937046-96-3|tert-Butyl (2-cyano-1H-pyrrol-1-yl)carbamate| Ambeed

Structure of 937046-96-3

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Quality Control of [ 937046-96-3 ] Purity: 98% SDS Specification

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Product Details of [ 937046-96-3 ]

CAS No. :	937046-96-3
Formula :	C₁₀H₁₃N₃O₂
M.W :	207.23
SMILES Code :	O=C(OC(C)(C)C)NN1C(C#N)=CC=C1
MDL No. :	MFCD12068393
InChI Key :	SXUSNFHKHIJDRN-UHFFFAOYSA-N
Pubchem ID :	50999066

Safety of [ 937046-96-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Application In Synthesis of [ 937046-96-3 ]

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

Downstream synthetic route of [ 937046-96-3 ]

[ 937046-96-3 ] Synthesis Path-Downstream 1~35

1
[ 1189-71-5 ]
[ 937046-95-2 ]
[ 937046-96-3 ]

Yield	Reaction Conditions	Operation in experiment
87%		Under the protection of inert gas, 1000g of intermediate I (5.49mol, 1.0eq) and 10L of anhydrous acetonitrile were added to a 20L three-necked bottle. After stirring thoroughly, the temperature was lowered to 0 C, and 500ml of chlorosulfonyl isocyanate was slowly added dropwise (5.77mol, 1.05eq). Keeping the internal temperature below 5 C, a white suspension can be observed in about 20 minutes. After 30 min, 1 L of anhydrous DMF was added, and the reaction solution became clear. Keep the reaction at 0 for 30min. After the reaction is completed, pour the reaction solution into a mixture of ice water and ethyl acetate, and stir to separate. The organic phase was washed successively with saturated sodium bicarbonate solution and brine, then dried over anhydrous sodium sulfate, separated and concentrated to obtain 980 g of white solid. That is the intermediate II (1-Boc-1-amino-(9ci)-1H-pyrrole-2-carbonitrile). The purity of this intermediate II was 97%, and the yield was 87%.
77%	In N,N-dimethyl-formamide; acetonitrile; at 0 - 20℃; for 1.83333h;	A 2L, 3-neck RB was fitted w/ stir bar, N2 inlet, rubber septum low-temp, thermometer and ice/acetone cooling bath. Pyrrol- 1-yl-carbamic acid tert-butyl ester (99.0 g, 0.543 mol) was added to the reactor, dissolved w/ anhydrous acetonitrile (700 mL) and the stirred solution was cooled to 0 0C. Chlorosulfonyl isocyanate (49.7 mL, 0.57 mol) was added dropwise via syringe (maintaining an internal temp, below 5 0C); after ~ 20 minutes a suspension was observed. After 45 minutes N,N-dimethylformamide (anhydrous, 100 mL) was added dropwise via addition funnel (keeping internal temp, below 5 0C) and the reaction mixture became a solution. Stirring @ 0 0C was continued for 45 minutes, then the reaction was allowed to warm to RT; monitoring by TLC (silica gel, 1:3 ethyl acetate/hexane, UV, ninhydrin stain) of a quenched sample indicated that the reaction had progressed to completion. The mixture was poured onto ice (~2L) and stirred with addition of EtOAc (2L). The layers were separated and the organic layer was dried over magnesium sulfate. The dried solution was filtered through a pad of 30/40 Magnesol and the filtrate was concentrated to dryness in vacuo, then the residue was dissolved in a minimum volume of dichloromethane and chromatographed on a plug of silica gel, eluting with ethyl <n="255"/>acetate/hexane, 0-50 % ethyl acetate. The clean, product-containing fractions were combined and concentrated to dryness in vacuo, to afford the desired product as a white solid, 69.8 g (62%). A somewhat impure fraction provided additional material, 16.8 g (15%), bringing the total recovery to 86.6 g, (77%). 1H-NMR (CD3OD): delta 7.01 (dd, IH, J = 3.0, 1.6 Hz), 6.82 (dd, IH, J = 4.4, 1.7 Hz), 6.19 (dd, IH, /=4.2, 2.9 Hz), 4.88 (s, IH, H2ONH-), 1.50 (br s, 9H, HN-BOC); MS: LC/MS (+esi), m/z=207.9 [M+H].
77%		A 2L, 3-neck RB was fitted w/ stir bar, N2 inlet, rubber septum low-temp, thermometer and ice/acetone cooling bath. Pyrrol-1-yl-carbamic acid tert-butyl ester (99.0 g, 0.543 mol) was added to the reactor, dissolved w/ anhydrous acetonitrile (700 mL) and the stirred solution was cooled to 0 0C. Chlorosulfonyl isocyanate (49.7 mL, 0.57 mol) was added dropwise via syringe (maintaining an internal temperature below 5 0C); after ~ 20 minutes a suspension was observed. After 45 minutes Lambda/,Lambda/-dimethylformamide (anhydrous, 100 mL) was added dropwise via addition funnel (keeping internal temp. below 5 0C) and the reaction mixture became a solution. Stirring (at) 0 0C was continued for 45 minutes, then the reaction was allowed to warm to RT; monitoring by TLC (silica gel, 1 :3 ethyl acetate/hexane, UV, ninhydrin stain) of a quenched sample indicated that <n="75"/>the reaction had progressed to completion. The mixture was poured onto ice (~2L) and stirred with addition of EtOAc (2L). The layers were separated and the organic layer was dried over magnesium sulfate. The dried solution was filtered through a pad of 30/40 Magnesol and the filtrate was concentrated to dryness in vacuo, then the residue was dissolved in a minimum volume of dichloromethane and chromatographed on a plug of silica gel, eluting with ethyl acetate/hexane, 0-50 % ethyl acetate. The clean, product- containing fractions were combined and concentrated to dryness in vacuo, to afford the desired product as a white solid, 69.8 g (62%). A somewhat impure fraction provided additional material, 16.8 g (15%), bringing the total recovery to 86.6 g, (77%). 1H-NMR (CD3OD): 87.01 (dd, 1H, J = 3.0, 1.6 Hz), 6.82 (dd, 1H, J = 4.4, 1.7 Hz), 6.19 (dd, 1H, J=4.2, 2.9 Hz), 4.88 (s, 1H, H2O+NH-), 1.50 (br s, 9H, HN-BOC); MS: LC/MS (+esi), m/z=207.9 [M+H]; Intermediate G: Step 2: Preparation of (2-Cvano-pyrrol-1-yl)-carbamic acid, fe/f-butvl esterA 2L, 3-neck flask was fitted with stir bar, N2 inlet, rubber septum, thermometer and ice/acetone cooling bath. Pyrrol-1-yl-carbamic acid terf-butyl ester (99.0 g, 0.543 mol) was added to the reactor, dissolved with anhydrous acetonitrile (700 mL) and the stirred solution was cooled to 0 0C. Chlorosulfonyl isocyanate (49.7 mL, 0.57 mol) was added dropwise via syringe (maintaining an internal temperature below 5 CC). After ~ 20 minutes a suspension was observed. After 45 minutes, Lambda/,Lambda/-dimethylformamide (anhydrous, 100 mL) was added dropwise via addition funnel (keeping internal temperature below 5 0C) and the reaction mixture became a solution. Stirring at 0 0C was continued for 45 minutes, then the reaction was allowed to warm to rt. Monitoring by TLC (silica gel, 1:3 ethyl acetate/hexane, UV, ninhydrin stain) of a quenched sample indicated that the reaction had progressed to completion. The mixture was poured onto ice (~2L) and stirred with addition of EtOAc (2L). The layers were separated and the organic layer was dried over magnesium sulfate. The dried solution was filtered through a pad of 30/40 <n="81"/>Magnesol and the filtrate was concentrated to dryness in vacuo, then the residue was dissolved in a minimum volume of dichloromethane and chromatographed on a plug of silica gel, eluting with ethyl acetate/hexane, 0-50 % ethyl acetate. The clean, product- containing fractions were combined and concentrated to dryness in vacuo, to afford the desired product as a white solid, 69.8 g (62%). A somewhat impure fraction provided additional material, 16.8 g (15%), bringing the total recovery to 86.6 g, (77%). 1H-NMR (CD3OD): delta 7.01 (dd, 1H, J= 3.0, 1.6 Hz), 6.82 (dd, 1H, J = 4.4, 1.7 Hz), 6.19 (dd, 1H, J= 4.2, 2.9 Hz), 4.88 (s, 1H), 1.50 (br s, 9H); MS: LC/MS (+esi), m/z=207.9 [M+H].

