Name: 158078-04-7|((3aR,4R,6R,6aR)-6-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol|97%
Brand: Ambeed
SKU: A776852
Rating: 94 (28 reviews)

1
[ 158078-04-7 ]
(S)-1-Aminoindane [ No CAS ]
[ 905580-21-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In butan-1-ol at 190℃; for 0.25h; Microwave irradiation;	39.b Step b { (3aR,4R,6JR>6aR)-6-r4-((S)-Indan-l-ylamino)-pyrrolor2,3-d1pyrimidin-7-yll-2,2- dimemyltetrahydro-furo[34-diri31dioxol-4-yl)-methanol; .[0296] A solution of [(3aR,4R,6R,6aR)-6-(4-CWoro-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimemyl-tetrahydro-furo[3,4-d][l,3]dioxol~4-yl]~methanol (574 mg, 1.76 mmol), diisopropylethylamine (1.2 mL, 7.04 mmol) and (S)-(+)-l-aminoindane (680 μL, 5.27 mmol) in n-butanol 3.3 mL) was divided into two portions and each portion was microwave irradiated at 190 °C for 900s. The solvent was removed in vacuo and the combined crude portions were purified by silica gel chromatography (0 to 5% MeOHZCH2Cl2) to afford 460 mg (62% over two steps) of the title compound.[0297] LCMS: R.t. 1.31 min, ES+ 423 (formic acid).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2006/84281, 2006, A1 Location in patent: Page/Page column 94

2
[ 16754-80-6 ]
[ 77-76-9 ]
[ 158078-04-7 ]

Yield	Reaction Conditions	Operation in experiment
60%	With toluene-4-sulfonic acid; In acetone; at 20℃; for 3h;	Suspend [(2R,3R,4R,5R)-3 ,4-dibenzoyloxy-5 -(4-chloropyrrolo [2,3-dlpyrimidin-7- yl)tetrahydrofuran-2-yllmethyl benzoate (80.5 g, 134.61 mmol) in MeOH (805 mL) andtreat with a solution of 0.5 M sodium methoxide in MeOH (53.8 mL, 26.92 mmol) at room temperature for 3 hr. Cool to 0 C and treat the mixture with DOWEX 50WX2 resin (up to pH <5). Filter and concentrate in vacuo to give a residue. Triturate from MTBE (100 mL). Decant the mixture and dry the resulting residue to give a white solid. Suspend the solid in acetone (1100 mL) and add 2,2-dimethoxypropane (41.5 mL, 336.5mmol) and p-toluenesulfonic acid monohydrate (25.6 g, 134.6 mmol) to the mixture. Stir the reaction mixture for 3 hr at room temperature. Remove up to 1/3 of the solvent under reduced pressure and add DCM (250 mL) and water (100 mL). Separate the organic layer and extract the aqueous layer with DCM (2 x 100 mL). Combine the organic extracts and wash with saturated aqueous NaHCO3 (150 mL; pH-9) and saturatedaqueous sodium chloride (100 mL). Dry the organic layer over sodium sulfate. Filter and remove the solvents under reduced pressure to give a crude mixture. Purify via silica gel chromatography eluting with 30% EtOAc in DCM to give the title compound (26.5 g, 60% yield) as colorless oil. ES/MS m/z (35C1/37C1) 326.0/328.0 [M+H1.
		Example 39: ((2R,3S,4K5R)-5-{4-[(lS)-2,3-Dihydro-lH-inden-l-ylamino]-7H-pyrrolo[2,3-d]- pyrimidin-7-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl sulfamate (1-9)Step a: [(3aR/4R/6R,6aR)-6-(4-Chloro-pyrrolor2,3-d1pyrimidin-7-yl)-2/2-dimethyl- tetrahydrofurof3,4-d1fl,31dioxol-4-yl1-methanol; .[0294] To a suspension of (2R,3R,4S,5R)-2-(4-chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol (0.5 g, 1.75 mmol) and 2,2-dimethoxypropane (1.12 mL, 8.75 mmol) in acetone (40 mL) was added 333 mg (1.75 mmol) p-TsOH monohydrate. The resulting clear solution was stirred for 13 hours and then saturated aq NaHCO3 was added. Approximately half the solvent was removed in vacuo and the resulting suspension was diluted with water and extracted with CH2Cl2 (4x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was used without further purification.- 93 - EPO <DP n="94"/>[0295] LCMS: R.t. 1.49 min, ES+ 326 (formic acid).
	With toluene-4-sulfonic acid; In acetone; at 25 - 60℃; for 2h;Inert atmosphere;	To a mixture of 6-chloro-7-deazapurinebeta-d-riboside (25.0 g, 87.5 mmol ) in acetone (330 mL) was added 2.2-dimethoxypropane (18.2 g, 1 75 mmol ) and 4- methylbenzenesulfonic acid (TosOH) (1.51 g, 8.75 mmol) in one portion at 25C under N2.The mixture was stirred at 60 C for 2 hours. The mixture was cooled to 25C. The reaction was quenched by adding saturated NaHCOs (100 mL) slowly and then extracted with ethyl acetate (125 mL x 5).The combined organic phase was washed with saturated brine (120 mL), dried with anhydrous MgS04, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (gradient elution: DCM/Ethyl acetate from 1 :0 to 2: 1 ) to afford crude intermediate 1 (38.0 g) as light yellow gum.

	With toluene-4-sulfonic acid; In acetone; at 60℃; for 2h;Inert atmosphere;	To a mixture of 6-chloro-7-deazapurinebeta-d-riboside (25.0 g, 87.5 mmol) in acetone (330 mL) was added 2,2-dimethoxypropane (18.2 g, 175 mmol) and TosOH (1.51 g, 8.75 mmol) in one portion at 25C under N2. The mixture was stirred at 60C for 2 hours. The mixture was cooled to 25C. The reaction was quenched by adding saturated NaHC03 (100 mL) slowly and then extracted with ethyl acetate (5 times 125 mL). The combined organic phases were washed with saturated brine (120 mL), dried with anhydrous MgS04, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (gradient elution: DCM/Ethyl acetate from 1 :0 to 2: 1) to afford crude intermediate 1 (38.0 g) as light yellow gum.
	With toluene-4-sulfonic acid; In acetone; at 20℃; for 2h;	To a solution of 10.0 g (35.0 mmol) of compound 2-2 in 200 mL of acetone was added 600 mg (3.48 mmol) of TsOH and 11.0 g (105.6 mmol) of 2,2-dimethoxypropane. The mixture was stirred at rt for 2 h. The reaction was then quenched by addition of 150 mL of water and extracted with three 150 mL portions of DCM. The combined organic extracts were washed with 150 mL of brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to afford compound 2-3, which was used in the next step without further purification. LC-MS: m/e = 326 [M+H]+.

Reference： [1]Patent: WO2016/178870,2016,A1 .Location in patent: Page/Page column 18; 19
[2]Patent: WO2006/84281,2006,A1 .Location in patent: Page/Page column 93
[3]Patent: WO2017/32840,2017,A1 .Location in patent: Page/Page column 123; 124
[4]Patent: WO2017/153186,2017,A1 .Location in patent: Page/Page column 79; 80
[5]Patent: WO2019/112719,2019,A1 .Location in patent: Paragraph 081; 083

3
[ 158078-04-7 ]
[ 192752-93-5 ]
[ 1243155-44-3 ]

Yield	Reaction Conditions	Operation in experiment
51%	Stage #1: [(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol; 3-methylsalicylchlorophosphane With N-ethyl-N,N-diisopropylamine In acetonitrile at 0℃; for 1h; Stage #2: With tert.-butylhydroperoxide In decane; acetonitrile at 0 - 20℃;

Reference： [1]Location in patent: experimental part Spacilova, Pavla; Naus, Petr; Pohl, Radek; Votruba, Ivan; Snasel, Jan; Zabranska, Helena; Pichova, Iva; Ameral, Ria; Birkus, Gabriel; Cihlar, Tomas; Hocek, Michal [ChemMedChem, 2010, vol. 5, # 8, p. 1386 - 1396]

4
[ 158078-04-7 ]
[ 142629-80-9 ]
[ 1268354-28-4 ]

Yield	Reaction Conditions	Operation in experiment
74%	Stage #1: [(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol With tert-butylmagnesium chloride In tetrahydrofuran Inert atmosphere; Stage #2: phenyl methoxyalaninyl phosphorochloridate In tetrahydrofuran at 20℃; Inert atmosphere;	4.1. General procedure for the synthesis of 6-chloro-7-deazapurine ribonucleoside ProTides 7-9 General procedure: Nucleoside 3 (1.22 mmol) was dissolved in THF (15 ml). Solution of t-BuMgCl in THF (1 M, 2 equiv) was added drop-wise and the reaction mixture was stirred for 15 min. Then solution of a phosphochloridate 4-6 (2.6 equiv) in THF (15 ml) was added and the reaction mixture was stirred overnight at room temperature. Saturated NH4Cl solution (2.5 ml) was added and reaction mixture was extracted with EtOAc and water. Organic layer was dried with MgSO4 and evaporated under reduced pressure. Crude product was purified using column chromatography (SiO2, hexane/EtOAc 2:1) Products were obtained as oils. Mixtures of diastereomers were obtained, ratios were determined by NMR spectra.

