion, the reaction mass was diluted with dichloromethane and washed with cold water. The organic layer was separated and dried over anhydrous sodium sulphate, filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography eluting with 0-4% methanol in dichloromethane. The desired fractions were concentrated to afford rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4,4-difluoropiperidin-1-yl)methanone (3) as white solid. Yield: 0.67 g, 67%; MS (ESI) m/z 601.01[M+1]+.
55%	Stage #1: rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.0833333h; Stage #2: 4,4-difluoropiperidine hydrochloride In dichloromethane at 0 - 20℃; for 16h;

Reference： [1]Current Patent Assignee: EFFECTOR THERAPEUTICS INC - US2017/145026, 2017, A1 Location in patent: Paragraph 1087; 1088
[2]Ernst, Justin T.; Thompson, Peggy A.; Nilewski, Christian; Sprengeler, Paul A.; Sperry, Samuel; Packard, Garrick; Michels, Theodore; Xiang, Alan; Tran, Chinh; Wegerski, Christopher J.; Eam, Boreth; Young, Nathan P.; Fish, Sarah; Chen, Joan; Howard, Haleigh; Staunton, Jocelyn; Molter, Jolene; Clarine, Jeff; Nevarez, Andres; Chiang, Gary G.; Appleman, Jim R.; Webster, Kevin R.; Reich, Siegfried H. [Journal of Medicinal Chemistry, 2020, vol. 63, # 11, p. 5879 - 5955]

30
[ 2247630-97-1 ]
[ 144230-52-4 ]
[ 2247631-19-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; Cooling with ice;	52 Example 52: ( 4-amino-2-(7-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl)pyrimidin-5-yl)( 4,4-difluoropiperidin-1-yl)methanone To N,N-dimethylformamide (10 mL) were added4-amino-2-(7 -fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl)pyrimidine-5-carboxylic acid (0.1 0 g,0.26 mmol) and 4,4-difluoropiperidine hydrochloride (0.050 g, 0.32 mmol). Then0-(7-azabenzotriazol-1-yl)-N,N,N,N-te-tramethyluronium hexafluorophosphate (0.12 g, 0.32mmol) and triethylamine (0.15 mL, 1.1 mmol) were added under an ice-bath condition. After theaddition, the mixture was stirred at room temperature overnight. To the reaction mixture wasadded ethyl acetate (60 mL), and the mixture was washed with water (60 mL) and saturated brine(60 mL). The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtratewas evaporated to remove the solvent, and the residue was purified by silica gel chromatographyeluted with dichloromethane/methanol (v/v = 200/1, 0.5% triethylamine) to give a white solid(0.11 g, 87%). MS (ESI, pos.ion) m/z: 485.3 (M+ 1);1H NMR (400 MHz, DMSO-d6) 8 (ppm) 8.49 (d, J = 7.9 Hz, 1H), 8.30 (s, 1H), 7.46-6.97(m, 8H), 5.87 (s, 2H), 3.68- 3.52 (m, 4H), 2.16-2.00 (m, 4H);19F NMR (376 MHz, DMSO-d6) 8 (ppm) -95.93 (s), -118.61 (d, J = 7.5 Hz), -133.67 (d, J =7.5 Hz).

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2018/188590, 2018, A1 Location in patent: Paragraph 00421

31
[ 2446874-31-1 ]
[ 144230-52-4 ]
[ 2446874-32-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 16h; Sealed tube;	3 Step 3 A mixture of 2-bromo-3-fluoro-N-(4-methoxybenzyl)-6-methylpyridin-4-amine (0.7 g, 2.153 mmol), 4,4-difluoropiperidine hydrochloride (0.407 g, 2.58 mmol), cesium carbonate (2.81 g, 8.61 mmol), Xantphos (0.249 g, 0.431 mmol) and Pd2(dba)3 (0.030 g, 0.032 mmol) in 1,4-dioxane (15 mL) was stirred in a sealed tube at 100°C for 16 h. Then the reaction mixture was filtered through a plug of CELITE and filtrate was diluted with EtOAc. The resulting solution was washed with water, brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 0 - 6 % ethyl acetate in petroleum ether to afford 2-(4,4-difluoropiperidin-1-yl)-3- fluoro-N-(4-methoxybenzyl)-6-methylpyridin-4-amine (0.67 g, 1.83 mmol, 85 % yield) as pale-yellow solid.1H NMR (300 MHz, DMSO-d6) d ppm 7.19- 7.29 (m, 2 H), 6.83- 6.93 (m, 2 H), 6.75 (m, 1H), 6.13 (d, J = 5.4 Hz, 1 H), 4.26 (d, J =6.3 Hz, 2 H), 3.72 (s, 3 H), 3.40 (d, J = 11.5 Hz, 4 H), 1.92- 2.14 (m, 7 H). m/z (ESI): 366.1 (M+H)+.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2020/132648, 2020, A1 Location in patent: Paragraph 0248