77%	In N,N-dimethyl-formamide; acetonitrile; at 0 - 5℃; for 1.83333h;	A 2L, 3 -neck RB was fitted w/ stir bar, N2 inlet, rubber septum low-temp, thermometer and ice/acetone cooling bath. Pyrrol- 1-yl-carbamic acid tert-butyl ester (99.0 g, 0.543 mol) was added to the reactor, dissolved w/ anhydrous acetonitrile (700 mL) and the stirred solution was cooled to 0 C. Chlorosulfonyl isocyanate (49.7 mL, 0.57 mol) was added dropwise via syringe (maintaining an internal temp, below 5 0C); after ~ 20 minutes a suspension was observed. After 45 minutes N,N-dimethylformamide (anhydrous, 100 mL) was added dropwise via addition funnel (keeping internal temp, below 5 0C) and the reaction mixture became a solution. Stirring @ 0 0C was continued for 45 minutes, then the reaction was allowed to warm to RT; monitoring by TLC (silica gel, 1:3 ethyl acetate/hexane, UV, ninydrin stain) of a quenched sample indicated that the reaction had progressed to completion. The mixture was poured onto ice (~2L) and stirred with addition of EtOAc (2L). The layers were separated and the organic layer was dried over magnesium sulfate. The dried solution was filtered through a pad of 30/40 Magnesol and the filtrate was concentrated to dryness in vacuo, then the residue was dissolved in a minimum volume of dichloromethane and chromatographed on a plug of silica gel, eluting with ethyl acetate/hexane, 0-50 % ethyl acetate. The clean, product-containing fractions were combined and concentrated to dryness in vacuo, to afford the desired product as a white solid, 69.8 g (62%). A somewhat impure fraction provided additional material, 16.8 g (15%), bringing the total recovery to 86.6 g, (77%). 1H-NMR (CD3OD): £7.01 (dd, IH, J = 3.0, 1.6 Hz), 6.82 (dd, IH, / = 4.4, 1.7 Hz), 6.19 (dd, IH, J=4.2, 2.9 Hz), 4.88 (s, IH,H2O+NH-), 1.50 (br s, 9H, HN-BOC); MS: LC/MS (+esi), m/z=207.9 [M+H]
66%		g. To a stirred solution of tert-butyl lH-pyrrol-1-ylcarbamate 12 (40 g, 219.52 mmol), in acetonitrile (350 mL) was added chlorosulfonyl isocyanate (32.62 g, 230.50 mmol) slowly at 0 C and continued stirring at 0 0C for 30 min. To the solution N, N-dimethyl formamide (40 mL) was added below 5 0C and continued stirring at 0 0C for 1 hr. The reaction mixture was poured into a mixture of crushed ice (1 L) and ethyl acetate (1 L). The layers were separated and the organic layer was washed with water (500 mL), brine (250 mL), dried and concentrated in vacuum to furnish crude (43 g) product. The crude was purified by flash chromatography (silica gel, eluting with ethyl acetate in hexane 0-50%) to afford pure tert-butyl 2-cyano-lH-pyrrol-l-ylcarbamate 13 (30 g, 66 %) as a colorless solid. 1H NMR (300 MHz, DMSO) delta 10.80 (s, IH, D2O exchangeable), 7.23 (dd, J = 1.7, 2.9, IH), 6.94 (dd, J= 1.7, 4.3, IH), 6.20 (dd, J= 2.9, 4.3, IH), 1.45 (s, 9H). HPLC (Zorbax SBC3, 3.0 x 150 mm, 5 mum, with ZGC SBC3, 2.1 x 12.5 mm guard cartridge. Mobile phase: 0.1 M ammonium acetate/ Acetonitrile) Rt = 16.216, (98.14 %). Analysis: CaIc for C10H13N3O2: C, 57.95; H, 6.32; N, 20.27 Found: C, 58.02; H, 6.45; N, 20.18.
66%		To a stirred solution of tert-butyl lH-pyrrol-l-ylcarbamate 12c (40 g, 219.52 mmol), in acetonitrile (350 mL) was added chlorosulfonyl isocyanate (32.62 g, 230.50 mmol) slowly at 0 C and continued stirring at 0 C for 30 min. To the solution N, N-dimethyl formamide (40 mL) was added below 5 C and continued stirring at 0 C for 1 hr. The reaction mixture was poured into a mixture of crushed ice (1 L) and ethyl acetate (1 L). The layers were separated and the organic layer was washed with water (500 mL), brine (250 mL), dried and concentrated in vacuum to furnish crude (43 g) product. The crude was purified by flash chromatography (silica gel, eluting with ethyl acetate in hexane 0-50%) to afford pure tert-butyl 2-cyano-lH-pyrrol-l- ylcarbamate 12d (30 g, 66 %) as a colorless solid. 1H NMR (300 MHz, DMSO) delta 10.80 (s, 1H, D20 exchangeable), 7.23 (dd, J= 1.7, 2.9, 1H), 6.94 (dd, J= 1.7, 4.3, 1H), 6.20 (dd, J= 2.9, 4.3, 1H), 1.45 (s, 9H). HPLC (Zorbax SBC3, 3.0 x 150 mm, 5 mu?iota, with ZGC SBC3, 2.1 x 12.5 mm guard cartridge. Mobile phase: 0.1 M ammonium acetate/ Acetonitrile) Rt = 16.216, (98.14 %). Analysis: Calc for C10H13N3O2: C, 57.95; H, 6.32; N, 20.27 Found: C, 58.02; H, 6.45; N, 20.18.
66%		Step 1:To a stirred solution of tert-butyl hydrazinecarboxylate 22b (50 g, 412.37 mmol) and 2,5-dimethoxytetrahydrofuran 22a (54.5 g, 412.37 mmol) in dioxane (300 mL) was added aqueous hydrochloric acid (5 mL, 2N). The reaction was set up using a dean-stark apparatus and heated at 90 C for 20 h. Reaction mixture was cooled to 20 C, neutralized with saturated sodium bicarbonate (18 mL) and filtered to remove inorganics. The filtrate was concentrated in vacuum and triturated with ether. The solid obtained was collected by filtration to furnish on drying tert-butyl lH-pyrrol-l-ylcarbamate 22c (43 g, 57.2%) as a yellow brown solid. 1H NMR (300 MHz, CD3OD) ? 