Name: 148644-09-1|3-Methoxyazetidine hydrochloride|97%
Brand: Ambeed
SKU: A133003
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1
[ 36476-82-1 ]
[ 148644-09-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: 1-(diphenylmethyl)-3-methoxyazetidine With hydrogen; palladium(II) hydroxide In methanol for 18h; Stage #2: With hydrogenchloride In methanol at 20℃; for 0.166667h;	3 Step 3To a solution of l-benzhydryl-3-methoxyazetidine [94] (1.0 g, 56 mmol) in MeOH (10 ml) was added Pd(OH)2 (0.3 g, 30% by weight). The resulting mixture was hydrogenated under hydrogen atmosphere in a Parr shaker at 50 psi for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, 2 N HCl (15 ml) was added and stirred for 10 min at RT. Pd(OH)2 was filtered out using celite. The filtrate was diluted with diethyl ether (100 ml) which was subsequently separated out and discarded. The aqueous layer was evaporated under reduced pressure by making an azeotropic mixture with Ethanol to produce a brown gel. This brown gel was triturated with n-hexane to yield 3-methoxyazetidine hydrochloride [98] as a white solid (0.73 g, 93%).ESIMS: 124.3 (M+ + 1)
88%	With hydrogen In methanol; ethanol for 18h;	41.2 2) Title Compound The above 1-benzhydryl-3-methoxyazetidine (4.27 g) was dissolved in methanol (90 mL), and, at room temperature, 1M HCl in ethanol (22 mL) and palladium hydroxide-carbon (20% wet, 2.11 g) were added to the solution, followed by stirring for 18 hours in a hydrogen atmosphere. The catalyst was removed through filtration, and the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether and hexane, and the organic layer was removed through decantation. The residue was dried under reduced pressure, to thereby give the title compound as an amorphous product (1.82 g, 88%). 1H-NMR(400MHz,DMSO-d6)δ:3.19(3H,s), 3.69-3.80(2H,m), 4.01-4.12(2H,m), 4.17-4.27(1H,m), 9.37(2H,br).
	Stage #1: 1-(diphenylmethyl)-3-methoxyazetidine With hydrogen In methanol for 2.5h; Stage #2: With hydrogenchloride In methanol; water	14 Preparation 14; To a solution of 1- (diphenylmethyl)-3-methoxy- azetidine (3. 4 g) in MeOH (35 ml), was added Oo palladium hydroxide on carbon (0.7 g). And then the mixture was stirred under hydrogen atmosphere for 2.5 hours. 1N HCl (20 ml) was added to the mixture and the catalyst was removed by filtration and washed with 1NHC1. The solvent was removed under reduced pressure. Water and EtOAc were poured into the residue, and the aqueous layer was separated, washed with EtOAc. The solvent was removed under reduced pressure and the residue was azeotrope with EtOH and dried in vacuo. n-Hexane was poured into the residue and a crystal was isolated by filtration, washed with n-hexane, and dried in vacuo to give 3-methoxyazetidine hydrochloride (1.58 g). 1H-NMR (DMSO-d6 No.) : 3.21 (3H, s), 3.6-3.9 (2H, m), 4.0-4.4 (3H, m) MS (ESI+) : 88 [M+H] + (free form)

With hydrogen In ethanol for 17h;

1 [Reference Example 1]; 3-Methoxyazetidine hydrochloride; [Show Image] 1-Benzhydryl-3-methoxyazetidine (J. Org. Chem., 1972, 37, 3953, 1.10 g) was dissolved in ethanol (40 ml), the solution was added with 20% palladium hydroxide/carbon (1.1 g), and catalytic reduction was performed for 17 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the reaction mixture was added with 1 N hydrochloric acid in ethanol (4.5 ml), concentrated, and then added with ether. The deposited solid was collected by filtration, and dried to obtain the title compound (480 mg) as colorless solid. 1H-NMR (400MHz, d6-DMSO) δ : 2.17 (3H, s), 3.75-3.79 (2H, m), 4.06-4.11 (2H, m), 4.21-4.27 (1H, m), 9.28 (2H, br). ESI-MS; m/z: 88 (M+H)+.

Reference： [1]Current Patent Assignee: SPHAERA PHARMA - WO2012/101654, 2012, A2 Location in patent: Page/Page column 65-66
[2]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1762568, 2007, A1 Location in patent: Page/Page column 58
[3]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2005/40151, 2005, A1 Location in patent: Page/Page column 56
[4]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1942109, 2008, A1 Location in patent: Page/Page column 13

2
[ 429669-07-8 ]
3-methoxyazetidine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; In 1,4-dioxane; at 0 - 20℃;	(2) 3-t-Butyldiphenylsilyloxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidine [1496] To a solution of <strong>[429669-07-8]1-t-butoxycarbonyl-3-methoxyazetidine</strong> (2.60 g, 13.9 mmol) (obtained as described in Reference Example 31(1)) in 1,4-dioxane (26 ml) was added a solution of 4N hydrogen chloride in 1,4-dioxane (26 ml) in an ice bath, and the mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was filtered, and to the residue was added ethyl acetate and diisopropyl ether. The resulting mixture was filtered, and the residue was washed with diisopropyl ether and then dried under reduced pressure to give <strong>[429669-07-8]3-methoxyazetidine hydrochloride</strong> (1.84 g, yield 100%) as white crystals. [1497] Subsequently, to a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (500 mg, 1.07 mmol) in toluene (25 ml) was added a solution of 0.67M 3-methoxyazetidine-trimethylaluminium in benzene (3.21 ml) at room temperature under an atmosphere of nitrogen. The mixture was stirred in a water bath (80 C.) for 1 hour. After checking the completion of the reaction, 10% aqueous acetic acid solution (20 ml) and ethyl acetate (50 ml) were added to the reaction mixture in an ice bath, and the resulting mixture was stirred at room temperature for 1 hour. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (366 mg, yield 67%) as a pale brown solid. [1498] 1H-NMR (400 MHz, CDCl3): delta (ppm) 7.64-7.60 (4H, m), 7.49-7.38 (6H, m), 7.36 (1H, s), 4.78-4.70 (2H, m), 4.42-4.36 (1H, m), 4.32-4.25 (1H, m), 4.24-4.18 (1H, m), 4.09 (2H, t, J=7.3 Hz), 4.03-3.96 (3H, m), 3.33 (3H, s), 1.07 (9H, s).
92%	With hydrogenchloride; In methanol; at 25℃; for 16h;	To a solution of compound A9-1 (0.8 g, 4.29 mmol) in methanol (20 mL) was added concentrated hydrochloric acid (5 mL). The resulting solution was stirred at 25 C for 16 h. The reac- tion mixture was concentrated in vacuum to dryness to afford the hydrochloric acid salt of 3- methoxy-azetidine A9 (0.48 g, 92%). 1H NMR (400 MHz, DMSO-d6): delta 9.56 (s, 1 H), 4.22- 4.25 (m, 1 H), 4.06-4.10 (m, 2 H), 3.74-3.79 (m, 2 H), 3.21 (s, 3 H),.
	With hydrogenchloride; In 1,4-dioxane; for 1h;Product distribution / selectivity;	Step 3:; 12c (339 mg) is dissolved in 1 .0 N HCI/dioxane (10 ml_), stirred for 1 h, then concentrated in vacuo to give compound R3b which is used as such without further purification.

With hydrogenchloride; In ethyl acetate; at 20℃; for 3h;

A solution of tert-butyl 3-methoxyazetidine-l-carboxylate (0.32 g, 1.71 mmol) in 3M hydrogen chloride in ethyl acetate (10 mL) was stirred at RT for 3 hours. The volatiles were removed in vacuo, ethyl acetate was added to the residue then decanted off and the residue dried in vacuo to give the desired compound. (0.16 g) 'H NMR No. (d6-DMSO) : 3.21 (s, 3H), 3.75 (m, 2H); 4.07 (m, 4.23 (m, 1H), 9.08 (brs. 1H).

Reference： [1]Patent: US2004/14962,2004,A1 .Location in patent: Page/Page column 135
[2]Patent: WO2013/53690,2013,A1 .Location in patent: Page/Page column 37; 38
[3]Patent: WO2011/63502,2011,A1 .Location in patent: Page/Page column 50-51
[4]Patent: WO2005/121110,2005,A1 .Location in patent: Page/Page column 154-155

3
[ 148644-09-1 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
57%	With triethylamine In water at 20 - 50℃; for 4h;	184 (3-Methoxy-1-azetidinyl)acetonitrile (276). A solution of 3-methoxyazetidine hydrochloride (275) (MacKenzie et al., PCT Int. Appl. WO 9605193, 1996) (3.0 g, 24.4 mmol), aqueous glycolonitrile (55%, 3.4 mL, 34.3 mmol) and Et3N (5.2 mL, 37.3 mmol) was stirred at 20 0C for 3 h, then heated at 50 0C for 1 h. The solution was cooled and partitioned between water (50 mL) and Et2O (50 mL). The organic fraction was washed with water (2 x 50 mL) and brine (50 mL), dried and the solvent evaporated to give nitrile 276 (1.76 g, 57%) as a colourless oil: 1H NMR 54.06 (p, J = 5.7 Hz, 1 H, CHO), 3.61-3.66 (m, 2 H, CH2N)1 3.49 (s, 2 H, CH2CN), 3.28 (s, 3 H, OCH3), 3.22-3.27 (m, 2 H, CH2N); MS (APCI) m/z 127 (MH+, 100%).

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF AUCKLAND - WO2006/104406, 2006, A1 Location in patent: Page/Page column 165

4
[ 148644-09-1 ]
[ 911300-31-7 ]
[ 911299-22-4 ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: 3-methoxyazetidine hydrochloride; 3-(1-oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)propanal In methanol at 0℃; for 0.5h; Stage #2: With sodium cyanoborohydride at 0℃; for 0.5h; Stage #3: With acetic acid at 20℃; for 16h;	77 Example 77 3-[3-(3-Methoxy-1-azetidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1-Oxide (82). 3-Azetidinyl methyl ether hydrochloride (275) (MacKenzie et al., PCT Int.Appl. WO 9605193, 1996) (0.60 g, 4.9 mmol) was added to a stirred solution of propanal75 (1.2 g, 4.9 mmol) in MeOH (100 mL) at 0 0C and the solution stirred for 30 min.NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0 0C for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20 °C for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL).The aqueous phase was extracted with DCM (2 x 200 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 82 (930 mg, 60%) as a yellow oil: 1H NMR δ 8.24 (s, 1 H, H-9), 7.74 (s, 1 H, H-5), 4.27^.39 (m, 3 H, CH2N, CHO), 3.49-3.53 (m, 2H, CH2N), 3.30 (s, 3 H, OCH3), 3.21-3.27 (m, 2 H, CH2N), 3.09-3.16 (m, 4 H, H-6, H-8), EPO 3.05 (t, J = 7.2 Hz, 2 H, CH2), 2.14-2.26 (m, 4 H, H-7, CH2); 13C NMR δ 163.9, 155.1, 149.3, 147.3, 132.3, 122.7, 144.2, 68.3, 60.9, 58.7, 56.6, 56.5, 33.5, 33.1 , 32.8, 25.7, 23.8; HRMS calcd for C17H22N4O2 (M+) m/z 314.1743, found 314.1742.

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF AUCKLAND - WO2006/104406, 2006, A1 Location in patent: Page/Page column 95-96

5
[ 148644-09-1 ]
[ 902148-42-9 ]
[ 929628-97-7 ]

Yield	Reaction Conditions	Operation in experiment
63%	With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1.5h;	To a stirred solution of 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxamide-6-carboxylic acid (80 mg, 0.15 mmol), 3-methoxyazetidine hydrochloride (28 mg, 0.22 mmol) and triethylamine (0.09 mL) in DMF (1.5 mL) was added HATU (85 mg, 0.22 mmol). The reaction mixture was stirred at rt for 1.5 h, diluted with H2O (5 mL), acidified with 1M HCl (aq.) (0.20 mL) and the precipitate was collected by filtration and flushed with H2O to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxamide, 3-methoxy, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[[3-methoxyazetidinyl]carbonyl]- (57 mg, 0.09 mmol, 63%) as a yellow solid. 1HNMR (500 MHz, CDCl3) δ 9.68 (s, 1H), 8.10 (s, 1H), 15 7.88 (d, J=8.5 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.11-7.05 (m, 2H), 6.09 (s, 1H), 5.59-5.47 (m, 1H), 4.39-3.95 (m, 6H), 3.91 (s, 3H), 3.28 (s, 3H), 3.06 (s, 6H), 2.86-2.77 (m, 1H), 2.14-1.14 (m 10H). LCMS: m/e 605 (M-H)-, ret time 3.07 min, column A, 4 minute gradient.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/78122, 2007, A1 Location in patent: Page/Page column 222

6
[ 148644-09-1 ]
[ 929628-98-8 ]
[ 929629-01-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1.5h;	To a stirred solution of 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N10-[(dimethylamino)sulfonyl]-3-methoxy-N6-methyl-N6-acetic acid (45 mg, 0.074 mmol), 3-methoxyazetidine hydrochloride (14 mg, 0.11 mmol) and triethylamine (0.05 mL) in DMF (1 mL) was added HATU (37 mg, 0.10 mmol). The reaction mixture was stirred at rt for 1.5 h, diluted with H2O (3 mL), acidified with 1N HCl(aq.) (0.1 mL) and the precipitate was collected by filtration and flushed with H2O. The solids were dissolved into MeOH and purified by preparative HPLC (MeOH/H2O with an NH4OAc buffer) to yield 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N10-[(dimethylamino)sulfonyl]-3-methoxy-N6-methyl-N6-[2-(3-methoxyazetidinyl)-2-oxoethyl]- (41 mg, 0.06 mmol, 82%) as a yellow solid. Mixture of rotamers. 1HNMR (500 MHz, CDCl3) δ 10.58-10.42 (m, 1H), 8.13-8.02 (m, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.69-7.59 (m, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.03 (dd, J=2.6, 8.4 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 6.83-6.72 (m, 1H), 5.07-4.93 (m, 1H), 4.52-3.92 (m, 6H), 3.87 (s, 3H), 3.60-2.92 (m, 2H), 3.26 (s, 3H), 3.04 (s, 6H), 2.84-2.73 (m, 1H), 2.55-1.11 (m, 13H). LCMS: m/e 673 (M+H)+, ret time 3.57 min, column B, 4 minute gradient.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/78122, 2007, A1 Location in patent: Page/Page column 223

7
[ 148644-09-1 ]
[ 1046469-25-3 ]
[ 1046468-92-1 ]

