Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14](Cl)(Cl)=[S:15].O>O1CCOCC1>[N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=[C:14]=[S:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccccc1N1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: S=C=Nc1ccccc1N1CCCCC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 2-piperidinoaniline (17.6 g) in dioxane (100 ml) was added over 25 minutes to a mixture of thiophosgene (10.2 ml) and water (200 ml) which had been cooled to 0° C. The temperature of the mixture was allowed to rise to ambient and the mixture was stirred for 4 hours. Ice (200 g) and water (200 ml) were added and the mixture extracted with ether (6×50 ml). The combined extracts were washed with water (100 ml) and brine (100 ml), dried and evaporated to give a residue which purified by chromatography on a silica column eluted with hexane to give 2 -piperidinophenyl isothiocyanate as an oil.
Reaction SMILES: [Rh:1].[S:2](=[O:6])(=[O:5])([OH:4])[OH:3]>>[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Rh+3:1].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Rh+3:1]
Reactant: [Rh]
Reactant: O=S(=O)(O)O
Product: O=S(=O)([O-])[O-]
Product: [Rh+3]

Procedure:
The technique for preparing this rhodium sulfate complex is described by the flow chart of FIG. 3. Rhodium is refluxed in sulfuric acid as shown to produce a rhodium sulfate concentrate. The rhodium sulfate is then neutralized with a mild base, in this case, ammonium hydroxide, by the two procedures shown in the figure. The first, Process A, is the conventional hydrolysis in which the acid and base are simply combined, with both reagents typically at room temperature. The neutralization reaction is exothermic, and the solution characteristically heats to a temperature substantially above room temperature. In the process of the invention, Process B, the neutralization reaction is controlled by cooling the rhodium sulfate to a temperature below room temperature, e.g., below 20° C., and maintaining the reagent mixture at a temperature below 25° C. during the reaction. This can be achieved by actively cooling the reaction vessel. In practice, it was found that using a jacketed reaction vessel, and flowing cool or cold water, e.g. water at 10° C., through the vessel jacket, the temperature of the reagent mixture can be controlled to a temperature below 25° C. Without active cooling during the reaction, as described above, the reagent mixture heats to a temperature above 25° C.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][N:12]=1)=[CH:8][C:7]([C:27]#N)=[CH:6][CH:5]=2.[OH-:29].[Na+].[ClH:31].[OH2:32]>>[ClH:31].[OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)(=[O:19])=[O:18])=[CH:13][N:12]=1)=[CH:8][C:7]([C:27]([OH:32])=[O:29])=[CH:6][CH:5]=2
Reactant: CN1CCN(S(=O)(=O)c2ccc(-c3c(O)[nH]c4ccc(C#N)cc34)nc2)CC1
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Product: CN1CCN(S(=O)(=O)c2ccc(-c3c(O)[nH]c4ccc(C(=O)O)cc34)nc2)CC1
Yield: 89 %

Procedure:
To a mixture of 2-hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carbonitrile (0.100 g, 0.25 mmol) in water (2 mL) was added 1 M aqueous sodium hydroxide solution (1.3 mL, 1.3 mmol) followed by water (1 mL) in a microwave vial. The mixture was subjected to microwave irradiation for 15 min at 140° C. The pH was adjusted to 5 with HCl (aq) (2 M). The solid was collected by filtration, washed with diethyl ether, and dried to afford 0.110 g (89% yield) of the title compound: MS (ESP) m/z 417 (M++1).
Reaction SMILES: CS[C:3]1[N:4]([CH2:15][CH2:16][CH3:17])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][N:7]=1>[Ni].C(O)C>[CH2:15]([N:4]1[C:5]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:6][N:7]=[CH:3]1)[CH2:16][CH3:17]
Reactant: CCCn1c(-c2ccc(O)cc2)cnc1SC
Agent: [Ni]
Solvent: CCO
Product: CCCn1cncc1-c1ccc(O)cc1
Yield: 61 %