6.62 (t, J= 2.3, 2H), 6.02 (t, J= 2.3, 2H), 1.48 (s, 9H); MS (ES+): 181.1 (M _1). Analysis: Calculated for C9Hi4N202: C, 59.32; H, 7.74; N, 15.37. Found: C, 59.32; H, 7.65; N, 15.02. Step 2:To a stirred solution of tert-butyl lH-pyrrol-l-ylcarbamate 22c (40 g, 219.52 mmol), in acetonitrile (350 mL) was added chlorosulfonyl isocyanate (32.62 g, 230.50 mmol) slowly at 0 C and continued stirring at 0 C for 30 min. To the solution N, N-dimethyl formamide (40 mL) was added below 5 C and continued stirring at 0 C for 1 hr. The reaction mixture was poured into a mixture of crushed ice (1 L) and ethyl acetate (1 L). The layers were separated and the organic layer was washed with water (500 mL), brine (250 mL), dried and concentrated in vacuum to furnish crude (43 g) product. The crude was purified by flash chromatography (silica gel, eluting with ethyl acetate in hexane0-50%) to afford pure tert-butyl 2-cyano-lH-pyrrol-l-ylcarbamate 22d (30 g, 66 %>) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) ? 10.80 (s, 1H, D20 exchangeable), 7.23 (dd, J= 1.7, 2.9, 1H), 6.94 (dd, J= 1.7, 4.3, 1H), 6.20 (dd, J= 2.9, 4.3, 1H), 1.45 (s, 9H). Analysis: Calculated for Ci0Hi3N3O2: C, 57.95; H, 6.32; N, 20.27. Found: C, 58.02; H, 6.45; N, 20.18. Step 3:To a stirred solution of tert-butyl 2-cyano-lH-pyrrol-l-ylcarbamate 22d (5 g, 24.12 mmol) in ethyl alcohol (100 mL) was added concentrated aqueous ammonium hydroxide solution (50 mL) at 20 C followed by hydrogen peroxide (7.4 mL, 72.38 mmol, 30 % in water) slowly at 20 C and stirred at the same temperature for 16 h. Reaction mixture was concentrated in vacuum and diluted with ethyl acetate (150 mL), washed with water (2 x 50 mL). The aqueous layer was extracted with ethyl acetate (150 mL). The combined ethyl acetate layers were washed with water (100 mL), brine (50 mL), dried, filtered, and concentrated in vacuum. The residue obtained was crystallized from diisopropyl ether and hexane to afford tert-butyl 2-carbamoyl-lH-pyrrol-l-ylcarbamate 22e (4.0 g, 73.6%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) ? 9.89 (s, 1H, D20 exchangeable), 7.31 (d, J = 38.5, 1H), 6.84 (dd, J= 1.9, 2.8, 2H, lH is D20 exchangeable), 6.76 (dd, J = 1.9, 4.2, 1H), 5.97 (dd, J= 2.8, 4.2, 1H), 1.40 (s, 9H); Analysis: Calculated for Ci0Hi5N3O3: C, 53.32; H, 6.71 ; N, 18.65. Found: C, 53.40; H, 6.74; N, 18.55. Step 4:To a solution of tert-butyl 2-carbamoyl-lH-pyrrol-l-ylcarbamate 22e (2g, 8.87 mmol) in dichloromethane (15 mL) was added trifluoro acetic acid (15 mL) at 20 C and stirred for 30 min. The reaction mixture was concentrated to dryness to remove excess trifluoroacetic acid and diluted with dichloromethane. Triethylorthoformate (30 mL) was added to the residue and was heated to 79 C overnight. Reaction mixture was concentrated to dryness and triturated with hexanes, the solid obtained was collected by filtration dried in vacuum to give crude pyrrolo[l ,2-f][l ,2,4]triazin-4-ol 22f (1.1 g, 91%) as a dark brown solid. 1H NMR (300 MHz, DMSO-d6) ? 11.63 (s, 1H, D20 exchangeable), 7.83 (d, J= 4.0, 1H), 7.59 (dd, J= 1.7, 2.6, 1H), 6.89 (dd, J= 1.6, 4.3, 1H), 6.54 (dd, J = 2.7, 4.3, 1H); MS (ES+): 136.2 (M + l). Step 5:The stirred solution of pyrrolo[l ,2-f][l ,2,4]triazin-4-ol 22f (1 g, 7.40 mmol), benzyltriethylammonium chloride (3.29 g, 14.80 mmol), and N,N-dimethylaniline (1.35 g, 1 1.10 mmol) in acetonitrile (25 mL) was heated to 80 C and at this temperature phosphorous oxy chloride (6.88 g, 44.40 mmol) was added and stirred at 80 C for 16 h. The reaction was concentrated to remove acetonitrile and phosphorus oxy chloride. The reaction was quenched by adding ice water (20 mL) and extracted with ethyl acetate (2 x 100 mL). The ethyl acetate extracts were combined washed with hydrochloric acid (1 N, 30 mL), water (50 mL), saturated sodium bicarbonate (1 x 20 mL), water (50 mL), brine (20 mL) dried and concentrated. The crude residue was purified by flash chromatography (silica gel, eluting with ethyl acetate in hexanes (0 to 5 %)) to furnish pure4-chloropyrrolo[l,2-fJ[l,2,4]triazine 22g (0.7 g, 61.6 %) as a colorless oil, which solidified on standing in refrigerator. 1H NMR (300 MHz, DMSO-d6) ? 8.44 (s, 1H), 8.27 (dd, J = 1.5, 2.5, 1H), 7.12 (qd, J= 2.0, 4.6, 2H). Step 6:A solution of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (10m) (2.3 g, 9.8 ...
		Example 2: tert-butyl (2-cyano- lH-pyrrol- 1 -yl)carbamateUnder an atmosphere of nitrogen, the suspension of the compound (322g) prepared in Example 1 in acetonitrile (2L) was added into a flask. The solution was cooled to -70C. Chlorosulfonyl isocyanate (162mL, 1.86mol) was dropped into the solution and was stirred for an hour at O0C. Then, N,N-dimethylformamide (DMF) (325mL) was dropped into the mixture and stirred for an hour at 5C. The reaction solution was poured into iced water (4L) and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 1:0 - >;4:1 ->; 3:1 - >; 3:2). The obtained solids were washed in hexane/diisopropylether (1:1; 40OmL) to obtain the title compound (148g) as a white solid. The filtrate was concentrated and washed in hexane/diisopropylether (10:1; 30OmL) to obtain the title compound (112g) as a white solid. A total of 26Og of the title compound having the following physical data was obtained.TLC: Rf 0.42 (hexane : ethyl acetate = 3:1);1HNMR (300 MHz, CDCl3) delta ppm 1.52 (s, 9 H) 6.19 (dd, J=4.4, 2.9 Hz, 1 H) 6.79 (dd, J=4.4, 1.8 Hz, 1 H) 6.90 (dd, J=2.9, 1.8 Hz, 1 H) 7.26 (s, 1 H).