Yield	Reaction Conditions	Operation in experiment
57%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 0.5 - 3h;	3 N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC-HCI, 1.4-1.9 equivalents) and a catalytic amount of 4-(dimethylamino)pyridine was added to a suspension of the corresponding carboxylic acid in dichloromethane (10-15 ml). Stirring at room temperature afforded a solution, which was treated with the hydrochloride salt of the corresponding amine (1.0-3.0 equivalents) and triethylamine (1.1 -6 equivalents). After a period of 0.5-3 h at room temperature, the corresponding title compound was isolated as described in work-up procedure 1. Isolation of carboxamides, work-up procedure 1After addition of water, the phases were separated. The organic phase was washed with sodium bicarbonate solution (1 -2 x) and water (1x). The combined aqueous phases were extracted with dichloromethane (1 -2x). The combined organic phases were dried over magnesium sulfate, the solvent was evaporated, and the crude product was purified by column chromatography. Preparation from (8S)-2,3-dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8- c(\|imidazole-5-carboxylic acid (example C, 0.9 g, 2.7 mmol) and 3-methoxyazetidine hydrochloride (380 mg, 3.1 mmol) according to general procedure 1 / work-up procedure 1. Eluant for column chromatography: dichloromethane / methanol = 50:1 (v/v) Yield: 57 % (650 mg of a colourless solid), m. p. 217 0C1H NMR (DMSOd6, 300 MHz): δ = 1 .97 (mc, 1 H), 2.20 (mc, 1 H), 2.38 (s, 3 H), 2.47 (s, 3 H), 2.79 (mc, 1 H), 3.03 (mc, 1 H), 3.21 (d, 3 H), 3.70, 3.83 (s, mc, 5 H), 4.10, 4.22 (mc, bs, 3 H), 5.31 (d, 1 H), 7.05 (s, 1 H), 7.26 (mc, 3 H), 7.46 (mc, 1 H).
57%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h;

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2008/95912, 2008, A2 Location in patent: Page/Page column 69-70; 72
[2]Location in patent: experimental part Palmer, Andreas M.; Chiesa, Vittoria; Schmid, Anja; Münch, Gabriela; Grobbel, Burkhard; Zimmermann, Peter J.; Brehm, Christof; Buhr, Wilm; Simon, Wolfgang-Alexander; Kromer, Wolfgang; Postius, Stefan; Volz, Jürgen; Hess, Dietmar [Journal of Medicinal Chemistry, 2010, vol. 53, # 9, p. 3645 - 3674]

8
3-methoxyazetidine hydrochloride [ No CAS ]
[ 287714-35-6 ]
[ 1314019-95-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 140℃; for 0.5h;Microwave irradiation;	Intermediate 10BA mixture of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (0.75g, 4.35mmol), 3-methoxyazetidine hydrochloride (0.8 l g, 6.5mmol) and DIPEA (2.27mL, 13.0mmol) in acetonitrile (5mL) was microwaved at 140 C for 30 min. The reaction was then diluted with EtOAc (40mL) and Na2C03 (sat. aq., 15mL). The phases were separated and the aqueous phase extracted with EtOAc (2 x 15mL). The combined organic phases were washed with brine (15mL), dried (MgS04), filtered and concentrated. Purified by Biotage Si column, 20-100% EtOAc / petrol to give methyl 2-(3-methoxyazetidin-l-yl)pyrimidine-5-carboxylate (908 mg, 94 %). NMR (400 MHz, CD3OD) delta ppm 8.78 (s, 2 H) 4.28 - 4.52 (m, 3 H) 3.96 - 4.13 (m, 2 H) 3.89 (s, 3 H) 3.37 (s, 3 H). MS (ES+) 224
94%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 140℃; for 0.5h;Microwave irradiation;	Intermediate 10B; A mixture of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (0.75 g, 4.35 mmol), 3-methoxyazetidine hydrochloride (0.81 g, 6.5 mmol) and DIPEA (2.27 mL, 13.0 mmol) in acetonitrile (5 mL) was microwaved at 140 C. for 30 min. The reaction was then diluted with EtOAc (40 mL) and Na2CO3 (sat. aq., 15 mL). The phases were separated and the aqueous phase extracted with EtOAc (2×15 mL). The combined organic phases were washed with brine (15 mL), dried (MgSO4), filtered and concentrated. Purified by Biotage Si column, 20-100% EtOAc/petrol to give methyl 2-(3-methoxyazetidin-1-yl)pyrimidine-5-carboxylate (908 mg, 94%).1H NMR (400 MHz, CD3OD) delta ppm 8.78 (s, 2H) 4.28-4.52 (m, 3H) 3.96-4.13 (m, 2H) 3.89 (s, 3H) 3.37 (s, 3H).MS (ES+) 224

Reference： [1]Patent: WO2011/83314,2011,A1 .Location in patent: Page/Page column 22
[2]Patent: US2011/172204,2011,A1 .Location in patent: Page/Page column 8

9
[ 148644-09-1 ]
[ 1314040-87-3 ]
[ 1314040-88-4 ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: 2-(methylthio)-6-((3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0℃; for 1.5h; Stage #2: 3-methoxyazetidine hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane for 1.5h;	2.2.22.e Step e) Intermediate 29- 2-(3-Methoxyazetidin-l-yl)-6-((3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lH-3-benzazepin-7- yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one To a solution of 2-(methylthio)-6-((3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l H-3- benzazepin-7-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one (Int 28) (5 g, 1 1.39 mmol) in DCM (43 ml) at 0 °C was added mCPBA (2.55 g, 11.4 mmol) and the reaction stirred at this temperature for 90 min. Further wCPBA (1.28 g ,5.7 mmol) was added to complete the conversion. The reaction mixture was diluted with DCM (20 ml) then 3-methoxyazetidine hydrochloride (2.1 1 g, 17.1 mmol) and DIPEA (7 ml, 39.9 mmol) were added and the reaction stirred for 90 min. The reaction mixture was washed with 10 % aq. citric acid and extracted with DCM (x 3). The combined organics were dried over MgS04, concentrated to dryness and the residue purified by column chromatography (Si02; 20-100 % EtO Ac/petrol then 0-15 % MeOH/EtOAc) to give 2-(3-methoxyazetidin-l-yl)-6-((3-(2,2,2-trifluoroacetyl)-2,3,4,5- tetrahydro-lH-3-benzazepin-7-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one (3.1 g, 58 %). NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1 H), 7.13 - 7.20 (m, 1H), 7.00 - 7.12 (m, 2H), 4.22 - 4.39 (m, 7H), 3.89 - 3.98 (m, 2H), 3.58 - 3.72 (m, 4H), 3.26 (s, 3), 2.88 - 3.01 (m, 4H).MS (ES+) 476

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2011/83316, 2011, A1 Location in patent: Page/Page column 55

10
[ 148644-09-1 ]
[ 1314040-47-5 ]
[ 1314040-80-6 ]

Yield	Reaction Conditions	Operation in experiment
55%	With N-ethyl-N,N-diisopropylamine In ethanol at 80℃; for 17h;	2.2.20.a Intermediate 23 6- (3-Methoxyazetidin-l-yl)-2-((3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l H-3-benzazepin-7- yl)methyl)-lH-pynolo[3,4-c]pyridin-3(2H)-one To a suspension of 6-chloro-2-((3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lH-3-benzazepin-7- yI)methyl)- l H-pyrrolo[3,4-c]pyridin-3(2H)-one (Int 11) (5.2 g, 12.27 mmol) in EtOH (100 ml) was added 3-methoxyazetidine hydrochloride (6.07 g, 49.1 mmol) and DIPEA (10.71 ml, 61.3 mmol) and the reaction heated to 80 °C for 17 h. The reaction was cooled to r.t. and aq. saturated sodium hydrogen carbonate was added. EtOH was removed under reduced pressure then the residue was extracted with EtOAc (x 2). The combined organics were washed with brine, dried (MgS04) and evaporated. Purification by column chromatography (Si02; 20-100 % EtOAc/petrol then 0-10% MeOH/DCM) gave 6-(3-methoxyazetidin-l-yl)-2-((3-(2,2,2- trifluoroacetyl)-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl)-lH-pyrrolo[3,4-c]pyridin- 3(2H)-one as a white solid (3.2 lg, 55 %). NMR (400 MHz, MeOD- 4) δ ppm 8.48 (s, 1 H), 7.05 - 7.26 (m, 3 H), 6.47 (s, 1 H), 4.70 (s, 2 H), 4.35 - 4.45 (m, 1 H), 4.22 - 4.36 (m, 4 H), 3.87 - 3.97 (m, 2 H), 3.67 - 3.83 (m, 4 H), 3.36 (s, 3 H), 2.90 - 3.08 (m, 4 H).MS (ES+) 475.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2011/83316, 2011, A1 Location in patent: Page/Page column 49-50

11
3-methoxyazetidine hydrochloride [ No CAS ]
[ 36070-80-1 ]
[ 1338556-23-2 ]

Yield	Reaction Conditions	Operation in experiment
51%		To a suspension of <strong>[36070-80-1]5-chloropyrazine-2-carboxylic acid</strong> (365 mg, 2.302 mmol) in anhydrous DCM (6 mL) was added oxalyl dichloride (1.381 mL, 2.76 mmol), followed by a few drops of DMF. The reaction mixture was stirred at room temperature overnight. Solvent was evaporated, the residue was dissolved in anhydrous DCM (6 mL), 3-methoxyazetidine hydrochloride (341 mg, 2.76 mmol) was added, followed by DIEA (1.404 mL, 8.06 mmol). The reaction mixture was stirred at room temperature for 5 h. Solvent was evaporated, the residue was dissolved in ethyl acetate, washed with 5% citric acid solution, saturated NaHC03 aqueous solution, brine, and dried over anhydrous Na2S04. The mixture was filtered and concentrated. The residue was purified by column chromatography with 60% ethyl acetate/hexanes to give the title compound (269 mg, 1.18 mmol, 51 % yield) as an off-white solid. Exact mass calculated for CgHioClNsOz: 227.1 , found: LCMS mlz = 228.0 [M+H]+; lU NMR (400 MHz, CDC13) delta 3.33 (s, 3H), 4.09-4.13 (m, 1H), 4.25-4.30 (m, 1H), 4.37-4.42 (m, 1H), 4.48-4.54 (m, 1H), 4.79-4.84 (m, 1H), 8.53 (d, J = 1.3 Hz, 1H), 9.10 (d, J = 1.3 Hz, 1H).

Reference： [1]Patent: WO2011/127051,2011,A1 .Location in patent: Page/Page column 197

12
[ 148644-09-1 ]
[ 1254036-06-0 ]
[ 1354791-75-5 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: 3-methoxyazetidine hydrochloride; 4-((1-(5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yl)oxy)benzaldehyde With triethylamine In dichloromethane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane for 2h; Stage #3: With water; sodium carbonate In dichloromethane	55.55 55. (3-(4-(3-Methoxyazetidin-1-yl)methyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone Intermediate 55A (0.15 g, 0.40 mmol) was dissolved in dry DCM (6 mL) and 3-methoxyazetidine hydrochloride (64 mg, 0.51 mmol) was added followed by triethylamine (0.071 mL, 0.51 mmol). The reaction mixture was stirred at RT for 30 min and then sodium triacetoxyborohydride (126 mg, 0.59 mmol) was added. The mixture was stirred for 2 h and then diluted with DCM and transferred to a separatory funnel. The organic layer was washed with an aqueous solution of Na2CO3, dried (phase separator) and evaporated. The crude product was purified by flash column chromatography eluting with a mixture of DCM and MeOH, which contained 2M NH3 (30:1). There was obtained 135 mg (76%) of 55 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.93 (m, 2H), 3.25 (s, 3H), 3.58 (m, 4H), 3.89 (s, 3H), 4.05 (m, 1H), 4.32 (m, 1H), 4.63 (m, 1H), 4.75 (m, 1H), 5.06 (m, 1H), 5.11 (m, 1H), 6.73 (d, 1H), 7.02 (d, 2H), 7.22 (d, 2H), 8.10 (d, 2H), MS (APCI+) m/z 451 [M+H]+, LC purity: 97%.

Reference： [1]Current Patent Assignee: PFIZER INC; ASTRAZENECA PLC; TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2012/10189, 2012, A1 Location in patent: Page/Page column 41-42

13
[ 148644-09-1 ]
[ 1380329-77-0 ]
[ 1380329-99-6 ]

Yield	Reaction Conditions	Operation in experiment
66.6%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; ethyl acetate at 20 - 70℃; Inert atmosphere;	24 Example 24 4-(3-Methoxyazetidine-1-carbonyl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), 3-methoxyazetidine hydrochloride (37.5 mg, 304 μmol), diisopropylethylamine (241 μl, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7.00 ml) is stirred for 3 hours at 70° C. under nitrogen atmosphere in a closed vessel, and then over the weekend at room temperature. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording 4-(3-Methoxyazetidine-1-carbonyl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (75 mg, 66.6%) as a very insoluble white solid. mp.: 269-270° C. MS: m/z=432.3 (M+H+).
66.6%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; ethyl acetate at 20 - 70℃; Inert atmosphere;	24 A mixture of l-methyl-5-(2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7-ylcarbamoyl)-lH-pyrazole-4- carboxylic acid (100 mg, 276 μιηο), 3-methoxyazetidine hydrochloride (37.5 mg, 304 μιηο) , diisopropylethylamine (241 μ, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μ, 690 μιηο) in tetrahydrofurane (7.00 ml) is stirred for 3 hours at 70 °C under nitrogen atmosphere in a closed vessel, and then over the weekend at room temperature. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording 4-(3-Methoxyazetidine-l- carbonyl)-l-methyl-N-(2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-lH-pyrazole-5-carboxamide (75 mg, 66.6%) as a very insoluble white solid, mp.: 269-270°C. MS: m/z= 432.3 (M+H+).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2012/142665, 2012, A1 Location in patent: Page/Page column 25
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2012/76430, 2012, A1 Location in patent: Page/Page column 71-72

14
3-methoxyazetidine hydrochloride [ No CAS ]
[ 19099-93-5 ]
C₁₇H₂₄N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: 3-methoxyazetidine hydrochloride; benzyl 4-oxo-1-piperidinecarboxylate With acetic acid In tetrahydrofuran at 20℃; for 0.666667h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; Cooling with ice;	4.1.15.1 A mixture of 5.0 g 1 -(Benzyloxycarbonyl)-4-piperidinone and 2.9 g 3-Methoxy-azetidine hydrochloride in 20 ml tetrahydrofuran was acidified with glacial acetic acid (pH 5 - 6) and stirred at ambient temperature for 40 min. The mixture was cooled with ice, 7.8 g sodium triacetoxyborohydride were added and the mixture was stirred at ambient temperature overnight. The mixture was quenched with aqueous potassium carbonate solution and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo. Yield: 6.5 g of 1.17 (99% of theory) Analysis: [M+H]+ = 305; HPLC-MS (method P) Rt = 0.90 min