32
[ 7461-50-9 ]
[ 144230-52-4 ]
[ 2028538-94-3 ]

Yield	Reaction Conditions	Operation in experiment
91%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 200℃; for 1h;	Intermediate 3: 2-(4,4-Difluoropiperidin-1-yl)pyrimidin-4-amine A glass microwave reaction vessel was successively charged with 2-chloro-4-aminopyrimidine (1.0 g, 7.7 mmol, Combi-Blocks, San Diego, CA), 4,4-difluoropiperidine hydrochloride (1.82 g, 11.58 mmol, Combi-Blocks, San Diego, CA) and DIPEA (4.04 mL, 23.2 mmol) in NMP (12 mL). The reaction mixture was stirred and heated in a microwave at 200 °C for 1 h. Reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (30 x 2 mL). The organic extract was washed with brine (30 x mL), dried over Na2SO4, concentrated in vacuo to give the crude material as a brownish sticky liquid. The crude material was absorbed onto a plug of silica gel and purified by flash chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with 0 % to 100 % ethyl acetate in heptane to provide the title compound as an off-white solid (6.02 g, 91 %).1H NMR (300 MHz, DMSO-d6) d ppm 7.21 (d, J = 5.6 Hz, 1H), 6.46 (br s, 2H), 5.77 (d, J = 5.6 Hz, 1H), 3.80 (t, J = 5.6 Hz, 4H), 1.85-1.90 (m, 4H). m/z (ESI): 215.2 (M+H)+.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2020/132648, 2020, A1 Location in patent: Paragraph 0230; 0231

33
[ 14394-60-6 ]
[ 144230-52-4 ]
[ 2446613-63-2 ]

Yield	Reaction Conditions	Operation in experiment
79%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 180℃; for 30h; Autoclave;	Intermediate 4: 2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine A mixture of 2-chloro-6-methylpyrimidin-4-amine (46 g, 320 mmol, Combi-Blocks, San Diego, CA), 4,4-difluoropiperidine hydrochloride (76 g, 481 mmol, Combi-Blocks, San Diego, CA) and DIPEA (166 mL, 961 mmol) in NMP (460 mL, 10.00 mL/g) was taken in an autoclave (1 L) and heated at 180 °C for 30 h. The reaction mixture was cooled to room temperature and quenched with water (500 mL), extracted with ethyl acetate (2 x 1000 mL). The organic layer was washed with brine (500 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was adsorbed onto a plug of silica gel and purified by column chromatography over silica gel (60-120 mesh), eluting with 50% to 100% ethyl acetate in hexanes as an eluent to give the product. This was re-dissolved in ethyl acetate (500 mL), washed with water (2 x 500 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The yellow solid was once again suspended in hexanes (400 mL) and stirred for 30 min. The slurry was filtered, washed with hexanes (100 mL), dried under vacuum to provide the title compound (58 g, 79% yield) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) d ppm 6.33 (s, 2H), 5.63 (s, 1H), 3.80- 3.78 (dd, J = 6.8, 4.7 Hz, 4H), 2.06 (s, 3H), 1.95- 1.85 (tt, J = 14.2, 5.7 Hz, 4H). m/z (ESI): 229.2 (M+H)+.
79%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 180℃; for 30h; Autoclave;	2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine A mixture of 2-chloro-6-methylpyrimidin-4-amine (46 g, 320 mmol, Combi-Blocks, San Diego, CA), 4,4-difluoropiperidine hydrochloride (76 g, 480 mmol, Combi-Blocks, San Diego, CA) and DIPEA (166 mL, 961 mmol) in NMP (460 mL) was taken in an autoclave and heated at 180 °C for 30 h. The reaction mixture was cooled to room temperature, quenched with water (500 mL), and extracted with ethyl acetate (2 x 1000 mL). The organic layer was washed with brine (500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was adsorbed onto a plug of silica gel and purified by column chromatography over silica gel (60-120 mesh), eluting with 50% to 100% ethyl acetate in hexanes to give the target compound, which was re-dissolved in ethyl acetate (500 mL), and washed with water (2 x 500 mL). The organic layer was taken, dried (Na2SO4), filtered, and concentrated under reduced pressure. The yellow solid obtained was once again suspended in hexanes (400 mL) and stirred for 30 min. The slurry was filtered, washed with hexanes (100 mL), and dried under vacuum to provide the title compound (58 g, 79% yield) as a pale-yellow solid.1H NMR (400 MHz, DMSO-d6) d 6.33 (s, 2H), 5.63 (s, 1H), 3.80- 3.78 (dd, J = 6.8, 4.7 Hz, 4H), 2.06 (s, 3H), 1.95- 1.85 (tt, J = 14.2, 5.7 Hz, 4H). m/z (ESI): 229.2 (M+H)+.
79%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 180℃; for 30h; Autoclave;	Intermediate 4: 2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine A mixture of 2-chloro-6-methylpyrimidin-4-amine (46 g, 320 mmol, Combi-Blocks, San Diego, CA), 4,4-difluoropiperidine hydrochloride (76 g, 481 mmol, Combi-Blocks, San Diego, CA) and DIPEA (166 mL, 961 mmol) in NMP (460 mL, 10.00 mL/g) was taken in an autoclave (1 L) and heated at 180 °C for 30 h. The reaction mixture was cooled to room temperature and quenched with water (500 mL), extracted with EtOAc (2 x 1000 mL). The organic layer was washed with brine (500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was adsorbed onto a plug of silica gel and purified by column chromatography over silica gel, eluting with 50 % to 100 % EtOAc in hexanes. The product was re-dissolved in EtOAc (500 mL) and washed with water (2 x 500 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The yellow solid was once again suspended in hexanes (400 mL) and stirred for 30 min. The slurry was filtered, washed with hexanes (100 mL), dried under vacuum to provide the title compound (58 g, 79 % yield) as a pale-yellow solid.1H NMR (400 MHz, DMSO-d6) d ppm 6.33 (s, 2 H), 5.63 (s, 1 H), 3.80 - 3.78 (dd, J = 6.8, 4.7 Hz, 4 H), 2.06 (s, 3 H), 1.95 - 1.85 (tt, J = 14.2, 5.7 Hz, 4 H). m/z (ESI): 229.2 (M+H)+.