Reference： [1]Location in patent: experimental part Perlíková, Pavla; Pohl, Radek; Votruba, Ivan; Shih, Robert; Birkuš, Gabriel; Cihlář, Tomáš; Hocek, Michal [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 1, p. 229 - 242]

5
[ 158078-04-7 ]
[ 183370-70-9 ]
[ 1268354-32-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: [(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol With tert-butylmagnesium chloride In tetrahydrofuran Inert atmosphere; Stage #2: phenyl(benzyloxy-L-alaninyl)phosphorochloridate In tetrahydrofuran at 20℃; Inert atmosphere;	4.1. General procedure for the synthesis of 6-chloro-7-deazapurine ribonucleoside ProTides 7-9 General procedure: Nucleoside 3 (1.22 mmol) was dissolved in THF (15 ml). Solution of t-BuMgCl in THF (1 M, 2 equiv) was added drop-wise and the reaction mixture was stirred for 15 min. Then solution of a phosphochloridate 4-6 (2.6 equiv) in THF (15 ml) was added and the reaction mixture was stirred overnight at room temperature. Saturated NH4Cl solution (2.5 ml) was added and reaction mixture was extracted with EtOAc and water. Organic layer was dried with MgSO4 and evaporated under reduced pressure. Crude product was purified using column chromatography (SiO2, hexane/EtOAc 2:1) Products were obtained as oils. Mixtures of diastereomers were obtained, ratios were determined by NMR spectra.

Reference： [1]Location in patent: experimental part Perlíková, Pavla; Pohl, Radek; Votruba, Ivan; Shih, Robert; Birkuš, Gabriel; Cihlář, Tomáš; Hocek, Michal [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 1, p. 229 - 242]

6
[ 158078-04-7 ]
[ 245078-14-2 ]
[ 1268354-30-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: [(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol With tert-butylmagnesium chloride In tetrahydrofuran Inert atmosphere; Stage #2: (2S)-ethyl 2-(chloro(phenoxy)phosphorylamino)propanoate In tetrahydrofuran at 20℃; Inert atmosphere;	4.1. General procedure for the synthesis of 6-chloro-7-deazapurine ribonucleoside ProTides 7-9 General procedure: Nucleoside 3 (1.22 mmol) was dissolved in THF (15 ml). Solution of t-BuMgCl in THF (1 M, 2 equiv) was added drop-wise and the reaction mixture was stirred for 15 min. Then solution of a phosphochloridate 4-6 (2.6 equiv) in THF (15 ml) was added and the reaction mixture was stirred overnight at room temperature. Saturated NH4Cl solution (2.5 ml) was added and reaction mixture was extracted with EtOAc and water. Organic layer was dried with MgSO4 and evaporated under reduced pressure. Crude product was purified using column chromatography (SiO2, hexane/EtOAc 2:1) Products were obtained as oils. Mixtures of diastereomers were obtained, ratios were determined by NMR spectra.

Reference： [1]Location in patent: experimental part Perlíková, Pavla; Pohl, Radek; Votruba, Ivan; Shih, Robert; Birkuš, Gabriel; Cihlář, Tomáš; Hocek, Michal [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 1, p. 229 - 242]

7
[ 158078-04-7 ]
[ 98437-24-2 ]
4-(dibenzofuran-4-yl)-7-(2,3-O-isopropylidene-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In toluene at 85℃;

Reference： [1]Perlikova, Pavla; Konecny, Petr; Naus, Petr; Snasel, Jan; Votruba, Ivan; Dzubak, Petr; Pichova, Iva; Hajduch, Marian; Hocek, Michal [MedChemComm, 2013, vol. 4, # 11, p. 1497 - 1500]

8
[ 158078-04-7 ]
[ 100124-06-9 ]
4-(dibenzofuran-4-yl)-7-(2,3-O-isopropylidene-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In toluene at 85℃;

Reference： [1]Perlikova, Pavla; Konecny, Petr; Naus, Petr; Snasel, Jan; Votruba, Ivan; Dzubak, Petr; Pichova, Iva; Hajduch, Marian; Hocek, Michal [MedChemComm, 2013, vol. 4, # 11, p. 1497 - 1500]

9
[ 158078-04-7 ]
[ 2958-09-0 ]
4-chloro-7-(2,3-O-isopropylidene-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-octadecylphosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: monostearyl phosphate With pyridine; 2-mesitylenesulphonyl chloride for 0.5h; Stage #2: [(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol In pyridine at 20℃;

Reference： [1]Perlikova, Pavla; Konecny, Petr; Naus, Petr; Snasel, Jan; Votruba, Ivan; Dzubak, Petr; Pichova, Iva; Hajduch, Marian; Hocek, Michal [MedChemComm, 2013, vol. 4, # 11, p. 1497 - 1500]

10
[ 158078-04-7 ]
[ 18162-48-6 ]
[ 115479-39-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 1H-imidazole In dichloromethane at 20℃;	1.1 Stage 1 7-[(3aR,4R,6R,6aR)-6- [Qert-butyldimethylsilyl)oxy]methyl} -2,2-dimethyl- tetrahydro-2H-furo[3 „4-d] [1. „3] dioxol-4-yl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidine TBSC1 (2.78 g, 18.42 mmol) was addedto a suspension of[(3aR,4R,6R,6aR)-6-{4- chloro-7H-pyrrolo[2,3 -d]pyrimidin-7-yl} -2,2-dimethyl-tetrahydro-2H-furo[3 „4-d] [1 „3]dioxol- 4-yl]methanol (5.00 g, 15.35 mmol) and imidazole (2.51 g, 36.84 mmol) in DCM (80 ml) at RT and stirred oyernight. The reaction rnixture was washed with 0.5 N HC1 (100 ml), dried oyer Na2SO4, filtered and eyaporated in yacuo. Purification by silica gel colunin chrornatography, on a Biotage Isolera system, using a 100 g KP-Sil SNAP cartridge, eluting with EtOAc:heptanes (2:98 - 1:4), gaye the desired product as yiscous oil (6.69 g, 99%): MS (ESF”) for C20H30C1N3O4Si m/z 440.0 [M+Hi”, LC purity 100% (ret. tirne, 2.71 mm); 1H NMR (250 MHz, Chloroform-d) 8.66 (s, 1H), 7.58 (d, J 3.7 Hz, 1H), 6.63 (d, J 3.7 Hz, H), 6.41 (d, J 3.0 Hz, 1H), 5i3 - 5.01 (m, H), 4.98 - 4.9 (m, 1H), 4.36 (q, .1= 3.3 Hz, H), 3.98 - 3.74 (m, 2H), 1.65 (s, 3H), 1.39 (s, 3H), 0.89 (s, 9H), 0.06 (d, J 1.1 Hz, 6H).

Reference： [1]Current Patent Assignee: EPIZYME, INC. - WO2014/152261, 2014, A1 Location in patent: Paragraph 0481; 0482

11
[ 158078-04-7 ]
(2R,3R,4S,5R)-2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1.1: 1H-imidazole / dichloromethane / 20 °C 2.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.5 h / 35 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.75 h / 0 °C 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 8 h / 0 - 20 °C 5.1: sodium azide / N,N-dimethyl-formamide / 8 h / 60 °C 6.1: trimethylphosphane / tetrahydrofuran / 2 h / 20 °C 7.1: hydrazine hydrate / ethanol / 1 h / 90 °C 8.1: acetic acid / 1,2-dichloro-ethane / 1 h / 20 °C 8.2: 2 h / 20 °C 9.1: acetic acid; sodium tris(acetoxy)borohydride / acetone / 20 °C 10.1: hydrogenchloride; water / methanol / 18 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: EPIZYME, INC. - WO2014/152261, 2014, A1

12
[ 158078-04-7 ]
7-[(3aR,4R,6R,6aR)-6-[(tert-butyldimethylsilyl)oxy]methyl}-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxo-4-yl]-5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1H-imidazole / dichloromethane / 20 °C 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.5 h / 35 °C

Reference： [1]Current Patent Assignee: EPIZYME, INC. - WO2014/152261, 2014, A1

13
[ 158078-04-7 ]
[(3aR,4R,6R,6aR)-6-{5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26.8%	With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 1h;	A8 Preparation of intermediate 27 To a stirred solution of intermediate 1 (5.39 g, 16.55 mmol) in DMF (25 mL) at room temperature was added portion wise N-bromo succinimide (2.95 g, 16.55 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with water, dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM/MeOH: 99/1) to afford intermediate 27 (1.8 g, 4.45 mmol, 26.8% yield)
	Multi-step reaction with 3 steps 1: 1H-imidazole / dichloromethane / 20 °C 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.5 h / 35 °C 3: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.75 h / 0 °C

