Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:3]1[NH:7][N:6]=[N:5][N:4]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH2:34]1[CH2:39][CH:38]([C:40]2([NH:53][C:54](NC3C=CC=C(NC4NN=NN=4)C=3)=[O:55])[N:46]=[CH:45][C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[N:42]([CH3:51])[C:41]2=[O:52])[CH2:37][CH2:36][CH2:35]1>O1CCCC1>[CH2:36]1[CH2:37][CH:38]([C@@:40]2([NH:53][C:54]([NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:8]([N:2]([CH3:1])[C:3]4[NH:7][N:6]=[N:5][N:4]=4)[CH:9]=3)=[O:55])[N:46]=[CH:45][C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[N:42]([CH3:51])[C:41]2=[O:52])[CH2:39][CH2:34][CH2:35]1
Reactant: CN(c1cccc(N)c1)c1nnn[nH]1
Reactant: CN1C(=O)C(NC(=O)Nc2cccc(Nc3nnn[nH]3)c2)(C2CCCCC2)N=Cc2ccccc21
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1C(=O)[C@@](NC(=O)Nc2cccc(N(C)c3nnn[nH]3)c2)(C2CCCCC2)N=Cc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 145 %

Procedure:
To a cooled (0° C.) and stirred milky solution of 3-[N-methyl-N-(tetrazol-5-yl)amino]aniline (230 mg) in anhydrous tetrahydrofuran (30 ml) was added solid triphosgene (120 mg) in one portion, under a nitrogen atmosphere. After 5 minutes of stirring, anhydrous triethylamine (505 μl) was added dropwise and the mixture was allowed to warm to 17° C. over 15 minutes. The reaction mixture was recooled to 0° C. and a solution of Intermediate 3 (225 mg) in anhydrous tetrahydrofuran (5 ml) was added dropwise via cannula over 4 minutes. After being stirred at 0° C. for 15 minutes, the mixture was allowed to warm to room temperature and stirred for a further 2 hours before a white precipitate was removed by filtration and the solvent was evaporated under reduced pressure. The remaining residue was partitioned between ethyl acetate (200 ml) and 10% aqueous citric acid (2×40 ml) and the organic phase was then washed with brine (1×40 ml), dried (Na2SO4) and concentrated to a yellow solid. Flash chromatography (silica gel, dichloromethane-methanol, 90:10) afforded the title compound (336 mg) as a solid; mp 222°-225° C. (methanol; decomposition); [α]D23 +15.9° (c=0.71, dimethylformamide); the spectroscopic properties (1H-NMR and MS spectra) of this material were identical to those described for its racemate (Example 3). (Found: C, 61.92; H, 5.87; N, 25.96. C25 H29N9O2 requires: C, 61.59; H, 6.00; N, 25.86%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:20][CH3:21]>CN(C=O)C.CCOC(C)=O>[CH3:16][O:15][C:13](=[O:14])[CH:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][CH:10]=1)[CH2:20][CH3:21]
Reactant: CCBr
Reactant: CCCCOc1ccc(CC(=O)OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(C(CC)C(=O)OC)cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 63 %

Procedure:
(Scheme 2, Compound E) The mixture of methyl 4-butoxyphenylacetate (1.20 g, 5.4 mmol) and NaH (60% in mineral oil, 0.50 g, 12.5 mmol) in DMF (25.0 mL) was stirred at 50° C. for 40 min. Bromoethane (2.0 g, 18.3 mmol) was added and the stirring continued at rt for one hour. The reaction mixture was diluted with EtOAc (300 mL), washed with H2O, and then was dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: EtOAc/Hexanes). This compound was obtained as a yellow oil (0.85 g, 3.4 mmol, 63% yield). 1H NMR (DMSO-d6) δ 7.16 (d, 2H, J=7.0 Hz), 6.87 (d, 2H, J=8.5 Hz), 3.92 (t, 2H, J=6.5 Hz), 3.55 (s, 3H), 3.45 (t, 1H, J=9.0), 1.93 (m, 1H), 1.63 (m, 2H), 1.42 (m, 2H), 0.97 (t, 3H, J=7.2 Hz), 0.79 (t, 3H, J=4.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:21][O:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.[I-].[Na+]>CN(C)C=O>[CH3:21][O:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:8]([C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])[C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Cc1cccc(C)c1NC(=O)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCCCBr
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
As described in example 1(a), the reaction is carried out with 11 g (42 mmol) of 4-chloro-N-(2.6-dimethylphenyl)-benzamide, 1.8 g (75 mmol) of sodium hydroxide, 12 g (50 mmol) of 8-bromocaprylic acid methyl ester, 100 cc. of dimethylformamide and 1.2 g (8 mmol) of sodium iodide. Reaction time: 4 hours, reaction temperature: 110°-120° C. The crude product is used in the next reaction step without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl.[NH:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1>C(#N)C>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:18]2[CH2:21][CH:20]([OH:22])[CH2:19]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cn1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)cn1
Temperature: 60 °C
Yield: 71.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with acetonitrile (50 mL), 5-fluoro-2-nitropyridine (1.2 g, 7.9 mmol), K2CO3 (2.1 g, 15.8 mmol), and azetidin-3-ol hydrochloride (1.3 g, 11.9 mmol). The mixture was heated at 60° C. for 1 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 20:1) to afford 314a (1.1 g, 73%) as a yellow solid. MS-ESI: [M+H]+ 196.0.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[N-:11]=[N+:12]=[N-:13].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N:11]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: OCCOCCOCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCCOCCO
Temperature: 120 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
In a 250 mL flask, 2-[2-(2-chloroethoxy)ethoxy]ethanol (1) (6000 mg, 35.7 mmol), NaN3 (6964 mg, 107 mmol) and tetrabutylammonium iodide (TBAI) (656 mg, 1.7 mmol) were added to 80 mL DMF. The temperature was slowly raised to 120° C. and the reaction mixture was stirred under argon overnight. The solvent was evaporated and the residue was purified by FCC to afford 2 as slightly yellow oil (4150 mg, 66%). 1H NMR (400 MHz, CDCl3): δ 3.29 (t, J=5.2 Hz, 2H), 3.50 (m, 2H), 3.57-3.64 (m, 8H). 13C NMR (100 MHz, CDCl3): δ 50.59, 61.60, 69.98, 70.34, 70.59, 72.56.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][C:12]([CH3:19])=[C:13]([CH3:18])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[N:28]=1>CN(C)C=O>[Br:26][C:27]1[N:28]=[C:29]([CH2:33][N:9]2[C:10]3[C:15](=[CH:14][C:13]([CH3:18])=[C:12]([CH3:19])[N:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:20]=[CH:21][C:22]([CH3:23])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1ccc(C(=O)c2c[nH]c3nc(C)c(C)cc3c2=O)cc1C
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3nc(C)c(C)cc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 2 of Example 1 were used with 69 mg (0.224 mmol) of 3-(3,4-Dimethyl-benzoyl)-6,7-dimethyl-1H-[1,8]naphthyridin-4-one, 11 mg (0.269 mmol, 60% dispersion in oil) of sodium hydride, 67.5 mg (0.269 mmol) of 2-bromo-6-bromomethyl-pyridine and 2.0 mL of N,N dimethylformamide. The crude brown solid was purified by flash column chromatography using 30-100% ethyl acetate in hexane to yield 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-6,7-dimethyl-1H-[1,8]naphthyridin-4-one as an off white solid. LC-MSD, m/z for C25H22BrN3O2 [M+H]: 476.09 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.8 min
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A mixture of fluorene (MW 166, 0.36M, 59.76 g), N-bromosuccinimide (MW 178, 0.36M, 64.1 g), benzoyl peroxide (MW 242, 0.0036M, 0.87 g) and carbon tetrachloride (360 ml) was stirred at reflux for 3 hours. After cooling to room temperature and screening, the filtrates were evaporated under reduced pressure to yield a dark oil, which after crystallisation from methanol gave 46.1 g of the title product (55% yield) as a yellow solid, m.p. 102°-104° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: ClCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC1(C)OB(c2cnn(Cc3ccncc3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 899.8 %

