Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11](O)[C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4C(OC(C)(C)C)=O)=[N:8][C:7]=2[CH:32]=1)#[N:2].C[O:34][C:35]([O:39][Si](C)(C)C)=[C:36]([CH3:38])[CH3:37].C([O-])(O)=O.[Na+]>C(Cl)Cl.O.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][NH:16]4)[C:36]([CH3:38])([CH3:37])[C:35]([OH:39])=[O:34])=[N:8][C:7]=2[CH:32]=1)#[N:2]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1nc2cc(C#N)ccc2o1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c2[nH]ccc2c1C(c1nc2cc(C#N)ccc2o1)C(C)(C)C(=O)O
Reaction time: 0.25 h

Procedure:
A solution of (±)-tert-butyl 4-((5-cyanobenzo[d]oxazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 125-A) (133 mg, 0.31 mmol) in DCM (10 mL) was treated with TiCl4 (1M in DCM, 1 mL, 1 mmol) at 0° C. The reaction mixture was stirred for 15 min, followed by the addition of ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (0.36 g, 2 mmol). The mixture was allowed to reach room temperature over 1 h. The reaction mixture was then poured into aqueous NaHCO3. The organic layer was extracted with ethyl acetate (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated to provide a residue. The resulting residue was suspended in water (5 mL) and was treated wtih Dowex ion exchange resin (200% w/w) (washed with water twice). The reaction was stirred at 120° C. overnight in a sealed tube. Reaction was cooled, filtered and directly subjected to purification by FCC1-5% (MeOH:DCM) to obtain the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.05 (br. s., 1H) 7.46-7.61 (m, 1H) 7.23 (t, J=2.78 Hz, 1H) 7.10 (d, J=8.34 Hz, 2H) 6.69 (s, 1H) 6.31-6.51 (m, 1H) 4.19 (s, 1H) 3.72 (s, 3H) 2.45 (s, 3H) 1.60 (s, 3H) 0.93 (s, 3H). HMRS calcd. for C23H21N3O4 (M+H)+ 404.1602. found 404.1595.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][N:31]([C:39](=[O:38])[CH2:40][OH:41])[CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f43) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:8]2(=[O:20])=[O:19])=[C:4]([F:23])[CH:3]=1.[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1)(=[O:27])=[O:26].CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I>[F:23][C:4]1[CH:3]=[C:2]([O:34][CH:31]2[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH2:30]2)[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:8]1(=[O:20])=[O:19]
Reactant: O=S1(=O)C(c2ccccc2)CCCN1Cc1ccc(Br)cc1F
Reactant: CS(=O)(=O)N1CCC(O)CC1
Agent: [Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: O=C([O-])[O-]
Product: CS(=O)(=O)N1CCC(Oc2ccc(CN3CCCC(c4ccccc4)S3(=O)=O)c(F)c2)CC1
Temperature: 135 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
2-(4-bromo-2-fluorobenzyl)-6-phenyl-1,2-thiazinane 1,1-dioxide (100 mg, 0.25 mmol), 1-methylsulfonylpiperidin-4-ol (67.2 mg, 0.38 mmol), copper(I) iodide (9.5 mg, 0.05 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (24 mg, 0.1 mmol) and cesium carbonate (123 mg, 0.38 mmol) were weighed out in a vial and the vial was purged with nitrogen. p-Xylene (1 mL) was then added and the reaction was stirred at 135° C. for 16 hours. The reaction was then filtered through diatomaceous earth, concentrated and purified by reverse-phase HPLC to give 2-(2-fluoro-4-((1-(methylsulfonyl)piperidin-4-yl)oxy)benzyl)-6-phenyl-1,2-thiazinane 1,1-dioxide (50.1 mg, 40% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5](C=O)=[CH:4][N:3]=1.C(O[CH:14]([O:19][CH:20]([CH3:22])[CH3:21])[O:15][CH:16]([CH3:18])[CH3:17])(C)C.CS(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH:20]([O:19][CH:14]([O:15][CH:16]([CH3:17])[CH3:18])[C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=1)([CH3:21])[CH3:22]