79%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 180℃; for 30h; Autoclave;	11 Intermediate 1: 2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine A mixture of 2-chloro-6-methylpyrimidin-4-amine (46 g, 320 mmol, Combi-Blocks, San Diego, CA), 4,4-difluoropiperidine hydrochloride (76 g, 481 mmol, Combi-Blocks, San autoclave (1 L) and heated at 180 °C for 30 h. The reaction mixture was cooled to room temperature and quenched with water (500 mL), extracted with ethyl acetate (2 x 1000 mL). The organic layer was washed with brine (500 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was adsorbed onto a plug of silica gel and purified by column chromatography over silica gel (60-120 mesh), eluting with 50% to 100% E in hexanes as an eluent to give the product. This was re-dissolved in ethyl acetate (500 mL), washed with water (2 x 500 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The yellow solid was once again suspended in hexanes (400 mL) and stirred for 30 min. The slurry was filtered, washed with hexanes (100 mL), dried under vacuum to provide the title compound (58 g, 79% yield) as a pale yellow solid.1H NMR (400 MHz, DMSO- d6) ppm 6.33 (s, 2H), 5.63 (s, 1H), 3.80 - 3.78 (dd, J = 6.8, 4.7 Hz, 4H), 2.06 (s, 3H), 1.95 - 1.85 (tt, J = 14.2, 5.7 Hz, 4H). m/z (ESI): 229.2 (M+H)+.
79%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 180℃; for 30h; Autoclave;	11 Intermediate 1: 2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine A mixture of 2-chloro-6-methylpyrimidin-4-amine (46 g, 320 mmol, Combi-Blocks, San Diego, CA), 4,4-difluoropiperidine hydrochloride (76 g, 481 mmol, Combi-Blocks, San autoclave (1 L) and heated at 180 °C for 30 h. The reaction mixture was cooled to room temperature and quenched with water (500 mL), extracted with ethyl acetate (2 x 1000 mL). The organic layer was washed with brine (500 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was adsorbed onto a plug of silica gel and purified by column chromatography over silica gel (60-120 mesh), eluting with 50% to 100% E in hexanes as an eluent to give the product. This was re-dissolved in ethyl acetate (500 mL), washed with water (2 x 500 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The yellow solid was once again suspended in hexanes (400 mL) and stirred for 30 min. The slurry was filtered, washed with hexanes (100 mL), dried under vacuum to provide the title compound (58 g, 79% yield) as a pale yellow solid.1H NMR (400 MHz, DMSO- d6) ppm 6.33 (s, 2H), 5.63 (s, 1H), 3.80 - 3.78 (dd, J = 6.8, 4.7 Hz, 4H), 2.06 (s, 3H), 1.95 - 1.85 (tt, J = 14.2, 5.7 Hz, 4H). m/z (ESI): 229.2 (M+H)+.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2020/132648, 2020, A1 Location in patent: Paragraph 0232; 0233
[2]Current Patent Assignee: AMGEN INC - WO2020/132649, 2020, A1 Location in patent: Paragraph 0194; 0195
[3]Current Patent Assignee: AMGEN INC; AMERICAN ANGHAI COMPANY - WO2021/26101, 2021, A1 Location in patent: Paragraph 0314-0315
[4]Current Patent Assignee: AMGEN INC - WO2021/211549, 2021, A1 Location in patent: Paragraph 00311; 00318-00319
[5]Current Patent Assignee: AMGEN INC - WO2021/211549, 2021, A1 Location in patent: Paragraph 00311; 00318-00319