References: [1]ChemMedChem,2018,vol. 13,p. 437 - 445.
[2]Patent: CN110845502,2020,A .Location in patent: Paragraph 0028-0037.
[3]Patent: WO2007/64883,2007,A2 .Location in patent: Page/Page column 253-254.
[4]Patent: WO2007/56170,2007,A2 .Location in patent: Page/Page column 72.-73; 78-79.
[5]Patent: WO2007/64931,2007,A2 .Location in patent: Page/Page column 161-162.
[6]Patent: WO2010/14930,2010,A2 .Location in patent: Page/Page column 29; 33-34.
[7]Patent: WO2011/150356,2011,A1 .Location in patent: Page/Page column 85.
[8]Patent: WO2013/33093,2013,A1 .Location in patent: Page/Page column 129; 130; 131.
[9]Patent: WO2010/126960,2010,A1 .Location in patent: Page/Page column 57.

2
[ 937046-96-3 ]
[ 937046-97-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogenchloride; In water; ethyl acetate; at 0℃; for 0.5h;Large scale;	Add 1000g of Compound II (4.83mol, 1.0eq) and 3L of anhydrous ethyl acetate to a 20L three-necked bottle, stir to dissolve, and lower the temperature to 0 C to obtain the reaction solution, which is ready for use 5L of an ethyl acetate solution with a concentration of 1 mol / l was prepared with acid as the solute and ethyl acetate as the solvent, and it was completely added to the prepared reaction solution.Keeping the reaction at 0 C, a large amount of white solid was observed for 30 min. After the reaction was monitored by TLC, suction filtration was performed, and the residue was washed with anhydrous ethyl acetate and dried in vacuo. 680 g of white solid was obtained as intermediate III (1-amino-(9ci)-1H-pyrrole-2-carbonitrile hydrochloride).The purity of this intermediate III was 99%, and the yield was 97%.
85%	With hydrogenchloride; In 1,4-dioxane; at 0 - 20℃; for 5.5h;	A 3L, 3-neck RB flask was fitted with a mechanical stirrer, nitrogen inlet, thermocouple/JKEM thermocontroller, addition funnel and ice water cooling bath. (2- Cyano-pyrrol-1-yl)-carbamic acid, tert-butyl ester (85 g, 0.41 mol) was added and dissolved with 1 ,4-dioxane (400 ml_), then the stirred orange solution was cooled to 0 0C and HCI/dioxane (4N, 820 ml_, 8 eq.) was slowly added from the addition funnel, maintaining an internal temperature below 5 0C. After -30 minutes the solution became cloudy and stirring (at) room temperature was continued for 5 hours; the reaction was monitored for completion by TLC (silica gel, GHLF, 1 :3 EtOAc/hexane, UV; Note: the free base may be observed as a high-Rf spot and can be misinterpreted as incomplete reaction). The reaction mixture was diluted with diethyl ether (2L) and the precipitated solids were collected by suction filtration and washed with ether (1 L). Drying (vacuum oven (at) 500C) afforded the desired product as 50.5 g (85%) of a tan solid. 1H-NMR (CD3OD): 87.05 (dd, 1H, J =2.8, 1.9 Hz ), 6.75 (dd, 1H, J =1.8, 4.2 Hz), 6.13 (dd, 1H, J =2.8, 4.4 Hz ), 5.08 (s, 3H, NH3+); MS: GC/MS, m/z= 108.2 [M+H].
85%	With hydrogenchloride; In 1,4-dioxane; at 0 - 20℃; for 5.5h;	A 3L, 3-neck RB flask was fitted with a mechanical stirrer, nitrogen inlet, thermocouple/JKEM thermocontroUer, addition funnel and ice water cooling bath. (2-Cyano-pyrrol-l-yl)-carbamic acid, tert-butyl ester (85 g, 0.41 mol) was added and dissolved with 1,4-dioxane (400 mL), then the stirred orange solution was cooled to 0 0C and <n="164"/>HCl/dioxane (4N, 820 mL, 8 eq.) was slowly added from the addition funnel, maintaining an internal temperature below 5 0C. After -30 minutes the solution became cloudy and stirring @ room temperature was continued for 5 hours; the reaction was monitored for completion by TLC (silica gel, GHLF, 1:3 EtOAc/hexane, UV; Note: the free base may be observed as a high-Rf spot and can be misinterpreted as incomplete reaction). The reaction mixture was diluted with diethyl ether (2L). and the precipitated solids were collected by suction filtration and washed with ether (IL). Drying (vacuum oven @ 5O0C) afforded the desired product as 50.5 g (85%) of a tan solid. 1H-NMR (CD3OD): 67.05 (dd, IH, / =2.8, 1.9 Hz ), 6.75 (dd, IH, J =1.8, 4.2 Hz), 6.13 (dd, IH, J =2.8, 4.4 Hz ), 5.08 (s, 3H, NH3+); MS: GCMS, m/z= 108.2 [M+H].