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2013/156608, 2013, A1 Location in patent: Page/Page column 67

15
3-methoxyazetidine hydrochloride [ No CAS ]
[ 19099-93-5 ]
[ 56553-60-7 ]
C₁₇H₂₄N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%		4.1.15 Synthesis of Amines with Formula 9 According to Scheme 1b Synthesis of 4-(3-Methoxy-azetidin-1-yl)-piperidine (9.3) for Example 70 [0396] Step 1 [0397] A mixture of 5.0 g 1-(Benzyloxycarbonyl)-4-piperidinone and 2.9 g 3-Methoxy-azetidine hydrochloride in 20 ml tetrahydrofuran was acidified with glacial acetic acid (pH 5-6) and stirred at ambient temperature for 40 min. The mixture was cooled with ice, 7.8 g sodium triacetoxyborohydride were added and the mixture was stirred at ambient temperature overnight. The mixture was quenched with aqueous potassium carbonate solution and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo. [0398] Yield: 6.5 g of I.17 (99% of theory) Analysis: [M+H]+=305; HPLC-MS (method P) Rt=0.90 min

Reference： [1]Patent: US2013/281430,2013,A1 .Location in patent: Paragraph 0395; 0396; 0397; 0398

16
[ 148644-09-1 ]
[ 1537208-12-0 ]
[ 1537207-71-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane at 90℃; Inert atmosphere;	x34 (S)-1-(6-(3-Methoxyazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine To a microwave vial containing 3-methoxyazetidine hydrochloride (500 mg, 4.05 mmol) were added KOt-Bu (1339 mg, 11.93 mmol) and DME (8 mL) under an atmosphere of nitrogen. The mixture was heated to 90°C in a sand bath. A solution of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (461 mg, 1.82 mmol) in DME (8 mL) was added dropwise to the hot suspension. The mixture was stirred at 90°C overnight. Additional KOt-Bu (1956 mg, 17.43 mmol) was added and the mixture was heated to 90°C for 90 minutes. The reaction mixture was subsequently concentrated in vacuo. The residue was dispersed in DMSO/MeOH (1 : 1, 10 mL), filtered, and purified by preparative HPLC eluting with 15-40% ACN in water (with 0.035% NH4HCO3). The fractions containing the desired product were combined and concentrated in vacuo to give the title compound as an off-white solid (469 mg, 99%). ESI-MS m/z [M+H]+ calc'd for C14H20N4O, 261; found 261.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2014/11568, 2014, A1 Location in patent: Paragraph 0273; 0274

17
[ 148644-09-1 ]
[ 1562374-89-3 ]
[ 1562375-00-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃;	2A; 2B.1 Step 1: Preparation of (1-(2-chloro-6-cyclopropylbenzoyl)-3-iodo- 1H-indazol-6-yl)(3-methoxyazetidin- 1-yl)methanone (C-i). Step 1: Preparation of (1-(2-chloro-6-cyclopropylbenzoyl)-3-iodo- 1H-indazol-6-yl)(3-methoxyazetidin- 1-yl)methanone (C-i).To a vial was added 1 -(2-chloro-6-cyclopropylbenzoyl)-3 -iodo- 1 H-indazole-6-carboxylic acid (889 mg, 1.905 mmol), 3-methoxyazetidine hydrochloride (330 mg, 2.67 mmol), HATU (1449mg 3 81 mmol) DIPEA (1331 tl 762 mmol) and DMF (3810 tl) The solution was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed 2x with aqueous sodium hydrogen carbonate and lx with brine. The aqueous layer was back extracted once with ethyl acetate, combined organic layers were dried with Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc/Hexane 10-95%) to give desired product as a yellow solid. (1.02 g,100%) LCMS (ESI) calc’d for C22H,9C11N303 [M+H]: 536, found: 536.
100%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃;	2A.1; 2B.1 Step 1: Preparation of (1-(2-chloro-6-cyclopropylbenzoyl)-3-iodo-1H-indazol-6-yl)(3-methoxyazetidin-1-yl)methanone (C-1) Step 1: Preparation of (1-(2-chloro-6-cyclopropylbenzoyl)-3-iodo-1H-indazol-6-yl)(3-methoxyazetidin-1-yl)methanone (C-1) [0315] To a vial was added 1-(2-chloro-6-cyclopropylbenzoyl)-3-iodo-1H-indazole-6-carboxylic acid (889 mg, 1.905 mmol), 3-methoxyazetidine hydrochloride (330 mg, 2.67 mmol), HATU (1449 mg, 3.81 mmol), DIPEA (1331 μl, 7.62 mmol), and DMF (3810 μl). The solution was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed 2× with aqueous sodium hydrogen carbonate and 1× with brine. The aqueous layer was back extracted once with ethyl acetate, combined organic layers were dried with Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc/Hexane 10-95%) to give desired product as a yellow solid. (1.02 g, 100%) LCMS (ESI) calc'd for C22H19ClIN3O3 [M+H]+: 536. found: 536.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/28597, 2014, A2 Location in patent: Page/Page column 63; 64
[2]Current Patent Assignee: MERCK & CO INC - US2015/191434, 2015, A1 Location in patent: Paragraph 0315

18
[ 148644-09-1 ]
[ 1562194-75-5 ]
[ 1562195-50-9 ]

Yield	Reaction Conditions	Operation in experiment
95.4%	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 40℃; for 3h;	10.A.i Preparation of (1-(2-chloro-6-(trifluoromethyl)benzyl)-4-fluoro-3-iodo-1H-indazol-6-yl)(3-methoxyazetidin-1-yl)methanone (K-2) i). Preparation of (1-(2-chloro-6-(trifluoromethyl)benzyl)-4-fluoro-3-iodo-1H-indazol-6-yl)(3-methoxyazetidin-1-yl)methanone (K-2) To a mixture of 1-(2-chloro-6-(trifluoromethyl)benzyl)-4-fluoro-3-iodo-1H-indazole-6-carboxylic acid (K-1) (500 mg, 1 mmol), HATU (456 mg, 1.2 mmol) and 3-methoxyazetidine hydrochloride (246 mg, 2 mmol) in DMF (10 mL) was added DIEA (387 mg, 3 mmol). The mixture was stirred at 40° C. for 3 h, and then poured into H2O (50 mL). The precipitated solid was collected by filtration, washed with water (20 mL*5) and dried in vacuo to afford the title compound (543 mg, 95.4%) as a yellow solid without further purification. LCMS (ESI) calc'd for C20H15ClF4IN3O2 [M+H]+: 568. found: 568.
543 mg	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 40℃; for 3h;	10A.i Preparation of (l-(2-chloro-6-(trifluoromethyl)benzyl)-4-fluoro-3-iodo-lH-indazol-6- yl)(3-methoxyazetidin-l-yl)methanone (K-2). To a mixture of l-(2-chloro-6-(trifluoromethyl)benzyl)-4-fluoro-3-iodo-lH-indazole-6- carboxylic acid (K-l) (500 mg, 1 mmol), HATU (456 mg, 1.2 mmol) and 3-methoxyazetidine hydrochloride (246 mg, 2 mmol) in DMF (10 mL) was added DIEA (387 mg, 3 mmol). The mixture was stirred at 40 °C for 3 h, and then poured into H20 (50 mL). The precipitated solid was collected by filtration, washed with water (20 mL x 5) and dried in vacuo to afford the title compound (543 mg, 95.4%) as a yellow solid without further purification. LCMS (ESI) calc'd for C2oHi5ClF4IN302 [M+H]+: 568, found: 568.

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2015/210687, 2015, A1 Location in patent: Paragraph 0310
[2]Current Patent Assignee: MERCK & CO INC - WO2014/28591, 2014, A2 Location in patent: Page/Page column 78-79

19
3-methoxyazetidine hydrochloride [ No CAS ]
[ 2486-69-3 ]
[ 1400287-07-1 ]

Yield	Reaction Conditions	Operation in experiment
59%	With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran;	General procedure: Preparation 92: (4-amino-3-methoxyphenyl)(3-methoxyazetidin-1 -yl)methanone Method G HATU (2.70 g, 7.10 mmol) was added to a solution of 4-amino-3- methoxybenzoic acid (880 mg, 5.26 mmol), 3-methoxyazetidine hydrochloride (0.971 g, 7.86 mmol) and DIPEA (2.85 mL, 16.32 mmol) in THF (15 mL) at room temperature. THF was removed under reduced pressure, and the residue partitioned between EtOAc and saturated aqueous NaHC03. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 100% EtOAc in cyclohexane followed by a second chromatography eluting with 0 to 4% MeOH in DCM to afford the title compound (728 mg, 59%). 1 H NMR (500 MHz, CDCI3): delta 7.24 (d, J = 1 .7 Hz, 1 H), 7.06 (dd, J = 8.1 , 1.8 Hz, 1 H), 6.66 (d, J = 8.0 Hz, 1 H), 4.42 (br s, 2H), 4.31 - 3.99 (m, 5H), 3.91 (s, 3H), 3.34 (s, 3H).
59%	With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; at 20℃;	Preparation 28: (4-amino-3-methoxyphenyl)(3-methoxyazetidin-1 -yl)methanone HATU (2.70 g, 7.10 mmol) was added to a solution of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (880 mg, 5.26 mmol), 3-methoxyazetidine hydrochloride (0.971 g, 7.86 mmol) and DIPEA (2.85 mL, 16.32 mmol) in THF (15 mL) at room temperature. THF was removed under reduced pressure, and the residue partitioned between EtOAc and saturated aqueous NaHC03. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 1 00% EtOAc in cyclohexane followed by a second chromatography eluting with 0 to 4% MeOH in DCM to afford the title compound (728 mg, 59%). 1 H NMR (500 MHz, CDCI3): delta 7.24 (d, J = 1 .7 Hz, 1 H), 7.06 (dd, J = 8.1 , 1 .8 Hz, 1 H), 6.66 (d, J = 8.0 Hz, 1 H), 4.42 (br s, 2H), 4.31 - 3.99 (m, 5H), 3.91 (s, 3H), 3.34 (s, 3H).

Reference： [1]Patent: WO2014/37751,2014,A1 .Location in patent: Paragraph 00358; 00359
[2]Patent: WO2014/37750,2014,A1 .Location in patent: Paragraph 0038-0041

20
3-methoxyazetidine hydrochloride [ No CAS ]
[ 619-14-7 ]
[ 1578484-81-7 ]

Yield	Reaction Conditions	Operation in experiment
66%	With triethylamine; HATU In dichloromethane at 20℃; for 0.5h;	115 Preparation 115: (3-Hydroxy-4-nitrophenyl)(3-methoxyazetidin-1 -yl)methanone Preparation 115: (3-Hydroxy-4-nitrophenyl)(3-methoxyazetidin-1 -yl)methanone HATU (2.1 g, 5.5 mmol) was added to a solution of 3-hydroxy-4-nitrobenzoic acid (915 mg, 5 mmol), triethylamine (1 .1 g, 1 1 mmol)) and 3-methoxyazetidine hydrochloride (740 mg, 5.5 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction was partitioned between EtOAc (30 mL) and water (30 mL). The organic phase was collected, washed with water, brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 100% ethyl acetate to 3% methanol in ethyl acetate to afford the title compound as a pale yellow solid (830 mg, 66%). 1 H NMR (500 MHz, DMSO-d6): δ 1 1 .3 (br s, 1 H), 7.88 (d, J = 8.5 Hz, 1 H), 7.33 (d, J = 1 .7 Hz, 1 H), 7.17 (dd, J = 8.4 1 .7 Hz, 1 H), 4.42 - 4.40 (m, 1 H), 4.26 - 4.21 (m, 2H), 4.1 1 - 4.09 (m, 1 H), 3.86 - 3.82 (m, 1 H), 3.22 (s, 3H). LCMS (ESI) R, = 1 .81 minutes MS m/z 253 [M+H]+

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK - WO2014/37751, 2014, A1 Location in patent: Paragraph 00398-00400

21
[ 148644-09-1 ]
[ 1382998-03-9 ]
[ 1426700-73-3 ]

Yield	Reaction Conditions	Operation in experiment
70%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 80℃; for 2h; Inert atmosphere;	319.1 Step 1. 4-acetyl-6-chloro-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile Step 1. 4-acetyl-6-chloro-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile To a mixture of 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile (50 mg, 0.1 mmol, Example 318, Step 1), 3-methoxyazetidine hydrochloride (21 mg, 0.17 mmol Chem-Impex catalogNo.20140) and cesium carbonate (70. mg, 0.21 mmol) in 1,4-dioxane (4 mL) was added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (40 mg, 0.07 mmol) and tris(dibenzylideneacetone)dipalladium (0) (60 mg, 0.07 mmol). The reaction mixture was degassed with N2. The reaction was heated at 80° C. for 2 hrs and was monitored by LCMS. The reaction was allowed to cool to room temperature, was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the crude product. The product was purified by FCC on silica gel eluting (hexanes: EtOAc 0-70%) gradient to give to 4-acetyl-6-chloro-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile as clear oil (0.030 g, 70%). LCMS calculated for C15H18ClN2O3(M+H)+: m/z=309.1. found: 309.1.