34
[ 402-65-3 ]
[ 144230-52-4 ]
[ 1785532-85-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 125℃; for 4h; Microwave irradiation;	2-(4,4-Difluoropiperidin-1-yl)isonicotinic acid A mixture of 2-fluoro-4-pyridinecarboxylic acid (0.90 g, 6.4 mmol, Matrix Scientific), 4,4- difluoropiperidine hydrochloride (1.106 g, 7.02 mmol, Matrix Scientific) and DIPEA (3.34 mL, 19.14 mmol, Sigma-Aldrich Corporation) in 5 mL of NMP was heated in a microwave at 125 oC for 4 h. The mixture was loaded on a silica gel column and eluted with 10% to 100% EtOAc in heptane to give a material that contained both 2-(4,4-difluoropiperidin-1-yl)isonicotinic acid and NMP. The material was stirred in 10 mL of heptane. The insoluble solid was collected and dried to give 2-(4,4-difluoropiperidin-1- yl)isonicotinic acid (1.40 g, 5.80 mmol, 91% yield) as a brown solid. m/z (ESI): 243.1 (M+H)+.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2020/132649, 2020, A1 Location in patent: Paragraph 0196-0198

35
[ 39621-00-6 ]
[ 144230-52-4 ]
[ 2446341-99-5 ]

Yield	Reaction Conditions	Operation in experiment
58%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 180℃; for 24h; Autoclave;	1 Step 1 To an autoclave was added 2,6-dichloro-4-methylpyridine (80 g, 490 mmol), 4,4- difluoropiperidine hydrochloride (86 g, 540 mmol), and DIPEA (342 mL, 1980 mmol) in NMP (800 mL). The reaction mixture was heated at 180 °C for 24 h. The reaction mixture was cooled to room temperature and basified to pH~9 using 10 % aqueous NaHCO3 solution. The reaction mixture was extracted with ethyl acetate (2 x 1500 mL), washed with water (1500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography over silica gel (60-120 mesh) using 5-10 % ethyl acetate in hexanes to give the mixture of 2,6-dichloro-4-methylpyridine and 2-chloro- 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine in 1:3 ratio (102 g) as a pale brown oil. This mixture (102 g) was further purified by reverse phase chromatography using 60% acetonitrile in water as an eluent to give 2-chloro-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine (70 g, 58% yield) as a pale brown liquid.1H NMR (400 MHz, DMSO-d6): d 6.76 (s, 1H), 6.57 (s, 1H), 3.66 (t, J = 5.6 Hz, 4H), 2.22 (s, 3H), 2.03- 1.91 (m, 4H). m/z (ESI): 247.1 (M+H)+.
58%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 180℃; for 24h; Autoclave;	1 Intermediate 6: 6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-amine Step 1: In an autoclave (3 L) were added 2,6-dichloro-4-methylpyridine (80 g, 490 mmol), 4,4- difluoropiperidine hydrochloride (86 g, 540 mmol), and DIPEA (342 mL, 1980 mmol) in NMP (800 mL). The reaction mixture was heated at 180 °C for 24 h. The reaction mixture was cooled to room temperature and basified to pH~9 using 10 % aq. NaHCO3 solution. The reaction mixture was extracted with EtOAc (2 x 1500 mL), washed with water (1500 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography over silica gel (60-120 mesh) using 5-10 % EtOAc in hexanes to give the mixture of 2,6-dichloro-4-methylpyridine and 2-chloro-6-(4,4- difluoropiperidin-1-yl)-4-methylpyridine in 1:3 ratio (102 g) as a pale brown oil. This mixture (102 g) was further purified by reverse phase chromatography using 60 % CH3CN/H2O as an eluent to give 2-chloro-6- (4,4-difluoropiperidin-1-yl)-4-methylpyridine (70 g, 58 % yield) as a pale brown liquid. 1H NMR (400 MHz, DMSO-d6): d 6.76 (s, 1 H), 6.57 (s, 1 H), 3.66 (t, J = 5.6 Hz, 4 H), 2.22 (s, 3 H), 2.03 - 1.91 (m, 4 H). m/z (ESI): 247.1 (M+H)+.
58%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 180℃; for 24h; Autoclave;	11.1 Step 1: To an autoclave was added 2,6-dichloro-4-methylpyridine (80 g, 490 mmol), 4,4-difluoropiperidine hydrochloride (86 g, 540 mmol), and DIPEA (342 mL, 1980 mmol) in NMP (800 mL). The reaction mixture was heated at 180 °C for 24 h. The reaction mixture was cooled to room temperature and basified to pH~9 using 10 % aqueous NaHCO3 solution. The reaction mixture was extracted with ethyl acetate (2 x 1500 mL), washed with water (1500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography over silica gel (60-120 mesh) using 5-10 % ethyl acetate in hexanes to give the mixture of 2,6-dichloro-4-methylpyridine and 2-chloro-6-(4,4-difluoropiperidin-1-yl)-4- methylpyridine in 1:3 ratio (102 g) as a pale brown oil. This mixture (102 g) was further purified by reverse phase chromatography using 60% acetonitrile in water as an eluent to give 2-chloro- 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine (70 g, 58% yield) as a pale brown liquid.1H NMR (400 MHz, DMSO-d6): 6.76 (s, 1H), 6.57 (s, 1H), 3.66 (t, J = 5.6 Hz, 4H), 2.22 (s, 3H), 2.03 - 1.91 (m, 4H). m/z (ESI): 247.1 (M+H)+.

