Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13]([C:15]1([OH:38])[CH2:20][C@@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:18](=[CH2:29])[C@H:17]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:16]1)=O>CCOCC>[Si:22]([O:21][C@H:19]1[C:18](=[CH2:29])[C@H:17]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:16][C:15]([CH2:13][OH:12])([OH:38])[CH2:20]1)([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:24])[CH3:23]
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)(C(=O)OC)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)(CO)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: -24 °C
Reaction time: 1.5 h
Yield: 21.4 %

Procedure:
Diisobutylaluminum hydride (1.5 M in toluene, 2.0 mL, 3 mmol) was added to a solution of the ester 3 (215 mg, 0.5 mmol) in anhydrous ether (3 mL) at −78° C. under argon. The mixture was stirred at −78° C. for 3 h and at −24° C. for 1.5 h, diluted with ether (10 mL) and quenched by the slow addition of 2N potassium sodium tartrate. The solution was warmed to room temperature and stirred for 15 min, then poured into brine and extracted with ethyl acetate and ether. The organic extracts were combined, washed with diluted (ca. 1%) HCl, and brine, dried (MgSO4) and evaporated. The crystalline residue was purified by flash chromatography. Elution with hexane/ethyl acetate (9:1) gave crystalline diol 4 (43 mg, 24%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][SiH:16]([CH:18]([SiH:23]([Cl:25])[Cl:24])[Si:19]([Cl:22])([Cl:21])[Cl:20])[Cl:17]>C1C=CC=CC=1>[Cl:17][Si:16]1([Cl:15])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[Si:23]([Cl:24])([Cl:25])[CH:18]1[Si:19]([Cl:22])([Cl:20])[Cl:21]
Reactant: Cl[SiH](Cl)C([SiH](Cl)Cl)[Si](Cl)(Cl)Cl
Reactant: C(#Cc1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cl[Si](Cl)(Cl)C1[Si](Cl)(Cl)C(c2ccccc2)C(c2ccccc2)[Si]1(Cl)Cl
Reaction time: 18 h
Yield: 13.8 %

Procedure:
Hydrosilation of diphenylacetylene with bis(dichlorosilyl)trichlorosilylmethane in the presence of Pt(C2H4)(PPh3)2. Into the same apparatus as described in Example 1 were added 0.99 g of bis(dichlorosilyl)trichlorosilylmethane, 0.102 g of Pt(C2H4)(PPh3)2, and 25 ml of dried benzene to form a mixture. To this mixture at reflux was added 0.52 g of diphenylacetylene in 10 ml of benzene over a 30 minute period. The resulting mixture was stirred for an additional 18 hours and then the solvent remove at atmospheric pressure. The residue was vacuum distilled at 67 Pa to yield a mixture comprising 0.61 g of 1,1,3,3-tetrachloro-2-trichlorosilyl-4,5-diphenyl-1,3-disilacyclopentane (TCD-GC area 13.8%).