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/153186, 2017, A1 Location in patent: Page/Page column 90
[2]Current Patent Assignee: EPIZYME, INC. - WO2014/152261, 2014, A1

14
[ 158078-04-7 ]
2-[(3aR,4R,6R,6aR)-6-{5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methyl}-2,3-dihydro-1H-isoindole-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 1H-imidazole / dichloromethane / 20 °C 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.5 h / 35 °C 3: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.75 h / 0 °C 4: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 8 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: EPIZYME, INC. - WO2014/152261, 2014, A1

15
[ 158078-04-7 ]
2-[(3aR,4R,6R,6aR)-6-{4-azido-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methyl}-2,3-dihydro-1H-isoindole-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 1H-imidazole / dichloromethane / 20 °C 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.5 h / 35 °C 3: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.75 h / 0 °C 4: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 8 h / 0 - 20 °C 5: sodium azide / N,N-dimethyl-formamide / 8 h / 60 °C

Reference： [1]Current Patent Assignee: EPIZYME, INC. - WO2014/152261, 2014, A1

16
[ 158078-04-7 ]
2-[[(3aR,4R,6R,6aR)-6-[4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyltetrahydro-2H-furo[3,4-d][1,3]dioxolane-4-yl]methyl]-2,3-dihydro-1H-isoindole-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 1H-imidazole / dichloromethane / 20 °C 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.5 h / 35 °C 3: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.75 h / 0 °C 4: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 8 h / 0 - 20 °C 5: sodium azide / N,N-dimethyl-formamide / 8 h / 60 °C 6: trimethylphosphane / tetrahydrofuran / 2 h / 20 °C

Reference： [1]Current Patent Assignee: EPIZYME, INC. - WO2014/152261, 2014, A1

17
[ 158078-04-7 ]
[ 1053695-56-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: 1H-imidazole / dichloromethane / 20 °C 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.5 h / 35 °C 3: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.75 h / 0 °C 4: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 8 h / 0 - 20 °C 5: sodium azide / N,N-dimethyl-formamide / 8 h / 60 °C 6: trimethylphosphane / tetrahydrofuran / 2 h / 20 °C 7: hydrazine hydrate / ethanol / 1 h / 90 °C

Reference： [1]Current Patent Assignee: EPIZYME, INC. - WO2014/152261, 2014, A1

18
[ 158078-04-7 ]
7-[(3aR,4R,6R,6aR)-6-[({3-[2-(5-tert-butyl-1H-1,3-benzodiazol-2-yl)ethyl]cyclobutyl}amino)methyl]-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]-5-brorno-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: 1H-imidazole / dichloromethane / 20 °C 2.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.5 h / 35 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.75 h / 0 °C 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 8 h / 0 - 20 °C 5.1: sodium azide / N,N-dimethyl-formamide / 8 h / 60 °C 6.1: trimethylphosphane / tetrahydrofuran / 2 h / 20 °C 7.1: hydrazine hydrate / ethanol / 1 h / 90 °C 8.1: acetic acid / 1,2-dichloro-ethane / 1 h / 20 °C 8.2: 2 h / 20 °C

Reference： [1]Current Patent Assignee: EPIZYME, INC. - WO2014/152261, 2014, A1

19
[ 158078-04-7 ]
7-[(3aR,4R,6R,6aR)-6-[({3-[2-(5-tert-butyl-1H-1,3-benzodiazol-2-yl)ethyl]cyclobutyl}(propan-2-yl)amino)methyl]-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: 1H-imidazole / dichloromethane / 20 °C 2.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.5 h / 35 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.75 h / 0 °C 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 8 h / 0 - 20 °C 5.1: sodium azide / N,N-dimethyl-formamide / 8 h / 60 °C 6.1: trimethylphosphane / tetrahydrofuran / 2 h / 20 °C 7.1: hydrazine hydrate / ethanol / 1 h / 90 °C 8.1: acetic acid / 1,2-dichloro-ethane / 1 h / 20 °C 8.2: 2 h / 20 °C 9.1: acetic acid; sodium tris(acetoxy)borohydride / acetone / 20 °C

Reference： [1]Current Patent Assignee: EPIZYME, INC. - WO2014/152261, 2014, A1

20
[ 158078-04-7 ]
1-[(3aR,4R,6S,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-1-(3,4-dichlorophenyl)ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: TurboGrignard / tetrahydrofuran / 1.25 h / -15 - 0 °C 3.2: 0.17 h / 0 °C 4.1: tetrahydrofuran; diethyl ether / 1 h / 0 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 18 h / 85 °C / Sealed tube

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

21
[ 158078-04-7 ]
1-[(3aR,4R,6S,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-1-(2-fluorophenyl)ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 1.5 h / 0 °C 3.2: 2.75 h / 0 - 20 °C 4.1: tetrahydrofuran; diethyl ether / 2 h / 0 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 22 h / 85 °C / Sealed tube

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

22
[ 158078-04-7 ]
1-[(3aR,4R,6S,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-1-[2-(trifluoromethyl)phenyl]ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 2 h / 0 - 20 °C 3.2: 3.5 h / 0 - 20 °C 4.1: tetrahydrofuran; diethyl ether / 0.5 h / 0 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 22 h / 85 °C / Sealed tube

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

23
[ 158078-04-7 ]
1-[(3aR,4R,6S,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-1-[4-(trifluoromethyl)phenyl]ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: isopropylmagnesium chloride / tetrahydrofuran / 24 h / 20 °C 3.2: 2 h / 20 °C 4.1: tetrahydrofuran; diethyl ether / 1 h / 0 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 22 h / 85 °C / Sealed tube

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

24
[ 158078-04-7 ]
(1R)-1-[(3aR,4R,6S,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-1-(4-chlorophenyl)ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3: tetrahydrofuran; diethyl ether / 1 h / -10 - 20 °C 4: tetrahydrofuran; 2-methyltetrahydrofuran / 2 h / 0 °C 5: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran; toluene / 6 h / 70 °C / Inert atmosphere; Sealed tube

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

25
[ 158078-04-7 ]
[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3 a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-chloro-2-fluorophenyl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 1 h / 0 °C 3.2: 5 h / 0 °C 4.1: N-[(1R,2R)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzenesulfonamide(chloro)ruthenium(II); formic acid/triethylamine complex 5:2 / 1 h / 20 °C 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran; toluene / 6 h / 80 °C / Inert atmosphere; Sealed tube

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

26
[ 158078-04-7 ]
1-[(3aR,4R,6S,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-1-(3,4-dichlorophenyl)ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: TurboGrignard / tetrahydrofuran / 1.25 h / -15 - 0 °C 3.2: 0.17 h / 0 °C 4.1: tetrahydrofuran; diethyl ether / 1 h / 0 °C 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / toluene; 1,4-dioxane / 8 h / 80 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

27
[ 158078-04-7 ]
(R)-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-chlorophenyl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3: tetrahydrofuran; diethyl ether / 1 h / -10 - 20 °C 4: ammonium formate; (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)] / water; dichloromethane / 1 h / 20 °C 5: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran; toluene / 6 h / 70 °C / Inert atmosphere; Sealed tube

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

28
[ 158078-04-7 ]
(2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3: tetrahydrofuran; diethyl ether / 1 h / -10 - 20 °C 4: ammonium formate; (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)] / water; dichloromethane / 1 h / 20 °C 5: ammonium hydroxide / water; 1,4-dioxane / 200 °C / 41372.9 Torr 6: hydrogenchloride / water; isopropyl alcohol / 44 h / 0 - 40 °C
	Multi-step reaction with 7 steps 1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3: tetrahydrofuran; diethyl ether / 1 h / -10 - 20 °C 4: L-Selectride / tetrahydrofuran / 4 h / -78 °C / Inert atmosphere 5: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 24 h / 20 °C / Inert atmosphere 6: ammonium hydroxide / water; 1,4-dioxane / 18 h / 110 °C / Sealed tube 7: hydrogenchloride / water; isopropyl alcohol / 44 h / 0 - 40 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1
[2]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