Procedure:
A mixture of 12 parts of 4-[2-(methylthio)-1-propyl-1H-imidazol-5-yl]phenol, 10 parts of Raney-nickel catalyst and 80 parts of ethanol is stirred and refluxed for 2 hours. The Raney-nickel is filtered off and the filtrate is stirred and refluxed for 2 hours with another 10 parts of Raney-nickel catalyst. The Raney-nickel catalyst is filtered off and the filtrate is evaporated, yielding 5.5 parts (61%) of 4-(1-propyl-1H-imidazol-5yl)phenol; mp. 160° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:4]([OH:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.O.[C:32]1(C)[CH:37]=CC(S(O)(=O)=O)=C[CH:33]=1>CC(C)=O>[CH3:33][C:32]1([CH3:37])[O:14][C@H:4](/[CH:5]=[CH:6]/[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:3]([N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:2][O:1]1
Reactant: Cc1ccc(/C=C/[C@@H](O)C(CO)N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(/C=C/[C@H]2OC(C)(C)OCC2N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 94 %

Procedure:
A mixture of 1,3-diol, 2-hydrazino (7B) (59 mg, 0.14 mmol) and p-toluene sulfonic acid monohydrate (2.7 mg, 0.014 mmol) in 5.0 mL anhydrous acetone was stirred at rt for 42 h. The reaction mixture was quenched with 5% NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, and removed in vacuo. Purification by flash chromatography on silica gel afforded the desired product as a white solid (94%).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[C:11](N2CC[C@H](O)C2)=[N:12][CH:13]=[C:14]([CH:29]=1)[C:15]([NH:17]C1C=CC(OC(Cl)(F)F)=CC=1)=[O:16].[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[N:42]1[C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45][CH:44]=[N:43]1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[N:42]1[C:46]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:29]=2)[C:15]([NH2:17])=[O:16])=[CH:45][CH:44]=[N:43]1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: NC(=O)c1cncc(-c2ccnn2C2CCCCO2)c1
Temperature: 110 °C

Procedure:
K3PO4 (41.3 mg, 0.195 mmol) was added to a solution of (S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 8.1, 30 mg, 0.067 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (36.2 mg, 0.13 mmol) in toluene (0.32 mL) in a vial which was flushed with argon. Pd(PPh3)4 (3.75 mg, 0.032 mmol) was added. The vial was sealed and heated at 110° C. for 18 h. After cooling at RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) to afford N-(4-(chlorodifluoromethoxy)phenyl)-6-(S)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide, a portion of which (21 mg, 0.039 mmol) was dissolved in DCM (0.5 mL), treated with TFA (0.141 mL, 1.82 mmol) and stirred at RT for 3 h. The RM was poured into 10% aq. Na2CO3 (10 mL) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) to afford the title compound. HPLC (Condition 4) tR=4.49 min, HPLC Chiral (CHIRALCEL® OD-H, 250×4.6 mm, eluent:n-heptane/EtOH/MeOH (85:10:5), 1 mL/min, UV DAD, tR=13.32 min, UPLC-MS (Condition 3) tR=0.92 min, m/z=450.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.76 (m, 1H) 1.77-1.92 (m, 1H) 2.86-2.97 (m, 1H) 3.18-3.35 (m, 2H) 3.34-3.47 (m, 1H) 4.10-4.24 (m, 1H) 4.66-4.93 (m, 1H) 6.28-6.42 (m, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.85 (d, J=8.99 Hz, 3H) 7.96-8.05 (m, 1H) 8.64-8.81 (m, 1H) 10.17 (s, 1H) 12.80-13.14 (m, 1H).
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]2=[O:24])[N:8]=1.[F-].[K+].C([Si](CC)(CC)[C:30]([F:33])([F:32])[F:31])C.CN(C=O)C>ClCCl.[Cu]I.CN1C(=O)CCC1>[CH3:21][C:20]1([CH3:22])[N:16]([CH2:15][CH2:14][NH:13][C:9]2[N:8]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[C:30]([F:33])([F:32])[F:31])[CH:12]=[CH:11][N:10]=2)[C:17](=[O:24])[NH:18][C:19]1=[O:23]
Reactant: CC[Si](CC)(CC)C(F)(F)F
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2sccc2I)n1
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2sccc2C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A sealed tube charged with 1-(2-(4-(3-iodothiophen-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (0.300 g, 0.656 mmol), copper (I) iodide (0.275 g, 1.44 mmol), spray-dried potassium fluoride (0.075 g, 1.3 mmol), triethyl(trifluoromethyl)silane (0.25 mL, 1.3 mmol), DMF (1.0 mL), and NMP (1.0 mL) was heated to 80° C. and allowed to stir for 72 h. At that time, the mixture was diluted with 20 mL dichloromethane and filtered. The pale green filtrate was then purified through Celite and the plug was washed with 10% MeOH/dichloromethane and H2O. The organic solvents were removed from the biphasic mixture in vacuo and the aqueous residue was then partitioned between dichloromethane and H2O. The organic phase was separated, concentrated and the residue purified by flash chromatography, eluting with 1-6% MeOH/dichloromethane to afford the product as a white solid. MS (M+H)+ 400.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>[OH-].[Na+].O1CCOCC1>[NH2:1][C@@H:2]([CH2:3][S:4][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([F:8])=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: N[C@@H](CS)C(=O)O
Reactant: Fc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N[C@@H](CSCc1ccc(F)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
L-cysteine (15.97 g) was dissolved in a mixture of 1.0 M aqueous sodium hydroxide (265 mL) and 1,4-dioxane (265 mL). 4-Fluorobenzylbromide (24.85 g) was added dropwise over 30 min. After stirring overnight, dioxane was removed and the pH of the residual aqueous solution was adjusted to pH-6 with 3M hydrochloric acid. A white precipitate began to form immediately upon addition of the acid and additional water (150 mL) was added to aid stirring of the thick suspension. The reaction mixture was cooled to 0° C. for 1 h and the precipitates were collected by filtration and washed with cold water, Et2O, and hexane, and dried under high vacuum to give 2(R)-amino-3-(4-fluorobenzylsulfanyl)-propionic acid (28.68 g) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:8]1[N:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1>>[N+:14]([C:11]1[CH:10]=[N:9][C:8]([N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)=[N:13][CH:12]=1)([O-:16])=[O:15]
Reactant: O[C@H]1CCNC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Product: O=[N+]([O-])c1cnc(N2CC[C@H](O)C2)nc1

Procedure:
This compound was prepared with the same method described before using (S)-3-hydroxypyrrolidine and 2-chloro-5-nitro-pyrimidine to give (S)—N-(5-nitropyrimidin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C8H10N4O3 m/e 210.19, obsd 211 (ES, M+H). Hydrogenation of the nitro compound, as above, provided (S)—N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:9][OH:10])[CH2:8][O:7][CH2:6][O:5][CH2:4]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]=[C:21]([CH2:23]I)[N:22]=2)=[CH:14][CH:13]=1.[H-].[Na+].FC1C=CC(C2OC=C(CO[C@@H]3CCC[C@H](OCC4C=CC=C(C)C=4C(OC)=O)C3)N=2)=CC=1>CN(C=O)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:19][CH:20]=[C:21]([CH2:23][O:1][CH2:2][C:3]3([CH2:9][OH:10])[CH2:8][O:7][CH2:6][O:5][CH2:4]3)[N:22]=2)=[CH:16][CH:17]=1
Reactant: OCC1(CO)COCOC1
Reactant: Fc1ccc(-c2nc(CI)co2)cc1
Agent: COC(=O)c1c(C)cccc1CO[C@H]1CCC[C@@H](OCc2coc(-c3ccc(F)cc3)n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCC1(COCc2coc(-c3ccc(F)cc3)n2)COCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 g (6.7 mmol) of 5-hydroxymethyl-1,3-dioxan-5-ylmethanol and 0.5 g (16.5 mmol) of 2 were dissolved in 20 ml of dry DMF. 300 mg of 55% NaH in paraffin oil were added, and the mixture was then stirred at room temperature for 1 hour. Work-up was carried out analogously to the synthesis of compound 5b. This gave 28 as a white amorphous solid. TLC (n-heptane/ethyl acetate 1:2). Rf=0.4. C16H18FNO5 (323.33) MS(ESI) 324.2 (M+H+). Methyl 2-{5-[2-(4-fluorophenyl)oxazol-4-ylmethoxymethyl]-1,3-dioxan-5-ylmethoxymethyl}-6-methylbenzoate 29
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([N+]([O-])=O)[C:15]=1[C:16]#[N:17])([O-:13])=[O:12].C1CCN2C(=NCCC2)CC1>C1COCC1>[OH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:10][C:18]1[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[C:15]=1[C:16]#[N:17]
Reactant: OCCCCCCCCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCCCCCCCCO)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.3 %

