Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].ClN([C:25]1[C:34]2[C:29](=[CH:30][C:31](O)=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][N:26]=1)C1C=CC=CC=1F.N1C=CC=CC=1>C(Cl)Cl>[CH3:36][O:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][C:31]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[N:28]=[CH:27][N:26]=[CH:25]2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2cncnc2cc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
Trifluoromethanesulphonic anhydride (0.55 ml, 3.3 mmol) was added to a stirred suspension of 4-(chloro-2-fluoroanilino)7-hydroxy-6-methoxyquinazoline (959 mg, 3 mmol), (prepared as described for the starting material in Example 2), in methylene chloride (2.2 ml) and pyridine (2.2 ml) under argon at 0° C. Thee reaction mixture was stirred for 1 hour at 0° C. allowed to warm to ambient temperature and stirred for a further 1.5 hours. The volatiles were removed by evaporation, the residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether/petroleum ether to give 444-chloro-2-fluoroanilino)6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline (270 mg, 60%) as a beige solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[C:11]([CH:13]=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH3:15]I>CN(C)C=O>[F:3][C:4]1[CH:12]=[C:11]([CH:13]=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:15])=[O:7]
Reactant: CI
Reactant: O=Cc1ccc(C(=O)O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (69 mg, 1.7 mmol) was added portionwise to a solution of 2-fluoro-4-formylbenzoic acid (0.30 g, 1.4 mmol) in N,N-Dimethylformamide (5.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred for 30 minutes. Methyl iodide (0.18 mL, 2.9 mmol) was introduced dropwise. After 2 hours, the mixture was quenched with 1 N HCl, and extracted with EtOAc. The extracts were washed with water (twice), brine (once), dried over sodium sulfate and concentrated. Flash column chromatography, eluting with a gradient from 0-15% ethyl acetate in hexanes afforded product as a white solid (190 mg, 72%). 1H NMR (300 MHz, CDCl3): δ 10.05 (d, 1H), 8.11 (dd, 1H), 7.73 (dd, 1H), 7.65 (dd, 1H), 3.98 (s, 3H); LCMS (M+H)+: 183.0.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(N(CC)CC)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[CH3:1][N:2]([S:18]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)(=[O:20])=[O:19])[NH2:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CNN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(N)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
Into a 100 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, and dropping funnel under an atmosphere of nitrogen was added THF (25 mL), methylhydrazine (2.53 g, 2.92 mL, 55 mmol), and triethylamine (4.35 g, 43 mmol). The temperature of the mixture was lowered to approximately 5° C. and crude 4-chlorophenylsulfonyl chloride (10.5 g, 50 mmol, contained 4-chlorophenyl sulfonic acid) dissolved in 25 mL of THF was added dropwise at a rate such that the temperature did not rise over 10° C. The cooling bath was removed and the mixture was allowed to warm to stir overnight at RT. Ether (100 mL was added to the reaction mixture and the resulting slurry was washed with water (50 mL), brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo to give 5.4 g (49% yield) of 2-methyl-2-[(4-chlorophenyl)sulfonyl] hydrazine. 1H NMR (CDCl3) δ 7.8 (d, 2H), 7.6 (d, 2H), 3.6 (s, b, 2H), 2.9 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH3:44])=[C:37]([O:45][CH2:46][CH3:47])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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>[CH2:46]([O:45][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][CH3:44])[CH3:47]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOc1ccc(OB([O-])[O-])cc1OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
A mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.3 g), 3-ethoxy-4-propoxyphenyl borate (0.16 g), 1M potassium carbonate solution (1.3 ml), ethanol (1.3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.03 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol to give 7-(3-ethoxy-4-propoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 125) (0.16 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH2:29][N:30]([CH2:41][CH2:42][OH:43])[S:31]([C:34]1[S:38][C:37]([NH2:39])=[N:36][C:35]=1[CH3:40])(=[O:33])=[O:32]>>[OH:27][CH2:28][CH2:29][N:30]([CH2:41][CH2:42][OH:43])[S:31]([C:34]1[S:38][C:37]([NH:39][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:1])([F:26])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])=[N:36][C:35]=1[CH3:40])(=[O:32])=[O:33]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)N(CCO)CCO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)N(CCO)CCO

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.8) according to general procedure II.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=3)[N:12]=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[C:1]1([CH2:7][CH2:8][C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=3)[N:12]=[C:11]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(Cn2nc(-c3ccc(C(F)(F)F)cc3)cc2CCc2ccccc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1ccc(Cn2nc(-c3ccc(C(F)(F)F)cc3)cc2CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A mixture of [4-({5-(2-phenylethyl)-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)phenyl]methanol (2.00 g, 4.58 mmol), manganese dioxide (7.00 g, 80.5 mmol) and tetrahydrofuran (50 mL) was stirred at room temperature for 2 hr. The insoluble material was filtered off and the filtrate was concentrated to give the title compound (1.70 g, yield 86%) as colorless crystals.
