Name: 91188-13-5|tert-Butyl azetidin-3-ylcarbamate|97%
Brand: Ambeed
SKU: A177395
Price: 41.0 USD
Availability: InStock
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1
[ 1179328-99-4 ]
[ 91188-13-5 ]
tert-butyl [1-(4-[6-(5-fluoro-1H-indol-2-yl)pyrazin-2-yl]amino}-3-methoxybenzoyl)azetidin-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20 - 140℃; for 6h;	4-({6-[l-(tert-Butoxycarbonyl)-5-fluoro-lH-indol-2-yl]pyrazin-2-yl}amino)-3- methoxybenzoic acid (100.0 mg, 0.21 mmol), tert-butyl azetidin-3-ylcarbamate (47.0 mg, 0.27 mmol), TBTU (87.0 mg, 0.27 mmol) and TEA (38.0 muL, 0.27 mmol) in DMF (2 mL) were stirred at ambient temperature for 3h, heated at 1400C for 3h, let to ambient temperature and purified using preparative HPLC system E. Yield 23.5 mg (21%). HPLC 97%, Rtau: 2.452 (10-97% MeCN over 3min). IH NMR (400 MHz, MeOD) D ppm 1.36 (s, 9 H) 3.88 (s, 3 H) 3.91 - 3.99 (m, J=3.01 Hz, 1 H) 4.22 (s, 1 H) 4.35 (s, 2 H) 4.59 (s, 1 H) 6.80 - 6.91 (m, 1 H) 7.02 (s, 1 H) 7.15 (dd, J=9.66, 2.38 Hz, 1 H) 7.19 - 7.29 (m, 2 H) 7.34 (dd, J=8.91, 4.39 Hz, 1 H) 8.09 (s, 1 H) 8.34 (s, 1 H) 8.55 (d, J=8.28 Hz, 1 H). MS 533 (M+H)+.

Reference： [1]Patent: WO2007/147874,2007,A1 .Location in patent: Page/Page column 178-179

2
C₂₀H₁₆FN₅O [ No CAS ]
[ 91188-13-5 ]
(1-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-pyrido[3,4-d]pyrimidin-6-yl}-azetidin-3-yl)-carbamic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: EP1249451,2002,A2 .Location in patent: Page 19

3
[ 75-44-5 ]
[ 91188-13-5 ]
C₉H₁₅ClN₂O₃ [ No CAS ]

Reference： [1]Patent: US6335324,2002,B1 .Location in patent: Page column 132

4
[ 635309-26-1 ]
[ 91188-13-5 ]
[ 635309-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; for 2h;	A solution of Example 7C (0.3 g) and 3-(tert-butoxycarbonylamino)azetidine (0.46 g) in dichloromethane (60 mL) was stirred for 2 hours, diluted with dichloromethane, washed with water, 10% citric acid, and brine, and dried (MgSO4), filtered, and concentrated.

Reference： [1]Patent: US2003/232818,2003,A1 .Location in patent: Page 42

5
[ 91188-13-5 ]
[ 684285-86-7 ]

Yield	Reaction Conditions	Operation in experiment
69%		Trimethylsilylethyl ether 44 (0.03 g, 0.0508 mmol) was dissolved in 0.5 ml dry tetrahydrofuran. To this was added triethylamine (0.028 ml, 0.2032 mmol) and 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (0. 1016 mL, 0.1016 mmol. ) Stirred at room temperature 10 minutes until starting material consumed. Diluted with dichloromethane, washed with washed with 1M HCl solution, saturated brine, dried (Na2S04,) concentrated to give crude. Dissolved in 0.5 ml dichloromethane, added catalytic dimethylaminopyridine, triethylamine (0.08 mL, 0.6 mmol) and cooled to 0 C. To this was added triphosgene (0.03 g, 0.1016 mmol) and stirred 30 minutes. Azetid-3-yl carbamic acid t-butyl ester (0.035 g, 0.2032 mmol) and triethylamine (0.08 mL, 0.6 mmol) was then added and stirred at room temperature for 50 minutes. Diluted with dichloromethane, washed with 1M HCl, brine, dried (Na2SO4,) concentrated volatiles to give crude. Chromatographed (10% to 50% ethylacetate/hexanes) to give product 142 (0.024 g, 0.035 mmol, 69%.) 1H NMR (CDCl3) delta 9.04 (dd, 1H), 8.17 (d, 1H), 8.03 (s, 1H), 7.74 (d, 4H), 7.51 (dd, 1H), 7.27 (m, 8H), 7.08 (dd, 2H), 5. 00 (m, 1H), 4.80 (s, 2H), 4.52 (m, 2H), 4.23 (s, 2H), 3.91 (m, 2H), 1.48 (s, 9H. ) MS: 689 (M+1)

Reference： [1]Patent: WO2004/35576,2004,A2 .Location in patent: Page 236;237

6
[ 727725-72-6 ]
[ 91188-13-5 ]
[ 727725-73-7 ]

Yield	Reaction Conditions	Operation in experiment
49%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h;	A mixture (101 mg, 0.27 mmol), XXA (57 mg), EDC (51 mg, 0.27 mmol) and (37 mg, 0.27 mmol) in DCM (2 ml) was stirred at rt for 3 h. The reaction was quenched with the addition of brine (10 ml). The mixture was then extracted with DCM (30 ml). The extract was dried (MgSO4) and evaporated to give the crude product which was purified by flash chromatography (silica, 0-4% MeOH/DCM) to give XXB (88 mg) as a colorless oil.

Reference： [1]Patent: US2004/147502,2004,A1 .Location in patent: Page/Page column 23; 25

7
[ 91189-18-3 ]
[ 91188-13-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 2h;	A mixture of (113 mg, 0.33 mmol) and 10% Pd/C (88 mg) in ethanol (3 ml) was stirred under hydrogen atmosphere at rt for 2 h. The reaction mixture was filtered and evaporated to give XXA (63 mg) as a white solid.
	With hydrogenchloride; hydrogen;palladium dihydroxide; In 1,4-dioxane; methanol; under 2585.81 Torr;	A solution of 1,1-dimethylethyl[1-(diphenylmethyl)-3-azetidinyl]carbamate in MeOH (10 mL) was treated with of 4.0 N HCI/dioxane (1 mL) and then reacted overnight with hydrogen gas at 50 psi. The reaction mixture was then filtered through a pad of Celite, concentrated and the crude residue was used without further purification.

Reference： [1]Patent: US2004/147502,2004,A1 .Location in patent: Page/Page column 23; 25
[2]Patent: WO2004/112793,2004,A1 .Location in patent: Page/Page column 147

8
[ 56-05-3 ]
[ 91188-13-5 ]
[ 854038-89-4 ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine; In ethanol; for 0.5h;Heating / reflux;	EXAMPLE 2-1 4- (3-aminoazetidin-1-yl)-6-phenylpyrimidin-2-amine dihydrochloride 1) tert-Butyl [1- (2-amino-6-chloropyrimidin-4-yl) azetidin-3-yl] carbamate A mixture of 2-amino-4, 6-dichloropyrimidine (0.243 g), tert-butyl azetidin-3-ylcarbamate (0.255 g), and N, N-diisopropylethylamine (0.387 ml) in EtOH (2.0 ml) was refluxed for 0.5 hour. The mixture was cooled to room temperature, and the resulting solid was collected by filtration, dried at 60C in vacuo to give tert-butyl [1- (2-amino-6-chloro- pyrimidin-4-yl) azetidin-3-yl] carbamate (0.314 g, 71% yield) as a solid. 1H NMR (500 MHz, CDC13) 61. 39 (s, 9H), 3.32 (br s, 1H), 3.76 (br s, 2H), 4.15 (t, J= 8.3 Hz, 2H), 4. 34-4. 45 (m, 1H), 5.65 (s, 1H), 6.53 (s, 2H), 7.56 (d, J= 7.3 Hz, 1H).

Reference： [1]Patent: WO2005/54239,2005,A1 .Location in patent: Page/Page column 38

9
[ 639482-02-3 ]
[ 91188-13-5 ]
[ 816425-17-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	With triethylamine; In dichloromethane; at 20℃; for 18h;	A mixture of Intermediate 35 (483mg, 0. 85MMOL), Et3N (0.5mL) and tert-butyl AZETIDIN-3-YLCARBAMATE (175mg, 1. 02MMOL) in DCM (20mL) was stirred at r. t. for 18 h. The reaction mixture was concentrated under vacuum and triturated with Et2O. The title compound was obtained as a yellow solid (386mg, 82%). 8H (DMSO-d6) 9.32 (1H, s), 7.71-7. 62 (3H, m), 7.57-7. 50 (2H, m), 7.45-7. 38 (1H, m), 7.36 (1H, d, J 9.7 Hz), 7.17-7. 10 (1H, m), 7.09-7. 00 (1H, m), 6.47 (1H, d, J 9.7 Hz), 4.60-4. 30 (3H, m), 3.90-3. 80 (2H, m), 3.35-3. 30 (1H, m), 1.40 (9H, s). LCMS (ES+) RT 3.58 minutes, 553 (M+H) +.

Reference： [1]Patent: WO2004/113347,2004,A1 .Location in patent: Page 89

10
[ 803736-57-4 ]
[ 91188-13-5 ]
C₂₅H₃₃ClN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutylammomium bromide; triethylamine; In acetonitrile; at 120℃; for 1h;Microwave heating;	3-Azetidinyl-carbamic acid, 1, 1-dimethylethyl ester (0.5 g) was added to 2, 6-DICHLORO-N- (cyclohexylmethyl) quinoline-5-carboxamide (Example 43 (a) ) (0.28 g), tetra- butylammonium bromide (0.28 g) and triethylamine (0.5 ML) in acetonitrile (4 mL). The reaction mixture was heated at 120C in a microwave for 1 hour, concentrated under reduced pressure and purified (SI02, methanol : dichloromethane 4: 96 as eluant). The residue (0.24 g) was dissolved in dichloromethane and trifluoroacetic acid (1 mL) added. The reaction mixture was stirred at room temperature for 1 hour, concentrated and then treated with 7M ammonia in methanol. Purification (Varian SCX cartridge using methanol and then 10% ammonia in methanol) gave the sub-titled compound as a solid (0.1 g). 1H NMR (400 MHz, d6-DMSO) 8 8.64-8. 60 (1H, t), 7.73-7. 70 (1H, d), 7. 57-7. 57 (2H, m), 6.82-6. 79 (1H, d), 4. 28-4. 23 (2H, t), 3.89-3. 80 (1H, q), 3. 71-3. 66 (2H, m), 3. 18-3. 14 (2H, t), 1.80-1. 34 (6H, m), 1.28-0. 91 (5H, m).