References: [1]Patent: CN110845502,2020,A .Location in patent: Paragraph 0038-0043.
[2]Patent: WO2007/56170,2007,A2 .Location in patent: Page/Page column 73.
[3]Patent: WO2007/64931,2007,A2 .Location in patent: Page/Page column 162-163.

3
[ 937046-96-3 ]
[ 937047-04-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; In acetonitrile; at -30 - 20℃; for 2h;	A IL, 3-neck RB flask was fitted with a mechanical stirrer, nitrogen inlet, thermocouple/JKEM thermocontroller, and a dry-ice acetonitrile cooling. 2-Cyano-pyrrol- l-yl)-carbamic acid, tert-butyl ester (2Og, 96.5 mmol) was added and dissolved in 350 inL acetonitrile. The resulting solution and cooled to below -30 0C. l,3-Dibromo-5,5- dimethylhydantoin (13.79g, 48.26 mmol) was added as a solid, and the reaction was allowed to warm to rt over 2h. Analysis by RP-HPLC at 2h indicated that about 10% starting material remained. The reaction was cooled again to below -30 0C and treated with additional l,3-dibromo-5,5-dimethylhydantoin (1.3 g, 4.8 mmol). The reaction was allowed to warm slowly to rt over 3h. Once RP-HPLC indicated that all starting material had been consumed, the reaction was diluted with 500 mL EtOAc and transferred to a separatory funnel. The organic was washed with IN sodium carbonate, water and brine and then dried with sodium sulfate. Filtration of the organic layer thru silica gel removed much of the colored impurities. Evaporation of the solvent under vacuum provided a reddish oil, which provided orange-brown crystals of the desired product upon seeding (27.16g, 98% yield). This material proved to be only about 90% pure by 1H -NMR. 1H-NMR (DMSO): delta 10.95 (bs, IH), 7.61 (d, IH, J = 2.0 Hz), 7.16 (d, IH, J = 2 Hz), 1.44 (s, 9H, J = 4.4, 1.7 Hz).
98%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; In acetonitrile; at -30 - 20℃; for 5h;Cooling with acetone-dry ice;	A 1 L, 3-neck RB flask was fitted with a mechanical stirrer, nitrogen inlet, thermocouple and thermocontroller, and dry-ice acetonitrile cooling. 2-Cyano-pyrrol-1-yl-carbamic acid, ferf-butyl ester (20 g, 96.5 mmol) was added and dissolved in 350 ml_ acetonitrile and cooled to below -30 0C. 1 ,3-Dibromo-5,5-dimethylhydantoin (13.79 g, 48.26 mmol) was added as a solid, and the reaction was allowed to warm to rt over 2h. Analysis by RP- HPLC at 2h indicated that about 10% starting material remained. The reaction was cooled again to below -30 0C and treated with additional 1 ,3-dibromo-5,5- dimethylhydantoin (1.3 g, 4.8 mmol). The reaction was allowed to warm slowly to rt over 3h. The reaction was diluted with 500 mL EtOAc and transferred to a separatory funnel. The organic layer was washed with 1 N aq sodium carbonate, water and brine and then dried with sodium sulfate. Filtration of the organic layer through silica gel removed much of the colored impurities. Evaporation of the solvent under vacuum provided reddish oil, which provided orange-brown crystals of the desired product upon seeding (27.16 g, 98%). 1H-NMR (DMSO): delta 10.95 (bs, 1 H), 7.61 (d, 1H, J= 2.0 Hz), 7.16 (d, 1H, J= 2 Hz), 1.44 (s, 9H, J= 4.4, 1.7 Hz). MS: LC/MS (+esi), m/z= [M+H].
	In acetonitrile; at -30 - 20℃;Inert atmosphere;	Example 3 : tert-butyl (4-bromo-2-cyano-lH-pyrrol-l-yl)carbamateUnder an atmosphere of nitrogen, a solution of the compound (27Og) prepared in Example 2 in acetonitrile was added into a flask and was cooled to -3O0C. l,3-Dibromo-5,5- dimethylimidazolidine-2,4-dione (205g) was added into the solution then the bath was removed and the reaction was allowed to warm to room temperature. The solution was added into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed in saturated sodium chloride aqueous solution, were dried over anhydrous sodium sulfate and solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 9:1 - » 5:1) to obtain the title compound (423g) having the following physical data as a yellow oily matter. TLC: Rf 0.44 (hexane : ethyl acetate = 3:1);1HNMR (300 MHz, CDCl3) delta ppm 1.52 (s, 9 H) 6.78 (dd, J=I.8, 0.6 Hz, 1 H) 6.92 (dd, J=I.8, 0.6 Hz, I H) 7.31 (s, l H).

References: [1]Patent: WO2007/64883,2007,A2 .Location in patent: Page/Page column 254.
[2]Patent: WO2007/56170,2007,A2 .Location in patent: Page/Page column 78-79.
[3]ChemMedChem,2018,vol. 13,p. 437 - 445.
[4]Patent: WO2010/126960,2010,A1 .Location in patent: Page/Page column 57.

4
[ 937046-96-3 ]
[ 1206824-76-1 ]