58%

With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 180℃; for 24h; Autoclave;

11.1 Step 1: To an autoclave was added 2,6-dichloro-4-methylpyridine (80 g, 490 mmol), 4,4-difluoropiperidine hydrochloride (86 g, 540 mmol), and DIPEA (342 mL, 1980 mmol) in NMP (800 mL). The reaction mixture was heated at 180 °C for 24 h. The reaction mixture was cooled to room temperature and basified to pH~9 using 10 % aqueous NaHCO3 solution. The reaction mixture was extracted with ethyl acetate (2 x 1500 mL), washed with water (1500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography over silica gel (60-120 mesh) using 5-10 % ethyl acetate in hexanes to give the mixture of 2,6-dichloro-4-methylpyridine and 2-chloro-6-(4,4-difluoropiperidin-1-yl)-4- methylpyridine in 1:3 ratio (102 g) as a pale brown oil. This mixture (102 g) was further purified by reverse phase chromatography using 60% acetonitrile in water as an eluent to give 2-chloro- 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine (70 g, 58% yield) as a pale brown liquid.1H NMR (400 MHz, DMSO-d6): 6.76 (s, 1H), 6.57 (s, 1H), 3.66 (t, J = 5.6 Hz, 4H), 2.22 (s, 3H), 2.03 - 1.91 (m, 4H). m/z (ESI): 247.1 (M+H)+.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2020/132651, 2020, A1 Location in patent: Paragraph 0191
[2]Current Patent Assignee: AMGEN INC; AMERICAN ANGHAI COMPANY - WO2021/26101, 2021, A1 Location in patent: Paragraph 0318-0319
[3]Current Patent Assignee: AMGEN INC - WO2021/211549, 2021, A1 Location in patent: Paragraph 00311; 00322-00323
[4]Current Patent Assignee: AMGEN INC - WO2021/211549, 2021, A1 Location in patent: Paragraph 00311; 00322-00323

36
[ 55346-97-9 ]
4,4-difluoropiperidine hydrochloride [ No CAS ]
5-(4,4-difluoropiperidin-1-yl)-4-fluoro-2-nitrophenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68.2%	With 4-methyl-morpholine In acetonitrile at 80℃; for 4h;
68.2%	With 4-methyl-morpholine In acetonitrile at 80℃; for 4h;	32.1 Step 1 Preparation of 5-(4,4-difluoropiperidin-1-yl)-4-fluoro-2-nitrophenol (intermediate 31) To a solution of 4,5-difluoro-2-nitrophenol (2.8 g, 16 mmol) in acetonitrile (15 mL) was added N-methylmorpholine (4 mL) and 4,4-difluoropiperidine hydrochloride (3.5 g, 22 mmol). The reaction was carried out at 80° C. for 4 hours. After cooling, water was added (15 mL) and the reaction stood and layered overnight and then the reaction was filtered. The obtained solid was purified by silica gel column chromatography (petroleum ether/dichloromethane=80/20) to obtain intermediate 31 (3 g, 68.2%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 10.83 (s, 1H), 7.75 (d, J=13.2 Hz, 1H), 6.47 (d, J=7.7 Hz, 1H), 3.47 (t, J=5.6 Hz, 4H), 2.22-2.07 (m, 4H).