Reference： [1]Patent: WO2004/106305,2004,A1 .Location in patent: Page 167-168

11
[ 156496-64-9 ]
[ 91188-13-5 ]
[ 865432-66-2 ]

Yield	Reaction Conditions	Operation in experiment
73%		Example 41; 2- (3-chlorophenoxy)-N- [1- ( { 1- [4- (trifluoromethyl) phenyl]-1H-pyrrol-3- yl} methyl) azetidin-3-yl] acetamide ; a) tert-butyl [1- ( 1- [4- (trifluoromethyl) phenyl]-1H-pyrrol-3-yl} methyl) azetidin-3- yl] carbamate; tert-butyl azetidin-3-ylcarbamate (200 mg, 1.16 mmol) and 1- [4- (trifluoromethyl) phenyl] - lH-pyrrole-3-carbaldehyde (1. 2eq) were dissolved/suspended in DCM (lOmL) in a 16 mL vial and stirred for 10 minutes. MP-BH (OAc) 3 (2.5eq) was then added and the vial loosely sealed with a cap and the reaction left for 3h. The reaction was filtered washing with DCM (2mL) and the filtrate evaporated in vacuo to yield a brown oil. Flash chromatography on the Biotage 40g column using isocratic EtOAc: MeOH: TEA (100: 3: 0.2) gave the product as a white solid (334mg, 73%). MS (ESI+): 396.1 (M+H+) ; MS (ESI-): 394.06 (M-H+)

Reference： [1]Patent: WO2005/90330,2005,A1 .Location in patent: Page/Page column 76

12
[ 401566-69-6 ]
[ 91188-13-5 ]
ethyl 6-(3-(tert-butoxycarbonylamino)azetidin-1-yl)-5-chloronicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; for 16h;Heating / reflux;	(a) Ethyl 6-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}-5-chloronicotinate; Ethyl 5,6-dichloronicotinate (1.00 g, 4.5 mmol) and tert-butyl azetidin-3-ylcarbamate (0.765 g, 3.8 mmol) were dissolved in DMA (10 mL) at room temperature. DIPEA (1.66 g, 9.5 mmol) was added and the system heated at reflux for 16 h. The reaction mixture was cooled to room temperature and the solvent concentrated under reduced pressure. The material was partitioned between EtOAc (100 mL) and a 50% mixture of saturated aqueous NaHCO3 and brine (1 x 80 mL). The organics were dried (Mg5O4) and concentrated under reduced pressure to afford the crude product. Flash Chromatography (4:1 hexanes/EtOAc) gave ethyl 6-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}-5-chloronicotinate. Yield: 1.02 g (50 %). 1HNMR (400 MHz, CDCi3): 6 1.38 (3H, t,J= 7.0 Hz), 1.46 (9H, s), 4.12-4.15(2H, m), 4.34 (2H, q, J= 71 Hz), 4.57 (1H, m), 4.65-4.70 (2H, m), 5.00 (1H, m), 7.98 (1H, s), 8.65 (1H, s). M5 m/z: 355 (M+l).
50%	With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 120℃; for 16h;	(a) Ethyl 6-(3-(tert-butoxycarbonylamino)azetidin-1-yl)-5-chloronicotinate Ethyl 5,6-dichloronicotinate (0.630 g, 2.86 mmol), tert-butyl azetidin-3-ylcarbamate (0.591 g, 3.43 mmol), and DIEA (1.66 g, 9.5 mmol), were dissolved in DMA (10 mL), and the system heated at 120 C. for 16 h. The reaction mixture was cooled to room temperature and the solvent concentrated under reduced pressure. EtOAc (100 mL) was added and the combined organics were washed with a 50% mixture of saturated aqueous NH4Cl in brine (80 mL), dried (MgSO4) and concentrated under reduced pressure. Flash chromatography (20% EtOAc in Hexanes), gave ethyl 6-(3-(tert-butoxycarbonylamino)azetidin-1-yl)-5-chloronicotinate. Yield: 0.510 g (50%). 1H NMR (400 MHz, CDCl3): delta 1.37 (3H, t, J=7.1 Hz), 1.46 (9H, s), 4.10-4.17 (2H, m), 4.34 (2H, q, J=7.1 Hz), 4.51-4.73 (3H, m), 4.96-5.05 (1H, m), 7.98 (1H, s), 8.65 (1H, s). MS m/z: 384 (M+1).
50%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; for 16h;Reflux;	5 (1.00 g, 4.50 mmol) and tert-butyl azetidin-3-ylcarbamate (0.765 g, 4.44 mmol) were dissolved in DMA (10 mL). DIPEA (1.66 g, 9.50 mmol)was added and the reaction mixturewas heated at reflux for 16 h. The reaction mixture was cooled to rt and concentrated. The crude was dissolved in EtOAc (100 mL) andextracted with saturated aq NaHCO3/brine 1:1 (80 mL). The organic phase were dried (MgSO4) and concentrated. The crude was purifiedby flash chromatography (4:1 hexanes/EtOAc). Yield: 1.02 g(50%).

Reference： [1]Patent: WO2006/73361,2006,A1 .Location in patent: Page/Page column 111
[2]Patent: US2007/244088,2007,A1 .Location in patent: Page/Page column 38
[3]European Journal of Medicinal Chemistry,2013,vol. 65,p. 360 - 375

13
[ 69045-84-7 ]
[ 91188-13-5 ]
[ 898271-35-7 ]

Yield	Reaction Conditions	Operation in experiment
34.8%	With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 0.25h;Microwave irradiation;	fer?-ButyI {l-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]azetidin-3-yl}carbamate; 2,3-Dichloro-5-(trifluoromethyl)pyridine (1.5Og, 6.94mmol), tert-butyl azetidin-3- ylcarbamate (1.67g, 9.72mmol) and K2CO3 (2.88g, 20.83mmol) were dissolved in dry DMF (13mL) under nitrogen atmosphere. The reaction mixture was heated in a microwave reactior 5 at 1500C for 15mins. The reaction mixture was filtered and diluted with EtOAc, washed with water, dried over MgSO4, filtrered and evaporated. The crude product was purified by column chromatography (ISOLUTE SI (2Og), eluated with DCM, DCM/MeOH (99:1)) affording the title compound (0.85g, 34.8%). 1H NMR (500MHz, CDCl3): delta 1.48 (s, 9H), 4.10-4.14 (m, 2H), 4.57 (bs, IH), 4.65 (t, 2H), 5.00 (bs, IH), 7.61 (s, IH), 8.28 (s, IH); 13C NMR (125MHz, 10 CDCl3): delta 28.56, 41.67, 60.34, 80.45, 115.51, 117.44 (q, Jc-F=33.2Hz), 123.83 (m, Jc- F=271.4Hz), 135.06, 143.75, 155.18, 157.35; Mass Spectrum: M-H+ 350.

Reference： [1]Patent: WO2006/73366,2006,A1 .Location in patent: Page/Page column 196

14
[ 64119-42-2 ]
[ 91188-13-5 ]
[ 898227-69-5 ]

Yield	Reaction Conditions	Operation in experiment
66%	With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃; for 1h;	(a) Ethyl 6-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}-5-cyano-2-methylnicotinate; Ethyl 6-chloro-5-cyano-2-methylnicotinate (6.20 g, 29.4 mmol), tert -butyl azetidin-3- ylcarbamate (5.07 g, 29.4 mmol), and DIPEA (5.13 mL, 29.4 mmol) were dissolved in DCE (40 mL) and stirred at r.t for 1 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (40 mL). The combined organics were washed with saturated NaHCO3 (2 x 30 mL), dried (Mg5O4) and concentrated under reduced pressure to afford the crude product. Flash chromatography (1:6 EtOAc/hexanes) gave ethyl 6-{3-[(tert- butoxycarbonyl)amino]azetidin-1-yl}-5-cyano-2-methyhiicotinate as a solid. Yield: 7.00 g (66.0 %) 1H NMR (400 MHz, CDCi): 6 1.37 (3H, t, J= 7.2 Hz), 1.46 (9H, s), 2.70 (1H, s), 4.18-4.22 (2H, m), 4.30 (2H, q, J= 7.2 Hz), 4.59 (1H, s), 4.67-4.72 (2H, m), 5.00 (1H, s), 8.26 (1H, s). M5 "V2: 361 (M+l).
66.0%	With N-ethyl-N,N-diisopropylamine; In DCE; at 20℃; for 1h;	Ethyl 6-chloro-5-cyano-2-methylnicotinate (6.20 g, 29.4 mmol), tert-butyl azetidin-3- ylcarbamate (5.07 g, 29.4 mmol), and DIPEA (5.13 mL, 29.4 mmol) were dissolved in DCE (40 mL) and stirred at r.t for 1 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (40 mL). The combined organics were washed with saturated NaHCtheta3 (2 x 30 mL), dried (MgSO4) and concentrated under reduced pressure to afford the crude product. Flash chromatography (1:6 EtOAc/hexanes) gave ethyl 6-{3-[(tert- butoxycarbonyl)amino]azetidin-l-yl}-5-cyano-2-methylnicotinate as a solid. Yield: 7.00 g (66.0 %)1H NMR (400 MHz, CDCi): delta 1.37 (3H, t, J= 7.2 Hz), 1.46 (9H, s), 2.70 (IH, s), 4.18-4.22 (2H, m), 4.30 (2H, q, J= 7.2 Hz), 4.59 (IH, s), 4.67-4.72 (2H, m), 5.00 (IH, s), 8.26 (IH, s). MS m/z: 361 (M+l).
66%	With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃; for 1h;	(a) Ethyl 6-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}-5-cyano-2-methylnicotinate Ethyl 6-chloro-5-cyano-2-methylnicotinate (6.20 g, 29.4 mmol), tert-butyl azetidin-3-ylcarbamate (5.07 g, 29.4 mmol), and DIPEA (5.13 mL, 29.4 mmol) were dissolved in DCE (40 mL) and stirred at r.t for 1 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (40 mL). The combined organics were washed with saturated NaHCO3 (2×30 mL), dried (MgSO4) and concentrated under reduced pressure to afford the crude product. Flash chromatography (1:6 EtOAc/hexanes) gave ethyl 6-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}-5-cyano-2-methylnicotinate as a solid. Yield: 7.00 g (66%) 1H NMR (400 MHz, CDCl3): delta 1.37 (3H, t, J=7.2 Hz), 1.46 (9H, s), 2.70 (1H, s), 4.18-4.22 (2H, m), 4.30 (2H, q, J=7.2 Hz), 4.59 (1H, s), 4.67-4.72 (2H, m), 5.00 (1H, s), 8.26 (1H, s). MS m/z: 361 (M+1).

66%

With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃; for 1h;

7 (6.20 g, 29.4 mmol), tert-butyl azetidin-3-ylcarbamate (5.07 g,29.4 mmol), and DIPEA (5.13 mL, 29.4 mmol) were dissolved in DCE (40 mL) and the reaction mixture was stirred at rt for 1 h. The mixture was concentrated and then diluted with EtOAc (40 mL). The organic phase was washed with NaHCO3 (2 30 mL, saturated,aq solution), dried (MgSO4) and concentrated. The crude was purifiedby flash chromatography (EtOAc/hexanes 1:6). Yield: 7.00 g (66%) as a solid.