Reactant: CC(C)OC(OC(C)C)OC(C)C
Reactant: Cc1ncc(C=O)cn1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1ncc(C(OC(C)C)OC(C)C)cn1
Temperature: 25 °C
Reaction time: 23 h
Yield: 29.1 %

Procedure:
To a mixture of 2-methylpyrimidine-5-carbaldehyde (1.0 g, 8.2 mmol) and triisopropoxymethane (2.3 g, 12 mmol) in isopropanol (15 ml) was added methanesulfonic acid (0.079 g, 0.053 ml, 0.819 mmol). The reaction was stirred at room temperature for 23 hours. Potassium carbonate (1.132 g, 8.19 mmol) was added and the mixture was filtered and the solution was concentrated in vacuo. The crude mixture was purified by flash chromatography to yield 5-(diisopropoxymethyl)-2-methylpyrimidine (536 mg, 29%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][C:11]([N:13]=[C:14]=[O:15])=[O:12].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:10][C:11](=[O:12])[NH:13][C:14]2=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C=NC(=O)CCl
Reactant: Nc1cccc(Br)c1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CN(c2cccc(Br)c2)C(=O)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-bromoaniline (1.0 mL, 9.18 mmol) and chloroacetyl isocyanate (0.780 mL, 9.18 mmol) in dioxane (100 mL) was stirred at room temperature for 2 hr. Dioxane (50 mL) and DBU (3.40 mL, 23.0 mmol) were added and the solution stirred at room temperature for 16 hr. The solution was concentrated in vacuo and the residue taken up in EtOAc and H2O. The mixture was then acidified with 1N HCl, then the aqueous phase extracted with EtOAc. The combined organics were then washed with H2O and brine and dried over Na2SO4. The solution was concentrated in vacuo and the residue recrystallized from EtOAc/hexanes to give 1-(3-bromophenyl)-2,4-imidazolidinedione as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.42 (s, 2H), 7.24-7.30 (m, 2H), 7.50-7.52 (m, 1H), 7.87 (s, 1H), 11.27 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([O:19]C)=[C:6]([CH:18]=1)[C:7]([N:9]([CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:8].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([OH:19])=[C:6]([CH:18]=1)[C:7]([N:9]([CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:8]
Reactant: COc1cc(Cl)c(Br)cc1C(=O)N(C)c1ccccc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
To a solution of DCM (15.0 mL) containing 5-bromo-4-chloro-2-methoxy-N-methyl-N-o-tolyl-benzamide (2.75 g, 7.5 mmol) at −78° C., was added BBr3 (38.0 mL, 1M in DCM) dropwise. The mixture was gradually warmed to room temperature and stirred for 12 hrs. The mixture was concentrated to yield a solid which was washed by ether to give 5-bromo-4-chloro-2-hydroxy-N-methyl-N-o-tolyl-benzamide (2.6 g). MS: 353.8 (M+H)+; tR=2.50 min (method 1).