29
[ 158078-04-7 ]
(2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-hydroxy(phenyl)methyl)tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: tetrahydrofuran; diethyl ether / 0.53 h / 0 °C 4.1: N-[(1R,2R)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzenesulfonamide(chloro)ruthenium(II); formic acid/triethylamine complex 5:2 / 4 h / 20 °C 5.1: ammonia / methanol / 8 h / 100 °C / Microwave irradiation; Sealed tube; Inert atmosphere 6.1: hydrogenchloride / water; 1,4-dioxane / 0.75 h / 20 °C
	Multi-step reaction with 6 steps 1.1: I,I-bis(acetoxy)iodobenzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 20 °C / Cooling with ice 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 20 °C / Cooling with ice 2.2: 72 h / 20 °C 3.1: diethyl ether; tetrahydrofuran / 0.53 h / 0 °C 4.1: (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine; triethylamine; formic acid / 4 h / 20 °C 5.1: ammonia / methanol / 8 h / 100 °C / Sealed tube; Microwave irradiation 6.1: hydrogenchloride; water / 1,4-dioxane / 0.75 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1
[2]Bonday, Zahid Q.; Cortez, Guillermo S.; Grogan, Michael J.; Antonysamy, Stephen; Weichert, Ken; Bocchinfuso, Wayne P.; Li, Fengling; Kennedy, Steven; Li, Binghui; Mader, Mary M.; Arrowsmith, Cheryl H.; Brown, Peter J.; Eram, Mohammad S.; Szewczyk, Magdalena M.; Barsyte-Lovejoy, Dalia; Vedadi, Masoud; Guccione, Ernesto; Campbell, Robert M. [ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 612 - 617]

30
[ 158078-04-7 ]
(2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-1-(4-chlorophenyl)-1-hydroxyethyl]tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3: tetrahydrofuran; diethyl ether / 1 h / -10 - 20 °C 4: tetrahydrofuran; 2-methyltetrahydrofuran / 2 h / 0 °C 5: ammonium hydroxide / water; 1,4-dioxane / 18 h / 110 °C / Sealed tube 6: hydrogenchloride / water; isopropyl alcohol / 6 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

31
[ 158078-04-7 ]
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[hydroxy-[4-(trifluoromethyl)phenyl]methyl]tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: isopropylmagnesium chloride / tetrahydrofuran / 24 h / 20 °C 3.2: 2 h / 20 °C 4.1: L-Selectride / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 5.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 5 h / 0 - 20 °C / Inert atmosphere 6.1: ammonium hydroxide / water; 1,4-dioxane / 18 h / 110 °C / Sealed tube 7.1: hydrogenchloride / water; isopropyl alcohol / 3 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

32
[ 158078-04-7 ]
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(3-chlorophenyl)hydroxymethyl]tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 1.17 h / 0 °C 3.2: 1 h / 0 °C 4.1: L-Selectride / tetrahydrofuran / 0.17 h / -78 °C / Inert atmosphere 5.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 19.5 h / 0 - 20 °C / Inert atmosphere 6.1: ammonium hydroxide / water; 1,4-dioxane / 48 h / 85 - 95 °C / Sealed tube 7.1: hydrogenchloride / methanol; water; 1,4-dioxane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

33
[ 158078-04-7 ]
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(4-chloro-2-fluorophenyl)-hydroxymethyl]tetrahydrofuran-3,4-diol hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 1 h / 0 °C 3.2: 5 h / 0 °C 4.1: N-[(1R,2R)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzenesulfonamide(chloro)ruthenium(II); formic acid/triethylamine complex 5:2 / 1 h / 20 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 15 h / 80 °C / Sealed tube 6.1: hydrogenchloride / methanol; water; 1,4-dioxane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

34
[ 158078-04-7 ]
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(2-fluorophenyl)-hydroxymethyl]tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 1 h / 0 °C 3.2: 5 h / 0 °C 4.1: N-[(1R,2R)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzenesulfonamide(chloro)ruthenium(II); formic acid/triethylamine complex 5:2 / 1 h / 20 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 15 h / 80 °C / Sealed tube 6.1: hydrogenchloride / methanol; water; 1,4-dioxane / 1 h / 20 °C 7.1: palladium 10% on activated carbon; hydrogen; triethylamine / ethanol / 48 h / 517.16 Torr

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

35
[ 158078-04-7 ]
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(3-ethylphenyl)-hydroxymethyl]tetrahydrofuran-3,4-diol hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: tetrahydrofuran / 0.5 h / 0 °C 4.1: N-[(1R,2R)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzenesulfonamide(chloro)ruthenium(II); formic acid/triethylamine complex 5:2 / 4 h / 20 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 12 h / 80 °C / Sealed tube 6.1: hydrogenchloride / methanol; water; 1,4-dioxane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

36
[ 158078-04-7 ]
4-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]-hydroxymethyl]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: TurboGrignard / tetrahydrofuran / 2 h / 0 °C 3.2: 2 h / 0 - 20 °C 4.1: (S)-tetrahydro-1-butyl-3,3-diphenyl-1H,3H-pyrrolo{2,1-c}{1,3,2}oxazaborole; borane-THF / tetrahydrofuran; toluene / 17 h / -15 - 20 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 18 h / 85 °C / Sealed tube 6.1: trifluoroacetic acid / water / 1 h / 0 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

37
[ 158078-04-7 ]
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(3,4-difluorophenyl)-hydroxymethyl]tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: isopropylmagnesium chloride / tetrahydrofuran / 1.25 h / -15 - 0 °C 3.2: 0.25 h / 0 °C 4.1: N-[(1R,2R)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzenesulfonamide(chloro)ruthenium(II); formic acid/triethylamine complex 5:2 / 1.5 h / 20 °C / Inert atmosphere 5.1: ammonium hydroxide / water; 1,4-dioxane / 18 h / 85 °C / Sealed tube 6.1: hydrogenchloride / water; 1,4-dioxane / 40 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

38
[ 158078-04-7 ]
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(3,4-dichlorophenyl)-hydroxymethyl]tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: TurboGrignard / tetrahydrofuran / 1.25 h / -15 - 0 °C 3.2: 0.17 h / 0 °C 4.1: (S)-tetrahydro-1-butyl-3,3-diphenyl-1H,3H-pyrrolo{2,1-c}{1,3,2}oxazaborole; borane-THF / tetrahydrofuran; toluene / 17 h / -15 - 20 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 18 h / 85 °C / Sealed tube 6.1: trifluoroacetic acid / water / 0.75 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

39
[ 158078-04-7 ]
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[hydroxy(p-tolyl)methyl]tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: tetrahydrofuran / 1 h / -15 °C 4.1: N-[(1R,2R)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzenesulfonamide(chloro)ruthenium(II); formic acid/triethylamine complex 5:2 / 1,4-dioxane / 4 h / 20 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 18 h / 85 °C / Sealed tube 6.1: trifluoroacetic acid / water / 1.5 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

40
[ 158078-04-7 ]
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(4-fluorophenyl)-hydroxymethyl]tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: tetrahydrofuran / 1.75 h / 0 - 20 °C 4.1: N-[(1R,2R)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzenesulfonamide(chloro)ruthenium(II); formic acid/triethylamine complex 5:2 / 1,4-dioxane / 2 h / 20 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 78 h / 75 - 85 °C / Sealed tube 6.1: hydrogenchloride / water; 1,4-dioxane / 1.08 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

41
[ 158078-04-7 ]
(2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[1-(4-chlorophenyl)-1-hydroxy-propyl]tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: tetrahydrofuran; diethyl ether / 1 h / -10 - 20 °C 4.1: tetrahydrofuran / 1.27 h / 0 - 20 °C 4.2: 6 h / 100 °C / Microwave irradiation 4.3: 1.5 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

42
[ 158078-04-7 ]
(2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[1-(3,4-dichlorophenyl)-1-hydroxyethyl]tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: TurboGrignard / tetrahydrofuran / 1.25 h / -15 - 0 °C 3.2: 0.17 h / 0 °C 4.1: tetrahydrofuran; diethyl ether / 1 h / 0 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 18 h / 85 °C / Sealed tube 6.1: trifluoroacetic acid / water / 1 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

43
[ 158078-04-7 ]
(2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[1-(2-fluorophenyl)-1-hydroxyethyl]tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 1.5 h / 0 °C 3.2: 2.75 h / 0 - 20 °C 4.1: tetrahydrofuran; diethyl ether / 2 h / 0 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 22 h / 85 °C / Sealed tube 6.1: trifluoroacetic acid / water / 0.5 h / 0 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

44
[ 158078-04-7 ]
(2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[1-hydroxy-1-[2-(trifluoromethyl)phenyl]ethyl]tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 2 h / 0 - 20 °C 3.2: 3.5 h / 0 - 20 °C 4.1: tetrahydrofuran; diethyl ether / 0.5 h / 0 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 22 h / 85 °C / Sealed tube 6.1: trifluoroacetic acid / water / 0.33 h / 0 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

45
[ 158078-04-7 ]
(2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[1-hydroxy-1-[4-(trifluoromethyl)phenyl]ethyl]tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: isopropylmagnesium chloride / tetrahydrofuran / 24 h / 20 °C 3.2: 2 h / 20 °C 4.1: tetrahydrofuran; diethyl ether / 1 h / 0 °C 5.1: ammonium hydroxide / water; 1,4-dioxane / 22 h / 85 °C / Sealed tube 6.1: trifluoroacetic acid / water / 0.75 h / 0 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