Reference： [1]Patent: WO2006/73361,2006,A1 .Location in patent: Page/Page column 135
[2]Patent: WO2007/8140,2007,A1 .Location in patent: Page/Page column 104
[3]Patent: US2007/244088,2007,A1 .Location in patent: Page/Page column 39
[4]European Journal of Medicinal Chemistry,2013,vol. 65,p. 360 - 375
[5]Theranostics,2018,vol. 8,p. 5400 - 5418

15
[ 898229-16-8 ]
[ 91188-13-5 ]
[ 898229-17-9 ]

Yield	Reaction Conditions	Operation in experiment
53%	With triethylamine; In ethanol; at 120℃; for 0.166667h;Microwave irradiation;	(h)tert-butyl l 1-P-cyano-S-tS-ethy 1-ljS-oxazo 1-Z-yl)-delta-methylpyridin-Z-yllazetidin-S- yl}carbamate; 2-Chloro-5-(5-ethyl-oxazol-2-yl)-6-methyl-nicotmonitrile (245 mg, 0.79 mmol), azetidin-3- yl-carbamic acid tert -butyl ester (160 mg, 0.93 mmol), and triethylamine (0.27 ml, 1.97 mmol) were mixed in 99.5% ethanol (4 ml) and heated at 120C for 10 min using a Emrys Optimizer microwave oven from Personal Chemistry. The solvent was evaporated and the crude mixture was dissolved in DCM (3 ml) and filtered through a 5 g / 25 ml silica gel column and concentrated to give the title compound as a yellow solid. Yield: 0.17O g (53%). 1H MvTR (400 MHz, CDCl5) 6 1.27 (3H, t, J = 7.5 Hz), 1.44 (9H, s), 2.71 (2H, q, J = 7.5 Hz), 2.75 (3H, s), 4.15 (2H, dd, J = 9.8, 4.9 Hz), 4.58 (1H, broad s), 4.66 (2H, m), 4.98 (1H, broad s), 6.80 (1H, s), 8.18 (1H, s) M5 m/z: 384 (M+l)

Reference： [1]Patent: WO2006/73361,2006,A1 .Location in patent: Page/Page column 206

16
1-[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H-imidazol-3-ium triflate [ No CAS ]
[ 91188-13-5 ]
3-Boc-amino-N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylazetidine-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃;	To a solution of 1-[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H-imidazol-3-ium (2.2 g, 4.9 mmol, see Example 10, Steps B-I for its preparation) and diisopropylethylamine (2.6 mL, 14.7 mmol) at rt in MeCN (30 mL), was added 3-N-Boc-ammo-azetidine (1.0 g, 5.9 mmol). The solution was stirred at rt overnight. After evaporation of the solvent, the residue was purified by flash chromatography (0-100% EtOAc in hexanes, 50 min; 100% EtOAc 10 min; 0-2% MeOH in EtOAc, 10 min) to provide the title compound (0.95 g, 36%). 1H NMR (400 MHz, CD3OD) delta 1.40 (s, 9 H) 1.49 - 1.65 (m, 5 H) 1.68 (s, 9 H) 2.30 - 2.45 (m, 1 H) 3.32 (s, 3 H) 3.33 - 3.39 (m, 2 H) 3.75 - 3.81 (m, 2 H) 3.89 - 4.00 (m, 4 H) 4.53 (d, J=7.62 Hz, 2 H) 7.65 (dd, J=8.98, 2.15 Hz, 1 H) 7.78 (d, J=2.15 Hz, 1 H) 7.95 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 535.8; Anal. (C, H, N) calcd for C26H41N5O5S+2.10CF3COOH+0.60H2O+0.45CH3CN: C 46.44, H 5.72, N 9.49; found C 46.42, H 5.73, N 9.51.

Reference： [1]Patent: WO2006/33633,2006,A1 .Location in patent: Page/Page column 63

17
[ 148550-51-0 ]
[ 91188-13-5 ]
[ 914938-19-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate; In acetonitrile; at 20℃; for 4h;	Intermediate A (267mg, 1.16mmol) was added to tert-butyl azetidin-3-yl-carbamic acid (200mg, 1.16mmol) and K2CO3 (481 mg, 3.48mmol) in MeCN (10ml) at r.t. under N2. The resultant white suspension was stirred at r.t. for 4 h. The reaction mixture was diluted with water (50ml) and extracted into EtOAc (3 x 50ml). The combined EPO <DP n="83"/>organic phases were washed with water (2 x 50ml), brine (50ml), dried (MgSO4) and concentrated in vacuo to give the title compound as a white solid (323mg, 86percent). LCMS purity 100percent, m/z 323 [M+H]\\ 1H NMR (400 MHz, CDCI3) delta: 1.37 (3H, t), 1.46 (9H, s), 4.04 (2H, m), 4.34 (2H, q), 4.53 (2H, t), 4.64 (1 H, br s), 5.02 (1 H, br s), 8.84 (2 H, s).

Reference： [1]Patent: WO2006/123121,2006,A1 .Location in patent: Page/Page column 21; 80-81

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE U 1,1-Dimethylethyl(3-azetidinyl)carbamate A solution of 14.2 g (42.0 mmole) of 1,1-dimethylethyl-[1-(diphenylmethyl)-3-azetidinyl]carbamate in 100 ml of tetrahydrofuran was shaken with 2 g of 20% palladium on carbon in a hydrogen atmosphere at 4.5*105 Pa for 24 hours. The reaction was filtered through Celite and the solvent was removed in vacuo. The residue was triturated several times with hexane to give, as the insoluble residue, 6.5 g of 1,1-dimethylethyl-(3-azetidinyl)carbamate, mp 138-140 C.

19
[ 79286-73-0 ]
[ 91188-13-5 ]
[ 91188-14-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In water; acetonitrile; trifluoroacetic acid;	EXAMPLE 16 7-(3-Amino- 1-azetidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid A suspension of 0.81 g (3.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1.0 g (6.0 mmole) of 1,1-dimethylethyl-(3-azetidinyl)carbamate, 1.0 g (10 mmole) triethylamine and 50 ml of acetonitrile was heated at reflux 35 for four hours. The solvent was removed in vacuo and the residue was dissolved in 10 ml of trifluoroacetic acid. The solution was stirred at room temperature for one hour, the solvent was removed in vacuo and the residue dissolved in water. The turbid solution was clarified by filtration and the filtrate adjusted to pH 7.3 with 1.0 N sodium hydroxide. The resulting precipitate was removed by filtration, washed successively with water, ethanol and ether. Drying in vacuo gave 0.2 g of 7-(3-amino-1-azetidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, mp 260-262 C.
	With triethylamine; In water; acetonitrile; trifluoroacetic acid;	EXAMPLE 16 7-(3-Amino-1-azetidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid A suspension of 0.81 g (3.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1.0 g (6.0 mmole) of 1,1-dimethylethyl-(3-azetidinyl)carbamate, 1.0 g (10 mmole) triethylamine and 50 ml of acetonitrile was heated at reflux 35 for four hours. The solvent was removed in vacuo and the residue was dissolved in 10 ml of trifluoroacetic acid. The solution was stirred at room temperature for one hour, the solvent was removed in vacuo and the residue dissolved in water. The turbid solution was clarified by filtration and the filtrate adjusted to pH 7.3 with 1.0N sodium hydroxide. The resulting precipitate was removed by filtration, washed successively with water, ethanol and ether. Drying in vacuo gave 0.2 g of 7-(3-amino-1-azetidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, mp 260-262 C.

Reference： [1]Patent: US4638067,1987,A
[2]Patent: US4771054,1988,A

20
[ 224190-91-4 ]
[ 91188-13-5 ]
[1-(3-Benzyloxy-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl)-azetidin-3-yl]-carbamic Acid tert-butyl Ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 2,4-dichlorophenoxyacetic acid dimethylamine; ethyl acetate;	EXAMPLE I-3 [1-(3-Benzyloxy-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl)-azetidin-3-yl]-carbamic Acid tert-butyl Ester A solution of 3-benzyloxy-7-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4dione (Example E-3, 0.20 g, 0.55 mmol) in DMA (3.0 mL) was reacted with <strong>[91188-13-5]azetidin-3-yl-carbamic acid tert-butyl ester</strong> (0.286 g, 1.66 mmol), triethylamine (0.76 mL, 5.5 mmol) and heated to 80 C. for 2 days. The mixture was then cooled, diluted with H2O, and extracted with ethyl acetate. The organic layers were combined, dried with sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, 3:1 hexanes/ethyl acetate to 1:1 hexanes/ethyl acetate) to provide 0.13 g of the title compound as a solid.

Reference： [1]Patent: US6331538,2001,B1

21
[ 91188-13-5 ]
[ 1548-13-6 ]
[ 920320-52-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	In dichloromethane; at 20℃; for 20h;	To a solution of azetidine-3-ylcarbamic acid tert-butyl ester (2.91g, 16.9mmol) in dichloroniethane (175 mL) was added 4-trifluoromethylphenylisocyanate (3.16g, 16.9mmol) and the reaction mixture was stirred for 2Oh at room temperature. The reaction mixture was evaporated in vacuo to form the title compound as a white solid. Yield 6g (99%). HPLC retention time, 3.72min (Solvent: CH3CN/H2O/0.05% NH3, 5-95% gradient H2O-6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 360 (M + H).

Reference： [1]Patent: WO2007/7057,2007,A1 .Location in patent: Page/Page column 33

22
[ 6328-74-1 ]
[ 91188-13-5 ]
[ 920320-58-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h;	To a suspension of EDC (2.1g, 10.96mmol) in dichloromethane (100ml) was added N,N-diisopropylethylamine (1.42g, 10.96mmol) followed by 4-phenoxyphenylacetic acid (2.5g, 10.96mmol) and azetidin-3-yl-carbamic acid tert butyl ester (1.8g,10.96rnmol) and the resulting solution was stirred at r.t. for ldeltahours. The reaction mixture was quenched with water (50ml) and the organics collected, dried and evaporated in vacuo. The residue was purified by flash chromatography eluting with EtOAc/hexanes (1:1) to afford the title compound as a white solid. Yield 3.2g (76%): HPLC retention time, 3.8min (Solvent: CH3CN/H2O/0.05% NH3, 5-95% gradient H2O-6min. Column: Xterra 50 x 4.60 i.d., C18 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 383 (M + H).

Reference： [1]Patent: WO2007/7057,2007,A1 .Location in patent: Page/Page column 39

23
[ 902148-42-9 ]
[ 91188-13-5 ]
[1-[[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]carbonyl]-3-azetidinyl]-carbamic acid 1,1-dimethylethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 5h;	Carbamic acid, [1-[[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]carbonyl]-3-azetidinyl]-, 1,1-dimethylethyl ester; To a stirred solution of 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxamide-6-carboxylic acid (300 mg, 0.56 mmol), tert-butyl azetidin-3-ylcarbamate (192 mg, 1.2 mmol) and triethylamine (0.33 mL) in DMF (3 mL) was added HATU (320 mg, 0.84 mmol). The reaction mixture was stirred at rt for 3 h, additional tert-butyl azetidin-3-ylcarbamate (100 mg, 0.58 mmol) and HATU (120 mg, 0.32 mmol) were added and the reaction mixture was stirred at rt for 2 h and then diluted with H2O and stirred. The resulting precipitate was collected by filtration, flushed with H2O, dissolved into MeOH and purified by preparative HPLC (CH3CN/H2O with 10 mM NH4OAc) to yield carbamic acid, [1-[[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]carbonyl]-3-azetidinyl]-, 1,1-dimethylethyl ester (282 mg, 0.041 mmol, 73%) as a yellow solid. 1HNMR (300 MHz, CDCl3) delta 8.23 (br s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.04 (dd, J=2.6, 8.8 Hz, 1H), 6.97 (br s, 1H), 6.86 (d, J=2.6 Hz, 1H), 5.66-5.42 (m, 1H), 4.56-3.83 (m, 6H), 3.89 (s, 3H), 3.01 (s, 6H), 2.87-2.72 (m, 1H), 2.12-1.08 (mm, 11H), 1.40 (s, 9H). LCMS: m/e 690 (M-H)-, ret time 3.26 min, column A, 4 minute gradient.