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:21])=[C:16](/[CH:18]=[N:19]/[OH:20])[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:22][O:23][C:24](=[O:31])[CH2:25][C:26](=[CH2:30])[C:27]([OH:29])=[O:28].Cl>C1COCC1>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:21])=[C:16]([C:18]2[CH2:30][C:26]([CH2:25][C:24]([O:23][CH3:22])=[O:31])([C:27]([OH:29])=[O:28])[O:20][N:19]=2)[CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=C(CC(=O)OC)C(=O)O
Reactant: O/N=C/c1cc(OCc2ccccc2)ccc1Br
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: COC(=O)CC1(C(=O)O)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
An aqueous sodium hypochlorite solution (5%, 146 g) was added to a mixture of (E)-1-(5-(benzyloxy)-2-bromophenyl)-N-hydroxymethanimine (27.2 g), 4-methoxy-2-methylene-4-oxobutanoic acid (12.8 g), and THF (270 mL) at 0 C. The obtained mixture was stirred at 0 C for 1 hour and at room temperature overnight. To the reaction mixture, 1 M hydrochloric acid was added, followed by extraction with ethyl acetate. The extract was washed with bline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and then, the obtained residue was washed with hexane/diethyl ether to obtain the title compound (26.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23](OC)[O:24]C)[CH:20]=[CH:19][C:18]=3[N+:28]([O-:30])=[O:29])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:18]=3[N+:28]([O-:30])=[O:29])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)c1
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A mixture of 3.2 g (7.1 mmole) of 4-(3-chloro-phenyl)-2-(5-dimethoxymethyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.2a), 30 mL of 2M hydrochloric acid and 5 mL of dimethylformamide was stirred at 60 degrees for 3 hours. The mixture was cooled and then concentrated under reduced pressure. The residue was taken up in 100 mL of dichloromethane and washed once with 100 mL of saturated sodium bicarbonate solution, once with 50 mL of brine, and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (50:50) to give 2.5 g of 4-(3-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.2b).
Reaction SMILES: [C:1]([C:3]([CH3:10])([CH3:9])[CH:4]([OH:8])[CH2:5][CH2:6][OH:7])#[N:2].C(=O)([O-])[O-].[K+].[K+].CO[C:19](OC)([CH3:21])[CH3:20]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:3]([CH:4]1[CH2:5][CH2:6][O:7][C:19]([CH3:21])([CH3:20])[O:8]1)([CH3:10])[CH3:9])#[N:2]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C#N)C(O)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)OCCC(C(C)(C)C#N)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Optically active 4-cyano-4-methyl-3-hydroxy-1-pentanol (500 mg, 3.49 mmol) was dissolved in 2,2-dimethoxypropane (5 mL) and p-toluenesulfonic acid (50 mg) was added. The mixture was stirred at room temperature for 30 min. Thereto was added a powder of potassium carbonate (100 mg) to neutralize the reaction mixture. The mixture was filtrated and concentrated under reduced pressure to give optically active 4-(1-cyano-1-methylethyl)-2,2-dimethyl-1,3-dioxane (614 mg, 3.35 mmol) (yield relative to optically active 4-cyano-4-methyl-3-hydroxy-1-pentanol: 96%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][CH:4]=1.C(C1C=C(C)C=C(C(C)(C)C)C=1[OH:36])(C)(C)C.ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[O-:36][N+:8]1[C:3]([C:2]([F:19])([F:1])[F:20])=[CH:4][CH:5]=[C:6]([C@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH3:10])[CH:7]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)nc1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClC(Cl)Cl
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)[n+]([O-])c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 423.2 %

Procedure:
To a solution of tert-butyl {(1R)-1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}carbamate (0.626 g, 2.157 mmol) in chloroform (10.0 mL) were added 2,6-di-tert-butyl-4-methylphenol (24 mg, 0.108 mmol) and 3-chloroperbenzoic acid (0.665 g, 2.70 mmol). The reaction mixture was stirred at 50° C. for 48 h. The reaction mixture was cooled to ambient temperature. Saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate were added. The mixture was extracted with dichloromethane (3×). The combined organics extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (75% hexanes/ethyl acetate 100% ethyl acetate) gave the title compound (140 mg). MS 307.0 (M+1).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[SiH4].Cl[CH2:8][Si:9]([O:12][CH3:13])([CH3:11])[CH3:10]>>[C:1]([O:4][CH2:8][Si:9]([O:12][CH3:13])([CH3:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CO[Si](C)(C)CCl
Agent: [Na+]
Agent: [SiH4]
Product: CO[Si](C)(C)COC(C)=O
Reaction time: 0.5 h

Procedure:
A mixture of 20 mL of high boiler solvent as per Table 1, 13.5 g (165 mmol) of sodium acetate (anhydrous) and the Table 1 amount of phase transfer catalyst (amount specified in mol % based on employed amount of silane) was heated to the temperature reported in Table 1 and dried at this temperature under a vacuum of 10 mbar for minutes. The vacuum was subsequently broken with argon, and (chloromethyl)methoxydimethylsilane (20.8 g, 150 mmol) was metered in at this temperature over 30 minutes under agitation. The mixture was further stirred at this temperature until a gas chromatogram (FID detector) or a 1H NMR spectrum indicated more than 99% conversion of the silane; the reaction times required for this are reported in Table 1. The product was subsequently distilled off at 10-90 mbar (head), 50-90° C. (head) and 70-120° C. (pot) through a Widmer column (20 cm) to obtain the Table 1 yields of (acetoxymethyl)methoxydimethylsilane as a colorless liquid having a purity of >99% (GC area %). The solvent, sodium chloride, excess sodium acetate and the phase transfer catalyst in the form of its chloride and acetate salts (and also of the bromide salt when a bromide was used) remained in the residue.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:25])[C:13]([C:15]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:25])[CH:13]([C:15]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)[OH:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)C1(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)C(O)C1(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of tert-butyl 1-((2S)-2-{[(benzyloxy)carbonyl]amino}propanoyl)cyclopropanecarboxylate (1.66 g) in methanol (25 mL) was cooled to 0° C., 90% sodium borohydride (305 mg) was added, and the mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/1) to give the title compound as a colorless oil (yield: 1.58 g, 94%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][NH:6][C:7](=[O:10])[CH2:8][CH3:9].Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]([N:20]2[C@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:21]2([CH3:30])[CH3:29])=[O:19])=[CH:14][C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.O>C1COCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:13]2[C:12]([O:3][CH2:4][CH2:5][NH:6][C:7](=[O:10])[CH2:8][CH3:9])=[N:17][CH:16]=[C:15]([C:18]([N:20]3[C@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:21]3([CH3:30])[CH3:29])=[O:19])[CH:14]=2)=[CH:32][CH:33]=1
Reactant: CCC(=O)NCCO
Reactant: CC(C)C[C@@H]1COC(C)(C)N1C(=O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)NCCOc1ncc(C(=O)N2[C@H](CC(C)C)COC2(C)C)cc1-c1ccc(Cl)cc1
Reaction time: 6 h
Yield: 33.2 %

Procedure:
Sodium hydride dispersion in oil (˜55%, 72 mg) was added in portions to a well stirred solution of N-(2-hydroxyethyl)propionamide (71 mg, 0.6 mmol) in THF (13 mL). After stirring the mixture for 15 min at RT [6-Chloro-5-(4-chloro-phenyl)-pyridin-3-yl]-((R)-4-isobutyl-2,2-dimethyl-oxazolidin-3-yl)-methanone (225 mg, 0.55 mmol) was added and stirring continued for 6 h at RT. The mixture was poured into water and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (cyclohexane/ethyl acetate 8:1) to yield 89 mg of the title compound as a white solid, MS (ISP) 488.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CC(O)CN1C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (8 g, 32.65 mmol) in DCM (200 ml), pyridinium dichromate (24.55 g, 65.3 mmol) was added at 0° C. It was stirred at room temperature for overnight. Reaction mixture was filtered through celite pad and DCM layer was concentrated. Purification by column chromatography offered 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a white solid (6 g, 76%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[C:23]1([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:31]2[CH2:32][CH2:33][CH:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: c1ccc(C2CCNC2)cc1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(c2ccccc2)C1