Reaction SMILES: C(O)CC.Cl.[CH2:6]([O:8][NH2:9])[CH3:7].[CH3:10][N:11]1[C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][O:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[CH3:33])=O)=[CH:14][CH:13]=[N:12]1>O>[CH2:6]([O:8][N:9]=[C:16]([C:15]1[N:11]([CH3:10])[N:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][O:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[CH3:33])[CH3:7]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)c2ccnn2C)c1
Reactant: CCON
Agent: Cl
Solvent: CCCO
Solvent: O
Product: CCON=C(c1ccccc1COc1cc(C)ccc1C)c1ccnn1C
Yield: 45.9 %

Procedure:
n-Propanol (2 ml) and ethoxyamine hydrochloride (0.18 g, 1.8 mmol) were added to 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone (0.20 g, 0.6 mmol), and the mixture was stirred under reflux for 3 days. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (0.11 g, 50.4%, as colorless crystals) and isomer B (0.10 g, 45.9%, as colorless crystals) of 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone O-ethyloxime.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[CH2:26]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCBr
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCc1ccco1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A dry 50 ml round bottom flask charged with furan (1.40 g, 20.6 mmol) and THF (10 ml), was cooled to -78° C. and n-butyllithium (13.6 ml, 1.50 M in hexanes, 20.6 mmol) was added dropwise. The solution was stirred for 30 mm at -78° C., then warmed to 0° C. and placed in an ice bath for 1 h. The mixture was then cooled to -78° C. and 1-bromopentadecane 9 (5 g, 17.2 mmol) in THF (10 ml) were added dropwise. The resulting solution was stirred for 1 h, then warmed to room temp and stirred 12 h. The reaction was quenched with a saturated solution of NH4Cl (5 ml). The organic layer was separated and the aqueous layer extracted with ether (3×20 ml). The combined organic layers were washed with saturated NaHCO3 (1×20 ml), brine (1×20 ml), dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography on silica, eluting with hexanes to afford a oily liquid that was recrystallized from methanol (~ 50 ml/g, cooling to 5° C.) to afford 4.8 g (64%) of 2-(pentadecyl)furan (1).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:13][C@H:14]([CH2:31][CH3:32])[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([Cl:29])[C:22]=3[CH3:30])=[N:17]2)=[O:12])[N:10]=1)(=[O:5])[CH3:4]>C(O)C>[Cl:29][C:23]1[C:22]([CH3:30])=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@H:14]([NH:13][C:11]([C:9]3[N:10]=[C:6]([CH:3]([OH:5])[CH3:4])[S:7][CH:8]=3)=[O:12])[CH2:31][CH3:32])[N:17]=2)[CH:26]=[CH:25][C:24]=1[C:27]#[N:28]
Reactant: CC[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2C)n1)NC(=O)c1csc(C(C)=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2C)n1)NC(=O)c1csc(C(C)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
Sodium borohydride (7.19 mg, 0.190 mmol) was added into a flask and the atmosphere was replaced with nitrogen. Dry ethanol was added and the reaction mixture was cooled to 0° C. (R)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)butan-2-yl)thiazole-4-carboxamide (42 mg, 0.095 mmol) was added and the reaction mixture was warmed slowly to RT while stirring overnight. The crude product was cooled to 0° C., the pH was adjusted to about 3 and the mixture was evaporated. 5% DCM/MeOH was added and the crude product was washed with 1M NaHCO3, water and dried. Yield 74.2%. 1H-NMR (400 MHz; CDCl3): δ 1.03 (m, 3H), 1.56-1.59 (m, 3H), 2.54 & 2.55 (2× broad s, 3H), 4.34-4.46 (m, 3H), 5.07 (dd, 1H), 6.41-6.43 (m, 1H), 7.46-7.54 (m, 3H), 7.80-7.89 (m, 1H), 8.02 (s, 1H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[C:14]([CH2:26][OH:27])=[C:15]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=[CH:17][CH:18]=1>C(Cl)Cl>[F:12][C:13]1[C:14]([CH:26]=[O:27])=[C:15]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:22])[CH3:23])[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(F)c1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(F)c1C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyridinium chlorochromate (596 mg, 2.76 mmol) was added to a solution of N-(3-fluoro-2-(hydroxymethyl) phenyl) pivalamide (415 mg, 1.84 mmol) in CH2Cl2 (50 mL) at 0° C. 5 min later the mixture was allowed stirring at room temperature for 3 hrs. The reaction mixture was passed through a thin pad layer of silica gel with CH2Cl2 (2×50 mL), concentrated on rotary vacuum, and purified on a flash chromatography column eluting with 20˜50% EtOAc/hexanes (600 mL) to afford the expected product, N-(3-fluoro-2-formylphenyl)pivalamide, as a white solid (396 mg, 46% yield after five steps); 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (s, 9 H), 6.76-6.83 (m, 1 H), 7.54 (td, J=8.44, 6.55 Hz, 1 H), 8.56 (d, J=8.56 Hz, 1 H), 10.38 (s, 1 H), 11.57 (s, 1 H); Mass spec. 224.11 (MH+), Calc. for C12H14FNO2 223.1.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1.[CH:22]1(B(O)O)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].N#N>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.O>[CH:22]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=3)[N:3]=2)[CH2:24][CH2:23]1