Reference： [1]Patent: US2007/78122,2007,A1 .Location in patent: Page/Page column 275

24
[ 91188-13-5 ]
1,1-dimethylethyl [1-({2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		2,4-Difluoro-6-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 muL, 0.5 mmol) and commercially available 1,1-dimethylethyl azetidin-3-ylcarbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:1 as eluent afforded 1,1-dimethylethyl [l-({2,4-difluoro-6-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (125 mg) as a colorless oil. [00295] The oil was taken into trifluoroacetic acid (1 mL) and allowed to stand at room temperature for 5 minutes then concentrated in vacuo. The residue was portioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic phase washed with brine then dried over anhydrous sodium sulfate. The organic solution was filtered and concentrated.

Reference： [1]Patent: WO2007/44515,2007,A1 .Location in patent: Page/Page column 211-212

25
[ 91188-13-5 ]
1,1-dimethylethyl [1-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 muL, 0.5 mmol) and commercially available 1,1 -dimethyl ethyl azetidin-3-ylcarbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:1 as eluent afforded 1,1-dimethylethyl [l-({4,5-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl] carbamate (131 mg) as a colorless oil. The oil was taken into trifluoro acetic acid (1 mL) and allowed to stand at room temperature for 5 minutes then concentrated in vacuo. The residue was portioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic phase washed with brine then dried over anhydrous sodium sulfate. The organic solution was filtered and concentrated.

Reference： [1]Patent: WO2007/44515,2007,A1 .Location in patent: Page/Page column 212-213

26
[ 391211-97-5 ]
[ 91188-13-5 ]
1,1-dimethylethyl [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 15h;	A solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (200 mg, 0.51 mmol), prepared using procedures similar to those in US 7,019,033, PyBOP (256 mg, 0.51 mmol), commercially available tert-butyl azetidin-3-ylcarbamate (131 mg, 0.77 mmol) and N, N-diisopropylethylamme (180 muL, 1.02 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 15 hours. The reaction mixture was partitioned between 5% aqueous lithium chloride and ethyl acetate. The organic portion was washed with 20% aqueous citric acid, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by silica gel column chromatography eluting with 30% ethyl acetate in hexanes to afford 1,1- EPO <DP n="172"/>dimethylethyl [l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin- 3-yI]carbamate (225 nig, 80% yield) as a colorless oil. 1H NMR (400 MHz, DMSO)'. 8.56 (s, IH), 7.60-7.55 (m, 2H), 7.38 (d, IH), 7.30-7.26 (m, IH), 7.20-7.13 (m, IH), 6.71-6.66 (m, IH), 4.37-4.20 (m, 2H), 4.18-4.06 (m, IH)5 3.98-3.93 (m, IH), 3.82-3.75 (m, IH), 1.37 (s, 9H). MS (EI) C2]H2IN3O3F3I: 548 (MH+).
80%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 15h;	A solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (200 mg, 0.51 mmol), prepared using procedures similar to those in US 7,019,033, PyBOP (256 mg, 0.51 mmol), commercially available tert-buty azetidin-3- ylcarbamate (131 mg, 0.77 mmol) and N,N-diisopropylethylamine (180 muL, 1.02 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 15 hours. The reaction mixture was partitioned between 5% aqueous lithium chloride and ethyl <n="336"/>acetate. The organic portion was washed with 20% aqueous citric acid, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by silica gel column chromatography eluting with 30% ethyl acetate in hexanes to afford 1,1- dimethylethyl [ 1 -( { 3 ,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (225 mg, 80% yield) as a colorless oil. 1H NMR (400 MHz, DMSO): 8.56 (s, IH), 7.60-7.55 (m, 2H), 7.38 (d, IH), 7.30-7.26 (m, IH), 7.20-7.13 (m, IH), 6.71-6.66 (m, IH), 4.37-4.20 (m, 2H), 4.18-4.06 (m, IH), 3.98-3.93 (m, IH), 3.82-3.75 (m, IH), 1.37 (s, 9H). MS (EI) C21H2JN3O3F3I: 548 (MH+).
80%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 15h;	A solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (200 mg, 0.51 mmol), prepared using procedures similar to those in US 7,019,033, PyBOP (256 mg, 0.51 mmol), commercially available tert-butyl azetidin-3-ylcarbamate (131 mg, 0.77 mmol) and lambdazetaiV-diisopropylethylamine (180 muL, 1.02 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 15 hours. The reaction mixture was partitioned between 5% aqueous lithium chloride and ethyl acetate. The organic portion was washed with 20% aqueous citric acid, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by silica gel column chromatography eluting with 30% ethyl acetate in hexanes to afford 1,1- dimethylethyl [ 1 -( { 3 ,4-difluoro-2- [(2-fluoro-4-iodophenyl)amino]phenyl } carbonyl)azetidin- 3-yl]carbamate (225 mg, 80% yield) as a colorless oil. 1H NMR (400 MHz, DMSO): 8.56 (s, IH), 7.60-7.55 (m, 2H), 7.38 (d, IH), 7.30-7.26 (m, IH), 7.20-7.13 (m, IH), 6.71-6.66 (m, IH), 4.37-4.20 (m, 2H), 4.18-4.06 (m, IH), 3.98-3.93 (m, IH), 3.82-3.75 (m, IH), 1.37 (s, 9H). MS (EI) C2IH21N3O3F3I: 548 (MH+).

Reference： [1]Patent: WO2007/44515,2007,A1 .Location in patent: Page/Page column 170-171
[2]Patent: WO2008/76415,2008,A1 .Location in patent: Page/Page column 334-335
[3]Patent: WO2008/124085,2008,A2 .Location in patent: Page/Page column 185

27
[ 350-46-9 ]
[ 91188-13-5 ]
[ 748183-68-8 ]

Yield	Reaction Conditions	Operation in experiment
		tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate tert-Butyl azetidin-3-ylcarbamate was reacted with 4-fluoronitrobenzene by method C. This resulted in the product with the molecular weight of 293.33 (C14H19N3O4); MS (ESI): 294 (M+H+).

Reference： [1]Patent: US2004/220191,2004,A1
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 2521 - 2527

28
[ 64119-42-2 ]
[ 91188-13-5 ]
ethyl 6-(3-((tert-butoxycarbonylamino)methyl)azetidin-1-yl)-5-cyano-2-methylnicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;	(d) Ethyl 6-(3-((tert-butoxycarbonylamino)methyl)azetidin-1-yl)-5-cyano-2-methylnicotinate Ethyl 6-chloro-5-cyano-2-methylnicotinate (1.00 g, 4.5 mmol), tert-butyl azetidin-3-ylmethylcarbamate (0.99 g, 5.30 mmol), and DIPEA (3.90 mL, 22.0 mmol) were dissolved in DCM (20 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (40 mL). The combined organics were washed with saturated NH4Cl (2×30 mL), H2O (1×20 mL), brine (1×30 mL), dried (MgSO4) and concentrated under reduced pressure to afford the crude product. Flash chromatography (25 to 35% EtOAc in hexanes) gave ethyl 6-(3-((tert-butoxycarbonylamino)methyl)azetidin-1-yl)-5-cyano-2-methylnicotinate as a solid. Yield: 1.49 g (90%). 1H NMR (400 MHz, CDCl3): delta 1.37 (3H, t, J=7.2 Hz), 1.45 (9H, s), 2.70 (3H, s), 2.88-2.99 (1H, m), 3.35-3.46 (2H, m), 4.02-4.14 (2H, m), 4.30 (2H, q, J=7.2 Hz), 4.39-4.50 (2H, m), 4.64-4.76 (1H, m), 8.26 (1H, s). MS m/z: 375 (M+1).

Reference： [1]Patent: US2007/244088,2007,A1 .Location in patent: Page/Page column 39

29
[ 934665-14-2 ]
[ 91188-13-5 ]
1,1-dimethylethyl [1-({2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 12.25h;	2,4-Difluoro-6-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 muL, 0.5 mmol) and commercially available 1,1-dimethylethyl azetidin-3-yl carbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of <n="382"/>the residue using hexanes:ethyl acetate 3:1 as eluent afforded 1,1-dimethylethyl [1- ({2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3- yljcarbamate (125 mg) as a colorless oil.
	With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 12.25h;	2,4-Difluoro-6-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 muL, 0.5 mmol) and commercially available 1,1 -dimethyl ethyl azetidin-3-ylcarbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:1 as eluent afforded 1,1-dimethylethyl [l-({2,4-difluoro-6-[(2-fluoro-4- iodophenyl)amino]phenyl} carbonyl)azetidin-3-yl]carbamate (125 mg) as a colorless oil. The oil was taken into trifluoroacetic acid (1 mL) and allowed to stand at room temperature for 5 minutes then concentrated in vacuo. The residue was portioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic phase washed with brine then dried over anhydrous sodium sulfate. The organic solution was filtered and concentrated then the <n="230"/>residue taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane until the solution was acidic. The solution was concentrated and the residue triturated with ethyl ether to give a thick precipitate. The solid was collected by filtration and dried in vacuo to give 1- ( { 2,4-difluoro-6- [(2-fluoro-4-iodophenyl)amino]phenyl } carbonyl)azetidin-3 -amine hydrochloride (58 mg, 48% overall yield). 1H-NMR (400 MHz, D6-DMSO): 8.67 (br s, 3H), 8.45 (s, IH), 7.71 (d, IH), 7.54 (d, IH), 7.25 (tr, IH), 6.77 (tr, IH), 6.48 (d, IH), 4.28-4.23 (m, 2H), 4.13-4.06 (m, 3H). MS (EI) for C16H13F3IN3O: 448 (MH+).

Reference： [1]Patent: WO2008/76415,2008,A1 .Location in patent: Page/Page column 380-381
[2]Patent: WO2008/124085,2008,A2 .Location in patent: Page/Page column 228-229

30
[ 391212-00-3 ]
[ 91188-13-5 ]
1,1-dimethylethyl [1-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 12.25h;	4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 muL, 0.5 mmol) and commercially available 1 ,1-dimethylethyl azetidin-3-ylcarbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:1 as eluent afforded 1,1-dimethylethyl [1- ({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3- yl]carbamate (131 mg) as a colorless oil. The oil was taken into trifluoroacetic acid (1 mL) and allowed to stand at room temperature for 5 minutes then concentrated in vacuo. The residue was portioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic phase washed with brine then dried over anhydrous sodium sulfate. The organic solution was filtered and concentrated then the residue taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane until the solution was acidic. The solution was concentrated and the residue triturated with ethyl ether to give a thick precipitate. The solid was collected by filtration and dried in vacuo to give l-({4,5-difluoro-2-[(2-fiuoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine hydrochloride (67 mg, 55% overall yield). 1H-NMR (400 MHz, D6-DMSO): 9.02 (s, IH), 8.54 (br s, 3H), 7.68 (dd, IH), 7.53-7 '.47 (m, 2H), 7.22 (tr, IH), 7.16 (dd, IH), 4.60 (br s, IH), 4.23 (br s, 2H), 4.03 (br m, 2H). MS (EI) for Ci6Hi3F3IN3O: 448 (MH+).
	With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 12h;	4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 muL, 0.5 mmol) and commercially available 1 , 1 -dimethylethyl azetidin-3-ylcarbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:1 as eluent afforded 1,1 -dimethylethyl [l-({4,5-difluoro-2-[(2-fluoro-4- <n="231"/>iodophenyl)amino]phenyl} carbonyl)azetidin-3-yl]carbamate (131 mg) as a colorless oil. The oil was taken into trifluoroacetic acid (1 mL) and allowed to stand at room temperature for 5 minutes then concentrated in vacuo. The residue was portioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic phase washed with brine then dried over anhydrous sodium sulfate. The organic solution was filtered and concentrated then the residue taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane until the solution was acidic. The solution was concentrated and the residue triturated with ethyl ether to give a thick precipitate. The solid was collected by filtration and dried in vacuo to give 1- ({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine hydrochloride (67 mg, 55% overall yield). 1H-NMR (400 MHz, D6-DMSO): 9.02 (s, IH), 8.54 (br s, 3H), 7.68 (dd, IH), 7.53-7 '.47 (m, 2H), 7.22 (tr, IH), 7.16 (dd, IH), 4.60 (br s, IH), 4.23 (br s, 2H), 4.03 (br m, 2H). MS (EI) for Ci6Hi3F3IN3O: 448 (MH+).