Procedure:
A mixture of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (750 mg, 0.387 mmol), 4-Chloromethyl-pyridine (740 mg, 0.581 mmol) and cesium carbonate (3.77 g, 1.16 mmol) was dissolved in acetonitrile (15 mL) was stirred overnight at room temperature. Stirring continued for 5 hrs at 60° C. and the reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (100% Ethyl acetate-4% 2M NH3 in MeOH/CH2Cl2) provided the title compound (993 mg, 90%). 1H NMR (300 MHz, CDCl3): δ 8.59-8.57 (m, 2H), 7.87 (s, 1H), 7.76 (s, 1H), 7.07-7.05 (m, 2H), 5.35 (s, 2H), 1.33 (s, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.O[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][C:31]1=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][O:33][CH2:32][C:31]5=[O:36])=[C:19]([O:24][CH3:25])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Reactant: O=C1COCCN1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN1CCOCC1=O
Temperature: 80 °C
Yield: 42.9 %

Procedure:
Combine 2-(4-chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (0.70 g, 1.82 mmol), 4-(2-hydroxy-ethyl)-morpholin-3-one (0.50 g, 3.45 mmol) and triphenylphosphine (0.50 g, 1.90 mmol) in THF (10.0 mL), stir for 10 min and add DIAD (0.77 g, 3.81 mmol). Heat to 80° C. for 2 days, cool the reaction mixture, and dilute with water. Extract with CH2Cl2 (2×), combine the organics, dry, and concentrate under vacuum. Purify the product by flash chromatography using 0-10% MeOH in CH2Cl2 to give the title compound (0.40 g, 43%). MS (ES+) 512.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 8.01 (d, 2H, J=8.6 Hz), 7.47 (d, 2H, J=8.6 Hz), 7.40 (d, 1H, J=7.5 Hz), 6.98-6.95 (m, 3H), 6.91 (dd, 1H, J=8.6, 2.4 Hz), 4.27 (t, 2H, J=5.2 Hz), 4.17 (s, 2H), 3.89-3.81 (m, 7H), 3.68 (t, 2H, J=5.1 Hz).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][C:7]=1[F:13])=[O:4].C(N(CC)CC)C.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C(OCC)C.[Cu](I)I>[NH2:1][C@@H:2]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:8][C:7]=1[F:13])=[O:4]
Reactant: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(I)cc1F
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(C#C[Si](C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
A solution of (2S,3S)-2-amino-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide (1.00 g, 2.51 mmol) in triethylamine (1.5 mL, 10.8 mmol) was thoroughly degassed with argon, bis-dichlorotriphenylphosphine palladium(II) (20.3 mg, 0.05 mmol) added followed by copper iodide (9.8 mg, 0.05 mmol) and trimethylsilylacetylene (277 mg, 2.77 mmol) and the mixture stirred under argon at ambient temperature for 3 hours. Additional triethylamine (1.5 mL, 10.8 mmol) was added to form a stirrable reaction mixture and stirring continued for an additional 20 hours. The reaction mixture was diluted with diethyl ether and a small amount of Celite added prior to filtration through Celite. The Celite was eluted with diethyl ether (4×20 mL) and the combined organic filtrates concentrated in vacuo. The resulting green oil was dissolved in a small amount of diethyl ether and diluted with hexanes (10 mL) to induce crystallization. The product was isolated by filtration, washed with hexanes and dried in vacuo to afford (2S,3S)-2-amino-N-(2-fluoro-4-trimethylsilanylethynyl-phenyl)-3-phenyl-butyramide as a grey solid (610 mg, 66%). A second crop of product was obtained by reprocessing of the mother liquors from the initial crystallization (168 mg, 18%).