Reference： [1]Zhao, Hongyi; Wang, Bin; Fu, Lei; Li, Gang; Lu, Haijia; Liu, Yuke; Sheng, Li; Li, Yan; Zhang, Baoxi; Lu, Yang; Ma, Chen; Huang, Haihong; Zhang, Dongfeng; Lu, Yu [Journal of Medicinal Chemistry, 2020, vol. 63, # 17, p. 9316 - 9339]
[2]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - US2021/188871, 2021, A1 Location in patent: Paragraph 0368-0371

37
[ 2267-40-5 ]
[ 144230-52-4 ]
[ 2497526-25-5 ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 1h;	1 General procedure K for the synthesis of compounds 5.2- 5.4 (scheme 5 ) . 4-Fluoro-3-chlorosulfonyl-benzoic acid 3.1 (1 mmol) solved in 2 mL of THF was added dropwise to 8 mL of an ice cold solution of the proper cyclic amine (3 mmol) in THF and stirred for 1 hr at RT . At reaction completion the reaction mixture was evaporated to dryness and the residue treated with water and HC1. The precipitated product was filtered and rinsed with water to afford the pure titled compounds. (0664) 4 -fluoro-3-pyrrolidin-l-ylsulfonyl-benzoic acid (0665) (compound 5.2, scheme 5) . (0666) Title compound was synthesized following the general procedure K previously described using intermediate 3.1 (250 mg, 1.04 mmol) and pyrrolidine (0.26 ml, 3.11 mmol) in THF (8 ml) . The described workup afforded pure titled compound (243.2 mg, yield 85%) . Characterization: Rt = 1.17 min; MS (ESI) m/ z : 272.4 [M-H]-. [M-H] - calculated: (0667) 273.05. 1H NMR (400 MHz, DMSO-d6) d 8.30 (dd, J = 6.8, 2.3 Hz, 1H) , 8.25 (ddd, J = 8.6, 4.8, 2.3 Hz, 1H) , 7.62 (dd, J = 10.1, 8.6 Hz, 1H) , 3.28 - 3.21 (m, 4H) , 1.81 - (0668) 1.73 (m, 4H) .

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF BOLOGNA; ISTITUTO ITALIANO DI TECNOLOGIA; UNIVERSITY OF GENOA - WO2020/202072, 2020, A1 Location in patent: Page/Page column 73; 89

38
[ 1480-87-1 ]
[ 144230-52-4 ]
[ 1774896-15-9 ]

Yield	Reaction Conditions	Operation in experiment
97.4%	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 10h;	23.1 The first step: 2-(4,4-difluoropiperidin-1-yl)-3-nitropyridine (23A) At room temperature, dissolve 2-fluoro-3-nitropyridine (300mg, 2.1mmol) in 10mL DMF, add cesium carbonate (2.06mg, 6.33mmol) and 4,4-difluoropiperidine hydrochloride(331mg, 2.1mmol) , React at room temperature for 10 hours, TLC monitoring shows that the reaction is complete. Add 30 mL of water, extract with 50 mL of ethyl acetate, separate the ethyl acetate layer, extract the aqueous layer with ethyl acetate (50 mL×2), combine the organic layers, wash 100 mL×2 with saturated brine, dry the organic layer with anhydrous sodium sulfate The phase was dried and then spin-dried to obtain 23A, a yellow oil (500 mg, 97.4%), which was directly used in the next reaction without further purification.

Reference： [1]Current Patent Assignee: CHENGDU PIONEER PHARMACEUTICAL DEVELOPMENT CO LTD; CHENGDU HITGEN PHARMACEUTICAL DEV - CN111848591, 2020, A Location in patent: Paragraph 0476-0479

39
[ 1579171-30-4 ]
[ 144230-52-4 ]
[ 2755728-28-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 3h;	General Method B General procedure: 3 (22mg, 0.056mmol), ethanamine hydrochloride (9mg, 0.11mmol), DIPEA (0.05mL, 0.28mmol) and HBTU (0.12mL, 0.080mmol) were dissolved in DMF (2mL) and allowed to stir for 3hat 20°C. The reaction was concentrated in vacuo and dissolved in EtOAc (15mL) and washed with 10% NaHCO3 (10mL), dried with anhydrous Na2SO4, filtered and concentrated. The crude material was then purified by reverse phase preparatory HPLC using a gradient of 95% water/ACN to 100% ACN to afford 16 as a solid (8.3mg, 39%).

Reference： [1]Nguyen, William; Dans, Madeline G.; Ngo, Anna; Gancheva, Maria R.; Romeo, Ornella; Duffy, Sandra; de Koning-Ward, Tania F.; Lowes, Kym N.; Sabroux, Helene Jousset; Avery, Vicky M.; Wilson, Danny W.; Gilson, Paul R.; Sleebs, Brad E. [European Journal of Medicinal Chemistry, 2021, vol. 214]

40
[ 144230-52-4 ]
[ 138500-85-3 ]
[ 1206594-03-7 ]

Yield	Reaction Conditions	Operation in experiment
85.3%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 6h;	1.2 Step 2: Synthesis of (4-((4,4-difluoropiperidin-1-yl)methyl)phenyl)boronic acid pinacol ester (2A) Add 4-bromomethylphenylboronic acid pinacol ester (55g, 0.18mol), 4,4-difluoropiperidine hydrochloride (35.0g, 0.22mol), potassium carbonate (30.4g, 0.22mol) to the reaction Add 500 mL of DMF to the bottle, stir and react at 80°C for 6 hours. After cooling to room temperature, the reaction solution was poured into 2500 mL of ice water, stirred for 30 minutes, and filtered with suction to obtain the title product, a white solid of 53.4 g, with a yield of 85.3%.