Reference： [1]Patent: WO2008/76415,2008,A1 .Location in patent: Page/Page column 382
[2]Patent: WO2008/124085,2008,A2 .Location in patent: Page/Page column 229-230

31
[ 98-09-9 ]
[ 91188-13-5 ]
[ 1039630-95-9 ]

Yield	Reaction Conditions	Operation in experiment
~ 26 - ~ 58%	With triethylamine; In dichloromethane; at 20℃; for 4h;	E. Preparation of tert-butyl l-(phenylsulfonyl)azetidin-3-ylcarbamate <n="37"/>BocHN [00132] To a stirred suspension of tert-butyl azetidin-3-ylcarbamate (4.61 g, contaminated with diphenylmethane 1 : 1, -13.39 mmoles) in dichloromethane (150 mL), was added triethylamine (3.73 mL, 26.77 mmoles) and benzenesulfonyl chloride (2.57 mL, 20.08 mmoles). The reaction was stirred at room temperature for -4 hours and became a solution. Sat. ammonium chloride was added to the mixture and the aqueous phase was extracted with dichloromethane (3x). The combined organic layers were dried over anhydrous magnesium sulphate, filtered and concentrated. The residue was precipitated from dichloromethane/hexanes 1: 1 to give the title material (1.073g, -26%) as a solid. The mother liquor was concentrated and the residue was purified on Biotage (0 to 20% acetonitrile in dichloromethane) to afford the title material (2.46g, -58%). 1H NMR 400 MHz CDCl3 delta (ppm): 1.42 (9H, s), 3.60 (2H, br s), 4.06 (2H, dd, J=8.7 and 7.7 Hz), 4.35 (IH, br s), 4.70 (IH, br s), 7.60-7.64 (2H, m), 7.68-7.72 (IH, m), 7.86-7.88 (2H, m).

Reference： [1]Patent: WO2008/86128,2008,A2 .Location in patent: Page/Page column 35-36

32
C₁₅H₁₁Cl₃O₅S [ No CAS ]
[ 91188-13-5 ]
C₂₃H₂₆Cl₂N₂O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃; for 72h;	Oxalyl chloride (1.0 ml) was added to a stirred solution of {4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenoxy}acetic acid (WO2005018529) (4.0 g) in DCM. DMF (cat.) was added. The reaction was stirred for 6 h then evaporated under reduced pressure. The solid was dissolved in DCM (40 ml) and to 10 ml of this solution was added triethylamine (1.5 ml), tert-butyl azetidin-3-ylcarbamate (0.53 g) and a further 10 ml of DCM. The mixture was stirred at RT for 72 h, partitioned between DCM and water, the organics separated, washed (aqueous NaHCO3 solution then water), dried (MgSO4) and evaporated under reduced pressure. The residue was crystallized from ethyl acetate and the resulting solid stirred in a solution of trifluoroacetic acid/water (1:1, 20 ml), evaporated under reduced pressure then purified by RPHPLC to give the title compound (0.07 g). 1H NMR DMSO-d6: delta 8.10 (1H, d), 7.78 (1H, dd), 7.39-7.34 (2H, m), 7.15 (1H, d), 6.98 (1H, d), 4.64 (2H, s), 4.18-4.15 (1H, m), 4.01-3.97 (1H, m), 3.67-3.60 (2H, m), 3.47-3.44 (1H, m), 3.26 (3H, s), 2.00 (2H, s). MS: ESI (+ve) 445/7 (M+H).

Reference： [1]Patent: US2008/293775,2008,A1 .Location in patent: Page/Page column 24

33
pentafluorophenyl 2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-sulfonate [ No CAS ]
[ 91188-13-5 ]
[ 1105070-99-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In dichloromethane; at 20℃; for 18h;	EXAMPLE 15tert-Butyl-[l-("{2-["f2-fluoro-4-iodophenyl)amino]thieno[2,3-?1pyridin-3-yl}sulfonyl)- azetidin-3-yl]carbamateIntermediate 7 (150 mg, 0.25 mmol) was dissolved in dichloromethane (6 mL), and triethylamine (75 ul, 0.50 mmol) and azetidin-3-ylcarbamic acid tert-bv?yl ester (86 mg, 0.50 mmol) were added. The reaction mixture was stirred at ambient temperature under nitrogen for 18 hours. Dichloromethane (20 mL) was added and the solution washed with water (10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was triturated with diethyl ether (10 mL), then washed with a further portion of diethyl ether (5 mL) to give the title compound as a white solid (140 mg, 95%). ?H (DMSO-d6) 9.04 (IH, br s), 8.36 (IH, dd, J 1.5, 4.7 Hz), 8.09 (IH, dd, J 1.5, 8.2 Hz), 7.85 (IH, dd, J 1.9, 9.8 Hz), 7.70 (IH, dd, J 1.0, 8.4 Hz), 7.52-7.41 (3H, m), 4.22-4.19 (IH, m), 3.96 (2H, t, J 7.5 Hz), 3.63 (2H, t, J 7.5 Hz), 1.31 (9H, s). LCMS (ES+) RT 3.48 minutes, pH3 method, 605 (M+H)+.

Reference： [1]Patent: WO2009/13462,2009,A1 .Location in patent: Page/Page column 44

34
[ 933477-60-2 ]
[ 91188-13-5 ]
[ 1043905-11-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3556 - 3561

35
[ 1141890-87-0 ]
[ 91188-13-5 ]
[ 1141891-12-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 1h;Microwave irradiation;Product distribution / selectivity;	Example 19 Synthesis of 7,7-dimethyl-4-[3-(methylamino)azetidin-1 -yl]-5,6,7,8- tetrahvdroquinazolin-2-amine (Compound 60) tert-Butyl azetidin-3-ylcarbamate (300mg) and Intermediate 17 (300mg) are dissolved in NMP (3ml) and triethylamine (0.5ml) is added. The mixture is heated at 1400C in a microwave reactor for 1 hour, then added to water and extracted with EtOAc (2 x 10ml). The solvent is washed with water, dried and evaporated and the crude product dissolved in THF (10ml). Lithium aluminium hydride (100mg) is added and the solution heated at reflux for 18 hours. Water (0.1 ml), sodium hydroxide (15% aq, 0.1 ml) and water (0.3ml) are added cautiously and the mixture stirred for 1 hour, then filtered and the filtrate evaporated in vacuo. The residue is purified by preparative HPLC (pH 5.8) to give the title compound as colourless solid (10mg). LCMS 262 [M+H]+, RT 1.99 mins (pH 5.8). 1H NMR 300 MHz (CDCI3) (delta ppm): 5.15 (2H, br s), 4.40 (2H, dd), 3.93 (2H, dd), 3.62 (1 H, m), 2.50(2H, t), 2.43 (3H, s), 2.35 (2H, s), 1 .48 (2H, t), 0.95 (6H, s).

Reference： [1]Patent: WO2009/47255,2009,A1 .Location in patent: Page/Page column 80

36
[ 247050-11-9 ]
[ 91188-13-5 ]
[ 1163128-31-1 ]

Yield	Reaction Conditions	Operation in experiment
30%	With magnesium sulfate; In methanol; at 40℃; for 3h;	A solution of (5)-oxiranylmethyl-carbamic acid benzyl ester (9.3 g, 45 mmol, 1.5 eq.) and <strong>[91188-13-5]azetidin-3-yl-carbamic acid tert-butyl ester</strong> (5.2 g, 30 mmol) in MeOH (60 mL) was treated with MgSO4 (7.9 g) and heated at 400C for 3 h. The mixture was partitioned between <n="88"/>EA/MeOH 19:1 (15O mL) and water (20O mL). The aq. layer was washed again with EA/MeOH 19:1 (15O mL) and the combined org. phases were washed with brine (15O mL), dried over MgSO4 and concentrated. The residue was triturated in EA and filtered to give the title intermediate as a colourless solid (3.4 g, 30% yield). MS (ESI, m/z): 380.2 [M+H+].

Reference： [1]Patent: WO2009/77989,2009,A1 .Location in patent: Page/Page column 85-86

37
[ 1072827-32-7 ]
[ 91188-13-5 ]
[ 1163128-28-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 80℃; for 72h;	A solution of the compound of preparation E (3.16 g, 8.7 mmol) and azetidin-3-yl- carbamic acid tert-hvXy ester (1.5 g, 1 eq.) in dry DMSO (30 mL) was treated with DIPEA (1.8 mL) and heated at 800C for 72 h. The mixture was partitioned between EA and water and the org. phase was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by FC (EA, EA/MeOH 9:1 + 1% NH4OH) to give the desired intermediate as a beige solid (2.5 g, 71% yield).1H NMR (DMSO d6) delta: 7.27 (dd, J = 7.0, 0.9 Hz, IH), 7.09 (d, J = 2.6 Hz, IH), 6.94 (m, IH), 6.83 (m, IH), 4.57 (m, IH), 4.21 (m, IH), 4.00 (m, 4H), 3.66 (dd, J = 8.8, 6.4 Hz, IH), 3.50 (q, J = 7.0 Hz, 2H), 2.91 (m, 2H), 2.65 (m, 2H), 1.35 (s, 9H).

Reference： [1]Patent: WO2009/77989,2009,A1 .Location in patent: Page/Page column 84

38
[ 1168106-57-7 ]
[ 91188-13-5 ]
[ 1168106-84-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 22h;	Description 65; Ethyl {5-bromo-4-[3-([(1,1-dimethylethyl)oxy]carbonyl}amino)-1-azetidinyl]-7H- pyrrolo[2,3-d]pyrimidin-7-yl}cetate (D65)Ethyl (5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (D30, 1.593 g, 5 mmol) was stirred in acetonitrile (10 mL) under argon and N,N-diisopropylethylamine (1.921 mL, 11 mmol) added, followed by 1 ,1-dimethylethyl 3-azetidinylcarbamate (0.861 g, 5 mmol). The mixture was stirred at room temperature for 22 hours. Ethyl acetate was added and the mixture washed with water (X2), dried (magnesium sulfate) and evaporated to a cream solid which was purified by flash chromatography, eluting with 30-100% ethyl acetate/isohexane to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 398, 400 (Ci8H24BrN5O4 requires [M-But+2H]+ at m/z 398, 400).