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[OH:4])[CH3:2].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:36])[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][CH3:24])[C:17]=2[NH:25][C:26]([C:28]2[S:29][CH:30]=[C:31]([CH2:34]Cl)[C:32]=2[Cl:33])=[O:27])=[N:12][CH:13]=1.CS(C)=O.C([O-])([O-])=O.[K+].[K+]>O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:36])[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][CH3:24])[C:17]=2[NH:25][C:26]([C:28]2[S:29][CH:30]=[C:31]([CH2:34][O:4][N:3]([CH2:5][CH3:6])[CH2:1][CH3:2])[C:32]=2[Cl:33])=[O:27])=[N:12][CH:13]=1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CCl)c1Cl
Reactant: CCN(O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCN(CC)OCc1csc(C(=O)Nc2c(OC)cc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c1Cl
Temperature: 40 °C
Reaction time: 48 h

Procedure:
In a manner similar to that described in Paragraph J above, to a solution of N,N-diethylhydroxylamine (0.45 g, 5.0 mmol), N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.51 g, 1.0 mmol), and DMSO (10 mL) was added K2CO3 (0.68 g, 4.9 mmol). The mixture was stirred at 40° C. for 2 days, then it was poured into water. The resulting mixture was extracted with CH2Cl2 (2×50 mL). The organic layer was washed with 1% K2CO3, brine, treated with charcoal and concentrated. Purification by silica gel chromatography using 10:1 CH2Cl2:CH3OH with 1% NH4OH followed by precipitation from CH2Cl2 and hexane afforded N-(5-chloropyridin-2-yl)-2-[((4-(((diethylamino)oxy)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide, as a white solid; NMR (DMSO-d6) 8.35 (s, 1H), 8.20 (s, 1H), 8.10 (d, 1H), 7.90 (dd, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 4.20 (s, 2H), 3.85 (s, 3H), 3.20-2.80 (m, 4H), 1.20 (t, 6H) ppm.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[CH:10]([O:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1)=[CH2:11].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:5][C:4]([F:6])([O:21][CH2:20][CH:17]1[CH2:18][CH2:19][CH:14]([CH2:13][O:12][CH:10]=[CH2:11])[CH2:15][CH2:16]1)[CH:3]([F:7])[C:2]([F:9])([F:8])[F:1]
Reactant: C=COCC1CCC(CO)CC1
Reactant: FC(F)=C(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=COCC1CCC(COC(F)(F)C(F)C(F)(F)F)CC1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
Hexafluoropropene (264 g, 1.76 mol) was added dropwise to a mechanically stirred mixture of 1,4-cyclohexanedimethanol vinyl ether (300 g, 1.76 mol), acetonitrile (600 mL), and K2CO3 (121 g, 0.88 mol), at 0° C. under N2. The reaction flask was placed in an ice bath to moderate the exothermic reaction during the addition of hexafluoropropene. After complete addition of hexafluoropropene, the reaction mixture was stirred for an additional hour at room temperature and filtered. The filtrate was added to 1.5 L water and mixed well. The lower layer formed was separated, washed with water (3×300 mL), and concentrated under reduced pressure (approximately 0.05 mm Hg) to afford 1,1,2,3,3,3-hexafluoro-1-{[4(vinyloxymethyl)cyclohexyl]methoxy}propane(cis/trans mixture) as a colorless liquid (428 g, 76% yield); b.p. 55-60° C./0.05 mm Hg; Refractive Index 1.4145 at 23.7° C.; GC/MS: m/z at 320 for M+; 19F and 1H NMR spectral data are consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[N+:20]([O-])([OH:22])=[O:21]>>[CH3:1][C:2]1[C:10]([N+:20]([O-:22])=[O:21])=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 101.4 %

Procedure:
2-methyl-5-(trifluoromethyl)benzoic acid (4 g, 19.6 mmol) was added to cooled conc. H2SO4 (27 mL) at −10° C. in small portions. After 10 minutes nitrating mixture {prepared by mixing conc. HNO3 (2.77 g, 44.44 mmol) with conc.H2SO4 (3.6 mL)} was added drop wise at −10° C. The resulting solution was stirred at −10° C. for 30 minutes. On completion, the reaction mixture was poured into ice cold water. The solid was filtered, washed with water and dried under vacuum to give 2-methyl-3-nitro-5-(trifluoromethyl)benzoic acid (4.95 g, 99%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:23])[CH2:11][CH2:12][O:13][CH2:14][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][CH:28]=[N:29][C:30]=2[N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Si:1]([O:8][CH2:9][CH:10]([O:23][N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][CH:28]=[N:29][C:30]=2[N:34]1[C:35](=[O:44])[C:36]2=[CH:43][CH:42]=[CH:41][CH:40]=[C:37]2[C:38]1=[O:39])[CH2:11][CH2:12][O:13][CH2:14][P:15]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1c1ncnc2c1ncn2O