Reference： [1]Current Patent Assignee: INCYTE CORP - US2014/249132, 2014, A1 Location in patent: Paragraph 0523

22
3-methoxyazetidine hydrochloride [ No CAS ]
[ 3993-78-0 ]
4-(3-methoxyazetidin-1-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With N-ethyl-N,N-diisopropylamine; In water; at 180℃; under 15001.5 Torr; for 0.5h;Ionic liquid; Microwave irradiation;	A microwave vial was charged with 4-chloropyrimidin-2-amine (300 mg, 2.32 mmol), isopropylamine (828 mg, 1.2 ml, 14.0 mmol) and water (1.0 mL). The vial was flushed with argon, closed and stirred at 180 C for 30 min under microwave irradiation (caution: the pressure reached >20 bar). The reaction mixture was cooled to room temperature and extracted with dichloromethane and water. The organic layer was washed with water and the aqueous layers were back-extracted with dichloromethane. The organic layers were combined, dried over Na2S04, filtered and concentrated. The product was obtained after triturating the residue with diethyl ether and a few drops of ethyl acetate as off-white solid (282 mg, 80 ).MS: m/z = 153.4 (M+H)+ ; The product was obtained starting from 4-chloropyrimidin-2-amine (300 mg, 2.32 mmol), 3- methoxyazetidine hydrochloride (572 mg, 4.63 mmol) and N,N-diisopropylethylamine (888 mg, 1.2 ml, 6.87 mmol) according to the method described in example 77, step 1 after final trituration with ethyl acetate as light yellow solid (179 mg, 43 ). MS: m/z = 181.4 (M+H)+

Reference： [1]Patent: WO2014/187762,2014,A1 .Location in patent: Page/Page column 67-69

23
[ 148644-09-1 ]
[ 39856-50-3 ]
[ 1434053-96-9 ]

Yield	Reaction Conditions	Operation in experiment
96%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 3h; Inert atmosphere;	323a Example 323a 5-(3-Methoxyazetidin-1-yl)-2-nitropyridine 323a Example 323a 5-(3-Methoxyazetidin-1-yl)-2-nitropyridine 323a A 100-mL round bottomed flask was equipped with a reflux condenser was charged with 3-methoxyazetidine hydrochloride (1.0 g, 8.09 mmol), 5-bromo-2-nitropyridine (1.97 g, 9.71 mmol), Pd2(dba)3 (370.1 mg, 0.404 mmol), Xantphos (467.6 mg, 0.809 mmol), Cs2CO3 (7.9 g, 24.3 mmol), and dioxane (50 mL). After bubbling nitrogen through the reaction mixture for 20 minutes, it was heated at 100°C under N2 protection for 3 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 323a as a yellow solid (1.63 g, 96%). MS-ESI: [M+H]+ 210.2

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - EP2773638, 2015, B1 Location in patent: Paragraph 1313; 1314

24
[ 148644-09-1 ]
[ 1268241-81-1 ]
[ 2083598-75-6 ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium acetate; sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 1h;	10 Intermediate 10 4-Chloro-12-[(3-methoxyazetidin-1 -yl)methyl1-6-(morpholin-4-yl)-8-oxa-3,5, 10- thazathcyclor7.4.0.0²'⁷1thdeca-1 ( 13), 2(7), 3, 5, 9, 1 1 -hexaene Intermediate 10 4-Chloro-12-[(3-methoxyazetidin-1 -yl)methyl1-6-(morpholin-4-yl)-8-oxa-3,5, 10- thazathcyclor7.4.0.02'71thdeca-1 ( 13), 2(7), 3, 5, 9, 1 1 -hexaene To a suspension of Intermediate 6 (2.0 g, 6.28 mmol, 1 eq), 3-methoxyazetidine hydrochloride (1 .94 g, 15.7 mmol, 2.5 eq) and NaOAc (1 .29 g, 15.7 mmol, 2.5 eq) in anhydrous 1 ,2-dichloroethane (80 mL) was added NaBH(OAc)3 (2.66 g, 12.6 mmol, 2 eq). The reaction mixture was stirred at rt for 1 h. Then, it was partitioned with 0.5N NaOH (50 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were dried over MgS04, filtered and the solvent was removed by evaporation in vacuo. Purification by silica gel column chromatography with EtOAc/MeOH (1 :0-19: 1 ) followed by recrystallization from EtOAc yielded Intermediate 10 as an off-white solid (1 .61 g, 66%). 1 H NMR (300 MHz, DMSO-de) δΗ: 8.56 (d, J=2.3Hz, 1 H), 8.43 (d, J=2.3Hz, 1 H), 3.92-4.08 (m, 5H), 3.72-3.86 (m, 6H), 3.46-3.54 (m, 2H), 3.15 (s, 3H), 2.89-2.99 (m, 2H). MS (ES+) 390.1 (100%, [M+H]+).

Reference： [1]Current Patent Assignee: CONVALIFE SHANGHAI - WO2017/29519, 2017, A1 Location in patent: Page/Page column 25

25
[ 148644-09-1 ]
[ 2083598-74-5 ]
[ 2083598-58-5 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium acetate; sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 22h;	E Example E 4-(5-Fluoro-1 H-indol-4-yl)-12-[(3-methoxyazetidin-1 -yl)methyl1-6-(morpholin-4- l)-8-oxa-3,5, 10-triazatricvclor7.4.0.0²'⁷1trideca-1 (13 2(7), 3, 5, 9, 1 1 -hexaene Example E 4-(5-Fluoro-1 H-indol-4-yl)-12-[(3-methoxyazetidin-1 -yl)methyl1-6-(morpholin-4- l)-8-oxa-3,5, 10-triazatricvclor7.4.0.02'71trideca-1 (13 2(7), 3, 5, 9, 1 1 -hexaene To a suspension of Intermediate 8 (50 mg, 0.12 mmol, 1 eq), 3- methoxyazetidine hydrochloride (44 mg, 0.36 mmol, 3 eq) and NaOAc (29 mg, 0.36 mmol, 3 eq) in anhydrous CH2CI2 (8 mL) was added NaBH(OAc)3 (51 mg, 0.24 mmol, 2 eq). The reaction mixture was stirred at rt for 22 h whereupon 1 M NaOH (10 mL) and CH2CI2 (5 mL) were added. The phases were separated and the aqueous phase re-extracted with CH2CI2 (2 x 5 mL). The combined organic phases were washed with 50% brine (5mL), dried (MgS04), and concentrated by evaporation in vacuo. The residue was dissolved in CH2CI2/MeOH (1 : 1 , 15 mL) and agitated with MP-TMT resin (300 mg, 0.68mmol/g, 5 eq) overnight. The resin was then filtered off, washed with CH2CI2/MeOH (1 : 1 , 20 mL) and the solvent was removed by evaporation in vacuo. Purification by silica gel column chromatography eluting with EtOAc/MeOH (1 :0-6: 1 ) yielded Example E as a white solid (41 mg, 70%). 1 H NMR (300MHz, CDCI3) δΗ: 8.57 (d, J=2.2 Hz, 1 H), 8.55 (d, J=2.2 Hz, 1 H), 8.39 (br s, 1 H), 7.41 (ddd, J=8.8, 3.9, 0.8 Hz, 1 H), 7.29-7.35 (m, 1 H), 7.08 (dd, J=10.9, 8.9 Hz, 1 H), 6.92-6.99 (m, 1 H), 4.17-4.27 (m, 4H), 4.10 (quin, J=5.7 Hz, 1 H), 3.84-3.95 (m, 6H), 3.69-3.78 (m, 2H), 3.27 (s, 3H), 3.05-3.14 (m, 2H). MS (ES+) 489 (100%, [M+H]+).

Reference： [1]Current Patent Assignee: CONVALIFE SHANGHAI - WO2017/29519, 2017, A1 Location in patent: Page/Page column 38

26
[ 148644-09-1 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
86%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 3h; Inert atmosphere;	1 Step 1: trans-4-((tert-Butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)-N-(3-(3-methoxyazetidin- 1- yl)phenyl)cyclohexanecarboxamide j00494j A mixture of Intermediate 2.6 (138 mg, 0.22 mmol), 3-methoxyazetidine hydrochloride (32 mg, 0.26 mmol), Cs2CO3 (215 mg, 0.66 mmol), Xantphos (17 mg, 0.029 mmol), Pd2(dba)3 (8 mg, 0.014 mmol) and dioxane (1.5 mL) was degassed with 3 vacuum/N2 cycles, stirred at 100 °C for 3 h, and then allowed to cool to rt. The reaction mixture was poured into 20 mL saturated NaHCO3 and extracted with 20 mL ethyl acetate. The organic layer was washed with 20 mL brine, dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography (0-20% ethyl acetate in hexanes) to give trans-4-((tert-butyldimethyl silyl)oxy)N-((trans-4-(4-methoxy-3 -methylphenyl)cyclohexyl)methyl)-N-(3 -(3 -methoxyazetidin- 1- yl)phenyl)cyclohexanecarboxamide (119 mg, 86%) as a pale yellow foam. ‘H NMR (400 IVIFIz, DMSO-d6): 7.25 (t, 1H), 6.98-6.93 (m, 2H), 6.78 (d, 1H), 6.55 (d, 1H), 6.44 (d, 1H), 6.27 (br s, 1H), 4.35-4.28 (m, 1H), 4.05 (t, 2H), 3.72 (s, 3H), 3.64-3.58 (m, 2H), 3.54-3.45 (m, 3H), 3.24 (s, 3H), 2.37-2.28 (m, 1H), 2.09 (s, 3H), 2.13-2.03 (m, 1H), 1.78-1.68 (m, 6H), 1.65-1.57 (m, 2H),1.50-1.38 (m, 3H), 1.35-1.22 (m, 2H), 1.09-0.96 (m, 2H), 0.80 (s, 9H), 0.92-0.77 (m, 2H), -0.013 (s, 6H); LCMS: 635.7 [M+H].

Reference： [1]Current Patent Assignee: METACRINE INC - WO2017/49173, 2017, A1 Location in patent: Paragraph 00494

27
[ 148644-09-1 ]
[ 1033956-26-1 ]
[ 2098570-89-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With chloro(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)[2-(2’-amino-1,1‘-biphenyl)]palladium(II) 2nd generation; caesium carbonate In toluene at 90℃; Inert atmosphere;	26 Intermediate 26 Methyl 2-methoxy-2-[3-(3-methoxyazetidin-1-yl)phenyl]acetate Intermediate 26 Methyl 2-methoxy-2-[3-(3-methoxyazetidin-1-yl)phenyl]acetateTo a mixture of methyl 2-(3-bromophenyl)-2-methoxyacetate (Intermediate 19, 524 mg, 2.02 mmol) and 3-methoxyazetidine hydrochloride (250 mg, 2.02 mmol) in toluene (20 mL) was added Ruphos palladium(II) phenethylamine chloride (61.1 mg, 0.07 mmol), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (31.2 mg, 0.07 mmol) and caesium carbonate (2307 mg, 7.08 mmol). The reaction was sparged with nitrogen for ˜5 minutes and then heated to 90° C., stirring under nitrogen overnight. The reaction was cooled to r.t. before being diluted with EtOAc and water. The organic layer was dried (MgSO4), filtered and the solvent evaporated under reduced pressure. Purification by FCC (SiO2, 0-25% EtOAc in heptanes) gave methyl 2-methoxy-2-[3-(3-methoxyazetidin-1-yl)phenyl]acetate (450 mg, 84%) as an oil. 1H NMR (400 MHz, CDCl3, 30° C.) δ3.33 (3H, s), 3.39 (3H, s), 3.68-3.74 (5H, m), 4.07-4.13 (2H, m), 4.29-4.36 (1H, m), 4.70 (1H, s), 6.43 (1H, ddd), 6.51-6.54 (1H, m), 6.79 (1H, d), 7.19 (1H, t). m/z: ES+ [M+H]+ 266.

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK - US2017/152255, 2017, A1 Location in patent: Paragraph 0317; 0318

28
[ 148644-09-1 ]
[ 2170143-77-6 ]
[ 2170136-55-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine In tetrahydrofuran at 20℃; for 0.75h;	54 Example 54: 2-((3,5-Dicyano-4-ethyl-6-(3-methoxyazetidin-1-yl)pyridin-2-yl)thio)-2- phenylacetamide A solution of 2-[(6-bromo-3,5-di yl]-2-phenyl-acetamide (synthesis described in example 6 step 1, 20 mg, 0.05 mmol) in tetrahydrofuran (1 mL) was treated with 3-methoxyazetidine hydrochloride (16 mg, 0.13 mmol) and triethylamine (0.02 mL, 0.13 mmol). The resultant solution was stirred at ambient temperature for 45 minutes, dry loaded onto SiO2 (0.9 g) and chromatographed on SiO2 (4 g RediSep cartridge) eluting with 0-5% MeOH/CH2Cl2 to give 2-[[3,5-dicyano-4-ethyl-6-(3-methoxyazetidin-1-yl)-2- pyridyl]sulfanyl]-2-phenyl-acetamide (20 mg, 100% yield) as a white solid. LCMS m/z = 408 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.86 (s, 1H), 7.57 - 7.46 (m, 2H), 7.44 - 7.28 (m, 4H), 5.55 (s, 1H), 4.60 (br s, 2H), 4.39 - 4.09 (m, 3H), 3.28 (br s, 3H), 2.69 (q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H).

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; GLAXOSMITHKLINE PLC - WO2017/216726, 2017, A1 Location in patent: Page/Page column 605

29
[ 148644-09-1 ]
[ 475279-45-9 ]
[ 2222716-64-3 ]

Yield	Reaction Conditions	Operation in experiment
62.97%	With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 48h;	180 Synthesis of compound 180.1 To a solution of N-(5-fluoro-2-nitrophenyl)-N-methylmethanesulfonamide (2.0g, 8.06mmol, l .Oeq) in Ν,Ν-dimethylformamide (20mL) was added cesium carbonate (1.35g, 9.83mmol, 1.22eq) followed by addition of 3-methoxyazetidine hydrochloride (1.21g, 9.83mmol, 1.22eq) dropwise. The reaction mixture was stirred at 60°C for 48h. After completion of reaction, reaction mixture was transferred into 10% solution of sodium phosphate (90mL) and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 35% ethyl acetate in hexane as eluent to obtain 180.1. (1.6g, 62.97%). MS(ES): m/z 316.34 [M+H]+

Reference： [1]Current Patent Assignee: NIMBUS THERAPEUTICS INC - WO2018/71794, 2018, A1 Location in patent: Paragraph 00830; 00831

30
3-methoxyazetidine hydrochloride [ No CAS ]
[ 42521-09-5 ]
methyl 2‐chloro‐6‐(3‐methoxyazetidin‐1‐yl)pyridine‐4‐carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	In N,N-dimethyl-formamide; at 20℃; for 8h;Inert atmosphere;	Under the protection of nitrogen,2,6-dichloro-4-carboxylic acid methyl pyridine 200 g (1 mol),N,N-dimethylformamide 3000g and 3-methoxyazetidine hydrochloride 123g (1mol) were added to the reaction flask and reacted at room temperature for 8 h.LCMS monitored the reaction of the starting material completely and added 10,000 mL of ethyl acetate.After stirring for 10 min, the reaction solution was washed with a saturated sodium chloride solution.Until the organic phase does not contain N-methylpyrrolidone, the organic phase is separated,After drying over anhydrous sodium sulfate, 1000 mL of methyl t-butyl ether was added.Stirring at 10 C,Drying by suction filtration to obtain methyl 2-chloro-4-carboxylate-6-(3-methoxyazetidinyl)pyridine235g, the yield is 92%.
84%	In 1-methyl-pyrrolidin-2-one; at 20℃; for 10h;Inert atmosphere;	Under the protection of nitrogen,The 2,6-dichloro-pyridine-4-carboxylate 20g (0.1mol)And N-methylpyrrolidone 200g,3-methoxyazetidine hydrochloride 12 g (0.1 mol) was added to the reaction flask,Reaction at room temperature for 10 h,LCMS monitors the reaction of the starting material completely,After adding 1000 mL of ethyl acetate and stirring for 10 min, the reaction solution was washed with a saturated sodium chloride solution until the organic phase did not contain N-methylpyrrolidone, and the organic phase was separated, dried over anhydrous sodium ,Stirring at 10 C,Drying by suction filtration to give methyl 2-chloro-6-(3-methoxyazetidin-1-yl)pyridine-4-Carboxylate 21g,The yield is 84%;

Reference： [1]Patent: CN108148068,2018,A .Location in patent: Paragraph 0053; 0060; 0061; 0062
[2]Patent: CN108329334,2018,A .Location in patent: Paragraph 0041; 0042; 0043; 0044; 0045; 0046

31
[ 148644-09-1 ]
[ 4746-97-8 ]
[ 2226531-66-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: 3-methoxyazetidine hydrochloride; cyclohexanedione monoethylene ketal With sodium acetate In 1,2-dichloro-ethane at 20℃; for 0.333333h; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃;	1 Step 1: to a solution of compound 14a-4 (1.36 g, 8.71 mmol) and compound 22a-1 (900 mg, 7.26 mmol) in 1,2-dichloroethane was added sodium acetate (1.48 g, 10.9 mmol). After the reaction was stirred for 20 min at room temperature,sodium triacetoxyborohydride (4.6 g, 21.8 mmol) was added, and the reaction solution was stirred at roomtemperature overnight. The reaction was followed by LC-MS until completion. The reaction solution was quenched witha saturated sodium hydroxide aqueous solution, adjusted to pH 8-9, and extracted with dichloromethane. The organicphase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound22a-2 as a yellow solid (1.4 g, 85%), MS m/z (ESI): 228[M+H]+.