Reaction SMILES: [Na:1].[O:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[O:18])[C:11]=1[CH3:28].Cl[C:30]1C(C)=C[N+]([O-])=C(C)C=1C>>[Na:1].[O:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][O:9][C:10]1[C:15]([CH3:30])=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:19]2[NH:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)=[O:18])[C:11]=1[CH3:28]
Reactant: Cc1c(OCC2COCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Cl
Agent: [Na]
Product: Cc1cnc(CS(=O)c2nc3ccccc3[nH]2)c(C)c1OCC1COCCO1
Yield: 18 %

Procedure:
The same procedure as in the steps (62a) to (62d) of Example 62 was repeated using 4-chloro-2,3,5-trimethylpyridine 1-oxide to obtain the title compound (355 mg, total yield: 18%) as a white solid.
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:26]([O:28]C)=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22].[OH-].[Na+].Cl>CO>[C:1]([NH:24][CH:25]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:26]([OH:28])=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22]
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)O
Temperature: 50 °C
Yield: 86.2 %

Procedure:
To a solution of methyl 2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoate (610 mg, 1.34 mmol) in MeOH (15 mL) was added 2M aqueous NaOH (30 mL). The reaction mixture was heated (50° C., 16 h), cooled (RT), and acidified with 2M aqueous HCl to pH 1. The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, (MeOH:DCM, 0-10%) to afford 2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoic acid (0.51 g, 89%) as a light yellow solid. Mass calculated for C28H43NO3=441.65; found: [M+H]+=442.1.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-])=O.C(N(C(C)C)CC)(C)C.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])C>>[CH2:24]([O:23][C:20](=[O:22])[NH:1][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:25]
Reactant: CCOC(C)=O
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
4-Nitro-aniline (100 g, 0.72 mol) is dissolved in ethyl acetate (800 mL) and diisopropylethylamine (89.6 mL, 0.936 mol) is added. Ethyl chloroformiate (252 mL, 1.45 mol) dissolved in ethyl acetate (200 mL) is added and the solution is stirred for 18 h at ambient temperature. The mixture is washed with 2M HCl (300 mL) and brine (300 mL), dried (MgSO4) and concentrated in vacuo to half of the original volume. To the resulting solution is added palladium on activated carbon (10 g, 5% Pd, 50% H2O) and the mixture is hydrogenated on a Parr apparatus (pH2=3 bar) at ambient temperature for 12 hours. The mixture is filtered through Celite and the solvent evaporated in vacuo to give 118 g (90%) of the title compound as crystalline product.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[CH:7]([OH:10])[S:6][C:5]1=[N:11][N:12]=[C:13]1[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][S:14]1)[CH:2]=[CH2:3].Cl[P:21]1(=[O:27])[N:25]([CH3:26])[CH2:24][CH2:23][O:22]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]1[C:8](=[O:9])[CH:7]([O:10][P:21]2(=[O:27])[N:25]([CH3:26])[CH2:24][CH2:23][O:22]2)[S:6][C:5]1=[N:11][N:12]=[C:13]1[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][S:14]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)C(O)SC1=NN=C1SCC(=O)N1C
Reactant: CN1CCOP1(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN1C(=O)C(OP2(=O)OCCN2C)SC1=NN=C1SCC(=O)N1C

Procedure:
In a manner analogous to that described in Example 24 starting from 7.5 g (0.025 mol) of 3-allyl-5-hydroxy-2-[[3-methyl-4-oxo-2-thiazolidinylidene]-hydrazono]-4-thiazolidinone, 7.8 g (0.05 mol) of 2-chloro-3-methyl-1,3,2-oxazaphospholidine-2-oxide and 4.53 ml (0.0325 mol) of triethylamine in 50 ml of methylene chloride there is obtained 2-[3-allyl-2-[[3-methyl-4-oxo-2-thiazolidinylidene]-hydrazono]-4-oxo-5-thiazol-idinoxy]-3-methyl-2-oxo-1,3,2-oxazaphospholidine having a melting point of 184°-185°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methoxy-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J9) (306 mg. 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white solid (301 mg).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC([N:49]1[C:53]2=[N:54][CH:55]=[CH:56][C:57](Br)=[C:52]2[CH:51]=[CH:50]1)=O)(C)(C)C>C1(C)C=CC=CC=1.[Cu]I>[CH3:40][C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:57]4[CH:56]=[CH:55][N:54]=[C:53]5[NH:49][CH:50]=[CH:51][C:52]=45)=[N:10][C:9]=3[CH:26]=2)[CH2:31][CH2:32]1)([CH3:41])[C:37]([NH2:39])=[O:38]
Reactant: CC(C)(C)OC(=O)n1ccc2c(Br)ccnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu]I
Solvent: Cc1ccccc1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4ccnc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributlystannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (0.331 g, 0.48 mmol), 4-bromopyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butylester (0.170 g, 0.573 mmol), Pd(Ph3)4 (55.1 mg, 0.048 mmol) and CuI (109 mg, 0.573 mmol) in toluene (8 mL) was purged with argon, then subjected to microwave irradiation at 140° C. for 20 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The residue was then dissolved in DCM/TFA (8 mL/8 mL) and the resulting solution stirred for 2 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The residue was purified by column chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 5:95) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 70:30 to 40:60) to give 695 as a white powder (0.049 g, 20%). LCMS (Method F): RT 5.07 min, [M+H]+ 521.3. 1H NMR (CDCl3, 400 MHz) δ 8.93 (s, 1 H); 8.43 (d, J=5.2 Hz, 1 H); 8.08 (d, J=5.2 Hz, 1 H); 7.43 (d, J=2.2 Hz, 2 H); 7.38 (s, 1 H); 7.09 (d, J=5.2 Hz, 1 H); 5.24 (d, J=5.2 Hz, 1 H); 4.10 (t, J=4.7 Hz, 4 H); 3.92 (t, J=4.7 Hz, 4 H); 3.86 (s, 2 H); 2.65-2.58 (m, 4 H); 1.60-1.55 (m, 4 H); 1.24 (s, 6 H)
Reaction SMILES: [CH:1]1([O:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:16][C@@H:17]1[C@H:21]([O:22]C(=O)C2C=CC=CC=2)[C@@H:20]([CH2:31][O:32]C(=O)C2C=CC=CC=2)[O:19][C@H:18]1[N:41]1[CH:49]=[N:48][C:47]2[C:42]1=[N:43][C:44]([Cl:51])=[N:45][C:46]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:51][C:44]1[N:45]=[C:46]([NH:7][O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:47]2[N:48]=[CH:49][N:41]([C:42]=2[N:43]=1)[C@@H:18]1[O:19][C@H:20]([CH2:31][OH:32])[C@@H:21]([OH:22])[C@H:17]1[OH:16]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NOC1CCCC1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NOC4CCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared according to method A as described in example 6 by reacting O-cyclopentylhydroxylamine (prepared by the overall procedure described in example 5) (0.78 g, 5.67 mmol) with 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (3.0 g, 4.74 mmol), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-chloro-N-cyclopentyloxyadenosine (0.11 g) (after column chromatography) as a solid, mp 116°-119° C., 1H NMR (DMSO-d6)γ 1.50-1.80 (8H, m, --CH2CH2CH2CH2 --), 3.52-3.58 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.94 (1H, q, H-4'), 4.13 (1H, q, H-3'), 4.51 (1H, q, H-2'), 4.57 (1H, br m,--OCH--), 5.06 (1H, t, 5'-- OH), 5.22, 5.50 (2H, 2d, 2'-and 3'--OH), 5.86 (1H, d, H-1'), 8.46 (1H, s, H-8), 11.40 (1H, s, N-H).