Procedure:
To a solution of 1,8-octanediol (3.87 mmol, 566 mg) in THF (dry, 10 mL) was added 2,6-dinitrobenzonitrile (1.29 mmol, 250 mg) and DBU (1.30 mmol, 194 μL). The reaction mixture was stirred for 24 hours at room temperature an evaporated. The oily residue was triturated with 10% citric acid/water and solid NaCl added. The precipitate was collected, washed with water, dried in vacuo and purified on silica gel (40% to 100% EtOAc in hexanes) to give the desired product (235 mg, 62.3%) as a pinkish solid. MS 293 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[C:8]([O:20][C:21](=[O:24])[NH:22][CH3:23])[CH:7]=1.C([Cl:44])C1C=CC=CC=1>CO.[Pd]>[Cl-:44].[OH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH3+:25])[C:3]([O:2][CH3:1])=[O:36])=[CH:7][C:8]=1[O:20][C:21](=[O:24])[NH:22][CH3:23]
Reactant: CNC(=O)Oc1cc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC)ccc1OCc1ccccc1
Reactant: ClCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)Oc1cc(C[C@H]([NH3+])C(=O)OC)ccc1O
Product: [Cl-]
Reaction time: 4 h

Procedure:
(S)-2-Benzyloxycarbonylamino-3-(4-benzyloxy-3-methylcarbamoyloxy-phenyl)-propionic acid methyl ester (427 mg) was dissolved in methanol (40 ml) containing 5% Pd—C (46 mg) and benzyl chloride (140 mg). The mixture was stirred under an atmosphere of hydrogen for 4 hours. The catalyst was removed by filtration and washed with methanol. The filtrate was evaporated to dryness giving a gum which was triturated with ether. (S)-2-(4-Hydroxy-3-methylcarbamoyloxy-phenyl)-1-methoxycarbonyl-ethyl-ammonium chloride was obtained as a white solid, 239 mg; NMR (500 MHz, d6 DMSO) 2.64 (ca 3H, d J 5), 2.97 (1H, dd J 14.5, 7), 3.04 (1H, dd J 14.5, 6), 3.67 (3H, s), 4.19 (1H, t J 6.5), 6.82-6.88 (3H, m), 7.44 (1H, q J 5 s exch D2O), 8.52 (3H, br s exch D2O), 9.57 (1H, s, exch D2O); HPLC/MS retention time 3.04 min, m/z 309 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][C:22]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:17]=4[C:15]=3[CH:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[ClH:31]>ClCCl.CO.C(OCC)C>[ClH:31].[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][C:22]4[CH2:21][CH2:20][NH:19][CH2:18][C:17]=4[C:15]=3[CH:16]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4cccc(F)c4)cc3c2C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: O=S(=O)(c1cccc(F)c1)c1ccc2oc3c(c2c1)CNCC3
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of the product from step C (135 mg, 0.30 mmol) in dichloromethane (1 mL) and methanol (0.5 mL) was added 2M HCl in diethyl ether (4 mL). After stirring for 14 h at ambient temperature the reaction mixture was diluted with diethyl ether to induce precipitation. The reaction mixture was concentrated in vacuo to give 8-(3-fluorophenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine hydrochloride (96 mg, 96%, AUC HPLC>99%) as an off-white solid: mp 262-272° C. dec; 1H NMR (CD3OD, 300 MHz) δ 8.31-8.27 (m, 1H), 7.97 (dd, J=8.7, 2.1 Hz, 1H), 7.84-7.78 (m, 1H), 7.76-7.69 (m, 2H), 7.64-7.56 (m, 1H), 7.42-7.35 (m, 1H), 4.49 (s, 2H), 3.69 (t, J=6.0 Hz, 2H), 3.23-3.17 (m, 2H); APCI MS m/z 332 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.C[Sn](C)(C)[Sn](C)(C)C.Br[C:28]1[C:29]([NH:36][C@H:37]2[CH2:42][C@H:41]([CH3:43])[CH2:40][N:39]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[CH2:38]2)=[N:30][C:31]([S:34][CH3:35])=[N:32][CH:33]=1>[Pd].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:47]([O:46][C:44]([N:39]1[CH2:38][C@@H:37]([NH:36][C:29]2[C:28]([C:2]3[N:3]=[C:4]4[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]4=[N:6][CH:7]=3)=[CH:33][N:32]=[C:31]([S:34][CH3:35])[N:30]=2)[CH2:42][C@H:41]([CH3:43])[CH2:40]1)=[O:45])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Reactant: CSc1ncc(Br)c(N[C@H]2C[C@H](C)CN(C(=O)OCc3ccccc3)C2)n1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)(C)[Sn](C)(C)C
Solvent: Cc1ccccc1
Product: CSc1ncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(N[C@H]2C[C@H](C)CN(C(=O)OCc3ccccc3)C2)n1
Yield: 35.5 %