Reference： [1]Patent: WO2009/80682,2009,A1 .Location in patent: Page/Page column 65

39
[ 1188914-98-8 ]
[ 91188-13-5 ]
[ 1188915-76-5 ]

Yield	Reaction Conditions	Operation in experiment
90%		Reaction of 1 -[4-chloro-6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole and tert-bv&y 3-azetidinylcarbamate gave 1 -[4- [2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl] -6-(4-morpholinyl)- l,3,5-triazin-2-yl]-3-azetidinylcarbamate in 90% yield: mp (Ceta2Cl2/hexanes) 217-220 0C; 1H NMR (DMSO-40 delta 7.98 (d, J = 8.0 Hz, IH), 7.73 (t, JHF = 53.0 Hz, IH), 8.24 (t, J = 8.2 Hz, IH), 6.95 (d, J - 7.8 Hz, IH), 4.42 and 4.36-4.32 (2m, 3H), 4.01-3.98 (m, 2H), 3.79-3.77 (m, 4H), 3.68 (m, 4H), 1.40 (s, 9 H); Anal. Calcd. for C24H30F2N8O4: C, 54.1 ; H, 5.7; N, 21.0; Found C, 54.4; H, 5.8; N, 21.2%.
90%	at 20℃;	Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole and <strong>[91188-13-5]tert-butyl 3-azetidinylcarbamate</strong> gave tert-butyl 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinylcarbamate in 90% yield: mp (CH2Cl2/hexanes) 217-220 C.; 1H NMR (DMSO-d6) delta 7.98 (d, J=8.0 Hz, 1H), 7.73 (t, JHF=53.0 Hz, 1H), 8.24 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.42 and 4.36-4.32 (2m, 3H), 4.01-3.98 (m, 2H), 3.79-3.77 (m, 4H), 3.68 (m, 4H), 1.40 (s, 9H). Anal. Calcd. for C24H30F2N8O4: C, 54.1; H, 5.7; N, 21.0; Found: C, 54.4; H, 5.8; N, 21.2%.
90%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;	Reaction of 8 and <strong>[91188-13-5]tert-butyl 3-azetidinylcarbamate</strong>, as for the synthesis of 66a, gave tert-butyl 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinylcarbamate (70a) in 90% yield: mp (CH2Cl2/hexanes) 217-220C; 1H NMR (DMSO-d6) d 7.98 (d, J = 8.0 Hz, 1H), 7.73 (t, JHF = 53.0 Hz, 1H), 8.24 (t, J = 8.2 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 4.42 and 4.36-4.32 (2m, 3H), 4.01-3.98 (m, 2H), 3.79-3.77 (m, 4H), 3.68 (m, 4H), 1.40 (s, 9H). Anal. Calcd. for C24H30F2N8O4: C, 54.1; H, 5.7; N, 21.0; Found: C, 54.4; H, 5.8; N, 21.2%.

Reference： [1]Patent: WO2009/120094,2009,A2 .Location in patent: Page/Page column 134
[2]Patent: US2010/249099,2010,A1 .Location in patent: Page/Page column 63-64
[3]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 5859 - 5874

40
[ 1172068-39-1 ]
[ 91188-13-5 ]
[ 1196507-94-4 ]

Yield	Reaction Conditions	Operation in experiment
37%	In butan-1-ol; at 110℃; for 24h;	[00373] Step A: N-(5-Bromo-4-fluoro-lH-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg, 0.3 mmol, Example 1, Step I) in n-BuOH (3 mL) and tert-butyl azetidin-3-ylcarbamate (154 mg, 0.9 mmol) were heated to 1100C in a sealed tube for 24 hours. After cooling down, the reaction was concentrated to dryness, and the residue purified by C- 18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH3CN/water gradient; 30 CV) <n="113"/>to yield tert-butyl l-(5-bromo-3-(nicotinamido)-lH-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3- ylcarbamate (54 mg, 37% yield) as a solid.

Reference： [1]Patent: WO2009/140320,2009,A1 .Location in patent: Page/Page column 111-112

41
[ 1192756-64-1 ]
[ 91188-13-5 ]
[ 1192755-79-5 ]

Yield	Reaction Conditions	Operation in experiment
43%	With N-ethyl-N,N-diisopropylamine; In dichloromethane;	To a stirred solution of 4-nitrophenyl (2-adamantyl)carbamate (40 mg, 0.12 mmol) in CH2CI2 (2 ml_) was added tert-butyl azetidin-3-ylcarbamate (40 mg, 0.23 mmol), followed by J-Pr2NEt (0.05 ml_, 0.28 mmol). The mixture was stirred over the weekend and applied to a 10-mL ChemElut cartridge prewetted with 5% aq HCI (6 ml_). The cartridge was eluted with ether (20 ml_). The eluate was evaporated to dryness and the residue was applied to 2-g silica SPE cartridge which was eluted sequentially with 0, 25, 50, 75, 100 and 100% EtOAc in hexanes (15 mL of each) to afford six fractions. Fraction 4 was concentrated to provide tert-butyl 1-(2- adamantylcarbamoyl)azetidin-3-ylcarbamate (19 mg, 43%). LC-MS Method 1 , tR = 1.74 min, m/z = 350, 294; 1H NMR (CDCI3) 1.45 (s, 9H), 1.60-1.95 (14H), 3.75 (m, 2H), 3.89 (m, 1 H), 4.22 (m, 2H), 4.39 (d, 1 H), 4.46 (1 H), 5.06 (1 H).

Reference： [1]Patent: WO2009/131669,2009,A2 .Location in patent: Page/Page column 82-83

42
[ 684284-66-0 ]
[ 32315-10-9 ]
[ 91188-13-5 ]
[ 684285-86-7 ]

Yield	Reaction Conditions	Operation in experiment
69%		Trimethylsilylethyl ether 44 (0.03 g, 0.0508 mmol) was dissolved in 0.5 mL dry tetrahydrofuran. To this was added triethylamine (0.028 mL, 0.2032 mmol) and 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (0.1016 mL, 0.1016 mmol. ) Stirred at room temperature 10 minutes until starting material consumed. Diluted with dichloromethane, washed with washed with 1M HCl solution, saturated brine, dried (Na2S04,) concentrated to give crude. Dissolved in 0.5 mL dichloromethane, added catalytic dimethylaminopyridine, triethylamine (0.08 mL, 0.6 mmol) and cooled to 0 C. To this was added triphosgene (0.03 g, 0.1016 mmol) and stirred 30 minutes. Azetid-3-yl carbamic acid t-butyl ester (0.035 g, 0.2032 mmol) and triethylamine (0.08 mL, 0.6 mmol) was then added and stirred at room temperature for 50 minutes. Diluted with dichloromethane, washed with 1M HCl, brine, dried (Na2S04,) concentrated volatiles to give crude. Chromatographed (10% to 50% ethylacetate/hexanes) to give product 142 (0.024 g, 0.035 mmol, 69%. ) ¹H NMR (CDCl3) 6 9.04 (dd, 1H), 8.17 (d, 1H), 8.03 (s, 1H), 7.74 (d, 4H), 7.51 (dd, 1H), 7.27 (m, 8H), 7.08 (dd, 2H), 5.00 (m, 1H), 4.80 (s, 2H), 4.52 (m, 2H), 4.23 (s, 2H), 3.91 (m, 2H), 1.48 (s, 9H. ) MS: 689 (M+1)

Reference： [1]Patent: WO2005/117904,2005,A2 .Location in patent: Page/Page column 473-474

43
[ 1193-21-1 ]
[ 91188-13-5 ]
[ 1201176-20-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In methanol; at 20℃;	A mixture of <strong>[91188-13-5]azetidin-3-yl-carbamic acid tert-butyl ester</strong> (635mg, 3.4mmol), 2,4- dichloropyhmidine (500mg, 3.4mmol) and thethylamine (0.5ml, 3.6mmol) in methanol (10ml) was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography (0-40% ethyl acetate/ petroleum ether) furnishing 561 mg title compound. MS: [M+H]+ = 283/285

Reference： [1]Patent: WO2009/150240,2009,A1 .Location in patent: Page/Page column 129

44
[ 872701-10-5 ]
[ 91188-13-5 ]
C₁₈H₃₃BN₂O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 7933 - 7948

45
[ 49682-96-4 ]
[ 91188-13-5 ]
[ 1214265-99-2 ]

Yield	Reaction Conditions	Operation in experiment
55%		Preparation 21: l-(l-(Cyclopropylmethyl)piperidin-4-yl)azetidin-3 -amine; [0137] To a solution of l-(cyclopropylmethyl)piperidin-4-one (500mg, 3.27 mmol) and A- (BOC amino)azetidine (559mg, 3.27 mmol) in THF (40 mL) was added AcOH (5 drops) and sodium triacetoxyborohydride (2.07 g, 9.8 mmol). This solution was allowed to stir 5 hours. Water (75 mL) was then added to the reaction. The aqueous layer was basified with sodium carbonate (100 mL sat.) and the product extracted into EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated to yield tert-bvXyl 1-(1- (cyclopropylmethyl)piperidin-4-yl)azetidin-3-ylcarbamate (509mg, 55%). MS (ES) [M+H] found 310. tert-Butyl l-(l-(cyclopropylmethyl)piperidin-4-yl)azetidin-3-ylcarbamate (509mg, 1.8 mmol) was dissolved in MeOH (30 mL), conc.HCl was added (3 mL) and the mixture was heated to 70 0C for 3 hours. The mixture was then cooled and the product was filtered off, washed with diethyl ether, and dried to yield the title compound as the hydrochloride salt (525 g, quant, yield) as a white solid. MS (ES) [M+H] found 210.

Reference： [1]Patent: WO2010/25073,2010,A1 .Location in patent: Page/Page column 31-32

46
[ 454-89-7 ]
[ 91188-13-5 ]
[ 1219626-10-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 180; 2-(2-oxo-3,3-diphenylpiperidin-l-yl)-7V-{l-[3-(trifluoromethyl)benzyl]azetidin-3- yl}acetamide; Example 180A; tert-buty l-[3-(trifluoromethyl)benzyl]azetidin-3-ylcarbamate; To a solution of tert-butyi azetidin-3-ylcarbamate (0.34 g, 2 mmol) in dichloroethane was added 3-(trifluoromethyl)benzaldehyde (0.45 g, 2.6 mmol) and sodium triacetoxyborohydride (0.64 g, 3 mmol). The resultant mixture was stirred at room temperature for 16 hours, and then the mixture was diluted with dichloromethane and washed with aqueous NaHCO3 solution. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 30-70% ethyl acetate/hexane to yield the title compound.

Reference： [1]Patent: WO2010/39947,2010,A1 .Location in patent: Page/Page column 148

47
[ 925449-98-5 ]
[ 91188-13-5 ]
[ 1232361-12-4 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 2521 - 2527

48
[ 124-63-0 ]
[ 91188-13-5 ]
[ 1239205-33-4 ]

Yield	Reaction Conditions	Operation in experiment
		Methanesulfonyl chloride (758 uL, 9.76 mmol) was added dropwise to a DCM (48 mL) solution of N,N'-diisopropylethylamine (12 mL) and N-BOC-3-amino-azetidine (2.0 g, 9.57 mmol) at 0 C. After 2 hours at 0 C., solvent was removed and to residue was added HCl (4.0 M) in dioxane at room temperature. After 4 hours the solvent was removed and azetidine-3-N-methanesulfonamide hydrochloride was used for the next step without further purification. Azetidine-3-N-methanesulfonamide hydrochloride (1.42 g 99%) was obtained as a pale yellow solid. MS (ESI) m/z=151.2 (MH+).