Temperature: 65 °C
Yield: 18.9 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 3-phenylpyrrolidine (0.060 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0067 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.31 g, 0.95 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated. The residue was purified on silica gel (eluting with dichloromethane) to give the desired product (22.6 mg, 19%). LCMS calculated for C21H20ClN2O (M+H)+: m/z=351.1; Found: 351.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([NH:9][CH:10]=[N:11]2)=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[N:6]=1)(=[O:3])[CH3:2].[C:18]([C@@:21]1([OH:36])[C@@H:25]([CH2:26][OH:27])[O:24][C:23](Cl)([C:28](=[O:30])[CH3:29])[C@:22]1([C:33](=[O:35])[CH3:34])[OH:32])(=[O:20])[CH3:19]>>[C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@:23]2([C:28](=[O:30])[CH3:29])[O:24][C@H:25]([CH2:26][OH:27])[C@@:21]([C:18](=[O:20])[CH3:19])([OH:36])[C@@:22]2([C:33](=[O:35])[CH3:34])[OH:32])=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(NC(C)=O)c2[nH]cnc2n1
Reactant: CC(=O)C1(Cl)O[C@H](CO)[C@](O)(C(C)=O)[C@]1(O)C(C)=O
Product: CC(=O)Nc1nc(NC(C)=O)c2ncn([C@]3(C(C)=O)O[C@H](CO)[C@](O)(C(C)=O)[C@]3(O)C(C)=O)c2n1

Procedure:
Generally speaking, compounds of this invention are prepared from 2-acetamido-adenosine-5'-carboxylic acid or from the corresponding 2',3'-isopropylidene derivatives. 2-acetamido-adenosine-5'-carboxylic acid is obtained by reacting 2,6-diaminopurine sulfate with sodium hydroxide to obtain 2,6-diaminopurine which is then reacted with acetic anhydride to yield 2,6-diacetamidopurine, which in turn is converted to a mercuri chloride complex. The mercuri chloride complex of 2,6-diacetamidopurine is then reacted with triacetyl D-ribofuranosyl chloride to obtain 2,6diacetamido-9-(triacetyl-β-D-ribofuranosyl) purine, which is then converted to the corresponding 2-acetamido adenosine by treatment with methanol in the presence of ammonia. Preparation of 2-acetamido adenosine from 2,6-diaminopurine sulfate has been described by J. Davoll & B. A. Lowy [J.A.C.S., 73, 1650 (1951)]. The corresponding isopropylidene compound is obtained by reacting 2-acetamido adenosine with acetone. Potassium permanganate oxidation affords the corresponding 5'-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:15][CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[C:6]=2[CH:7]=1.O1CCCC1.C([Li])CCC.[C:26](=[O:28])=[O:27]>CCCCCC>[O:9]1[CH2:10][CH2:11][O:12][C:8]21[C:6]1[CH:7]=[C:2]([C:26]([OH:28])=[O:27])[CH:3]=[CH:4][C:5]=1[S:15][CH2:14][CH2:13]2
Reactant: O=C=O
Reactant: Brc1ccc2c(c1)C1(CCS2)OCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)C1(CCS2)OCCO1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
13.58 g (0.047 mol) of the title compound of Step C was added to 150 mL of tetrahydrofuran. The solution was cooled to about -65° C. and 23 mL (0.057 mol) of 2.5 M n-butyllithium in hexane (purchased from Aldrich Chemical Company) was added dropwise while keeping the temperature below -55° C. After stirring under nitrogen for 1 h, excess solid CO2 was added in one portion, and the mixture was stirred overnight while warming to room temperature. 100 mL of hexane was added to the mixture, and it was then filtered. To the solid residue was added 500 mL of water and 400 mL of methylene chloride. The solution was cooled to about 0° C., acidified to pH 1 with concentrated hydrochloric acid, and extracted with methylene chloride (3×400 mL). The resulting solution was dried (MgSO4), filtered, and evaporated to dryness to yield 8.58 g of the title compound of Step D as a solid melting at 186.7° C. (dec). 1H NMR (Me2SO-d6): δ2.2 (m,2H), 3.2 (m,2H), 4.1 (m,4H), 7.2-8.0 (3H), 12.8 (br s,1H).