Procedure:
A degassed toluene (15 ml) solution of 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 3.0 mmol), 1,1,1,2,2,2-hexamethyldistannane (1.0 g, 3.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (176 mg, 0.15 mmol) was treated in a similar manner as Example 76, step 3. To this was added (3S,5S)-benzyl 3-(5-bromo-2-(methylthio)pyrimidin-4-ylamino)-5-methylpiperidine-1-carboxylate (1.37 g, 3.0 mmol) and another 176 mg of palladium catalyst and following Example 76, step 3. (3S,5S)-3-methyl-5-{2-methylsulfany-l-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-ylamino}-piperidine-1-carboxylic acid benzyl ester (660 mg, 35%) could be isolated as an oil and taken to the next step. (0227-160)
Reaction SMILES: [H][H].[NH3:3].Cl[C:5]1[N:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C@@H:26]1[O:38][C@H:37]([CH2:39][O:40]C(=O)C)[C@@H:32]([O:33]C(=O)C)[C@H:27]1[O:28]C(=O)C>>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][CH2:15][O:14][C:12]2[N:13]=[C:5]([NH2:3])[C:6]3[N:7]=[CH:8][N:9]([C:10]=3[N:11]=2)[C@@H:26]2[O:38][C@H:37]([CH2:39][OH:40])[C@@H:32]([OH:33])[C@H:27]2[OH:28])[CH:23]=[CH:22][CH:21]=1
Reactant: [H][H]
Reactant: N
Reactant: COc1cccc(CCCOc2nc(Cl)c3ncn([C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]4OC(C)=O)c3n2)c1
Product: COc1cccc(CCCOc2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Yield: 10 %

Procedure:
A compound having a structure of the above formula was prepared where the substituents R1 and R2 are hydrogen and R3 is —CH2CH2CH2(3-OCH3)C6H4. The compound (C20H25N5O6) was prepared by reaction of ammonia with 6-chloro-2-[3-(3-methoxyphenyl)propyloxy]-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (Example 7) as described in Example 2, Step E. The final product was isolated in 10% yield as a solid with a melting point of 85-87° C. 1H-NMR (DMSO-d6): 1.97 (t, 2H, J=6); 2.69 (t, 2H, J=6); 3.54 (m, 2H); 3.71 (s, 3H); 3.95 (m, 1H); 4.15 (m, 3H); 4.58 (m, 1H); 5.19 (m, 2H); 5.42 (d, 1H, J=6); 5.77 (d, 1H, J=6); 6.77 (m, 3H); 7.19 (t, 1H, 8); 7.3 (bs, 2H); 8.14 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@@H:15]2[C@@H:18]([C:19]#[C:20][S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:17][C:16]2=[O:28])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)C(O)=[O:34].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(Cl)Cl.C(OCC)(=O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@@H:15]2[C@@H:18]([CH2:19][C:20]([S:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:34])[NH:17][C:16]2=[O:28])[CH3:14])=[O:11])=[CH:29][CH:30]=1)([O-:3])=[O:2]
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1C#CSc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)Sc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 448 mg of (3S, 4S)-3-[(R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-4-[(phenylthio)ethynyl]-2-azetidinone in 5 ml of anhydrous methylene chloride was added, under an atmosphere of nitrogen gas, 0.4 ml of trifluoroacetic acid, with stirring and ice-cooling. Stirring was continued for 30 minutes under ice-cooling and for a further 1.5 hours at room temperature. The reaction mixture was then poured into a mixture of 1.0 g of sodium bicarbonate, 10 ml of water and 20 ml of ethyl acetate. The mixture was saturated with sodium chloride and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The organic layer and the ethyl acetate extracts were combined, and the combined solution was washed successively with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate. The solvent was distilled off under reduced pressure and the residue was subjected to column chromatography through silica gel, eluted with a 1:1 by volume mixture of cyclohexane and ethyl acetate, to afford 95.0 mg (yield 63.0%) of the title thioester compound, as a viscous oil.