46
[ 158078-04-7 ]
(2S,3S,4R,5R)-2-[(1R)-(1-(4-chlorophenyl)-1-hydroxyethyl)]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3: tetrahydrofuran; diethyl ether / 1 h / -10 - 20 °C 4: tetrahydrofuran; 2-methyltetrahydrofuran / 2 h / 0 °C 5: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran; toluene / 6 h / 70 °C / Inert atmosphere; Sealed tube 6: hydrogenchloride / methanol; water; 1,4-dioxane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

47
[ 158078-04-7 ]
(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxole-6-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; I,I-bis(acetoxy)iodobenzene In water; acetonitrile at 20℃; for 1h; Cooling with ice;
	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In water; acetonitrile at 0 - 20℃; for 1h;	(3aR,4R,65,6a5)-4-(4-Chloropyrrolo[2,3-dlpyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3 ,4-dl [1 ,3ldioxole-6-carboxylic acid Dissolve [(3aR,4R,6R,6aR)-4-(4-chloropyrrolo [2,3-dlpyrimidin-7-yl)-2,2- dimethyl-3a,4,6,6a-tetrahydrofuro[3 ,4-dl [1 ,3ldioxol-6-yllmethanol (60.0 g, 184.2 mmol) in ACN (250 mL). Add water (180 mL) and cool the mixture to 0 °C. Add iodobenzenediacetate (160 g, 496.8 mmol) portion wise at 0 °C followed by the portion wise addition of TEMPO (14 g, 89.6 mmol). Stir the mixture for 1 hr at room temperature. Remove the solvent under reduced pressure and dissolve the crude residue in EtOAc (300 mL). Add water (100 mL) at 0 °C and separate the resulting organic layer. Extract the aqueous with EtOAc (3 x 100 mL). Combine the organic extracts and wash with a 10% aqueoussolution of thiosulfate (2x100 mL) and water (2x100 mL). Dry the organic layer over sodium sulfate, filter, and remove the solvents under reduced pressure to give a pale yellow solid. Mix the crude material with hexanes (400 mL) and stir the mixture for 1 hr at room temperature. Filter the resulting solid, wash with hexanes (100 mL), and dry to give the title compound (66.7 g, 89% purity, 100% crude) as a yellow solid. ES/MS m/z(35C1137C1) 340.00/342.00 [M+Hf.
12 g	With sodium chlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In aq. phosphate buffer; water; acetonitrile at 35℃; for 16h;	85.2 Synthesis of (3aS,4S,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid To a two phase mixture of MM-i (20 g, 49 mmol)and TEMPO (3.07 g, 19.6 mmol) in CH3CN (200 mE) andphosphate buffer (146 mE, 0.67 M, pH=6.7) was added asolution of NaC1O2 (12.3 g, 123 mmol) in water (54 mE) at35° C. The mixture was stirred at 35° C. for another 16 hrs. The mixture was changed into a dark color. TLC (petroleum etherEtOAc=1 :1) showed most of SM was consumed. The mixture was concentrated in vacuo to remove CH3CN, in which precipitate formed. The mixture was adjusted with iN HC1 to pH=2. The solid was collected by filtration. The solid was dissolved in EtOAc (50 mE), washed with brine (30 mE), dried over Na2504 and concentrated in vacuo to dryness to affordMM-2 (12 g, 72%) as awhite solid. ECMS [M+1] 340; ‘HNMR (400 MHz, DMSO-d5) ö ppm 12.82 (bt s., 1H), 8.61 (s, 1H), 7.89 (d, J=3.8 Hz, 1H), 6.72 (d, J=3.5 Hz, 1H), 6.45 (s, 1H), 5.64-5.26 (m, 2H), 4.70 (d, J=1.5 Hz, 1H), 1.53 (s, 3H), 1.36 (s, 3H)

Reference： [1]Bonday, Zahid Q.; Cortez, Guillermo S.; Grogan, Michael J.; Antonysamy, Stephen; Weichert, Ken; Bocchinfuso, Wayne P.; Li, Fengling; Kennedy, Steven; Li, Binghui; Mader, Mary M.; Arrowsmith, Cheryl H.; Brown, Peter J.; Eram, Mohammad S.; Szewczyk, Magdalena M.; Barsyte-Lovejoy, Dalia; Vedadi, Masoud; Guccione, Ernesto; Campbell, Robert M. [ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 612 - 617]
[2]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1 Location in patent: Page/Page column 19
[3]Current Patent Assignee: PFIZER INC - US2016/244475, 2016, A1 Location in patent: Paragraph 0439; 0441

48
[ 158078-04-7 ]
(2R,3S,4R,5R)-2-[(4-chloro-2-fluorophenyl)-hydroxymethyl]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 1 h / 0 °C 3.2: 5 h / 0 °C 4.1: N-[(1R,2R)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzenesulfonamide(chloro)ruthenium(II); formic acid/triethylamine complex 5:2 / 1 h / 20 °C 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran; toluene / 6 h / 80 °C / Inert atmosphere; Sealed tube 6.1: hydrogenchloride / methanol; water; 1,4-dioxane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

49
[ 158078-04-7 ]
(2R,3S,4R,5R)-2-[(2-fluorophenyl)-hydroxymethyl]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 1 h / 0 °C 3.2: 5 h / 0 °C 4.1: N-[(1R,2R)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzenesulfonamide(chloro)ruthenium(II); formic acid/triethylamine complex 5:2 / 1 h / 20 °C 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran; toluene / 6 h / 80 °C / Inert atmosphere; Sealed tube 6.1: hydrogenchloride / methanol; water; 1,4-dioxane / 1 h / 20 °C 7.1: palladium 10% on activated carbon; hydrogen; triethylamine / ethanol / 15 h / 20 °C / 517.16 Torr

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

50
[ 158078-04-7 ]
(2S,3S,4R,5R)-2-[1-(3,4-dichlorophenyl)-1-hydroxyethyl]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: TurboGrignard / tetrahydrofuran / 1.25 h / -15 - 0 °C 3.2: 0.17 h / 0 °C 4.1: tetrahydrofuran; diethyl ether / 1 h / 0 °C 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / toluene; 1,4-dioxane / 8 h / 80 °C 6.1: trifluoroacetic acid / water / 1 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

51
[ 158078-04-7 ]
(2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)hydroxy-methyl]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3: tetrahydrofuran; diethyl ether / 1 h / -10 - 20 °C 4: ammonium formate; (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)] / water; dichloromethane / 1 h / 20 °C 5: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran; toluene / 6 h / 70 °C / Inert atmosphere; Sealed tube 6: hydrogenchloride / methanol; water; 1,4-dioxane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

52
[ 158078-04-7 ]
(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d] pyrimidin-7-yl)-N-methoxy-N,2,2-trimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxole-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium chlorite / water; acetonitrile; aq. phosphate buffer / 16 h / 35 °C 2: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 h / 15 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1
[2]Current Patent Assignee: PFIZER INC - US2016/244475, 2016, A1

53
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-morpholino-methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C
	Multi-step reaction with 2 steps 1.1: I,I-bis(acetoxy)iodobenzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 20 °C / Cooling with ice 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 20 °C / Cooling with ice 2.2: 72 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1
[2]Bonday, Zahid Q.; Cortez, Guillermo S.; Grogan, Michael J.; Antonysamy, Stephen; Weichert, Ken; Bocchinfuso, Wayne P.; Li, Fengling; Kennedy, Steven; Li, Binghui; Mader, Mary M.; Arrowsmith, Cheryl H.; Brown, Peter J.; Eram, Mohammad S.; Szewczyk, Magdalena M.; Barsyte-Lovejoy, Dalia; Vedadi, Masoud; Guccione, Ernesto; Campbell, Robert M. [ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 612 - 617]

54
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-phenyl-methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: tetrahydrofuran; diethyl ether / 0.53 h / 0 °C
	Multi-step reaction with 3 steps 1.1: I,I-bis(acetoxy)iodobenzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 20 °C / Cooling with ice 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 20 °C / Cooling with ice 2.2: 72 h / 20 °C 3.1: diethyl ether; tetrahydrofuran / 0.53 h / 0 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1
[2]Bonday, Zahid Q.; Cortez, Guillermo S.; Grogan, Michael J.; Antonysamy, Stephen; Weichert, Ken; Bocchinfuso, Wayne P.; Li, Fengling; Kennedy, Steven; Li, Binghui; Mader, Mary M.; Arrowsmith, Cheryl H.; Brown, Peter J.; Eram, Mohammad S.; Szewczyk, Magdalena M.; Barsyte-Lovejoy, Dalia; Vedadi, Masoud; Guccione, Ernesto; Campbell, Robert M. [ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 612 - 617]