Reference： [1]Current Patent Assignee: CHINA MEDICINE RES DEVELOPMENT CENTER - CN112812117, 2021, A Location in patent: Paragraph 0068; 0070; 0073-0074

41
[ 144230-52-4 ]
[ 935259-98-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: 4,4-difluoropiperidine hydrochloride With sodium hydroxide In water at 20℃; for 1h; Stage #2: With acetic acid; sodium nitrite In water at 20℃; for 2h;	17 Compound 17a (200mg, 1.27mmol) was dissolved in water (3mL), then sodium hydroxide solution (2 M, 0.70mL) was added and stirred at room temperature for one hour, and sodium nitrite (175mg , 2.54mmol) and acetic acid solution (0.1mL) were stirred at room temperature for 2 hours.After the reaction is completed, it is extracted with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phases are combined. The organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and separated and purified by silica gel column chromatography ( Petroleum ether: ethyl acetate = 4:1) to obtain a pale yellow solid compound 17b (190 mg, yield 94%).

Reference： [1]Current Patent Assignee: HANGZHOU INNOGATE PHARMA CO LTD - CN113200981, 2021, A Location in patent: Paragraph 0193-0195

42
[ 2761292-67-3 ]
[ 144230-52-4 ]
[ 2761292-68-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	With N-ethyl-N,N-diisopropylamine In iso-butanol at 90℃; for 120h; Sealed tube; Inert atmosphere;	32 Example 32: 4-((7-(benzyloxy)-2-(4,4-difluoropiperidin-1-yl)-6-methoxyquinazolin-4- yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide, (Compound-134) Preparation:To a suspension of 4-((7-(benzyloxy)-2-chloro-6- methoxyquinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (1.30 g, 2.90 mmol) and DIPEA (0.44 mL, 2.53 mmol) in anhydrous 2-butanol (20 mL) was added 4,4- difluoropiperidine hydrochloride (2.29 g, 14.51 mmol). The sealed tube was stirred and heated to 90oC under argon atmosphere. Upon completion after 5 days, the cooled reaction mixtures were quenched with sat. NaHCO3 and extracted with 8:2 dichloromethane/isopropanol mixtures (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude solid was suspended and sonicated in minimum amount of dichloromethane and the precipitated product was collected by filtration to give 4-((7-(benzyloxy)-2-(4,4-difluoropiperidin-1-yl)-6- methoxyquinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (1.35 g, 87%) as a white solid. 1H NMR (400 MHz, DMSO-d): δ 7.52 (d, 1H, J = 8.0 Hz), 7.51 (s, 1H), 7.52 (d, 2H, J = 8.0 Hz), 7.40 (m, 2H), 7.34 (m 1H), 6.87 (s, 1H), 5.18 (s, 2H), 4.48 (m, 1H), 3.91 (m, 4H), 3.83 (s, 3H), 3.43 (td, 2H, J = 12.0, 4.0 Hz), 3.14 (d, 2H, J = 12.0 Hz), 2.25 (m, 2H), 2.13 (m, 2H), 1.95 (m, 4H). MS (ESI): Calcd. for C26H30F2N4O4S: 532, found 533 (M+H)+.
87%	With N-ethyl-N,N-diisopropylamine In iso-butanol at 90℃; for 120h; Sealed tube; Inert atmosphere;	32 Example 32: 4-((7-(benzyloxy)-2-(4,4-difluoropiperidin-1-yl)-6-methoxyquinazolin-4- yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide, (Compound-134) Preparation:To a suspension of 4-((7-(benzyloxy)-2-chloro-6- methoxyquinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (1.30 g, 2.90 mmol) and DIPEA (0.44 mL, 2.53 mmol) in anhydrous 2-butanol (20 mL) was added 4,4- difluoropiperidine hydrochloride (2.29 g, 14.51 mmol). The sealed tube was stirred and heated to 90oC under argon atmosphere. Upon completion after 5 days, the cooled reaction mixtures were quenched with sat. NaHCO3 and extracted with 8:2 dichloromethane/isopropanol mixtures (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude solid was suspended and sonicated in minimum amount of dichloromethane and the precipitated product was collected by filtration to give 4-((7-(benzyloxy)-2-(4,4-difluoropiperidin-1-yl)-6- methoxyquinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (1.35 g, 87%) as a white solid. 1H NMR (400 MHz, DMSO-d): δ 7.52 (d, 1H, J = 8.0 Hz), 7.51 (s, 1H), 7.52 (d, 2H, J = 8.0 Hz), 7.40 (m, 2H), 7.34 (m 1H), 6.87 (s, 1H), 5.18 (s, 2H), 4.48 (m, 1H), 3.91 (m, 4H), 3.83 (s, 3H), 3.43 (td, 2H, J = 12.0, 4.0 Hz), 3.14 (d, 2H, J = 12.0 Hz), 2.25 (m, 2H), 2.13 (m, 2H), 1.95 (m, 4H). MS (ESI): Calcd. for C26H30F2N4O4S: 532, found 533 (M+H)+.