Yield	Reaction Conditions	Operation in experiment
73.6%	With ammonium hydroxide; dihydrogen peroxide; In ethanol; water; at 20℃;	h. To a stirred solution of tert-butyl 2-cyano-lH-pyrrol-l-ylcarbamate 13 (5g, 24.12 mmol) in ethyl alcohol (100 ml) was added concentrated aqueous ammonium hydroxide solution (50 mL) at 20 0C followed by hydrogen peroxide (7.4 mL, 72.38 mmol, 30 % in water) slowly at 20 0C and stirred at the same temperature for 16 h. Reaction mixture was concentrated in vacuum and diluted with ethyl acetate (150 mL), washed with water ( 2 x 50 mL). The aqueous layer was extracted with ethyl acetate (150 mL). The combined ethyl acetate layers were washed with water (100 mL), brine (50 mL), dried, filtered, and concentrated in vacuum. The residue obtained was crystallized from diisopropyl ether and hexane to afford tert-butyl 2-carbamoyl-lH-pyrrol-l-ylcarbamate 14 (4.0 g, 73.6%) as a colorless solid. 1H NMR (300 MHz, DMSO) delta 9.89 (s, IH, D2O exchangeable), 7.31 (d, J= 38.5, IH), 6.84 (dd, J= 1.9, 2.8, 2H, IH is D2O exchangeable), 6.76 (dd, J= 1.9, 4.2, IH), 5.97 (dd, J= 2.8, 4.2, IH), 1.40 (s, 9H). HPLC (Zorbax SBC3, 3.0 x 150 mm, 5 mum, with ZGC SBC3, 2.1 x 12.5 mm guard cartridge. Mobile phase: 0.1 M ammonium acetate/ Acetonitrile) Rt = 12.817, (97.6861 %). Analysis: CaIC fOr C10H15N3O3: C, 53.32; H, 6.71; N, 18.65 Found: C, 53.40; H, 6.74; N, 18.55.
73.6%	With ammonium hydroxide; dihydrogen peroxide; In ethanol; water; at 20℃; for 16h;	To a stirred solution of tert-butyl 2-cyano-lH-pyrrol-l-yl carbamate 12d (5g, 24.12 mmol) in ethyl alcohol (100 ml) was added concentrated aqueous ammonium hydroxide solution (50 mL) at 20 C followed by hydrogen peroxide (7.4 mL, 72.38 mmol, 30 % in water) slowly at 20 C and stirred at the same temperature for 16 h. Reaction mixture was concentrated in vacuum and diluted with ethyl acetate (150 mL), washed with water ( 2 x 50 mL). The aqueous layer was extracted with ethyl acetate (150 mL). The combined ethyl acetate layers were washed with water (100 mL), brine (50 mL), dried, filtered, and concentrated in vacuum. The residue obtained was crystallized from diisopropyl ether and hexane to afford tert-butyl 2-carbamoyl- lH-pyrrol-l-ylcarbamate 12e (4.0 g, 73.6%) as a colorless solid. 1H NMR (300 MHz, DMSO) delta 9.89 (s, 1H, D20 exchangeable), 7.31 (d, J= 38.5, 1H), 6.84 (dd, J= 1.9, 2.8, 2H, 1H is D20 exchangeable), 6.76 (dd, J= 1.9, 4.2, 1H), 5.97 (dd, J= 2.8, 4.2, 1H), 1.40 (s, 9H). HPLC (Zorbax SBC3, 3.0 x 150 mm, 5 mu?iota, with ZGC SBC3, 2.1 x 12.5 mm guard cartridge. Mobile phase: 0.1 M ammonium acetate/ Acetonitrile) Rt = 12.817, (97.6861 %). Analysis: Calc for C10H15N3O3: C, 53.32; H, 6.71 ; N, 18.65 Found: C, 53.40; H, 6.74; N, 18.55.
73.6%	With ammonium hydroxide; water; dihydrogen peroxide; In ethanol; at 20℃; for 16h;	Step 1:To a stirred solution of tert-butyl hydrazinecarboxylate 22b (50 g, 412.37 mmol) and 2,5-dimethoxytetrahydrofuran 22a (54.5 g, 412.37 mmol) in dioxane (300 mL) was added aqueous hydrochloric acid (5 mL, 2N). The reaction was set up using a dean-stark apparatus and heated at 90 C for 20 h. Reaction mixture was cooled to 20 C, neutralized with saturated sodium bicarbonate (18 mL) and filtered to remove inorganics. The filtrate was concentrated in vacuum and triturated with ether. The solid obtained was collected by filtration to furnish on drying tert-butyl lH-pyrrol-l-ylcarbamate 22c (43 g, 57.2%) as a yellow brown solid. 1H NMR (300 MHz, CD3OD) ? 