55
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-chlorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3: tetrahydrofuran; diethyl ether / 1 h / -10 - 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

56
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[4-(trifluoromethyl)phenyl]methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: isopropylmagnesium chloride / tetrahydrofuran / 24 h / 20 °C 3.2: 2 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

57
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(3-chlorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 1.17 h / 0 °C 3.2: 1 h / 0 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

58
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-chloro-2-fluorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 1 h / 0 °C 3.2: 5 h / 0 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

59
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(3-ethylphenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: tetrahydrofuran / 0.5 h / 0 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

60
[ 158078-04-7 ]
4-[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxole-6-carbonyl]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: TurboGrignard / tetrahydrofuran / 2 h / 0 °C 3.2: 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

61
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(3,4-difluorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: isopropylmagnesium chloride / tetrahydrofuran / 1.25 h / -15 - 0 °C 3.2: 0.25 h / 0 °C
	Multi-step reaction with 3 steps 1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium chlorite / water; acetonitrile; aq. phosphate buffer / 16 h / 35 °C 2: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 h / 15 °C 3: tetrahydrofuran / 1 h / 5 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1
[2]Current Patent Assignee: PFIZER INC - US2016/244475, 2016, A1

62
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(3,4-dichlorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: TurboGrignard / tetrahydrofuran / 1.25 h / -15 - 0 °C 3.2: 0.17 h / 0 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

63
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(p-tolyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: tetrahydrofuran / 1 h / -15 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

64
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-fluorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: tetrahydrofuran / 1.75 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

65
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(2-fluorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 1.5 h / 0 °C 3.2: 2.75 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

66
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[2-(trifluoromethyl)phenyl]methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 2 h / 0 - 20 °C 3.2: 3.5 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

67
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[4-chloro-3-(cyclopropoxy)phenyl]methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: magnesium; iodine / tetrahydrofuran / 0.5 h / Reflux 3.2: 0.67 h / 20 - 40 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

68
[ 158078-04-7 ]
(1R)-1-[(3aR,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-1-(4-chlorophenyl)ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3: tetrahydrofuran; diethyl ether / 1 h / -10 - 20 °C 4: tetrahydrofuran; 2-methyltetrahydrofuran / 2 h / 0 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

69
[ 158078-04-7 ]
1-[(3aR,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-1-(3,4-dichlorophenyl)ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: TurboGrignard / tetrahydrofuran / 1.25 h / -15 - 0 °C 3.2: 0.17 h / 0 °C 4.1: tetrahydrofuran; diethyl ether / 1 h / 0 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

70
[ 158078-04-7 ]
1-[(3aR,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-1-(2-fluorophenyl)ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 1.5 h / 0 °C 3.2: 2.75 h / 0 - 20 °C 4.1: tetrahydrofuran; diethyl ether / 2 h / 0 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

71
[ 158078-04-7 ]
1-[(3aR,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-1-[2-(trifluoromethyl)phenyl]ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: TurboGrignard / tetrahydrofuran / 2 h / 0 - 20 °C 3.2: 3.5 h / 0 - 20 °C 4.1: tetrahydrofuran; diethyl ether / 0.5 h / 0 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

72
[ 158078-04-7 ]
1-[(3aR,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-1-[4-(trifluoromethyl)phenyl]ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3.1: isopropylmagnesium chloride / tetrahydrofuran / 24 h / 20 °C 3.2: 2 h / 20 °C 4.1: tetrahydrofuran; diethyl ether / 1 h / 0 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

73
[ 158078-04-7 ]
(R)-(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl-phenylmethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: tetrahydrofuran; diethyl ether / 0.53 h / 0 °C 4.1: N-[(1R,2R)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzenesulfonamide(chloro)ruthenium(II); formic acid/triethylamine complex 5:2 / 4 h / 20 °C
	Multi-step reaction with 4 steps 1.1: I,I-bis(acetoxy)iodobenzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 20 °C / Cooling with ice 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 20 °C / Cooling with ice 2.2: 72 h / 20 °C 3.1: diethyl ether; tetrahydrofuran / 0.53 h / 0 °C 4.1: (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine; triethylamine; formic acid / 4 h / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1
[2]Bonday, Zahid Q.; Cortez, Guillermo S.; Grogan, Michael J.; Antonysamy, Stephen; Weichert, Ken; Bocchinfuso, Wayne P.; Li, Fengling; Kennedy, Steven; Li, Binghui; Mader, Mary M.; Arrowsmith, Cheryl H.; Brown, Peter J.; Eram, Mohammad S.; Szewczyk, Magdalena M.; Barsyte-Lovejoy, Dalia; Vedadi, Masoud; Guccione, Ernesto; Campbell, Robert M. [ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 612 - 617]

74
[ 158078-04-7 ]
(R)-[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-phenylmethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 0 - 20 °C 2.2: 72 h / 20 °C 3.1: tetrahydrofuran; diethyl ether / 0.53 h / 0 °C 4.1: N-[(1R,2R)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzenesulfonamide(chloro)ruthenium(II); formic acid/triethylamine complex 5:2 / 4 h / 20 °C 5.1: ammonia / methanol / 8 h / 100 °C / Microwave irradiation; Sealed tube; Inert atmosphere
	Multi-step reaction with 5 steps 1.1: I,I-bis(acetoxy)iodobenzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 20 °C / Cooling with ice 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.75 h / 20 °C / Cooling with ice 2.2: 72 h / 20 °C 3.1: diethyl ether; tetrahydrofuran / 0.53 h / 0 °C 4.1: (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine; triethylamine; formic acid / 4 h / 20 °C 5.1: ammonia / methanol / 8 h / 100 °C / Sealed tube; Microwave irradiation

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1
[2]Bonday, Zahid Q.; Cortez, Guillermo S.; Grogan, Michael J.; Antonysamy, Stephen; Weichert, Ken; Bocchinfuso, Wayne P.; Li, Fengling; Kennedy, Steven; Li, Binghui; Mader, Mary M.; Arrowsmith, Cheryl H.; Brown, Peter J.; Eram, Mohammad S.; Szewczyk, Magdalena M.; Barsyte-Lovejoy, Dalia; Vedadi, Masoud; Guccione, Ernesto; Campbell, Robert M. [ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 612 - 617]

75
[ 158078-04-7 ]
(R)-[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-chlorophenyl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3: tetrahydrofuran; diethyl ether / 1 h / -10 - 20 °C 4: ammonium formate; (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)] / water; dichloromethane / 1 h / 20 °C 5: ammonium hydroxide / water; 1,4-dioxane / 200 °C / 41372.9 Torr
	Multi-step reaction with 6 steps 1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile; water / 1 h / 0 - 20 °C 2: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 72 h / 20 °C / Inert atmosphere 3: tetrahydrofuran; diethyl ether / 1 h / -10 - 20 °C 4: L-Selectride / tetrahydrofuran / 4 h / -78 °C / Inert atmosphere 5: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 24 h / 20 °C / Inert atmosphere 6: ammonium hydroxide / water; 1,4-dioxane / 18 h / 110 °C / Sealed tube

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1
[2]Current Patent Assignee: ELI LILLY & CO - WO2016/178870, 2016, A1

76
[ 115479-39-5 ]
[ 158078-04-7 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutyl ammonium fluoride In tetrahydrofuran at 15℃;	85.1 Synthesis of ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol To a solution of crude C-5 (32.5 g, 66 mmol) inTHF (325 mE) was added 1 M solution of TI3AF in THF (6.65 mE, 6.65 mmol) at rt (15° C.). The yellow solution was stirred at it (15° C.) for a weekend. TEC (petroleum ether/EtOAc=8: 1) showed a lot of SM was remaining. 1M TI3AF (6.65 mE, 6.65 mmol) was added. The mixture was stirred at it (15°C.) for 24 hrs. TEC showed most of SM was consumed and desired spot was clean. The mixture was concentrated in vacuo to 100 mE. The residue was diluted with EtOAc (500 mE) and washed with water (200 mEx2), brine (200 mE), dried over Na2504 and concentrated in vacuo to afford crude MM-i (22.5 g, 100%) as slight yellow oil, used in the next step directly. HNMR showed the purity of product was about 80%. ECMS [M+i] 326; ‘HNMR (400 MHz, CDC13)ö ppm 8.64 (s, 1H), 7.33 (d, J=3.5 Hz, 1H), 6.64 (d, J=3.8 Hz, 1H), 5.87 (d, J=5.0 Hz, 1H), 5.35 (d, J=i0.8 Hz, 1H), 5.24 (t, J=5.4 Hz, 1H), 5.12 (dd, J=i.5, 6.0 Hz, 1H), 4.50 (d, J=i.8 Hz, 1H), 4.01-3.93 (m, 1H), 3.85-3.77 (m, 1H), 1.65 (s, 3H), 1.39-1.34 (m, 3H)