Reactant: CCOP(=O)(COCCC(O)CO[Si](C)(C)C(C)(C)C)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(COCCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(N3C(=O)c4ccccc4C3=O)ncnc21)OCC
Temperature: 20 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
A solution of diethyl 4-t-butyldimethylsilyloxy-3-hydroxybutoxymethylphosphonate (0.49 g, 1.31 mmol), 9-hydroxy-6-phthalimidopurine (0.5 g, 1.31 mmol) and triphenylphosphine (0.52 g, l.97 mmol) in dry tetrahydrofuran (50 ml) was stirred under nitrogen at O° C. during the addition of diethyl azodicarboxylate (0.31 ml, 1.97 mmol). The solution was then stirred at 20° C. for 4 h and evaporated in vacuo. The residue was chromatographed on silica, eluting with hexane-acetone 4:1, affording 9-[1-(t-butyldimethylsilyloxy)-4-(diethoxyphosphorylmethoxy)but-2-oxy]-6-phthalimidopurine (575mg, 69%) as a clear oil. νmax (film) 3500, 1790, 1740, 1600 and 1580 cm-1 ; δH [(CD3)2SO] 0.04 (6H, s, CH3SiCH3), 0.74 (9H, s, (CH3)3CSi), 1.22 (6H, t, J6.9 Hz, 2×CH3CH 2), 2.04 (2H, m, SiOCH2CHCH2), 3.79 (2H, m, CH2OSi), 3.88 (2H, d, J8.2 Hz, CH2P), 3.96 (2H, m, CH2OCH2P), 4.03 (4H, m, 2×CH3CH2), 4.69 (1H, m, CHON), 8.05 (4H, m, ArH), 8.91 (1H, s, H-2/H-8), 9.07 (1H, s, H-2/H-8); m/z (FAB+ve Ion), 656 (MNa+) and 634 (MH+). Found: C, 53.10 H, 6.30; N, 10.83%; C28H40N5O8PSi requires C, 53.07; H, 6.36,; N, 11.05%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[O:8])=[CH:5][C:4]=1[O:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1.[OH:34]O>C(O)(=O)C.O>[CH3:1][S:2]([C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18]2)=[O:8])=[CH:5][C:4]=1[O:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)=[O:34]
Reactant: CSc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(C)c1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)ccc2S(C)=O)c1

Procedure:
The compound of example 4 (100 mg, 0.216 mmol) was dissolved in acetic acid (7.5 ml), hydrogen peroxide (74 mg of a 30% solution in water, 0.65 mmol) was added, and the mixture was reacted at room temperature for 9 h. The mixture was partitioned between EA and a 1% aqueous sodium sulfite solution, the aqueous phase extracted with EA, and the organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was stirred with diethyl ether, filtered, and dried in vacuo to give 79 mg of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:44])[O:14][CH2:15][C@@H:16]([N:30]([CH3:43])[C:31]([NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=3[Cl:42])=[O:32])[CH2:17][C@@H:18]([OH:29])[CH2:19][O:20][P:21]([O:26]CC)([O:23]CC)=[O:22])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si](I)(C)(C)C>C(#N)C>[C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:44])[O:14][CH2:15][C@@H:16]([N:30]([CH3:43])[C:31]([NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=3[Cl:42])=[O:32])[CH2:17][C@@H:18]([OH:29])[CH2:19][O:20][P:21]([OH:26])([OH:23])=[O:22])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOP(=O)(OCC)OC[C@H](O)C[C@@H](COC(=O)Nc1cc(-c2ccccc2)no1)N(C)C(=O)NCc1cccc(F)c1Cl
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc(-c2ccccc2)no1)C[C@@H](O)COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a mixture of (2S,4R)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(diethoxyphosphoryloxy)-4-hydroxypentyl 3-phenylisoxazol-5-ylcarbamate (56 mg, 0.085 mmol, 1.0 equiv.) in acetonitrile (5 mL) was added TMSI (0.115 mL, 0.85 mmol, 10.0 equiv.) at ° C. After stirring at RT for 10 min, the reaction wag quenched with MeOH. The solvent was removed, and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O (with 0.1% TFA buffer). The fractions of product was concentrated, dissolved in a mixture of methanol and water (2:1), followed by addition of HCl (4 N in 1,4-dioxane, 2 mL). The mixture was concentrated to give (2S,4R)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-hydroxy-5-(phosphonooxy)pentyl 3-phenylisoxazol-5-ylcarbamate (48 mg, 94%) as a white solid. LRMS (M+H+) m/z 601.5.