6.62 (t, J= 2.3, 2H), 6.02 (t, J= 2.3, 2H), 1.48 (s, 9H); MS (ES+): 181.1 (M _1). Analysis: Calculated for C9Hi4N202: C, 59.32; H, 7.74; N, 15.37. Found: C, 59.32; H, 7.65; N, 15.02. Step 2:To a stirred solution of tert-butyl lH-pyrrol-l-ylcarbamate 22c (40 g, 219.52 mmol), in acetonitrile (350 mL) was added chlorosulfonyl isocyanate (32.62 g, 230.50 mmol) slowly at 0 C and continued stirring at 0 C for 30 min. To the solution N, N-dimethyl formamide (40 mL) was added below 5 C and continued stirring at 0 C for 1 hr. The reaction mixture was poured into a mixture of crushed ice (1 L) and ethyl acetate (1 L). The layers were separated and the organic layer was washed with water (500 mL), brine (250 mL), dried and concentrated in vacuum to furnish crude (43 g) product. The crude was purified by flash chromatography (silica gel, eluting with ethyl acetate in hexane0-50%) to afford pure tert-butyl 2-cyano-lH-pyrrol-l-ylcarbamate 22d (30 g, 66 %>) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) ? 10.80 (s, 1H, D20 exchangeable), 7.23 (dd, J= 1.7, 2.9, 1H), 6.94 (dd, J= 1.7, 4.3, 1H), 6.20 (dd, J= 2.9, 4.3, 1H), 1.45 (s, 9H). Analysis: Calculated for Ci0Hi3N3O2: C, 57.95; H, 6.32; N, 20.27. Found: C, 58.02; H, 6.45; N, 20.18. Step 3:To a stirred solution of tert-butyl 2-cyano-lH-pyrrol-l-ylcarbamate 22d (5 g, 24.12 mmol) in ethyl alcohol (100 mL) was added concentrated aqueous ammonium hydroxide solution (50 mL) at 20 C followed by hydrogen peroxide (7.4 mL, 72.38 mmol, 30 % in water) slowly at 20 C and stirred at the same temperature for 16 h. Reaction mixture was concentrated in vacuum and diluted with ethyl acetate (150 mL), washed with water (2 x 50 mL). The aqueous layer was extracted with ethyl acetate (150 mL). The combined ethyl acetate layers were washed with water (100 mL), brine (50 mL), dried, filtered, and concentrated in vacuum. The residue obtained was crystallized from diisopropyl ether and hexane to afford tert-butyl 2-carbamoyl-lH-pyrrol-l-ylcarbamate 22e (4.0 g, 73.6%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) ? 9.89 (s, 1H, D20 exchangeable), 7.31 (d, J = 38.5, 1H), 6.84 (dd, J= 1.9, 2.8, 2H, lH is D20 exchangeable), 6.76 (dd, J = 1.9, 4.2, 1H), 5.97 (dd, J= 2.8, 4.2, 1H), 1.40 (s, 9H); Analysis: Calculated for Ci0Hi5N3O3: C, 53.32; H, 6.71 ; N, 18.65. Found: C, 53.40; H, 6.74; N, 18.55. Step 4:To a solution of tert-butyl 2-carbamoyl-lH-pyrrol-l-ylcarbamate 22e (2g, 8.87 mmol) in dichloromethane (15 mL) was added trifluoro acetic acid (15 mL) at 20 C and stirred for 30 min. The reaction mixture was concentrated to dryness to remove excess trifluoroacetic acid and diluted with dichloromethane. Triethylorthoformate (30 mL) was added to the residue and was heated to 79 C overnight. Reaction mixture was concentrated to dryness and triturated with hexanes, the solid obtained was collected by filtration dried in vacuum to give crude pyrrolo[l ,2-f][l ,2,4]triazin-4-ol 22f (1.1 g, 91%) as a dark brown solid. 1H NMR (300 MHz, DMSO-d6) ? 11.63 (s, 1H, D20 exchangeable), 7.83 (d, J= 4.0, 1H), 7.59 (dd, J= 1.7, 2.6, 1H), 6.89 (dd, J= 1.6, 4.3, 1H), 6.54 (dd, J = 2.7, 4.3, 1H); MS (ES+): 136.2 (M + l). Step 5:The stirred solution of pyrrolo[l ,2-f][l ,2,4]triazin-4-ol 22f (1 g, 7.40 mmol), benzyltriethylammonium chloride (3.29 g, 14.80 mmol), and N,N-dimethylaniline (1.35 g, 1 1.10 mmol) in acetonitrile (25 mL) was heated to 80 C and at this temperature phosphorous oxy chloride (6.88 g, 44.40 mmol) was added and stirred at 80 C for 16 h. The reaction was concentrated to remove acetonitrile and phosphorus oxy chloride. The reaction was quenched by adding ice water (20 mL) and extracted with ethyl acetate (2 x 100 mL). The ethyl acetate extracts were combined washed with hydrochloric acid (1 N, 30 mL), water (50 mL), saturated sodium bicarbonate (1 x 20 mL), water (50 mL), brine (20 mL) dried and concentrated. The crude residue was purified by flash chromatography (silica gel, eluting with ethyl acetate in hexanes (0 to 5 %)) to furnish pure4-chloropyrrolo[l,2-fJ[l,2,4]triazine 22g (0.7 g, 61.6 %) as a colorless oil, which solidified on standing in refrigerator. 1H NMR (300 MHz, DMSO-d6) ? 8.44 (s, 1H), 8.27 (dd, J = 1.5, 2.5, 1H), 7.12 (qd, J= 2.0, 4.6, 2H). Step 6:A solution of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (10m) (2.3 g, 9.8 ...