Reference： [1]Current Patent Assignee: PFIZER INC - US2016/244475, 2016, A1 Location in patent: Paragraph 0439; 0440

77
[ 158078-04-7 ]
[ 135-19-3 ]
C₂₄H₂₂ClN₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With cyanomethylenetributyl-phosphorane In toluene at 80℃; for 18h;	A.A21 Preparation of intermediate 71 To a solution of intermediate 1 ( 1 .00 g, -2.92 mmol ) and 2-naphthol (463 mg, 3.21 mmol) in toluene (30 ml_) was added C BP ( 1 .15 mL, 4.38 mmol). The solution was heated at 80 °C for 18 hours and was then cooled down to room temepature. The reaction mixture was evaporated in vacuo. The residues were purified by preparative LC ( Irregular SiOH 15-40 iim, 120 g Grace, DCM deposit, mobile phase gradient: heptane /EtOAc from 80/20 to 70/30) to giv e intermediate 71 as a colourless gum (1.00 g, 76% yield).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1 Location in patent: Page/Page column 157;158

78
[ 158078-04-7 ]
[ 124-41-4 ]
C₁₅H₁₉N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	In methanol at 20℃; for 1h;	A.A75.1 Preparation of intermediate 363 A mixture of intermediate 1 (250 mg, 0.77 mmol) and MeONa (331.5 mg, 6. 14 mmol ) in MeOH was stirred at room temperature for l h. The mixture was diluted with water (20 niL), and was extracted with CH2CI2 ( 50 mL x 3). The organic phase was washed with brine ( 10 mL ), dried over Na2SC>4, filtered and concentrated to give intermediate 363 (250 mg, 96% yield ) which was used for the next reaction step without further purification.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1 Location in patent: Page/Page column 250; 251

79
[ 158078-04-7 ]
C₂₃H₂₂BrN₅O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: di-isopropyl azodicarboxylate / tetrahydrofuran / 20 °C 2: ammonia / methanol / 2 h / 130 °C / Microwave irradiation
	Multi-step reaction with 2 steps 1: di-isopropyl azodicarboxylate / tetrahydrofuran / 18 h 2: ammonia / methanol / 2 h / 130 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US11279970, 2022, B2

80
[ 158078-04-7 ]
C₂₀H₁₈BrN₅O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: di-isopropyl azodicarboxylate / tetrahydrofuran / 20 °C 2: ammonia / methanol / 2 h / 130 °C / Microwave irradiation 3: hydrogenchloride / lithium hydroxide monohydrate; 1,4-dioxane / 18 h / 20 °C
	Multi-step reaction with 6 steps 1.1: ammonium hydroxide / 1,4-dioxane / 20 h / 100 °C / Sealed tube 2.1: 1H-imidazole / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere 3.1: 4-dimethylaminopyridine / tetrahydrofuran / 3 h / 20 °C 3.2: 18 h / 20 °C 4.1: triethylamine; 4-dimethylaminopyridine / dichloromethane / 5 h / 20 °C / Cooling with ice 5.1: Cs₂CO₃ / N,N-dimethyl-formamide / 16 h / 20 °C 6.1: hydrogenchloride / lithium hydroxide monohydrate; methanol / 72 h / 20 °C
	Multi-step reaction with 3 steps 1: di-isopropyl azodicarboxylate / tetrahydrofuran / 18 h 2: ammonia / methanol / 2 h / 130 °C / Microwave irradiation 3: hydrogenchloride / methanol; 1,4-dioxane / 18 h / 20 °C

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1
[3]Current Patent Assignee: JOHNSON & JOHNSON INC - US11279970, 2022, B2

81
[ 158078-04-7 ]
[ 16739-75-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With ammonium hydroxide In 1,4-dioxane at 100℃; for 20h; Sealed tube;	A.A8 Preparation of intermediate 18 Intermediate 1 ( 1 00.0 g, theoretically 307 mmol ) was dissolved in 400 mL of l , 4- dioxane. Then 400 mL of Ammonia water (28- 30% N3 basis) was added. The mixture was stirred in a sealed tube at 1 00°C for 20 hours. The mixture was cooled to room temperature. The reaction mixture was evaporated in vacuum to remove half of the solvent. Water (200 mL) was added and extracted with EtOAc (500 mL x 3 ). The combined organic layers were washed with brine (200 ml x 2), dried and concentrated to give Intermediate 18 as white solid ( 93 g, 93% yield ).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1 Location in patent: Page/Page column 133

82
[ 158078-04-7 ]
[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Dess-Martin periodane In dichloromethane at 0℃; for 3h; Inert atmosphere;	A.A13 Preparation of intermediate 33 To a mixture of intermediate 1 (2.00 g, theoretically 6.18 mmol) in DCM (40 mL) was added Dess-Martin period inane ( 5.24 g, 12.36 mmol ) in one portion at 0 C under N2.The mixture was stirred at 0 C for 3 hours. To the mixture was added Na2S203 (4 g) in saturated NaHCC (20 mL) and stirred for 10 min. The aqueous phase was extracted with DCM (20 ml, x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried with anhydrous MgSOi, filtered and concentrated in vacuum to afford intermediate 33 (1.80 g, crude) as light yellow gum. The crude product was directly used for the next reaction step without further purification.
	With Dess-Martin periodane In dichloromethane at 0℃; for 3h; Inert atmosphere;	A10 Preparation of intermediate 29 To a mixture of intermediate 1 (2.00 g, 6.18 mmol) in DCM (40 mL) was added Dess- Martin periodinane (5.24 g, 12.36 mmol) in one portion at 0 C under N2.The mixture was stirred at 0°C for 3 hours. To the mixture was added Na2S203 (4 g) in saturated NaHCC"3 (20 mL) and the mixture was stirred for 10 min. The aqueous phase was extracted with DCM ( three times 20 mL ).The combined organic phases were washed with saturated brine ( two times 20 mL), dried with anhydrous MgS04, filtered and concentrated in vacuum to afford intermediate 29 (1.80 g, crude) as light yellow gum. The crude product was directly used for the next reaction step without further purification.
	With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile at 50℃; for 16h;	2.2.4; 2 Step 4: To a solution of 10.0 g (30.7 mmol) of compound 2-3 in 1 10 mL of acetonitrile was added 12.9 g (46.1 mmol) of IBX. The mixture was stirred at 50 °C for 16 h and then cooled with an ice water bath. After filtration, the filtrate was concentrated to afford crude compound 2-4, which was used in the next step without further purification. LC-MS: m/e = 324 [M+H]+

	With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere;
	With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile at 50℃; for 16h; Inert atmosphere;	3.4 Step 4: To a solution of 10.0 g (30.7 mmol) of compound 3-3 in 110 mL of acetonitrile was added 12.9 g (46.1 mmol) of IBX. The mixture was stirred at 50 °C for 16 h and then cooled with an ice water bath. After filtration, the filtrate was concentrated to afford crude compound 3-4, which was used in the next step without further purification. LC-MS: m/e = 324 [M+H]+.
	With Dess-Martin periodane In dichloromethane at 0℃; for 3h; Inert atmosphere;	Preparation of Intermediate 33 To a mixture of intermediate 1 (2.00 g, theoretically 6.18 mmol) in DCM (40 mL) was added Dess-Martin periodinane (5.24 g, 12.36 mmol) in one portion at 0°C. under N2. The mixture was stirred at 0°C. for 3 hours. To the mixture was added Na2S2O3 (4 g) in saturated NaHCO3 (20 mL) and stirred for 10 min. The aqueous phase was extracted with DCM (20 mL3). The combined organic phase was washed with saturated brine (20 mL2), dried with anhydrous MgSO4, filtered and concentrated in vacuum to afford intermediate 33 (1.80 g, crude) as light yellow gum. The crude product was directly used for the next reaction step without further purification.
	With Dess-Martin periodane In dichloromethane at 0℃; for 3h; Inert atmosphere;	Preparation of Intermediate 33 To a mixture of intermediate 1 (2.00 g, theoretically 6.18 mmol) in DCM (40 mL) was added Dess-Martin periodinane (5.24 g, 12.36 mmol) in one portion at 0°C. under N2. The mixture was stirred at 0°C. for 3 hours. To the mixture was added Na2S2O3 (4 g) in saturated NaHCO3 (20 mL) and stirred for 10 min. The aqueous phase was extracted with DCM (20 mL3). The combined organic phase was washed with saturated brine (20 mL2), dried with anhydrous MgSO4, filtered and concentrated in vacuum to afford intermediate 33 (1.80 g, crude) as light yellow gum. The crude product was directly used for the next reaction step without further purification.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1 Location in patent: Page/Page column 140
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/153186, 2017, A1 Location in patent: Page/Page column 91
[3]Current Patent Assignee: ANGEX PHARMACEUTICAL - WO2019/112719, 2019, A1 Location in patent: Paragraph 081; 084
[4]Pande, Vineet; Sun, Weimei; Beke, Lijs; Berthelot, Didier; Brehmer, Dirk; Brown, David; Corbera, Jordi; Irving, Steve; Meerpoel, Lieven; Nys, Thomas; Parade, Marc; Robinson, Colin; Sommen, Cois; Viellevoye, Marcel; Wu, Tongfei; Thuring, Jan Willem [ACS Medicinal Chemistry Letters, 2020, vol. 11, # 11, p. 2227 - 2231]
[5]Current Patent Assignee: ANGEX PHARMACEUTICAL - WO2020/243178, 2020, A1 Location in patent: Paragraph 082; 101
[6]Current Patent Assignee: JOHNSON & JOHNSON INC - US11279970, 2022, B2 Location in patent: Paragraph 20
[7]Current Patent Assignee: JOHNSON & JOHNSON INC - US11279970, 2022, B2 Location in patent: Paragraph 20