Reference： [1]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - EP3441388, 2019, A1 Location in patent: Paragraph 0155-0156

32
[ 148644-09-1 ]
[ 2230979-04-9 ]
[ 2230979-05-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-ethyl-N,N-diisopropylamine In butan-1-ol at 100℃; for 4h;	775.3 Step 3: Preparation of N-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxyazetidin-1-yl)pyrido[3,4-d]pyrimidine-2-amine N-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-8-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl) pyrido[3,4-d]pyrimidine-2-amine (325 mg, 0.68 mmol), 3-methoxyazetidine hydrochloride (252 mg, 2.04 mmol) and DIPEA (439 mg, 3.4 mmol) were dissolved in n-butanol (15 mL), the mixture was heated to 100° C. for 4 h, and then the mixture was concentrated, extracted with ethyl acetate and separated by silica gel column chromatography to obtain compound N-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxy azetidin-1-yl)pyrido[3,4-d]pyrimidine-2-amine (350 mg, yield: 97%). MS m/z (ESI): 529 [M+H]+.

Reference： [1]Current Patent Assignee: ABBISKO THERAPEUTICS CO., LTD.; ABBISKO PHARMACEUTICALS - US2019/270742, 2019, A1 Location in patent: Paragraph 0401-0402

33
[ 148644-09-1 ]
[ 2375477-39-5 ]
[ 2375477-41-9 ]

Yield	Reaction Conditions	Operation in experiment
77%	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 20℃;	DR 6-(3-Methoxyazetidine-1-carbonyl)-/V-(pyrazin-2-yl)-/V-({5-[5- (0901) (trifluoromethyl)-1,2,4-oxadiazol-3-yl]thiophen-2-yl}methyl)pyridazin-3- amine To a solution of (1) (51 mg, 0.1 1 mmol) in DMF (1 ml_) was added diisopropylethylamine (0.08ml_, 0.45mmol) followed by HATU (65mg, 0.17mmol) and 3-methoxyazetidine hydrochloride (28mg, 0.22mmol). The reaction mixture was stirred at rt overnight. It was then diluted with EtOAc (10ml_) and washed with HCI solution (1 M, 2 x 10ml_), then brine (10ml_). The organics were dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel column chromatography with EtOAc/MeOH (1 :0-4: 1 ) yielded (DR) as an off-white solid (45mg, 77%). (0904) LCMS (ES): Found 518.9 [M+Hf. (0905) 1H NMR (300 MHz, DMSO-cf6), d: 8.87 (d, J=1.1 Hz, 1 H), 8.43-8.55 (m, 1 H), 8.38 (d, J=2.4 Hz, 1 H), 7.99 (d, J= 9.2 Hz, 1 H), 7.82 (d, J=9.4 Hz, 1 H), 7.75 (d, J= 3.8 Hz, 1 H), 7.31 (d, J= 3.8 Hz, 1 H), 5.77 (s, 2H), 4.73-4.86 (m, 1 H), 4.40 (m, 1 H), 4.21 -4.35 (m, 2H), 3.83-3.97 (m, 1 H), 3.25 (s, 3H). (0906) 19F NMR (282 MHz, DMSO-cf6), d: -64.79 (s, 3F).

Reference： [1]Current Patent Assignee: KARUS THERAPEUTICS LIMITED - WO2019/166824, 2019, A1 Location in patent: Page/Page column 117; 118

34
3-methoxyazetidine hydrochloride [ No CAS ]
[ 101066-61-9 ]
C₁₀H₁₃ClN₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium acetate; sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 2h;	To a suspension of <strong>[101066-61-9]2-chloroisonicotinaldehyde</strong> (1) (1.00 g, 7.07 mmol), 3-methoxyazetidine hydrochloride (1.75 g, 14.13 mmol), and sodium acetate (1.74 g, 21.19 mmol) in 1 ,2-dichloroethane (20 mL) was added sodium triacetoxyborohydride (2.99 g, 14.13 mmol) and the mixture was stirred at rt for 2 hr. The reaction mixture was quenched with NaOH solution (5%, 20 mL) and phases separated. The aqueous phase was saturated with NaCI (ca 5 g required) and extracted with EtOAc (2 c 20 mL). The combined organics were concentrated in vacuo to afford 2 as a mobile yellow oil (1.53 g, quantitative).

Reference： [1]Patent: WO2019/166824,2019,A1 .Location in patent: Page/Page column 183; 184

35
[ 148644-09-1 ]
[ 2387402-99-3 ]
[ 2387403-11-2 ]

Yield	Reaction Conditions	Operation in experiment
67%	Stage #1: 3-methoxyazetidine hydrochloride With N-ethyl-N,N-diisopropylamine In methanol at 20℃; for 0.5h; Stage #2: methyl 7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxole-5-carboxylate In tetrahydrofuran; methanol at 20℃; for 1h; Stage #3: With lithium borohydride In tetrahydrofuran; methanol at -70℃; for 0.5h;	1 Step 1: Synthesis of methyl 7-chloro-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate A solution of 3-methoxyazetidine hydrochloride salt (8 g, 64.75 mmol) and N,N-diisopropylethylamine (12 mL, 68.9 mmol) in methanol (30 mL) was stirred at room temperature for 30 min before a solution of another solution of methyl 7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)-1,3-benzodioxole-5-carboxylate (Intermediate 4-Peak 2) (4.1 g, 12.10 mmol) in tetrahydrofuran (30 mL) was added. The reaction mixture was stirred at room temperature for 1 h then cooled to -70° C. Lithium borohydride (500 mg, 22.96 mmol) was added and the reaction stirred at -70° C. for 30 min [or until complete consumption of the starting material was observed by TLC, ethyl acetate/methanol 5:1]. Next, two batches of the reaction were combined and quenched with a saturated aqueous solution of ammonium chloride (120 mL) at 0° C. and the desired product was extracted with dichloromethane (200 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, gradient 0 to 14% methanol in dichloromethane) to give title compound (8.05 g, 67% yield, 83% purity) as a light yellow oil. A sample (50 mg) was purified further by preparative thin layer chromatography (silica gel, ethyl acetate:methanol 15:1). LCMS [M+H]+ m/z: calc'd. 410.2; found 410.1. 1H NMR (400 MHz, Methanol-d4) δ 7.39 (s, 1H), 3.95-3.91 (m, 1H), 3.73 (s, 3H), 3.59-3.51 (m, 2H), 3.16 (s, 3H), 2.97 (br dd, J=6.4, 8.0 Hz, 2H), 2.26 (s, 3H), 2.11-2.02 (m, 1H), 1.91-1.73 (m, 5H), 1.54 (s, 3H), 1.22-1.12 (m, 2H), 0.98-0.86 (m, 2H).
	Stage #1: 3-methoxyazetidine hydrochloride With N-ethyl-N,N-diisopropylamine In methanol at 20℃; for 0.5h; Stage #2: methyl 7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxole-5-carboxylate In tetrahydrofuran; methanol at 20℃; for 1h; Stage #3: With lithium borohydride In tetrahydrofuran; methanol at -70℃; for 0.5h;	1 Step 1: Synthesis of methyl 7-chloro-2-(4-(3-methoxyazetidin-l- yl)cyclohexyl)-2,4-dimethylbenzo [d] [1 ,3] dioxole-5-carboxylate A solution of 3-methoxyazetidine hydrochloride salt (8 g, 64.75 mmol) and N,N- diisopropylethylamine (12 mL, 68.9 mmol) in methanol (30 mL) was stirred at room temperature for 30 min before a solution of another solution of methyl 7-chloro-2,4-dimethyl- 2-(4-oxocyclohexyl)-l,3-benzodioxole-5-carboxylate (Intermediate 1- Peak 2) (4.1 g, 12.10 mmol) in tetrahydrofuran (30 mL) was added. The reaction mixture was stirred at room temperature for 1 h then cooled to -70 °C. Lithium borohydride (500 mg, 22.96 mmol) was added and the reaction stirred at -70 °C for 30 min [or until complete consumption of the starting material was observed by TLC, ethyl acetate/methanol 5: 1] Next, two batches of the reaction were combined and quenched with a saturated aqueous solution of ammonium chloride (120 mL) at 0 °C and the desired product was extracted with dichloromethane (200 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash (0087) chromatography (silica gel, gradient 0 to 14% methanol in dichloromethane) to give title compound (8.05 g, 67% yield, 83% purity) as a light yellow oil. A sample (50 mg) was purified further by preparative thin layer chromatography (silica gel, ethyl acetate: methanol 15: 1). LCMS [M+H]+ m/z: calc’d. 410.2; found 410.1. 1H MR (400 MHz, Methanol-^) d 7.39 (s, 1H), 3.95 - 3.91 (m, 1H), 3.73 (s, 3H), 3.59 - 3.51 (m, 2H), 3.16 (s, 3H), 2.97 (br dd, 7= 6.4, 8.0 Hz, 2H), 2.26 (s, 3H), 2.11 - 2.02 (m, 1H), 1.91 - 1.73 (m, 5H), 1.54 (s, 3H), 1.22 - 1.12 (m, 2H), 0.98 - 0.86 (m, 2H).

Reference： [1]Current Patent Assignee: MORPHOSYS AG - US2019/322651, 2019, A1 Location in patent: Paragraph 0128; 0129
[2]Current Patent Assignee: MORPHOSYS AG - WO2021/16409, 2021, A1 Location in patent: Paragraph 0052-0053

36
[ 148644-09-1 ]
[ 6684-39-5 ]
[ 1857062-52-2 ]

Yield	Reaction Conditions	Operation in experiment
77%	With triethylamine In dichloromethane at 22℃; for 1h; Inert atmosphere;	Intermediate 11.39: 2-Chloro-5-(3-methoxy-azetidine-1-sulfonyl)-pyridine A solution of 6-chloro-pyridine-3-sulfonyl chloride (200 mg; 0.94 mmol) in DCM (5.00 mL) was treated with TEA (0.26 mL; 1.88 mmol) and 3-methoxy-azetidine hydrochloride (117 mg; 0.94 mmol) was added to the reaction mixture. The mixture was stirred for 1 h, diluted with 30 ml_ DCM and washed twice with water. The organic phase was dried over sodium sulfate, concentrated in vacuo and triturated with diisopropyl ether to give intermediate II.39. (0448) Yield: 190 mg (77%), ESI-MS: m/z = 263 [M+H]+, Rt (HPLC): 0.44 min (HPLC-1 )

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2020/89025, 2020, A1 Location in patent: Page/Page column 54; 78; 79

37
[ 148644-09-1 ]
[ 33252-30-1 ]
[ 1874590-76-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 2h; Microwave irradiation; Inert atmosphere;	167 Synthesis of 2-(3-methoxyazetidin-l-yl)isonicotinonitrile (A-332) To a stirred solution of 2-chloropyridine-4-carbonitrile (500 mg, 3.61 mmol) in NMP (5.0 mL) was added DIPEA (1.89 mL, 10.83 mmol) and 3-methoxyazetidine hydrochloride (0.54 g, 4.33 mmol) at room temperature under nitrogen and the reaction mixture was irradiated in microwave at 120 °C for 2 h. The reaction mixture was cooled to room temperature and treated with water (30 mL). The mixture was extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (20 mL), dried over Na2SC>4 and concentrated. The crude was purified by column chromatography on silica gel with 10% EtOAc/PE to afford compound A-332 (650 mg, 3.43 mmol, 95% yield). LCMS: 190.2 (M+H), Rt 1.29 min; Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 pm; Mobile Phase: A: 0.1% HCOOH in water, B: ACN; Flow Rate: 1.5 mL/min

Reference： [1]Current Patent Assignee: PRAXIS PRECISION MEDICINES INC; PRAKISS PREC DRUG CO LTD - WO2020/227101, 2020, A1 Location in patent: Paragraph 000772

38
[ 148644-09-1 ]
[ 56844-12-3 ]
[ 2714515-94-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With triethylamine In 1,4-dioxane at 100℃;	General procedure: A mixture of 6-bromo-4-chlorothieno[2,3-d]pyrimidine (0.749g, 3.0mmol), morpholine (0.392g, 4.5mmol) and TEA (0.607g, 6.0mmol) in 1,4-dioxane (15mL) was stirred at 100°C overnight. The reaction mixture was concentrated in vacuo, diluted with water (30mL), and extracted with EtOAc (30mL×3). The combined organic layers were washed with water (50mL) and brine (50mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, PE/EtOAc=7:1) to afford the product as a yellow solid (0.791g, 88% yield). 1H NMR (500MHz, DMSO-d6) δ 8.40 (s, 1H), 7.87 (s, 1H), 3.82 (t, J=4.8Hz, 4H), 3.72 (t, J=4.8Hz, 4H).