References: [1]Patent: WO2010/14930,2010,A2 .Location in patent: Page/Page column 29; 34.
[2]Patent: WO2011/150356,2011,A1 .Location in patent: Page/Page column 85-86.
[3]Patent: WO2013/33093,2013,A1 .Location in patent: Page/Page column 129; 130; 131.

5
[ 870-46-2 ]
[ 937046-96-3 ]

References: [1]Patent: WO2011/150356,2011,A1 .
[2]ChemMedChem,2018,vol. 13,p. 437 - 445.
[3]Patent: WO2013/33093,2013,A1 .
[4]Patent: CN110845502,2020,A .

6
[ 937046-96-3 ]
[ 888720-29-4 ]

References: [1]Patent: WO2011/150356,2011,A1 .
[2]Patent: WO2013/33093,2013,A1 .

7
[ 937046-96-3 ]
[ 159326-71-3 ]

References: [1]Patent: WO2011/150356,2011,A1 .
[2]Patent: WO2013/33093,2013,A1 .

8
[ 937046-96-3 ]
[ 1350882-22-2 ]

References: [1]Patent: WO2011/150356,2011,A1 .

9
[ 937046-96-3 ]
4-(1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine hydrochloride [ No CAS ]

References: [1]Patent: WO2011/150356,2011,A1 .

10
[ 937046-96-3 ]
[ 1426665-87-3 ]