83
[ 158078-04-7 ]
C₂₁H₂₁N₅O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: di-isopropyl azodicarboxylate / tetrahydrofuran / 20 °C 2: ammonia / methanol / 2 h / 130 °C / Microwave irradiation 3: hydrogenchloride / water; 1,4-dioxane / 18 h / 20 °C 4: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 16 h / 190 °C / Inert atmosphere
	Multi-step reaction with 7 steps 1.1: ammonium hydroxide / 1,4-dioxane / 20 h / 100 °C / Sealed tube 2.1: 1H-imidazole / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere 3.1: dmap / tetrahydrofuran / 3 h / 20 °C 3.2: 18 h / 20 °C 4.1: triethylamine; dmap / dichloromethane / 5 h / 20 °C / Cooling with ice 5.1: caesium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C 6.1: hydrogenchloride / water; methanol / 72 h / 20 °C 7.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 16 h / 190 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1

84
[ 158078-04-7 ]
C₂₃H₂₃N₅O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: di-isopropyl azodicarboxylate / tetrahydrofuran / 20 °C 2: ammonia / methanol / 2 h / 130 °C / Microwave irradiation 3: hydrogenchloride / water; 1,4-dioxane / 18 h / 20 °C 4: potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / water; 1,4-dioxane / 80 °C / Inert atmosphere
	Multi-step reaction with 7 steps 1.1: ammonium hydroxide / 1,4-dioxane / 20 h / 100 °C / Sealed tube 2.1: 1H-imidazole / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere 3.1: dmap / tetrahydrofuran / 3 h / 20 °C 3.2: 18 h / 20 °C 4.1: triethylamine; dmap / dichloromethane / 5 h / 20 °C / Cooling with ice 5.1: caesium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C 6.1: hydrogenchloride / water; methanol / 72 h / 20 °C 7.1: potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / water; 1,4-dioxane / 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1

85
[ 158078-04-7 ]
7-hydroxyquinoline-2-methyl carboxylate [ No CAS ]
C₂₅H₂₃ClN₄O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	A.A91.1 Preparation of intermediate 414 To the solution of intermediate 1 ( 1 .0 g, 4.9 mmol). 7-hydroxyquinoline-2- methylearboxylate (1.36 g, 4.18 mmol) and PPh3 (2.58 g, 9.84 mmol) in THF ( 1 0 mL) was added DIAD ( 1 .99 g, 9.84 mmol ) at 0 C. The mixture was st irred at room temperature overnight under N2. Water (25 mL) was added and the mixture was extracted with ethyl acetate ( 100 mL x 3 ). The combined organic layers were washed with brine ( 1000 mL). The organic phase was dried over anhydrous Na2S04, filtered and concentrated to give the crude product as an oil. The crude product was purified by column chromatography over silica gel (edition : petroleum ether/ethyl acetate ratio 1/1). The desired fractions were collected and concentrated to give the product intermediate 414 (1.2 g, 3 1 % yield ) as a solid.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1 Location in patent: Page/Page column 270; 271

86
[ 158078-04-7 ]
[ 98-59-9 ]
C₂₁H₂₂ClN₃O₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With dmap; triethylamine In dichloromethane at 0 - 20℃;	AA7 Preparation of intermediate 15 The intermediate 1 ( 10.0 g, -28.6 mmol ), TEA ( 12 mL, 85.7 mmol ) and DMAP (0.70 g, 5.71 mmol) were dissolved in CH2CI2 ( 100 m L ). p-toluenesulfonyl chloride ( 10.9 g, 57. 1 mmol) was added at 0°C. The mixture was stirred at room temperature overnight. Water ( 100 mL) was added to the above solution. The aqueous layer was extracted with DCM ( 1 00 mL x 3). The combined organic layer was dried over and concentrated to dryness. The residue was purified by flash column (gradient edition: petroleum ether EtOAc from 1 to 3/1). The product fractions were collected and the solvent was evaporated to give intermediate 15 as yellow oil ( 14.5 g, 97 % yield ).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1 Location in patent: Page/Page column 132

87
[ 158078-04-7 ]
[ 1576-35-8 ]
C₂₁H₂₂ClN₅O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: [(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; Stage #2: toluene-4-sulfonic acid hydrazide In methanol; dichloromethane for 3h;	A.A18 Preparation of intermediate 44 A solution of intermediate 1 (2.00 g, theoretically 6.18 mmol) in DCM (30.00 mL) was added dropwise to a suspension of Dess-Martin periodinane (3.14 g, 7.41 mmol) in DCM (30.00 mL) at 0°C under N2. The reaction mixture was allowed to warm to room temperature and stirred until oxidation was finished (2 hours). Subsequently, MeOH (60 mL) and tosylhydrazide (1.50 g, 8.03 mmol) were added and stirring was continued for 3 hours. Water and ethyl acetate were added to the reaction mixture, the organic phase was separated and washed with saturated Na2C03, dried with anhydrous MgS04, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol from 100:0 to 98.5: 1.5). The desired fractions were collected and the solvent was evaporated to yield intermediate 44 as a white powder (2.60 g, 70% yield: (E)).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1 Location in patent: Page/Page column 149

88
[ 158078-04-7 ]
[ 75-86-5 ]
C₁₅H₁₅ClN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 1h;	A.A55.1 Preparation of intermediate 222 DIAD (7.6 mL, 38.4 mmol, 2.5 eq) was added to a solution of intermediate 2 (5.0 g, 15.3 mmol, 1 .0 eq ), triphenylphosphine ( 10.0 g, 38.4 mmol, 2.5 eq ) and acetone cyanohydrin (5.6 mL, 61 .4 mmol, 4.0 eq ) in anhydrous THF (75 mL) at r.t.. The reaction mixture was stirred for 1 hour and then concentrated in vacuo. The crude product was purified by normal phase flash chromatography using heptane and DCM as eluent (Si02 column, gradient: 50% to 100% DCM , isocratic 100% DCM ) and then followed by a preparative reversed phase flash chromatography using acetonitrile and water with 0.2% NH4HCO3 as eluent to afford intermediate 222 as white solid product (2.8 g, 8.5 mmol, yield 55%)

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/32840, 2017, A1 Location in patent: Page/Page column 150; 151

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	158078-04-7	MDL No. :	MFCD30187909
Formula :	C₁₄H₁₆ClN₃O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	POIWYPNJASWVSL-VWMGYNLJSA-N
M.W :	325.75	Pubchem ID :	86654222
Synonyms :

Num. heavy atoms :	22
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.57
Num. rotatable bonds :	2
Num. H-bond acceptors :	6.0
Num. H-bond donors :	1.0
Molar Refractivity :	77.68
TPSA :	78.63 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.59 cm/s

Log Po/w (iLOGP) :	2.81
Log Po/w (XLOGP3) :	0.98
Log Po/w (WLOGP) :	1.17
Log Po/w (MLOGP) :	0.61
Log Po/w (SILICOS-IT) :	0.87
Consensus Log Po/w :	1.29

[ CAS No. 158078-04-7 ] {[proInfo.proName]}

Quality Control of [ 158078-04-7 ]

Related Doc. of [ 158078-04-7 ]

Product Details of [ 158078-04-7 ]

Calculated chemistry of [ 158078-04-7 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 158078-04-7 ]

Application In Synthesis of [ 158078-04-7 ]

[ 158078-04-7 ] Synthesis Path-Downstream 1~88

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

Log S (ESOL) :	-2.65
Solubility :	0.733 mg/ml ; 0.00225 mol/l
Class :	Soluble
Log S (Ali) :	-2.22
Solubility :	1.97 mg/ml ; 0.00603 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.58
Solubility :	0.859 mg/ml ; 0.00264 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	4.15

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-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.
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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.
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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.
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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
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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