Reference： [1]Patent: US2010/204265,2010,A1 .Location in patent: Page/Page column 107

49
[ 1239205-35-6 ]
[ 91188-13-5 ]
[ 1239205-36-7 ]

Yield	Reaction Conditions	Operation in experiment
36%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;	HATU (673 mg, 1.77 mmol) was added to a DMF (4 mL) solution of 6-(5-Bromo-furan-3-yl)-8-trifluoromethyl-imidazo[1,2-a]pyridine-2-carboxylic acid (332 mg, 0.885 mmol), DIEA (570 uL, 4.42 mmol), and 3-tert-butoxycarbonyl aminoazetadine at room temperature. After 18 hours, water was added and the precipitate was filtered. Column chromatography of the crude gave {1-[6-(5-bromo-furan-3-yl)-8-trifluoromethyl-imidazo[1,2-a]pyridine-2-carbonyl]-azetidin-3-yl}-carbamic acid tert-butyl ester (168 mg 36%) as a white solid. MS (ESI) m/z=529.0 (MH+).

Reference： [1]Patent: US2010/204265,2010,A1 .Location in patent: Page/Page column 109

50
4-[6-[(3,4-dichlorophenyl)methylamino]imidazo[1,2-b]pyridazin-3-yl]benzoic acid [ No CAS ]
[ 91188-13-5 ]
C₂₈H₂₈Cl₂N₆O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5113 - 5118

51
[ 1252615-58-9 ]
[ 91188-13-5 ]
[ 1252615-59-0 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 4-benzo[1,3]dioxol-5-yl-cyclohex-3-enone (as prepared in the previous step, 680 mg, 3.15 mmol) and <strong>[91188-13-5]azetidin-3-yl-carbamic acid tert-butyl ester</strong> (BetaPharma, 542 mg, 3.15 mmol) in DCM (10 mL) was treated with NaBH(OAc)3 (Aldrich, 2.0 g, 9.45 mmol) at room temperature. The reaction was stirred for 4 hours and quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash system using hexanes and ethyl acetate as eluent (from pure hexanes to pure ethyl acetate) to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3) delta 7.85 (s, 1H), 7.82 (d, J=7.0 Hz, 1H), 7.75 (d, J=6.8 Hz, 1H), 5.95 (s, 2H0, 5.90 (s, br, 1H), 4.35 (s, br, 1H), 3.76 (m, 2H), 3.18 (s, br, 2H), 2.45 (m, 1H), 2.35 (m, 4H0, 2.02 (m, 2H), 1.45 (s, 9H).

Reference： [1]Patent: US2010/267689,2010,A1 .Location in patent: Page/Page column 44-45

52
[ 15996-84-6 ]
[ 530-62-1 ]
[ 91188-13-5 ]
[ 920320-49-6 ]

Yield	Reaction Conditions	Operation in experiment
67%		To a solution of l-[4-(trifluoromethyl)phenyl]ethylamine (1.Og, 5.2 mmol) in dichloromethane (20 ml) at 3O0C was added a suspension of 1,1 '-carbonyl diimidazole (0.86g, 5.2mmol) in dichloromethane (7 ml) and the reaction was stirred at 3O0C for 1 hour. A suspension of azetidine-3-yl-carbamic acid terf-butyl ester (0.89g, 5.2mmol) in dichloromethane (5ml) was added and the reaction stirred at 30 for 5 hours. The reaction was cooled to room temperature (r.t.) and the product obtained by filtration as a white solid. Yield 1.35 g (67%): HPLC retention time, 3.56min (Solvent: CH3CN/H2O/0.05% NH3, 5-95% gradient H2O-6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 388 (M + H).

Reference： [1]Patent: WO2007/7057,2007,A1 .Location in patent: Page/Page column 31

53
[ 34916-10-4 ]
[ 91188-13-5 ]
[ 1252690-19-9 ]

Yield	Reaction Conditions	Operation in experiment
		Step A: [1-(4-Cyano-cyclohexyl)-azetidin-3-yl]-carbamic acid tent-butyl ester To a solution of 4-oxo-cyclohexanecarbonitrile (2.66 g, 21.5 mmol, prepared according to the procedure from Tremblay, Maxime, PCT Int. Appl. (2007), WO 2007013848) and azetidine-3-yl-carbonic acid tert-butyl ester (Beta Pharma, 3.70 g, 21.5 mmol) in DCM (20 mL) was added NaBH(OAc)3 (Aldrich, 6.84 g, 32.25 mmol). The resulting mixture was stirred at rt for 6 h and quenched with saturated NaHCO3. Workup and purification by column chromatograph (eluent: 80% EtOAc in hexanes to EtOAc only) gave the product as a mixture of cis/trans isomers. LC/MS: 280.2 [M+H].

Reference： [1]Patent: US2010/267688,2010,A1 .Location in patent: Page/Page column 74

54
[ 1001020-01-4 ]
[ 91188-13-5 ]
C₂₇H₃₄F₃N₅O₄S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5753 - 5756

55
[ 868963-98-8 ]
[ 91188-13-5 ]
[ 1256957-19-3 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In 1,4-dioxane; water; at 20℃; for 1h;	To a solution of tert-butyl azetidin-3-ylcarbamate (64 mg, 0.37 mmol) and potassium carbonate (102 mg, 0.74 mmol) in dioxane (2 mL) and water (400 uL) was added 2-amino-5- bromopyridine-3-sulfonyl chloride (100 mg, 0.37 mmol, prepared according to the methods in WO2008144463). The reaction mixture was stirred for 1 h at room temperature then quenched by addition of saturated aqueous sodium bicarbonate, and the aqueous solution was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to provide tert-butyl l-(2-amino-5- bromopyridin-3-ylsulfonyl)azetidin-3-ylcarbamate (120 mg, 0.30 mmol, 80% yield) as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.31 (d, IH), 8.00 (d, IH), 5.76 (br s, 2H), 4.80 (br s, IH), 4.50-4.36 (m, IH), 4.11 (t, 2H), 3.75 (t, 2H), 1.42 (s, 9H).; MS (EI) for Ci3Hi9BrN4O4S: 407, 409 (Br isotopes, MH+).
80%		To a solution of tert-butyl azetidin-3-yIcarbamate (64 mg, 0.37 mmol) and potassium carbonate (102 mg, 0.74 mmol) in dioxane (2 mL) and water (400 uL) was added 2-amino-5-bromopyridine-3-suIfonyl chloride (100 mg, 0.37 mmol, prepared according to the methods in WO2008144463). The reaction mixture was stirred for 1 h at room temperature then quenched by addition of saturated aqueous sodium bicarbonate, and the aqueous solution was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to provide tert-butyl l-(2-amino-5- bromopyridin-3-ylsulfonyl)azetidin-3-ylcarbamate (120 mg, 0.30 mmol, 80% yield) as a white solid. NMR (400 MHz, CDCI3) 5 8.31 (d, 1H), 8.00 (d, lH), 5.76 (br s, 2H), 4.80 (br s, 1H), 4.50-4.36 (m, 1H), 4.11 (t, 2H), 3.75 (t, 2H), 1.42 (s, 9H).; MS (EI) forCi3H19BrN404S: 407, 409 (Br isotopes, MH+).

Reference： [1]Patent: WO2010/138487,2010,A1 .Location in patent: Page/Page column 143
[2]Patent: WO2012/71509,2012,A2 .Location in patent: Page/Page column 177-178

56
[ 75-15-0 ]
[ 19718-49-1 ]
[ 91188-13-5 ]
[ 1269795-81-4 ]

Reference： [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 1118 - 1121

57
[ 1275607-79-8 ]
[ 91188-13-5 ]
[ 1275602-43-1 ]

Yield	Reaction Conditions	Operation in experiment
		5-chloro-6-ethyl-2-(pyridin-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (Example 47) (5 mg) was dissolved into 1 mL DMF, then 10 mg BOP and 20 DBU was added into the solution at 0-5 C, the solution was stirred for 10 min, then er/-butyl azetidin- 3-ylcarbamate 10 mg was added into the previous solution, the reaction solution was stirred for overnight, and then the reaction solution was injected to reverse phase HPLC and purified. The purified compounds was dried and re-dissolved into 1 mL TFA and stirred for 0.5 hour, then removed the excess TFA to give the title compound, LCMS: 343 (M+H).

Reference： [1]Patent: WO2011/32050,2011,A2 .Location in patent: Page/Page column 82

58
[ 1275607-77-6 ]
[ 91188-13-5 ]
[ 1275600-19-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 1-methyl-pyrrolidin-2-one; for 8h;	tert-butyl azetidin-3-ylcarbamate (8.3 mg, 0.048 mmol) was added to a stirring solution of Et3N (20 mu) tert-butyl 4-(lH-benzo[d][l,2,3]triazol-l-yloxy)-5-bromo-6- ethyl-2-(3-isopropyl-3H-[l,2,3]triazolo[4,5-b]pyridin-6-ylamino)-7H-pyrrolo[2,3- d]pyrimidine-7-carboxylate (Example 39) (15 mg, 0.024 mmol) in NMP (0.7 mL). The stirring was continued for 8 h . LC-MS indicated the reaction was completed. DMSO (0.5 mL) was added to the mixture. The solution was subjected to prep-HPLC (CH3CH-H20, in 0.1% TFA) to give the desired product. MS (ESI) m/z 571 (M + H)+.

Reference： [1]Patent: WO2011/32050,2011,A2 .Location in patent: Page/Page column 78

59
[ 1334135-63-5 ]
[ 91188-13-5 ]
[ 1334135-66-8 ]

Yield	Reaction Conditions	Operation in experiment
33%	In ethanol;Reflux;	A 50 mL round bottom flask was charged with 8-chloro-5-(thiophen-2-yl)- [l,2,4]triazolo[4,3-a]pyrazine (0.25 g, 1.1 mmol), tert-butyl azetidin-3-ylcarbamate (540 mg, 3.1 mmol) and ethanol (5 mL). The resulting solution was refluxed overnight. Work-up: the solvent was evaporated. The residue was purified by flash column chromatography on silica gel with a 1 :2 EtO Ac/petroleum ether and then a 1:50 methanol/dichloromethane, to afford 130 mg (33%) of the product as a white solid. MS m/z: 373 (M+H+).

Reference： [1]Patent: WO2011/112766,2011,A2 .Location in patent: Page/Page column 71; 74

60
[ 612-62-4 ]
[ 91188-13-5 ]
[ 1350607-88-3 ]

Yield	Reaction Conditions	Operation in experiment
53%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃;	A mixture of Cs2C03 (3.2 g, 10.0 mmol), 2-chloro-quinoline (0.8 g, 5.0 mmol) and tert-butyl azetidin-3-ylcarbamate (0.8 g, 5.0 mmol) was dissolved in DMF (20 mL) and the resulting mixture was heated to 100 C overnight. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were combined and washed with water (20 mL) and brine (20 mL), dried over Na2S04, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 70% EtOAc in petroleum ether) to give tert-butyl (l-(quinolin-2-yl)azetidin-3- yl)carbamate (0.8 g, 2.9 mmol, 53% yield) as white solid. ESI-MS (M+l): 300 calc. for

Reference： [1]Patent: WO2011/143495,2011,A1 .Location in patent: Page/Page column 82

61
[ 870483-69-5 ]
[ 91188-13-5 ]
tert-butyl (4-hydroxy-4-(thiazol-5-yl)cyclohexyl)azetidin-3-ylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃;	Step H tert-butyl (1-((1r, 4r)-4-hydroxy-4-(thiazol-5-yl)cyclohexyl)azetidin-3-yl)carbamate A solution of 4-hydroxy-4-(thiazol-5-yl)cyclohexanone (412 mg, 2.09 mmol) and tert-butyl azetidin-3-ylcarbamate (30 mg, 2.09 mmol) in DCM (30 mL) was treated with NaBH(OAc)3 (1.33 g, 6.28 mmol) and stirred overnight at room temperature. The mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 5-20% 7N NH3-MeOH/ethyl acetate) with the titled isomer eluting before the minor isomer. 1H NMR (ACETONITRILE-d3) delta: 8.72 (s, 1H), 7.71 (s, 1H), 5.62 (br. s., 1H), 3.99-4.13 (m, 1H), 3.49 (s, 2H), 3.35-3.45 (m, 1H), 2.72 (s, 2H), 2.16 (s, 6H), 1.70-1.80 (m, 2H), 1.58-1.70 (m, 2H), 1.39 (s, 11H)

Reference： [1]Patent: US2011/306592,2011,A1 .Location in patent: Page/Page column 93

62
[ 75-36-5 ]
[ 76-05-1 ]
[ 91188-13-5 ]
N-(azetidin-3-yl)acetamide trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 42 (S)-N-(1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)acetamide 100 mg of t-butyl azetidin-3-ylcarbamate was dissolved in 5 ml of methylene chloride, and 225 mg of N,N-diisopropylethylamine was added. Under ice-cooling, the reaction mixture was added with 68 mg of acetyl chloride, and stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with 5% citric acid aqueous solution and brine in turn, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 146 mg of a brown oily matter. The obtained residue was dissolved in 2.5 ml of methylene chloride, and 1 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then 66 mg of N-(azetidin-3-yl)acetamide trifluoroacetate was obtained.