Reference： [1]Current Patent Assignee: ATHOS THERAPEUTICS - WO2022/31939, 2022, A1 Location in patent: Paragraph 0296; 0357
[2]Current Patent Assignee: ATHOS THERAPEUTICS - WO2022/31939, 2022, A1 Location in patent: Paragraph 0296; 0357

43
[ 1600960-38-0 ]
[ 144230-52-4 ]
[ 2758809-32-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine In methanol at 65℃; for 16h;	Intermediate _ 30: tert- butyl 4-{2-[(4-bromopyridin-2- yl)carbamoyl]ethyl}piperazine-1-carboxylate General procedure: Intermediate 29 (150 mg, 0.66 mmol) was dissolved in THF (5 mL), 1- piperazinecarboxylic acid tert-butyl ester (2701 mg, 1.45 mmol) was added and the reaction solution was stirred at 65 °C for 16 hrs. Volatiles were removed under vacuum and the residue was purified by flash chromatography on Biotage silica cartridge (from cHex to EtOAc) to afford Intermediate 30 (125 mg, 0.30 mmol, 46% yield) as foam. (0372) LC-MS (ESI): mlz (M+1): 415.2 (Method 1)
94%	With triethylamine In methanol at 65℃; for 16h;	Intermediate _ 30: tert- butyl 4-{2-[(4-bromopyridin-2- yl)carbamoyl]ethyl}piperazine-1-carboxylate General procedure: Intermediate 29 (150 mg, 0.66 mmol) was dissolved in THF (5 mL), 1- piperazinecarboxylic acid tert-butyl ester (2701 mg, 1.45 mmol) was added and the reaction solution was stirred at 65 °C for 16 hrs. Volatiles were removed under vacuum and the residue was purified by flash chromatography on Biotage silica cartridge (from cHex to EtOAc) to afford Intermediate 30 (125 mg, 0.30 mmol, 46% yield) as foam. (0372) LC-MS (ESI): mlz (M+1): 415.2 (Method 1)

Reference： [1]Current Patent Assignee: Valline SRL - WO2022/13307, 2022, A1 Location in patent: Page/Page column 97; 174
[2]Current Patent Assignee: Valline SRL - WO2022/13307, 2022, A1 Location in patent: Page/Page column 97; 174

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	144230-52-4	MDL No. :	MFCD03095381
Formula :	C₅H₁₀ClF₂N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OABUKBBBSMNNPM-UHFFFAOYSA-N
M.W :	157.59	Pubchem ID :	2758351
Synonyms :	4,4-Difluoropiperidine hydrochloride	Chemical Name :	4,4-Difluoropiperidine hydrochloride

Num. heavy atoms :	9
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	37.86
TPSA :	12.03 Å²

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.01 cm/s

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.76
Log Po/w (WLOGP) :	2.27
Log Po/w (MLOGP) :	1.49
Log Po/w (SILICOS-IT) :	1.98
Consensus Log Po/w :	1.5

[ CAS No. 144230-52-4 ] {[proInfo.proName]}

Quality Control of [ 144230-52-4 ]

Related Doc. of [ 144230-52-4 ]

Product Details of [ 144230-52-4 ]

Calculated chemistry of [ 144230-52-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 144230-52-4 ]

Application In Synthesis of [ 144230-52-4 ]

[ 144230-52-4 ] Synthesis Path-Downstream 1~43

Related Functional Groups of
[ 144230-52-4 ]

Fluorinated Building Blocks

Related Parent Nucleus of
[ 144230-52-4 ]

Aliphatic Heterocycles

Piperidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

Log S (ESOL) :	-1.93
Solubility :	1.87 mg/ml ; 0.0119 mol/l
Class :	Very soluble
Log S (Ali) :	-1.63
Solubility :	3.69 mg/ml ; 0.0234 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.82
Solubility :	2.39 mg/ml ; 0.0152 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.15

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

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
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P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
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P230	Keep wetted
P231	Handle under inert gas.
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P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
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P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
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P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling