Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[C:8]#N)([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=[O:26].[Na+].[Na+]>C1(C)C=CC=CC=1>[OH:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[CH:8]=[O:26])([CH3:4])[CH3:3]
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: CC(C)(O)c1cc(C#N)ccn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(O)c1cc(C=O)ccn1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of 2-(2-hydroxypropan-2-yl)isonicotinonitrile (41.4 g, 0.255 mol) in toluene (500 mL) was added dropwise a solution of diisobutylaluminum hydride (1 mol/L in hexane, 765 mL, 0.765 mol) at −70° C. over a period of 1.5 h. The reaction mixture was stirred at −70° C. for 30 min. Methanol (30 mL) was added followed by a 20% aqueous solution of sodium tartrate (700 mL) while stirring. The layers were separated and the aqueous layer was extracted with dichloromethane (400 mL×2). The combined organics were washed with a 20% aqueous solution of sodium tartrate (700 mL). The organic phase was stirred with a 10% aqueous solution of sulfuric acid (800 mL) for 15 min. The organics were dried over sodium carbonate and sodium sulfate and concentrated under reduced pressure. A saturated aqueous solution of sodium bisulfate (400 mL) was added to the residue and the mixture was extracted with ethyl acetate (100 mL×3). The aqueous layer was neutralized with aqueous sodium carbonate and extracted with ethyl acetate (200 mL×3). The combined organics were dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (23 g, 54%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2nc(C)c3ccc([N+](=O)[O-])cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
3-Methyl-6-nitro-1H-indazole (436 mg, 2.46 mmol) was dissolved in 25 ml of dichloromethane at room temperature. DMAP (5 mg) and pyridine (1.1 eq, 0.38 ml) were added followed by tosyl chloride (1.1 eq, 516 mg). The mixture was allowed to stir at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 4:1 Hexanes/Ethyl Acetate) to give 3-methyl-6-nitro-1-(toluene-4-sulfonyl)-1H-indazole (850 mg, quant) as a light brown crystalline solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[CH2:29][CH2:28]2)[CH:24]=[CH:23][C:21]=1[NH2:22]>>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:6]2[C:5]([CH3:17])=[CH:4][N:3]=[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:25]([N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]5)[CH2:29][CH2:28]4)=[CH:26][C:20]=3[O:19][CH3:18])[N:7]=2)=[CH:9]1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (INTERMEDIATE 1) and 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27).
Reaction SMILES: CCO[Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[CH2:14]1[CH2:18]O[CH2:16][CH2:15]1.[Br-]>CCCCCC>[CH2:12]([O:11][Si:4]([O:5][CH2:6][CH3:7])([O:8][CH2:9][CH3:10])[C:14]1[CH:18]=[CH:18][C:14]([CH:15]=[CH2:16])=[CH:16][CH:15]=1)[CH3:13]
Reactant: C1CCOC1
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: [Br-]
Solvent: CCCCCC
Product: C=Cc1ccc([Si](OCC)(OCC)OCC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 6 %

Procedure:
Firstly, dist. THF (1 mL) was added to Mg (2 g, 11 mmol) that has been activated under vacuum, and subsequently a small amount of I2 was added to the resultant mixture to obtain a mixed solution. Then, the activation of the Mg in the mixed solution was checked. Once such activation was confirmed, the mixed solution was added with dist. THF (16 mL). After that, at room temperature, a solution containing 4-bromostyrene (2 g, 11 mmol) and dist. THF (5 mL) was added dropwise to obtain a reaction solution. Then, the obtained reaction solution was stirred under a nitrogen atmosphere and a reflux condition (at 80° C.) for 20 hours to obtain 4-styrenemagnesium bromide. After that, TEOS (2.2 mL, 8.8 mmol)/dist. THF (10 mL) was added dropwise to the obtained 4-styrenemagnesium bromide under a nitrogen atmosphere at room temperature (25° C.) to obtain a reaction mixture. Subsequently, the obtained reaction mixture was stirred under a nitrogen atmosphere and a reflux condition (80° C.) for 15 hours, and then was left standing to cool to room temperature. The cooled reaction mixture was added with distilled hexane (dist. hexane: 50 mL) to make the excess Mg salt be precipitated. The salt thus formed was removed through a celite filtration process, and an organic layer was concentrated under reduced pressure to obtain a residue. Then, the obtained residue was purified through a reduced-pressure distillation process (0.01 mmHg, 80° C.) to obtain 4-(triethoxysilyl) styrene (176 mg, 6% yield).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH:20]1([NH2:23])[CH2:22][CH2:21]1>ClCCl>[CH:20]1([NH:23][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1NC1CC1
Temperature: 90 °C

Procedure:
2,4-Difluoronitrobenzene (1.00 g, 6.29 mmol), potassium fluoride (0.365 g, 6.29 mmol), potassium carbonate (0.869 g, 6.29 mmol), and cyclopropylamine (0.52 mL, 7.54 mmol) were added to a vial and heated in a microwave at 90° C. for 10 min. The reaction was then diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, and concentrated to provide the title compound: LCMS m/z 196.95 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.20 (dd, J=9.5, 6.0 Hz, 2 H), 6.95 (dd, J=11.4, 2.6 Hz, 1 H), 6.43-6.39 (m, 1 H), 2.58-2.53 (m, 1 H), 0.96-0.92 (m, 2 H), 0.69-0.66 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([C@@H:18]([NH:42]C(=O)OC(C)(C)C)[CH2:19][C:20](=[O:41])[NH:21]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[NH:15][C:14]=2[CH:50]=1.FC(F)(F)C(O)=O>>[NH2:42][C@H:18]([C:16]1[NH:17][C:13]2[CH:12]=[CH:11][C:10]([C:3]3[CH:4]=[CH:5][C:6]([C:8]#[N:9])=[CH:7][C:2]=3[Cl:1])=[CH:50][C:14]=2[N:15]=1)[CH2:19][C:20]([NH2:21])=[O:41]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc2ccc(-c3ccc(C#N)cc3Cl)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2ccc3[nH]c([C@@H](N)CC(N)=O)nc3c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To (S)-tert-butyl (1-(6-(2-chloro-4-cyanophenyl)-1H-benzo[d]imidazol-2-yl)-3-oxo-3-(tritylamino)propyl)carbamate (Preparation 15, 35 mg, 0.051 mmol) was added trifluoroacetic acid (1.3 mL, 17 mmol) and the mixture stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo and azeotroped with methanol. The residue was purified using silica gel column chromatography eluting with 0-100% CMA80/methylene chloride to afford the title compound (14 mg, 65%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:20][C:21]1[N:22]=[C:23]([Cl:39])[C:24]2[C:29](I)=[CH:28][N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25]=2[N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O.O1CCOCC1>[Cl:20][C:21]1[N:22]=[C:23]([Cl:39])[C:24]2[C:29]([C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([CH3:1])[O:3][C:4]=4[CH:10]=3)=[CH:28][N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:25]=2[N:26]=1
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2o1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Temperature: 85 °C
Yield: 58 %

Procedure:
2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (1 equiv), 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), sodium carbonate (3 equiv) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (0.04 equiv) were combined in a 5:1 mixture of 1,4-dioxane and water (0.27 M). The mixture was heated to 85° C. for 1.5 h. The crude product was purified on silica gel (0-10% ethyl acetate in petroleum ether) to give an impure brown oil. The product was purified on silica gel (0-20% ethyl acetate in petroleum ether) to give the title compound (58% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.70 (d, J=8 Hz, 1H), 7.62 (s, 1H), 7.44 (m, 2H), 5.68 (s, 2H), 3.65 (m, 2H), 2.69 (s, 3H), 0.99 (m, 2H), 0.05 (s, 9H). MS (ESI) m/z 449.0 [M+1]+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].O.[Se](=O)=[O:15]>O1CCOCC1>[CH3:1][S:2]([NH:5][C:6]1[C:7]([CH:12]=[O:15])=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: O=[Se]=O
Reactant: Cc1ncccc1NS(C)(=O)=O
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cccnc1C=O
Yield: 83.6 %

Procedure:
To a solution of 3-methylsulfonamido-2-methylpyridine (310 mg, 1.66 mmol) in dioxane (8 mL) was added water (0.8 mL) and selenium(IV) oxide (241 mg, 2.17 mmol) and the mixture stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (Hexanes/ethyl acetate, 1:1) to afford the title compound (278 mg, 83%). 1H NMR (CDCl3) □ 3.14 (s, 3H), 7.53 (dd, 1H, J=9, 6 Hz), 8.16 (dd, 1H, J=9, 3 Hz), 8.53 (dd, 1H, J=6, 3 Hz), 10.09 (s, 1H), 10.41 (br s, 1H, NH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][NH:16][CH2:17][CH2:18][O:19][C:20]2[C:30]([Br:31])=[CH:29][C:28]([O:32]S(C)(=O)=O)=[C:27]([CH3:37])[C:21]=2[C:22]([O:24]CC)=O)=[C:13]([CH3:38])[CH:12]=[C:11]([CH3:39])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[CH:43](N(CC)C(C)C)([CH3:45])[CH3:44].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])[O-].[Cs+].[Cs+].IC(C)C>CO.O>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:24])[C:21]3[C:27]([CH3:37])=[C:28]([O:32][CH:43]([CH3:45])[CH3:44])[CH:29]=[C:30]([Br:31])[C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:38])[CH:12]=[C:11]([CH3:39])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1c(C)c(OS(C)(=O)=O)cc(Br)c1OCCNCc1c(C)cc(C)nc1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC(C)I
Solvent: CO
Product: Cc1cc(C)c(CN2CCOc3c(Br)cc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 25003.4 %

Procedure:
To a solution of ethyl 2-(2-(((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)amino)-ethoxy)-3-bromo-6-methyl-5-((methylsulfonyl)oxy)benzoate (116f, 0.54 g, 0.86 mmol) in methanol (2 mL) was added sodium hydroxide solution (50% in water, 0.73 g, 9.2 mmol). The reaction mixture was heated at 120° C. in the microwave for 1 hour then diluted with water and acidified with concentrated hydrochloric acid to pH ˜4. The resulting precipitate was collected by vacuum filtration then taken up in N,N-dimethylacetamide (5 mL). N,N-diisopropylethyl amine (0.38 mL, 2.2 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 0.39 g, 1.0 mmol) were added and the reaction was stirred at room temperature overnight. The crude reaction was diluted with water (10 mL) and extracted with dichloromethane (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was dissolved in N,N-dimethylacetamide (5 mL) and cesium carbonate (0.51 g, 1.6 mmol) and 2-iodopropane (0.12 mL, 1.2 mmol) were added. The mixture was heated at 75° C. for 1 hour, cooled to room temperature then diluted with water (10 mL) and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over magnesium sulfate, concentrated under vacuum, and purified by column chromatography (30% EtOAc/Heptane) to give 4-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-9-bromo-7-isopropoxy-6-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (116 g, 242 mg, 48% yield) as a clear sticky solid.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[N:18]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=[N:16][N:15]=3)=[CH:10][C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:6][CH:5]=1)[CH:2]=[CH2:3]>[Pd].C(O)C>[CH3:31][CH:30]([CH3:32])[CH2:29][CH2:28][O:27][C:7]1[C:8]2[C:9](=[O:26])[CH:10]=[C:11]([C:14]3[N:18]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=[N:16][N:15]=3)[O:12][C:13]=2[C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: C=CCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnnn3Cc3ccccc3)oc12
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnnn3Cc3ccccc3)oc12
Reaction time: 20 h

Procedure:
A solution of 5.34 parts of 5-[8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]-N-benzyltetrazole in 1000 parts of ethanol was hydrogenated at room temperature and pressure for 20 hours using 0.14 parts of 5% palladium on charcoal as catalyst. The reaction mixture was filtered and the solvent removed by evaporation. Crystallisation of the residue from chloroform/light petroleum (40:60) gave 1.89 parts of 5-[5-(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H-1-benzopyran-2-yl]-N-benzyltetrazole, m.p. 87°-87.5°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12](O)=[O:13])[C:8]([C@@H:15]([N:17]1[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]1=[O:27])[CH3:16])=[CH:7]2.C(=O)(O)[O-].[Na+].[C:33]([NH:36][NH2:37])(=[O:35])[CH3:34]>CN(C=O)C.C(OCC)(=O)C.O>[C:33]([NH:36][NH:37][C:12]([C:9]1[C:8]([C@@H:15]([N:17]2[C:18](=[O:27])[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]2=[O:26])[CH3:16])=[CH:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1)=[O:13])(=[O:35])[CH3:34]
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: CC(=O)NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)c1nc2c(Cl)cccc2cc1[C@H](C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-8-chloro-3-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-quinoline-2-carboxylic acid (100 mg, 0.26 mmol) in DMF (3.0 mL) was added sodium bicarbonate (66 mg, 0.79 mmol), hoat (54 mg, 0/39 mmol), acetic hydrazide (23 mg, 0.31 mmol) and edc (76 mg, 0.39 mmol). The reaction was stirred at r.t. for 2 hours and then it was diluted with ethyl acetate (60 mL) and water (20 mL). The separated aqueous layer was extracted with ethyl acetate (30 mL) and the combined organic layers were washed with LiCl (1.0 M aqueous solution, 30 mL), brine (30 mL) and then dried (MgSO4), filtered and evaporated in vacuo to give (S)—N′-acetyl-8-chloro-3-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-quinoline-2-carbohydrazide. 1H NMR (400 MHz, CDCl3) δ ppm 10.45 (1H, s), 8.88 (1H, s), 8.64 (1H, s), 7.70-7.84 (4H, m), 7.64-7.66 (2H, m), 7.52 (1H, dd, J=5.3, 2.9 Hz), 6.87 (1H, q, J=7.0 Hz), 2.13 (3H, s), 1.98 (3H, d, J=7.0 Hz). Mass Spectrum (ESI) m/e=437.0 (M+1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.O[CH2:32][C@H:33]([CH2:46][CH2:47][O:48][C:49](=[O:67])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:34][N:35]1[CH:43]=[N:42][C:41]2[C:40](=[O:44])[NH:39][C:38]([NH2:45])=[N:37][C:36]1=2.CN(C)C=O>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([NH:8][C@H:9]([C:13]([O:15][CH2:32][C@H:33]([CH2:46][CH2:47][O:48][C:49](=[O:67])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:34][N:35]1[CH:43]=[N:42][C:41]2[C:40](=[O:44])[NH:39][C:38]([NH2:45])=[N:37][C:36]1=2)=[O:14])[CH:10]([CH3:11])[CH3:12])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Yield: 39.3 %

Procedure:
A mixture of N-Boc-L-valine (528 mg; 2.1 mmol) and N,N′-dicyclohexyl carbodiimide (250 mg; 1.21 mg) in dichloromethane (20 ml) was stirred over night at room temperature, dicyclohexylurea filtered off and extracted with a small volume of dichloromethane, and the filtrate evaporated in vacuo to a small volume. (R)-9-[2-Hydroxymethyl-4-(stearoyloxy)butyl]guanine (340 mg; 0.654 mmol), 4-dimethylaminopyridine (25 mg; 0.205 mmol), and dry N,N-dimethylformamide (15 ml) were added and the mixture was stirred for 4 h at 50° C. under N2. The solvent was evaporated in vacuo to a small volume. Column chromatography on silica gel, then on aluminum oxide (ethyl acetate:methanol:water 15:2:1 as eluent) gave 185 mg (39%) pure title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:16](=[O:22])[CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.S([N:34]=[N+:35]=[N-])(C)(=O)=O.[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1([C:16](=[O:22])[C:17](=[N+:34]=[N-:35])[C:18](=[O:21])[CH2:19][CH3:20])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:8]1
Reactant: CCC(=O)CC(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)C(=[N+]=[N-])C(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.8 %

Procedure:
To a solution of tert-butyl 4-methoxy-4-(1,3-dioxopent-1-yl)piperidine-1-carboxylate (0.227 g, 0.724 mmol) from Step C in dichloromethane (10 mL) was added triethylamine (0.101 mL, 0.724 mmol). Next, a solution of mesyl azide (0.087 g, 0.724 mmol) in dichloromethane (1 mL) was added. The reaction mixture was stirred for 3.5 h at room temperature. Additional mesyl azide (0.026 g, 0.217 mmol) was added. After 2 h, the reaction mixture was diluted with dichloromethane, poured into 1N sodium hydroxide solution, and extracted three times with dichloromethane. The organic layers were combined, washed with saturated sodium chloride, dried over sodium sulfite, filtered, and concentrated. The residue was purified by flash chromatography eluting with 5% ethyl acetate/dichloromethane to afford the title compound (0.174 g). MS/EI (acetonitrile/water): m/z 362 (M+Na) retention time=3.37 min.
Reaction SMILES: Cl[O-].[Na+].ClCl.[CH2:6]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:10]=1[CH:11]=[N:12][OH:13])[CH:7]=[CH2:8].C([O-])(=O)C.[Na+]>C(Cl)Cl>[Cl:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:9]2[C:10]=1[C:11]1=[N:12][O:13][CH2:8][CH:7]1[CH2:6]2
Reactant: C=CCc1cccc(Cl)c1C=NO
Agent: CC(=O)[O-]
Agent: ClCl
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cccc2c1C1=NOCC1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At room temperature, 37.0 ml of a sodium hypochloride [sic] solution (12.5% of active chlorine) were added dropwise to a solution of 8.4 g (42.9 mmol) of 2-allyl-6-chlorobenzaldehyde oxime in 100 ml of methylene chloride, and a spatula tip of sodium acetate was added. The mixture was stirred at room temperature for 2 hours, the organic phase was separated off, the aqueous phase was extracted with methylene chloride and the combined organic phases were washed with saturated ammonium chloride solution and dried, and the solvent was removed. This gave 7.0 g (94%) of 8-chloro-3a,4-dihydro-3H-indeno[1,2-c]isoxazol in the form of a viscous oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[C:25]1([C@@:31]2(CO)[CH2:33][C@H:32]2[CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:24][CH2:20][C@:31]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:33][C@H:32]1[CH2:34][O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: OC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of polymer-bound triphenylphosphine (31.64 g, 67.08 mmol, 3 eq) and carbon tetrachloride (6.5 mL, 67.08 mmol, 3 eq) in 300 mL DCM was stirred at ambient temperature for 30 min. To this was added a solution of ((1R,2R)-1-phenyl-2{[(phenylmethyl)oxy]methyl)cyclopropyl)methanol (6.0 g, 22.36 mmol, 1 eq), accessed via the method of Preparation 20B, in 50 mL DCM and the entire reaction mixture was stirred at ambient temperature for 16 h. The mixture was then filtered and the resin washed with excess DCM. The organics were concentrated down to give the title compound (6.4 g, 22.36 mmol, 100%) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 7.38-7.17 (m, 10H), 4.31-4.16 (m, 2H), 4.10-4.07 (m, 1H), 3.56-3.53 (m, 1H), 3.08-3.04 (m, 1H), 2.92-2.87 (m, 1H), 1.63-1.56 (m, 1H), 1.08-0.99 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:4].[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)Cl)([CH3:20])([CH3:19])[CH3:18].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(CCl)Nc1cccc2ccc(O)cc12
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2cccc(NC(=O)CCl)c2c1)(c1ccccc1)c1ccccc1

Procedure:
A solution of product from Step H (13.6 g, 57.87 mmol), tert-butyldiphenylchlorosilane (14.86 mL, 69.45 mmol), and imidazole (5.9 g, 86.8 mmol) in DMF (250 mL) was stirred at room temperature for 72 hours. The reaction was poured into EtOAc (200 mL), and washed with H2O (3×100 mL). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (15% ethyl acetate/hexane) to provide the title compound as a brown solid.