Reference： [1]Sun, Yan; Fu, Rong; Lin, Songwen; Zhang, Jingbo; Ji, Ming; Zhang, Yan; Wu, Deyu; Zhang, Kehui; Tian, Hua; Zhang, Mingyi; Sheng, Li; Li, Yan; Jin, Jing; Chen, Xiaoguang; Xu, Heng [Bioorganic and Medicinal Chemistry, 2021, vol. 29]

39
[ 148644-09-1 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine; 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 20℃; for 2h;	11.1 Step 1. Compound 3 Compound 1 (33mg, 0.065mmol, 1.0eq) was dissolved in anhydrous DMF (5mL),Then add HATU (32mg, 0.084mmol, 1.3eq),Triethylamine (0.3mL, 0.194mmol, 3.0eq)And compound 2 (12mg, 0.084mmol, 1.5eq).The reaction solution was stirred at room temperature for 2 hours.The reaction solution was added with 20 mL of water, and extracted with ethyl acetate (3×20 mL).The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate and concentrated.The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain compound 3 (30 mg, 80%) as a yellow oil.

Reference： [1]Current Patent Assignee: SHANGHAI ZHIMENG BIOPHARMA - CN112390795, 2021, A Location in patent: Paragraph 0338-0342

40
[ 148644-09-1 ]
[ 2412136-48-0 ]
[ 2412134-80-4 ]

Yield	Reaction Conditions	Operation in experiment
56%	With caesium carbonate In N,N-dimethyl-formamide at 70℃;	43.1 Step 1: To a stirring solution of compound 39a (80 mg, 0.09 mmol) and compound 43a (17 mg, 0.14 mmol) in DMF (3 mL) was added Cs2CO3 (59 mg, 0.18 mmol). The reaction mixture was heated at 70 °C overnight, and LCMS indicated the reaction was complete. The reaction mixture was purified directly by reversed phase preparative HPLC to give compound 43 (47 mg, 56% yield) as a white solid. ESI-MS (m/z): 908.0 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 12.79 (br s, 1H), 12.64 (br s, 1H), 7.94 (s, 1H), 7.89 (s, 1H), 7.69 (t, J = 6.0 Hz, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.37-7.21 (m, 4H), 6.51 (s, 1H), 6.43 (s, 1H), 4.73-4.66 (m, 1H), 4.62-4.44 (m, 5H), 4.43-4.28 (m, 2H), 4.24-4.17 (m, 1H), 4.12-3.98 (m, 2H), 3.92-3.84 (m, 1H), 3.52-3.45 (m, 2H), 3.14 (q, J = 6.5 Hz, 2H), 3.08 (s, 3H), 2.94 (s, 2H), 2.89-2.83 (m, 2H), 2.06-1.88 (m, 10H), 1.82-1.71 (m, 2H), 1.31-1.18 (m, 6H).

Reference： [1]Current Patent Assignee: ADLAI NORTYE BIOPHARMA CO LTD; HANGZHOU ADLAI NORTYE BIOMEDICAL TECH; ADLAI NORTYE BIOPHARMA - EP3848366, 2021, A1 Location in patent: Paragraph 0350-0352

41
[ 148644-09-1 ]
[ 619-66-9 ]
[ 2719768-19-9 ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: 4-Carboxybenzaldehyde 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 20℃; for 3h; Stage #2: 3-methoxyazetidine hydrochloride In N,N-dimethyl-formamide at 20℃;
50%	Stage #1: 4-Carboxybenzaldehyde 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 20℃; for 3h; Stage #2: 3-methoxyazetidine hydrochloride In acetonitrile at 20℃;	General procedure: General procedure 3 (19a-u). To a solution of 4-carboxybenzaldehyde (0.32 mmol, 1 Eq.) in DMF (1.5 ml) were added DIPEA (1.28 mmol, 4 Eq.) and HATU (0.35 mmol, 1.1 Eq.). The reaction mixture was stirred at room temperature for 3 hours, followed by addition of the corresponding amine (or amine HC1 salt) (0.38 mmol, 1.2 Eq.). After complete consumption of the starting materials - monitored by TLC (Cyclohexane/Ethyl acetate 1:3) and UHPLC-MS - the reaction mixture was diluted with 1.5 ml of NaHCCE saturated solution and extracted with DCM (3 x 2 ml). The organic layer was then washed with brine (3 x 6 ml). After separation, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude reaction mixture was purified by preparative HPLC. 4-(3-methoxyazetidine-1-carbonyl)benzaldehyde (19a). Compound 19a was synthesized using general procedure 3 and 3-azetidinyl methyl ether hydrochloride (18a). The crude reaction was purified using preparative HPLC to afford the desired compound as a yellow oil (35 mg, 50% yield) with a purity of 99% by UHPLC-MS. UHPLC-MS (ESI + APCI) m/z calcd. for C12H13NO3 [M+H]+ = 220. Found: 220. Retention time: 0.93 min. 1H NMR (300 MHz, CDCl3) d 10.05 (s, 1H), 7.92 (d, / = 8.19 Hz, 2H), 7.76 (d, J = 8.22 Hz, 2H), 4.38 (m, 2H), 4.26 (m, 1H), 4.13 (m, 2H), 3.31 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) d 191.3, 169.0, 138.3, 137.6, 129.5, 128.2, 69.1, 59.9, 56.0 and 55.8 ppm.
50%	Stage #1: 4-Carboxybenzaldehyde 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 20℃; for 3h; Stage #2: 3-methoxyazetidine hydrochloride In acetonitrile at 20℃;	General procedure: General procedure 3 (19a-u). To a solution of 4-carboxybenzaldehyde (0.32 mmol, 1 Eq.) in DMF (1.5 ml) were added DIPEA (1.28 mmol, 4 Eq.) and HATU (0.35 mmol, 1.1 Eq.). The reaction mixture was stirred at room temperature for 3 hours, followed by addition of the corresponding amine (or amine HC1 salt) (0.38 mmol, 1.2 Eq.). After complete consumption of the starting materials - monitored by TLC (Cyclohexane/Ethyl acetate 1:3) and UHPLC-MS - the reaction mixture was diluted with 1.5 ml of NaHCCE saturated solution and extracted with DCM (3 x 2 ml). The organic layer was then washed with brine (3 x 6 ml). After separation, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude reaction mixture was purified by preparative HPLC. 4-(3-methoxyazetidine-1-carbonyl)benzaldehyde (19a). Compound 19a was synthesized using general procedure 3 and 3-azetidinyl methyl ether hydrochloride (18a). The crude reaction was purified using preparative HPLC to afford the desired compound as a yellow oil (35 mg, 50% yield) with a purity of 99% by UHPLC-MS. UHPLC-MS (ESI + APCI) m/z calcd. for C12H13NO3 [M+H]+ = 220. Found: 220. Retention time: 0.93 min. 1H NMR (300 MHz, CDCl3) d 10.05 (s, 1H), 7.92 (d, / = 8.19 Hz, 2H), 7.76 (d, J = 8.22 Hz, 2H), 4.38 (m, 2H), 4.26 (m, 1H), 4.13 (m, 2H), 3.31 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) d 191.3, 169.0, 138.3, 137.6, 129.5, 128.2, 69.1, 59.9, 56.0 and 55.8 ppm.

Reference： [1]Wolter, Madita; Valenti, Dario; Cossar, Peter J.; Hristeva, Stanimira; Levy, Laura M.; Genski, Thorsten; Hoffmann, Torsten; Brunsveld, Luc; Tzalis, Dimitrios; Ottmann, Christian [Journal of Medicinal Chemistry, 2021, vol. 64, # 12, p. 8423 - 8436]
[2]Current Patent Assignee: EINDHOVEN UNIVERSITY OF TECHNOLOGY; TAROS CHEMICALS; UNIVERSITY OF CALIFORNIA - WO2021/203016, 2021, A2 Location in patent: Paragraph 0041; 1043-1044
[3]Current Patent Assignee: EINDHOVEN UNIVERSITY OF TECHNOLOGY; TAROS CHEMICALS; UNIVERSITY OF CALIFORNIA - WO2021/203016, 2021, A2 Location in patent: Paragraph 0041; 1043-1044

42
[ 148644-09-1 ]
[ 49708-81-8 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
54.27%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 2h;	34.1 [0352] Step 1. Preparation of [4-(4-chlorophenyl)cyclohexyl]-(3-methoxyazetidin-1-yl)methanone [0353] To a solution of 4-(4-chlorophenyl)cyclohexanecarboxylic acid (1 g, 4.19 mmol, 1 eq), 3-methoxyazetidine;hydrochloride (517.80 mg, 4.19 mmol, 1 eq) and DIEA (1.62 g, 12.57 mmol, 2.19 mL, 3 eq) in THF (10 mL) was added dropwise T3P (4.00 g, 6.29 mmol, 3.74 mL, 50% purity, 1.5 eq) at 20°C. The reaction mixture was stirred at 20°C for 2 h. LC-MS showed the desired compound was detected. The reaction mixture was partitioned between EA (20 mL) and water (20 mL). The organic phase was separated, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give [4-(4-chlorophenyl)cyclohexyl]-(3-methoxyazetidin-1-yl)methanone (0.7 g, 2.27 mmol, 54.27% yield).[0354]1H NMR (400 MHz, CHLOROFORM-d) δ = 7.31 - 7.27 (m, 2H), 7.18 - 7.14 (m, 2H), 4.40 - 4.31 (m, 1H), 4.29 - 4.15 (m, 2H), 4.11 - 4.04 (m, 1H), 3.96 - 3.87 (m, 1H), 3.35 (s, 3H), 2.57 (tt, J = 3.2, 12.4 Hz, 1H), 2.25 (tt, J = 3.6, 12.0 Hz, 1H), 2.05 - 1.94 (m, 2H), 1.94 - 1.83 (m, 2H), 1.74 (s, 1H), 1.72 - 1.66 (m, 1H), 1.53 - 1.40 (m, 2H).
54.27%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 2h;	34.1 [0352] Step 1. Preparation of [4-(4-chlorophenyl)cyclohexyl]-(3-methoxyazetidin-1-yl)methanone [0353] To a solution of 4-(4-chlorophenyl)cyclohexanecarboxylic acid (1 g, 4.19 mmol, 1 eq), 3-methoxyazetidine;hydrochloride (517.80 mg, 4.19 mmol, 1 eq) and DIEA (1.62 g, 12.57 mmol, 2.19 mL, 3 eq) in THF (10 mL) was added dropwise T3P (4.00 g, 6.29 mmol, 3.74 mL, 50% purity, 1.5 eq) at 20°C. The reaction mixture was stirred at 20°C for 2 h. LC-MS showed the desired compound was detected. The reaction mixture was partitioned between EA (20 mL) and water (20 mL). The organic phase was separated, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give [4-(4-chlorophenyl)cyclohexyl]-(3-methoxyazetidin-1-yl)methanone (0.7 g, 2.27 mmol, 54.27% yield).[0354]1H NMR (400 MHz, CHLOROFORM-d) δ = 7.31 - 7.27 (m, 2H), 7.18 - 7.14 (m, 2H), 4.40 - 4.31 (m, 1H), 4.29 - 4.15 (m, 2H), 4.11 - 4.04 (m, 1H), 3.96 - 3.87 (m, 1H), 3.35 (s, 3H), 2.57 (tt, J = 3.2, 12.4 Hz, 1H), 2.25 (tt, J = 3.6, 12.0 Hz, 1H), 2.05 - 1.94 (m, 2H), 1.94 - 1.83 (m, 2H), 1.74 (s, 1H), 1.72 - 1.66 (m, 1H), 1.53 - 1.40 (m, 2H).
54.27%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 2h;	34.1 [0352] Step 1. Preparation of [4-(4-chlorophenyl)cyclohexyl]-(3-methoxyazetidin-1-yl)methanone [0353] To a solution of 4-(4-chlorophenyl)cyclohexanecarboxylic acid (1 g, 4.19 mmol, 1 eq), 3-methoxyazetidine;hydrochloride (517.80 mg, 4.19 mmol, 1 eq) and DIEA (1.62 g, 12.57 mmol, 2.19 mL, 3 eq) in THF (10 mL) was added dropwise T3P (4.00 g, 6.29 mmol, 3.74 mL, 50% purity, 1.5 eq) at 20°C. The reaction mixture was stirred at 20°C for 2 h. LC-MS showed the desired compound was detected. The reaction mixture was partitioned between EA (20 mL) and water (20 mL). The organic phase was separated, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give [4-(4-chlorophenyl)cyclohexyl]-(3-methoxyazetidin-1-yl)methanone (0.7 g, 2.27 mmol, 54.27% yield).[0354]1H NMR (400 MHz, CHLOROFORM-d) δ = 7.31 - 7.27 (m, 2H), 7.18 - 7.14 (m, 2H), 4.40 - 4.31 (m, 1H), 4.29 - 4.15 (m, 2H), 4.11 - 4.04 (m, 1H), 3.96 - 3.87 (m, 1H), 3.35 (s, 3H), 2.57 (tt, J = 3.2, 12.4 Hz, 1H), 2.25 (tt, J = 3.6, 12.0 Hz, 1H), 2.05 - 1.94 (m, 2H), 1.94 - 1.83 (m, 2H), 1.74 (s, 1H), 1.72 - 1.66 (m, 1H), 1.53 - 1.40 (m, 2H).