Reaction SMILES: Cl.[CH:2]1[C:10]2[N:9]3[C:11]([C@@H:14]4[C@H:18]([CH3:19])[CH2:17][C@H:16]([NH2:20])[CH2:15]4)=[CH:12][N:13]=[C:8]3[CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]([F:37])([F:36])[CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[CH:2]1[C:10]2[N:9]3[C:11]([C@@H:14]4[C@H:18]([CH3:19])[CH2:17][C@H:16]([NH:20][S:32]([CH2:31][CH2:30][C:29]([F:37])([F:36])[F:28])(=[O:34])=[O:33])[CH2:15]4)=[CH:12][N:13]=[C:8]3[CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: C[C@@H]1C[C@H](N)C[C@@H]1c1cnc2cnc3[nH]ccc3n12
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1C[C@H](NS(=O)(=O)CCC(F)(F)F)C[C@@H]1c1cnc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a 2 L flask (1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine hydrochloride (248.0 g, 733 mmol), water (1240 ml), THF (124 ml) and activated carbon (24.12 g) was added and stirred for about 10 min. The resulting mixture was filtered through celite rinsing with a mixture of water (100 mL) and THF (24 mL). Potassium carbonate (668 g, 4836 mmol) and THF (1736 ml) were added and a solution of 3,3,3-trifluoropropane-1-sulfonyl chloride (315 g, 1524 mmol, Matrix) in THF (620 ml) was added over about 1 hr. After cooling to ambient temperature the layers were separated and the aqueous layer extracted with THF (500 mL). The combined organic layers were washed with aqueous ammonium chloride (3×100 mL) and concentrated to approximately 1 L. Water (1770 mL) was added slowly at about 50° C. and the slurry cooled to about 23° C. The solids were collected by filtration, washed with 35% THF in water (750 mL) and dried in a vacuum oven. The crude material was dissolved in MeOH (4.5 L) and treated with activated carbon (28.3 g). After filtering through celite and rinsing with MeOH (500 mL), the solution was concentrated under reduced pressure to approximately 1 L and water (800 mL) was added slowly at about 50° C. then cooled to 35° C. when additional water (360 mL) was added. The product was collected by filtration, washed with 1:1 MeOH:water (2×350 mL) and dried in a vacuum oven to afford N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide (215.3 g, 71%) as a white crystalline solid (m.p. 225° C.). 1H NMR (400 MHz, DMSO) δ 11.99 (bs, 1H), 8.30 (s, 1H), 7.40 (bs, 1H), 7.38 (s, 1H), 7.27-7.07 (m, 1H), 6.62 (d, J=3.4 Hz, 1H), 3.75 (dt, J=10.1, 7.8 Hz, 1H), 3.70-3.55 (m, 1H), 3.15-3.02 (m, 2H), 2.61-2.40 (m, 2H), 2.40-2.29 (m, 1H), 2.23 (dd, J=13.3, 6.9 Hz, 1H), 2.16-2.03 (m, 1H), 1.94-1.77 (m, 1H), 1.20-0.99 (m, 1H), 0.17 (d, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[O:20])[O:5][C:6]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[N:16][O:17][CH3:18])[CH2:11][CH2:10]2.C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][O:17][N:16]=[C:12]1[C:13]2[C:9](=[CH:8][C:7]([C:6]3[O:5][C:4]([CH:19]=[O:20])=[CH:3][C:2]=3[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:15][CH:14]=2)[CH2:10][CH2:11]1
Reactant: CON=C1CCc2cc(-c3oc(C=O)cc3Br)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CON=C1CCc2cc(-c3oc(C=O)cc3-c3ccncc3)ccc21
Yield: 68.7 %

Procedure:
A degassed mixture of the product of Step 4 (2.0 g, 6.0 mmol) and 4-tributylstannylpyridine (2.5 g, 6.8 mmol) in toluene (100 ml) was treated with triphenylphosphine (156 mg, 0.6 mmol) and palladium acetate (67 mg, 0.3 mmol) then heated under reflux for 60 hours. The reaction mixture was concentrated in vacuo and the product purified by silica gel chromatography eluting with ethyl acetate/hexane (1:1) and then ethyl acetate to give the title compound (1.37 g, 69%); MS(ES+) m/e 333 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:15][CH:16]([CH2:18][O-:19])[CH3:17].[Na+]>>[CH2:18]([O:19][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[N:10]=1)[C:5]([OH:7])=[O:6])[CH:16]([CH3:17])[CH3:15]
Reactant: CC(C)Oc1cc(C(=O)O)cc(Cl)n1
Reactant: CC(C)C[O-]
Agent: [Na+]
Product: CC(C)COc1cc(C(=O)O)cc(OC(C)C)n1
Temperature: 210 °C
Yield: 25 %

Procedure:
To a flask containing 2-chloro-6-isopropoxyisonicotinic acid (1.05 g, 4.83 mmol) was added 28 mL (9.66 mmol) of freshly prepared sodium isobutoxide (0.35 M in isobutanol). This mixture was split evenly into two 20 mL microwave vials and each vial was heated under microwave irradiation at 210° C. for 20 min. The reaction mixture was purified by C18 medium pressure chromatography using a gradient of acetonitrile in water to afford 310 mg (25%) of 2-isobutoxy-6-isopropoxyisonicotinic acid. 1H NMR (300 MHz, DMSO-d6) δ 0.95 (d, 6H, J=7 Hz), 1.27 (d, 61-1, J=6 Hz), 1.96-2.05 (m, 1H), 3.96 (d, 2H, J=7 Hz), 5.05-5.13 (m, 1H), 6.59 (s, 1H), 6.63 (s, 1H).