Reference： [1]Patent: US2011/288065,2011,A1 .Location in patent: Page/Page column 33-34

63
[ 1353628-60-0 ]
[ 91188-13-5 ]
[ 1353623-36-5 ]

Yield	Reaction Conditions	Operation in experiment
75%		Compound 52Dissolved intermediate 55 (S)-N-(4-chloro-2-(2-(5-chloro-7-methylpyrazolo[l ,5-a]pyrimidin-2- yl) piperidine-l -carbonyl)phenyl)methanesulfonamide (lOmg, 0.021mmol) in THF (2mL). Added 3-N-Boc-amino azetidine (36mg, 0.21mmol). Stirred (at) 70C for 2hrs. Concentrated under reduced pressure. Dissolved in 4N HCl in dioxane (2mL) and stirred for lhr. Concentrated under reduced pressure. Purified with Prep HPLC to give compound 52 (l Omg, 75% yield). NMR (400MHz, CD3OD): delta 7.51 (m, 3H), 6.19 (s, 1H), 6.10 (m, 1H), 4.55 (m, 3H), 4.27- 4.20 (m, 3H), 3.40 (m, 1H), 2.99 (s, 3H), 2.73 (s, 3H), 2.38-2.05 (m, 2H), 1.72-1.56 (m, 4H). LC/MS (m/z) 518.3 [M+H]+

Reference： [1]Patent: WO2011/163518,2011,A1 .Location in patent: Page/Page column 219-220

64
(x)C₂HF₃O₂*C₂₀H₂₁Cl₂N₅O₃S [ No CAS ]
[ 91188-13-5 ]
[ 1353628-82-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In methanol; at 70℃;	Compound 97Compound 90 (47 mg, 0.1 mmol) in MeOH (1 mL) was treated with TEA (270 yL, 1.9 mmol) and fert-butyl azetidin-3-ylcarbamate (167 mg, 1.0 mmol). The mixture was stirred at 70 C overnight. The solution was concentrated to afford the product as a white solid which was used without further purification: m/z [M + H]+ 619, [M + Na]+ 641. The product (60 mg, 0.1 mmol) was treated with 4 N HCl/dioxane (1 mL) and the mixture was stirred for 3 h. The solution was concentrated and purified via preparative HPLC (5-100% MeCN/ H20, 0.1% trifluoroacetic acid modifier) to afford compound 97 (13 mg, 60%) as a white solid (TFA salt): 1H-NMR (CD3OD, 400 MHz): delta 8.84 (s, 1H), 8.38 (s, 1H), 7.70 (m, 1 H), 7.47 (s, 1H), 7.43 (s, 1H), 6.10 (m, 1H), 4.63 (m, 1H), 4.28 (m, 2H), 4.18 (m, 2H), 3.20 (m, 2H), 3.01 (m, 1H), 2.97 (s, 3H), 2.40 (m, 1H), 2.25 (s, 3H), 2.05 (m, 1H), 1.75 (m, 1H), 1.55 (m, 1H), 1.45 (m, 1H). m/z [M + H]+ 519.HPLC (RP: 6-98% MeCN-H20 gradient, 0.05% TFA modifier) tR = 3.314 min (>95% purity (at) 254 nM).

Reference： [1]Patent: WO2011/163518,2011,A1 .Location in patent: Page/Page column 266

65
[ 150617-68-8 ]
[ 91188-13-5 ]
C₁₉H₂₂N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Compound III (0.10 g, 1.0 eq) and commercially available tert-butyl azetidin-3-ylcarbamate (83 mg, 1.05 eq) were taken up in N,N-dimethylacetamide (1.5 ml). The mixture was then treated with 60% NaH oil dispersion (22 mg, 1.2 eq). After stirring for lh, reaction was quenched with 10% HC1 aq. (0.5ml) then H20 (1 ml). A solid formed that was collected and dried. Half of this solid was suspended in 1,4 dioxane ( 3ml) and treated with 4N HC1 in dioxane (1.0 ml). Reaction stirred for 15h before concentrating to residue and triturating with diethyl ether. Product was obtained as a yellow solid (76 mg 100% yield for two steps, calc M+H 255, obs M+H 255).

Reference： [1]Patent: WO2012/9649,2012,A1 .Location in patent: Page/Page column 100

66
[ 586-75-4 ]
[ 91188-13-5 ]
[ 1373525-73-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0℃; for 2h;	To a solution of compound 16a (1.02 g, 5.92 mmol) and Et3N (1.24 mL, 8.88 mmol) in CH2Cl2 (25 mL) at 0 C. was slowly added a solution of compound 16b (1.36 g, 6.22 mmol) in CH2Cl2 (5 mL). The reaction was stirred at 0 C. for 2 h, diluted with CH2Cl2, and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, 35% EtOAc/hexanes) to give compound 16c (810 mg). MS m/z (M+H+) 356.0.

Reference： [1]Patent: US2012/101081,2012,A1 .Location in patent: Page/Page column 41; 42

67
[ 98-74-8 ]
[ 91188-13-5 ]
C₁₄H₁₉N₃O₆S [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 731 - 735

68
[ 1131393-06-0 ]
[ 91188-13-5 ]
[ 1347645-23-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	With N-ethyl-N,N-diisopropylamine; In ethanol; at 120℃; for 0.666667h;Microwave irradiation;	200 mg (0.7 mmol) of the compound from Example 23 and 252 mg (1.5 mmol) of tert-butyl azetidin-3-ylcarbamate are suspended in 6 ml of ethanol and reacted at 120 C. in a single-mode microwave oven (CEM Explorer) for 40 min. The solid formed is filtered off, washed twice with in each case 0.5 ml of ethanol and dried under high vacuum.Yield: 227 mg (76% of theory)LC-MS (Method 9): Rt=0.72 min; MS (ESIpos): m/z=410 [M+H]+;1H-NMR (400 MHz, DMSO-d6): delta=9.05 (s, 1H), 9.45 (s, 1H), 9.40 (s, 1H), 9.32 (d, 1H), 8.20 (d, 1H), 7.67 (d, 1H), 7.36 (dd, 1H), 4.55-4.45 (m, 1H), 4.35 (t, 2H), 3.98-3.91 (m, 2H), 1.40 (s, 9H).

Reference： [1]Patent: US2012/264704,2012,A1 .Location in patent: Page/Page column 31

69
[ 870483-69-5 ]
[ 91188-13-5 ]
C₁₇H₂₇N₃O₃S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1063 - 1069

70
[ 84243-02-7 ]
[ 91188-13-5 ]
C₁₈H₂₄FN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; triethylamine; In acetonitrile; at 70℃; for 16h;	General procedure: 1 b) Procedure for halogen derivatives (IVb) where X represents CIA mixture of halogen derivative (IVb) (2.43 mmol), amine (IVa) (2.68 mmol), potassium carbonate (5.36 mmol), triethylamine (5.36 mmol) in acetonitrile (15 mL) was stirred at 70 C for 16 hours. Then the inorganic precipitate was filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride/methanol 95:5 v/v as eluent. Then the resulting protected amine Boc-(lla) was deprotected according to the following procedure.

Reference： [1]Patent: WO2013/1505,2013,A2 .Location in patent: Page/Page column 38

71
[ 4361-27-7 ]
[ 91188-13-5 ]
[ 1431961-14-6 ]

Yield	Reaction Conditions	Operation in experiment
10%	With triethylamine; HATU; In dichloromethane;	HUTU (1.14g, 3 mmol) was added into a stirring solution of 3-cyclohexylpropiolic acid (300 mg, 2 mmol), tert-butyl azetidin-3-ylcarbamate (345 mg, 2 mmol) and Et3N (0.83 ml, 6 mmol) in dichloromethane (15 ml). The next day water was added and the reaction was extracted with DCM. The combined organic was washed with saturated NaHC03, dried over MgS04 and the ten concentrated under reduced pressure. The residue was purified by flash chromatography to yield TH04303-013 (60 mg, 10%

Reference： [1]Patent: WO2013/62945,2013,A1 .Location in patent: Page/Page column 151; 152

72
[ 1429171-32-3 ]
[ 91188-13-5 ]
(3-aminoazetidin-1-yl)-[3-ethyl-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]methanone hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 1-aza-bicyclo[2.2.2]oct-3-ylamine (17 mg, 0.135 mmol) in 1 mL of DMF, N-methyl morpholine was added (42 mg, 0.42 mmol) followed by 3-ethyl-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (34 mg, 0.12 mmol) dissolved in 0.5 mL of DMF. Then a solution of TOTU (43 mg, 0.13 mmol) in 0.5 mL DMF was added and the mixture stirred at r.t. over the weekend. The mixture was treated with 0.1 mL TFA, filtered off and purified by prep. HPLC to obtain the desired product 3-ethyl-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (1-aza-bicyclo[2.2.2]oct-3-yl)-amide as TFA salt. In order to change from TFA salt to HCl salt and deprotection (for compounds bearing BOC-protecting groups) the compound was dissolved in 2 mL of 5-6M HCl iPrOH and the reaction was stirred at r.t. overnight. Then 10 mL of water were added and the mixture was freezed dried to give the desired product 3-ethyl-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (1-aza-bicyclo[2.2.2]oct-3-yl)-amide as hydrochloride salt (12.7 mg, 23%). LC/MS (Method LC10): Rt=2.07 min; m/z=392.27 [M+H]+. 1H-NMR (500 MHz, d6-DMSO): 1.20 (t, 3H), 1.70-1.80 (m, 1H), 1.91-1.99 (m, 2H), 2.08-2.14 (m, 1H), 2.23 (m, 1H), 2.87 (dd, 2H), 3.12 (dd, 1H), 3.24 (m, 4H), 3.75 (m, 1H), 4.42 (m, 1H), 6.91 (d, 2H), 7.70 (s, 1H), 8.07 (d, 2H), 9.10 (d, 1H), 9.6 (s, 1H), 9.9 (bs, 1H), 13.35 (s, bs, 1H).

Reference： [1]Patent: US2013/85128,2013,A1 .Location in patent: Paragraph 1996; 1997; 1998; 1999

73
[ 17201-43-3 ]
[ 91188-13-5 ]
[ 1429644-99-4 ]