Reference： [1]Current Patent Assignee: TEON THERAPEUTICS - WO2021/236893, 2021, A1 Location in patent: Paragraph 0352-0354
[2]Current Patent Assignee: TEON THERAPEUTICS - WO2021/236893, 2021, A1 Location in patent: Paragraph 0352-0354
[3]Current Patent Assignee: TEON THERAPEUTICS - WO2021/236893, 2021, A1 Location in patent: Paragraph 0352-0354

43
[ 148644-09-1 ]
[ 2758167-49-4 ]
[ 2758167-86-9 ]

Yield	Reaction Conditions	Operation in experiment
78%	With N-ethyl-N,N-diisopropylamine In dimethylsulfoxide-d6 at 130℃; Inert atmosphere;	90A 90A Ethyl (5R)-2-[6-(3-methoxyazetidin-l-yl)pyridin-3-yl]-5-methyl-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate A solution of intermediate 81A (200 mg, 0.66 mmol), 3-methoxyazetidine hydrochloride (324 mg, 2.62 mmol) and DIPEA (913 μL, 5.24 mmol) in anhydrous DMSO (3 mL) was heated at 130 °C overnight. The reaction was cooled to rt, partitioned between brine and EtOAc (10 mL each) and the aqueous layer extracted with EtOAc (4× 15 mL). The combined organic extracts were washed with brine (3× 15 mL), dried (Na2SO4) and the solvent removed under reduced pressure. Purification by flash chromatography [10-36% (EtOH:CH2Cl2:NH4OH;50:8:1) in CH2Cl2] afforded a pale brown solid (191 mg, 78%).1H NMR (400 MHz, DMSO-d6) δ 8.25 (dd, J= 2.3, 0.8 Hz, 1H), 7.70 (dd, J= 8.6, 2.3 Hz, 1H), 6.39 (dd, J= 8.7, 0.8 Hz, 1H), 4.61 - 4.50 (m, 1H), 4.37 - 4.29 (m, 1H), 4.19 - 4.03 (m, 6H), 3.80 - 3.73 (m, 2H), 3.25 (s, 3H), 2.31 - 2.20 (m, 1H), 2.07 - 1.93 (m, 1H), 1.43 (d, J = 6.3 Hz, 3H), 1.15 (t, J= 7.1 Hz, 3H). LRMS m/z (APCI+) 373.6 [M+H]+.
78%	With N-ethyl-N,N-diisopropylamine In dimethylsulfoxide-d6 at 130℃; Inert atmosphere;	90A 90A Ethyl (5R)-2-[6-(3-methoxyazetidin-l-yl)pyridin-3-yl]-5-methyl-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate A solution of intermediate 81A (200 mg, 0.66 mmol), 3-methoxyazetidine hydrochloride (324 mg, 2.62 mmol) and DIPEA (913 μL, 5.24 mmol) in anhydrous DMSO (3 mL) was heated at 130 °C overnight. The reaction was cooled to rt, partitioned between brine and EtOAc (10 mL each) and the aqueous layer extracted with EtOAc (4× 15 mL). The combined organic extracts were washed with brine (3× 15 mL), dried (Na2SO4) and the solvent removed under reduced pressure. Purification by flash chromatography [10-36% (EtOH:CH2Cl2:NH4OH;50:8:1) in CH2Cl2] afforded a pale brown solid (191 mg, 78%).1H NMR (400 MHz, DMSO-d6) δ 8.25 (dd, J= 2.3, 0.8 Hz, 1H), 7.70 (dd, J= 8.6, 2.3 Hz, 1H), 6.39 (dd, J= 8.7, 0.8 Hz, 1H), 4.61 - 4.50 (m, 1H), 4.37 - 4.29 (m, 1H), 4.19 - 4.03 (m, 6H), 3.80 - 3.73 (m, 2H), 3.25 (s, 3H), 2.31 - 2.20 (m, 1H), 2.07 - 1.93 (m, 1H), 1.43 (d, J = 6.3 Hz, 3H), 1.15 (t, J= 7.1 Hz, 3H). LRMS m/z (APCI+) 373.6 [M+H]+.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2022/8911, 2022, A1 Location in patent: Page/Page column 45; 102-103
[2]Current Patent Assignee: PFIZER INC - WO2022/8911, 2022, A1 Location in patent: Page/Page column 45; 102-103

44
[ 148644-09-1 ]
[ 2765741-01-1 ]
[ 2765741-96-4 ]

Yield	Reaction Conditions	Operation in experiment
58%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 18h;	B13.1 Step 1: N-[5-(lH-benzimidazol-2-yl)-l-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-(3- methoxyazetidin-l-yl)pyridine-3-carboxamide. N-[5-(lH-Benzimidazol-2-yl)-l-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-chloro- pyridine-3-carboxamide (L-l) (100 mg, 0.218 mmol), 3-methoxyazetidine hydrochloride (40.4 mg, 0.327 mmol), and DIEA (149 μL , 0.872 mmol) were dissolved in DMSO (1 mL). The mixture was stirred at 100 °C for 18 h. Water (25 mL) was added. The mixture was filtered, and the solid was purified by silica gel chromatography eluting with hexanes and EtOAc (0-100%) to provide the title compound as a solid (64.1 mg, 58%). (400 1H NMR MHz, DMSO) δ 13.12 (s, 1H), 10.87 (s, 1H), 8.76 (dd, J= 2.4, 0.7 Hz, 1H), 8.13 (dd, J= 8.8, 2.4 Hz, 1H), 7.72 (d, J= 8.0 Hz, 1H), 7.56 - 7.51 (m, 2H), 7.31 - 7.20 (m, 4H), 6.87 - 6.83 (m, 2H), 6.42 (d, J= 8.8 Hz, 1H), 6.02 (s, 2H), 4.35 (td, J= 6.3, 3.2 Hz, 1H), 4.23 (ddd, J = 9.1, 6.1, 0.7 Hz, 2H), 3.85 (dd, J= 10.4, 3.9 Hz, 2H), 3.68 (s, 3H), 3.26 (s, 3H). m/z (ES+), [M+H]+ 510.2. HPLC (A05) tR = 2.39 min.
58%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 18h;	B13.1 Step 1: N-[5-(lH-benzimidazol-2-yl)-l-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-(3- methoxyazetidin-l-yl)pyridine-3-carboxamide. N-[5-(lH-Benzimidazol-2-yl)-l-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-chloro- pyridine-3-carboxamide (L-l) (100 mg, 0.218 mmol), 3-methoxyazetidine hydrochloride (40.4 mg, 0.327 mmol), and DIEA (149 μL , 0.872 mmol) were dissolved in DMSO (1 mL). The mixture was stirred at 100 °C for 18 h. Water (25 mL) was added. The mixture was filtered, and the solid was purified by silica gel chromatography eluting with hexanes and EtOAc (0-100%) to provide the title compound as a solid (64.1 mg, 58%). (400 1H NMR MHz, DMSO) δ 13.12 (s, 1H), 10.87 (s, 1H), 8.76 (dd, J= 2.4, 0.7 Hz, 1H), 8.13 (dd, J= 8.8, 2.4 Hz, 1H), 7.72 (d, J= 8.0 Hz, 1H), 7.56 - 7.51 (m, 2H), 7.31 - 7.20 (m, 4H), 6.87 - 6.83 (m, 2H), 6.42 (d, J= 8.8 Hz, 1H), 6.02 (s, 2H), 4.35 (td, J= 6.3, 3.2 Hz, 1H), 4.23 (ddd, J = 9.1, 6.1, 0.7 Hz, 2H), 3.85 (dd, J= 10.4, 3.9 Hz, 2H), 3.68 (s, 3H), 3.26 (s, 3H). m/z (ES+), [M+H]+ 510.2. HPLC (A05) tR = 2.39 min.

Reference： [1]Current Patent Assignee: FORKHEAD BIOTHERAPEUTICS - WO2022/66938, 2022, A1 Location in patent: Paragraph 00386; 00426
[2]Current Patent Assignee: FORKHEAD BIOTHERAPEUTICS - WO2022/66938, 2022, A1 Location in patent: Paragraph 00386; 00426

45
[ 148644-09-1 ]
[ 2765741-11-3 ]
[ 2765738-89-2 ]

Yield	Reaction Conditions	Operation in experiment
55%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 18h;	B15 Preparation of Compound A-97 (N-[5-(lH-benzimidazol-2-yl)-l-methyl-pyrazol-3-yl]-6-(3- methoxyazetidin-l-yl)pyridine-3-carboxamide). N-[5-(l H-B enzimidazol -2-y I)- 1 -methy 1 -pyrazol-3 -yl] -6-chloro-pyridine-3 - carboxamide (L-ll) (50 mg, 0.142 mmol), 3-methoxyazetidine hydrochloride (26.3 mg, 0.213 mmol) and DIEA (98.7 μL , 0.567 mmol) were dissolved in DMSO (0.500 mL). The mixture was stirred at 100 °C for 18 h. Water (25 mL) was added. The mixture was filtered, and the solid was purified by silica gel chromatography eluting with hexanes and EtOAc (0- 100%) to provide the title compound as a solid (31.2 mg, 55%). 1H NMR (400 MHz, DMSO) 8 13.07 (s, 1H), 10.84 (s, 1H), 8.78 (d, J= 1.9 Hz, 1H), 8.15 (dd, J= 8.8, 2.3 Hz, 1H), 7.79 - 7.63 (m, 1H), 7.63 - 7.51 (m, 1H), 7.48 (s, 1H), 7.34 - 7.15 (m, 2H), 6.44 (d, J= 8.8 Hz, 1H), 4.41 - 4.33 (m, 1H), 4.31 (s, 3H), 4.24 (dd, J= 8.9, 6.5 Hz, 2H), 3.86 (dd, J= 9.5, 3.5 Hz, 2H), 3.28 (s, 3H). m/z (ES+), [M+H]+ 404.6. HPLC (A05) tR = 2.06 min.
55%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 18h;	B15 Preparation of Compound A-97 (N-[5-(lH-benzimidazol-2-yl)-l-methyl-pyrazol-3-yl]-6-(3- methoxyazetidin-l-yl)pyridine-3-carboxamide). N-[5-(l H-B enzimidazol -2-y I)- 1 -methy 1 -pyrazol-3 -yl] -6-chloro-pyridine-3 - carboxamide (L-ll) (50 mg, 0.142 mmol), 3-methoxyazetidine hydrochloride (26.3 mg, 0.213 mmol) and DIEA (98.7 μL , 0.567 mmol) were dissolved in DMSO (0.500 mL). The mixture was stirred at 100 °C for 18 h. Water (25 mL) was added. The mixture was filtered, and the solid was purified by silica gel chromatography eluting with hexanes and EtOAc (0- 100%) to provide the title compound as a solid (31.2 mg, 55%). 1H NMR (400 MHz, DMSO) 8 13.07 (s, 1H), 10.84 (s, 1H), 8.78 (d, J= 1.9 Hz, 1H), 8.15 (dd, J= 8.8, 2.3 Hz, 1H), 7.79 - 7.63 (m, 1H), 7.63 - 7.51 (m, 1H), 7.48 (s, 1H), 7.34 - 7.15 (m, 2H), 6.44 (d, J= 8.8 Hz, 1H), 4.41 - 4.33 (m, 1H), 4.31 (s, 3H), 4.24 (dd, J= 8.9, 6.5 Hz, 2H), 3.86 (dd, J= 9.5, 3.5 Hz, 2H), 3.28 (s, 3H). m/z (ES+), [M+H]+ 404.6. HPLC (A05) tR = 2.06 min.

Reference： [1]Current Patent Assignee: FORKHEAD BIOTHERAPEUTICS - WO2022/66938, 2022, A1 Location in patent: Paragraph 00538-00539
[2]Current Patent Assignee: FORKHEAD BIOTHERAPEUTICS - WO2022/66938, 2022, A1 Location in patent: Paragraph 00538-00539

46
[ 148644-09-1 ]
[ 2765741-13-5 ]
[ 2765738-95-0 ]

Yield	Reaction Conditions	Operation in experiment
59%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 18h;	B15 Preparation of Compound A-137 N-[5-(4-fluoro-lH-benzimidazol-2-yl)-l-methyl-pyrazol- 3-yl]-6-(3-methoxyazetidin-l-yl)pyridine-3-carboxamide. 6-Chloro-N-[5-(4-fluoro-lH-benzimidazol-2-yl)-l-methyl-pyrazol-3-yl]pyridine-3- carboxamide (L-13) (45 mg, 0.121 mmol), 3-methoxyazetidine hydrochloride (0.0225 g, 0.182 mmol), and DIEA (0.0623 mL, 0.364 mmol) were dissolved in DMSO (1 mL). The mixture was stirred at 100 °C for 18 h. EtOAc (100 mL) was added. The organic phase was washed with water (3 x 50 mL) and brine (50 mL), dried (Na2SO4) , filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) eluting with DCM and MeOH (0-20%). The product was dissolved in DMSO (0.500 mL). Water (10 mL) was added, the mixture was filtered, and the solid was dried to provide the title compound as a solid in a 4: 1 mixture of tautomers (30.4 mg, 59%). (400 MHz, 1H NMR DMSO) δ [13.51] 13.32 (s, 1H), 10.81 [10.78] (s, 1H), 8.72 (dd, J= 2.4, 0.7 Hz, 1H), 8.08 (dd, J= 8.8, 2.4 Hz, 1H), 7.44 (s, 1H), 7.32 (d, J= 7.3 Hz, 1H), 7.22 - 7.14 (m, 1H), 7.00 (dd, J= 11.1, 8.0 Hz, 1H), 6.38 (d, J= 9.3 Hz, 1H), 4.34 - 4.27 (m, 1H), 4.25 [4.24] (s, 3H), 4.21 - 4.15 (m, 2H), 3.80 (dd, J= 10.4, 3.9 Hz, 2H), 3.22 (s, 3H). 19F NMR (376 MHz, DMSO) δ -128.73 (s). m/z (ES+), [M+H]+ 422.0. HPLC (A05) tR = 2.14 min.
59%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 18h;	B15 Preparation of Compound A-137 N-[5-(4-fluoro-lH-benzimidazol-2-yl)-l-methyl-pyrazol- 3-yl]-6-(3-methoxyazetidin-l-yl)pyridine-3-carboxamide. 6-Chloro-N-[5-(4-fluoro-lH-benzimidazol-2-yl)-l-methyl-pyrazol-3-yl]pyridine-3- carboxamide (L-13) (45 mg, 0.121 mmol), 3-methoxyazetidine hydrochloride (0.0225 g, 0.182 mmol), and DIEA (0.0623 mL, 0.364 mmol) were dissolved in DMSO (1 mL). The mixture was stirred at 100 °C for 18 h. EtOAc (100 mL) was added. The organic phase was washed with water (3 x 50 mL) and brine (50 mL), dried (Na2SO4) , filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) eluting with DCM and MeOH (0-20%). The product was dissolved in DMSO (0.500 mL). Water (10 mL) was added, the mixture was filtered, and the solid was dried to provide the title compound as a solid in a 4: 1 mixture of tautomers (30.4 mg, 59%). (400 MHz, 1H NMR DMSO) δ [13.51] 13.32 (s, 1H), 10.81 [10.78] (s, 1H), 8.72 (dd, J= 2.4, 0.7 Hz, 1H), 8.08 (dd, J= 8.8, 2.4 Hz, 1H), 7.44 (s, 1H), 7.32 (d, J= 7.3 Hz, 1H), 7.22 - 7.14 (m, 1H), 7.00 (dd, J= 11.1, 8.0 Hz, 1H), 6.38 (d, J= 9.3 Hz, 1H), 4.34 - 4.27 (m, 1H), 4.25 [4.24] (s, 3H), 4.21 - 4.15 (m, 2H), 3.80 (dd, J= 10.4, 3.9 Hz, 2H), 3.22 (s, 3H). 19F NMR (376 MHz, DMSO) δ -128.73 (s). m/z (ES+), [M+H]+ 422.0. HPLC (A05) tR = 2.14 min.

Reference： [1]Current Patent Assignee: FORKHEAD BIOTHERAPEUTICS - WO2022/66938, 2022, A1 Location in patent: Paragraph 00538; 00545
[2]Current Patent Assignee: FORKHEAD BIOTHERAPEUTICS - WO2022/66938, 2022, A1 Location in patent: Paragraph 00538; 00545

47
[ 148644-09-1 ]
[ 2765741-14-6 ]
[ 2765739-10-2 ]

Yield	Reaction Conditions	Operation in experiment
57%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 100℃; for 20h;	B15 Preparation of Compound A187 (N-[5-(7-fluoro-5-methoxy-lH-benzimidazol-2-yl)-l- methyl-pyrazol-3-yl]-6-(3-methoxyazetidin-l-yl)pyridine-3-carboxamide). DIEA (0.0217 mL, 0.125 mmol) was added to a solution of 3-methoxyazetidine hydrochloride (11.5 mg, 0.0936 mmol) and 6-chloro-N-[5-(7-fluoro-5-methoxy-lH- benzimidazol-2-yl)-l-methyl-pyrazol-3-yl]pyridine-3-carboxamide (L-14) (25 mg, 0.0624 mmol) in DMF (1 mL). The mixture was heated at 100 °C for 20 h. The mixture was cooled to 23 °C, and water (10 mL) was added. The aq. phase was extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with sat. NaHCO3 (10 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (7 g cartridge) eluting with DCM and MeOH (0-10%). The product was purified by preparative HPLC (BEH C18 30x150) eluting with water (10 mM (NH4)(HCO3)) and MeCN (37-47%) to provide the title compound as a solid (16 mg, 57%). 1H NMR (400 MHz, DMSO) δ 10.84 - 10.79 (m, 1H), 8.77 (d, J= 2.4 Hz, 1H), 8.13 (dd, J= 8.8, 2.4 Hz, 1H), 7.43 (s, 1H), 6.86 (d, J= 2.0 Hz, 1H), 6.72 (dd, J= 12.4, 2.1 Hz, 1H), 6.43 (d, J= 8.9 Hz, 1H), 4.35 (d, J= 6.3 Hz, 1H), 4.27 (s, 3H), 4.23 (dd, J= 8.8, 6.7 Hz, 2H), 3.85 (dd, J= 10.4, 3.9 Hz, 2H), 3.82 (s, 3H), 3.27 (s, 3H). m/z (ES ), [M-H]- 450.8. HPLC (A05) tR = 2.15 mm.
57%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 100℃; for 20h;	B15 Preparation of Compound A187 (N-[5-(7-fluoro-5-methoxy-lH-benzimidazol-2-yl)-l- methyl-pyrazol-3-yl]-6-(3-methoxyazetidin-l-yl)pyridine-3-carboxamide). DIEA (0.0217 mL, 0.125 mmol) was added to a solution of 3-methoxyazetidine hydrochloride (11.5 mg, 0.0936 mmol) and 6-chloro-N-[5-(7-fluoro-5-methoxy-lH- benzimidazol-2-yl)-l-methyl-pyrazol-3-yl]pyridine-3-carboxamide (L-14) (25 mg, 0.0624 mmol) in DMF (1 mL). The mixture was heated at 100 °C for 20 h. The mixture was cooled to 23 °C, and water (10 mL) was added. The aq. phase was extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with sat. NaHCO3 (10 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (7 g cartridge) eluting with DCM and MeOH (0-10%). The product was purified by preparative HPLC (BEH C18 30x150) eluting with water (10 mM (NH4)(HCO3)) and MeCN (37-47%) to provide the title compound as a solid (16 mg, 57%). 1H NMR (400 MHz, DMSO) δ 10.84 - 10.79 (m, 1H), 8.77 (d, J= 2.4 Hz, 1H), 8.13 (dd, J= 8.8, 2.4 Hz, 1H), 7.43 (s, 1H), 6.86 (d, J= 2.0 Hz, 1H), 6.72 (dd, J= 12.4, 2.1 Hz, 1H), 6.43 (d, J= 8.9 Hz, 1H), 4.35 (d, J= 6.3 Hz, 1H), 4.27 (s, 3H), 4.23 (dd, J= 8.8, 6.7 Hz, 2H), 3.85 (dd, J= 10.4, 3.9 Hz, 2H), 3.82 (s, 3H), 3.27 (s, 3H). m/z (ES ), [M-H]- 450.8. HPLC (A05) tR = 2.15 mm.

Reference： [1]Current Patent Assignee: FORKHEAD BIOTHERAPEUTICS - WO2022/66938, 2022, A1 Location in patent: Paragraph 00538; 00560
[2]Current Patent Assignee: FORKHEAD BIOTHERAPEUTICS - WO2022/66938, 2022, A1 Location in patent: Paragraph 00538; 00560

48
[ 148644-09-1 ]
[ 2765741-22-6 ]
[ 2765742-38-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 18h;	B13.1 Step 1: N-[5-(lH-benzirmdazol-2-yl)-l-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-5-(3- methoxyazetidin-l-yl)pyrazine-2-carboxamide 3-Methoxyazetidine hydrochloride (20.7 mg, 0.167 mmol) was added to a solution ofN-[5-(lH-benzimidazol-2-yl)-l-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-5-chloro- pyrazine-2-carboxamide (L-23) (70 mg, 0.152 mmol) and DIEA (0.0782 mL, 0.457 mmol) in DMSO (1 mL). The mixture was stirred at 100 °C for 18 h. Water (20 mL) was added, and the mixture was filtered. The solid was purified by silica gel chromatography (12 g cartridge) eluting with DCM and MeOH (0-10%) to provide the title compound as a solid (58 mg, 75%). ‘H NMR (400 MHz, DMSO) δ 13.14 (s, 1H), 10.18 (s, 1H), 8.72 (d, J= 1.4 Hz, 1H), 7.90 (d, J= 1.4 Hz, 1H), 7.73 (d, J= 7.4 Hz, 1H), 7.54 (d, J= 7.8 Hz, 1H), 7.51 (s, 1H), 7.27 (dd, J= 19.2, 7.4 Hz, 4H), 6.84 (d, J= 8.8 Hz, 2H), 6.01 (s, 2H), 4.43 - 4.33 (m, 3H), 4.04 - 3.96 (m, 2H), 3.68 (s, 3H), 3.28 (s, 3H). m/z (ES+), [M+H]+ 511.2. HPLC (A05) tR = 2.49 min.
75%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 18h;	B13.1 Step 1: N-[5-(lH-benzirmdazol-2-yl)-l-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-5-(3- methoxyazetidin-l-yl)pyrazine-2-carboxamide 3-Methoxyazetidine hydrochloride (20.7 mg, 0.167 mmol) was added to a solution ofN-[5-(lH-benzimidazol-2-yl)-l-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-5-chloro- pyrazine-2-carboxamide (L-23) (70 mg, 0.152 mmol) and DIEA (0.0782 mL, 0.457 mmol) in DMSO (1 mL). The mixture was stirred at 100 °C for 18 h. Water (20 mL) was added, and the mixture was filtered. The solid was purified by silica gel chromatography (12 g cartridge) eluting with DCM and MeOH (0-10%) to provide the title compound as a solid (58 mg, 75%). ‘H NMR (400 MHz, DMSO) δ 13.14 (s, 1H), 10.18 (s, 1H), 8.72 (d, J= 1.4 Hz, 1H), 7.90 (d, J= 1.4 Hz, 1H), 7.73 (d, J= 7.4 Hz, 1H), 7.54 (d, J= 7.8 Hz, 1H), 7.51 (s, 1H), 7.27 (dd, J= 19.2, 7.4 Hz, 4H), 6.84 (d, J= 8.8 Hz, 2H), 6.01 (s, 2H), 4.43 - 4.33 (m, 3H), 4.04 - 3.96 (m, 2H), 3.68 (s, 3H), 3.28 (s, 3H). m/z (ES+), [M+H]+ 511.2. HPLC (A05) tR = 2.49 min.

Reference： [1]Current Patent Assignee: FORKHEAD BIOTHERAPEUTICS - WO2022/66938, 2022, A1 Location in patent: Paragraph 00386; 00513
[2]Current Patent Assignee: FORKHEAD BIOTHERAPEUTICS - WO2022/66938, 2022, A1 Location in patent: Paragraph 00386; 00513

49
[ 148644-09-1 ]
[ 2765741-23-7 ]
[ 2765742-37-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 18h;	B13.1 Step 1: N-[5-(lH-benzimidazol-2-yl)-l-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-2-(3- methoxyazetidin-l-yl)pyrimidine-5-carboxarmde. 3-Methoxyazetidine hydrochloride (20.7 mg, 0.167 mmol) was added to a solution ofN-[5-(lH-benzimidazol-2-yl)-l-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-2-chloro- pyrimidine-5-carboxamide (L-24) (70 mg, 0.152 mmol) and DIEA (0.0782 mL, 0.457 mmol) in DMSO (1 mL). The mixture was stirred at 100 °C for 18 h. Water (20 mL) was added, and the mixture was filtered. The solid was purified by silica gel chromatography (12 g cartridge) eluting with DCM and MeOH (0-10%) to provide the title compound as a solid (58 mg, 75%). 1H NMR (400 MHz, DMSO) δ 13.13 (s, 1H), 11.04 (s, 1H), 8.92 (s, 2H), 7.72 (d, J= 7A Hz, 1H), 7.56 - 7.49 (m, 2H), 7.30 - 7.20 (m, 4H), 6.87 - 6.83 (m, 2H), 6.03 (s, 2H), 4.35 - 4.29 (m, 3H), 3.95 - 3.92 (m, 2H), 3.68 (s, 3H), 3.27 (s, 3H). m/z (ES+), [M+H]+ 511.2. HPLC (A05) tR = 2.33 min.
75%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 18h;	B13.1 Step 1: N-[5-(lH-benzimidazol-2-yl)-l-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-2-(3- methoxyazetidin-l-yl)pyrimidine-5-carboxarmde. 3-Methoxyazetidine hydrochloride (20.7 mg, 0.167 mmol) was added to a solution ofN-[5-(lH-benzimidazol-2-yl)-l-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-2-chloro- pyrimidine-5-carboxamide (L-24) (70 mg, 0.152 mmol) and DIEA (0.0782 mL, 0.457 mmol) in DMSO (1 mL). The mixture was stirred at 100 °C for 18 h. Water (20 mL) was added, and the mixture was filtered. The solid was purified by silica gel chromatography (12 g cartridge) eluting with DCM and MeOH (0-10%) to provide the title compound as a solid (58 mg, 75%). 1H NMR (400 MHz, DMSO) δ 13.13 (s, 1H), 11.04 (s, 1H), 8.92 (s, 2H), 7.72 (d, J= 7A Hz, 1H), 7.56 - 7.49 (m, 2H), 7.30 - 7.20 (m, 4H), 6.87 - 6.83 (m, 2H), 6.03 (s, 2H), 4.35 - 4.29 (m, 3H), 3.95 - 3.92 (m, 2H), 3.68 (s, 3H), 3.27 (s, 3H). m/z (ES+), [M+H]+ 511.2. HPLC (A05) tR = 2.33 min.

Reference： [1]Current Patent Assignee: FORKHEAD BIOTHERAPEUTICS - WO2022/66938, 2022, A1 Location in patent: Paragraph 00386; 00511
[2]Current Patent Assignee: FORKHEAD BIOTHERAPEUTICS - WO2022/66938, 2022, A1 Location in patent: Paragraph 00386; 00511

50
[ 148644-09-1 ]
[ 1020718-59-5 ]
[ 2768547-25-5 ]

Yield	Reaction Conditions	Operation in experiment
78%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 16h;	55 Synthesis of 55.1. To a solution of methyl 4-(6-chloropyrazin-2-yl)benzoate (50.1,130 mg, 0.52 mmol, 1 eq) in dimethylsulfoxide (5 mL) were added 3-methoxyazetidine hydrochloride (193.8 mg, 1.57 mmol, 3 eq) and DIEA (1 mL, 5.74 mmol, 10.9 eq) at room temperature. The resulting mixture was stirred for 16h at room temperature. The residue was purified by reverse flash with the following conditions: Column, Cl 8 Column; Mobile Phase, water (lOmmol/mL NH4HCO3) and ACN (10% ACN up to 40% in 10 min); UV detection at 254/220 nm. methyl 4- [6-(3 -methoxy azeti din- l-yl)pyrazin-2-yl]benzoate (55.1, 122 mg, 78%) as a brown oil, MS (ES): m/z 300 [M+H]+.
78%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 16h;	55 Synthesis of 55.1. To a solution of methyl 4-(6-chloropyrazin-2-yl)benzoate (50.1,130 mg, 0.52 mmol, 1 eq) in dimethylsulfoxide (5 mL) were added 3-methoxyazetidine hydrochloride (193.8 mg, 1.57 mmol, 3 eq) and DIEA (1 mL, 5.74 mmol, 10.9 eq) at room temperature. The resulting mixture was stirred for 16h at room temperature. The residue was purified by reverse flash with the following conditions: Column, Cl 8 Column; Mobile Phase, water (lOmmol/mL NH4HCO3) and ACN (10% ACN up to 40% in 10 min); UV detection at 254/220 nm. methyl 4- [6-(3 -methoxy azeti din- l-yl)pyrazin-2-yl]benzoate (55.1, 122 mg, 78%) as a brown oil, MS (ES): m/z 300 [M+H]+.

Reference： [1]Current Patent Assignee: NIMBUS CLOTHO - WO2022/87634, 2022, A1 Location in patent: Paragraph 00533
[2]Current Patent Assignee: NIMBUS CLOTHO - WO2022/87634, 2022, A1 Location in patent: Paragraph 00533

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	148644-09-1	MDL No. :	MFCD06804514
Formula :	C₄H₁₀ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KSXGQRBTBLQJEF-UHFFFAOYSA-N
M.W :	123.58	Pubchem ID :	22242858
Synonyms :

Num. heavy atoms :	7
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	33.99
TPSA :	21.26 Å²

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.85 cm/s

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.29
Log Po/w (WLOGP) :	0.03
Log Po/w (MLOGP) :	-0.16
Log Po/w (SILICOS-IT) :	0.59
Consensus Log Po/w :	0.15

[ CAS No. 148644-09-1 ] {[proInfo.proName]}

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[ 148644-09-1 ] Synthesis Path-Downstream 1~50

Related Functional Groups of
[ 148644-09-1 ]

Ethers

Related Parent Nucleus of
[ 148644-09-1 ]

Aliphatic Heterocycles

Azetidines

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

Log S (ESOL) :	-0.72
Solubility :	23.4 mg/ml ; 0.189 mol/l
Class :	Very soluble
Log S (Ali) :	-0.3
Solubility :	62.1 mg/ml ; 0.503 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.56
Solubility :	34.4 mg/ml ; 0.279 mol/l
Class :	Soluble

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

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

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.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
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.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
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