Reactant: OB(O)C1CC1
Reactant: Cc1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
3-Bromo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (10.0 g, 28.8 mmol), cyclopropylboronic acid (6.2 g, 72.0 mmol), palladium acetate (0.2 g, 0.9 mmol), triphenylphosphine (0.5 g, 1.7 mmol) and potassium carbonate (15.9 g, 115.2 mmol) were added to a mixture of H2O (50 mL) and toluene (50 mL) in a 250 mL round bottomed flask equipped with mechanical stirring, a thermal couple, a reflux condenser and a static pressure N2 line. The solution was degassed by sparging with N2 for 15 minutes and then heated with stirring under N2 at 90° C. for 18 hours. The solution was cooled to ambient temperature, treated with activated carbon, filtered through Celite®, and the filter cake was rinsed with toluene (100 mL). The filtrate was partitioned using a reparatory funnel and after extraction of the organic phase with H2O (2×50 mL) the organic layer was concentrated to dryness. The crude product was triturated with isopropyl alcohol (50 mL). The solids were collected by vacuum filtration, washed with heptane and dried under vacuum to afford 3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (6.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[CH3:20][NH:21][NH2:22]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([N:21]([CH3:20])[NH2:22])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: CNN
Solvent: CO
Product: CN(N)C1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
A suspension of 8.6 g. (0.03 mole) of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione (I) (prepared as in U.S. Pat. No. 3,422,091) in 600 ml. of methanol; is treated with 5.53 g. (0.12 mole) of methylhydrazine (II) and stirred at room temperature for about 2.5 hours. A vigorous stream of nitrogen is bubbled through the mixture during this period to remove liberated hydrogen sulfide. The mixture is concentrated under vacuum to a small volume, diluted with ice water and extracted with chloroform. The extract is washed with cold, dilute sodium chloride solution, dried with sodium sulfate and concentrated under vacuum. The residue is chromatographed on 400 g. of silica gel with a mixture of 1.5% methanol-98.5% chloroform. The product is crystallized on a rotary evaporator at about 25° C. by replacing the chloroform of a methanolchloroform solution, first with ethyl acetate and then with Skellysolve B. The yields of 7-chloro-2-(1-methylhydrazino)-5-phenyl-3H-1,4-benzodiazepine (III) are 5.07 g. having a melting point of 166.6° to 173° C. and 0.52 g. having a melting point of 175° to 176° C. The analytical sample is recrystallized from ethyl acetate-Skellysolve B having a melting point of 178.5° to 179.5° C.; ultraviolet (EtOH) end absorption, λmax. 232mμ (ε=21,400), 269 (18,300), 352 (2920); infrared absorption (Nujol) 3290, 3180 cm-1 (NH), 1645, 1590, 1575, 1565 (C=N/C=C).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][N:22]([CH3:34])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:30][CH2:31][CH2:32][NH2:33])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:33][CH2:32][CH2:31][CH2:30][NH:29][C:26]3[CH:25]=[CH:24][C:23]([N:22]([CH3:21])[CH3:34])=[CH:28][CH:27]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CN(C)c1ccc(NCCCN)cc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNCCCNc1ccc(N(C)C)cc1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 3-(4-dimethylamino-phenylamino)-propylamine analogously to Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[N:18]1[C:22](=[O:23])[NH:21][N:20]=[C:19]1[CH2:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32]C(C)(C)C)=O)[CH2:26]1.Cl.[CH:38]([N:41](CC)[CH:42](C)C)(C)C.CNN(NC)C(Cl)=O.[NH4+].[Cl-]>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[N:18]1[C:22](=[O:23])[NH:21][N:20]=[C:19]1[CH2:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:30]([N:41]([CH3:42])[CH3:38])=[O:32])[CH2:26]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2F)C1
Agent: CNN(NC)C(=O)Cl
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)C(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 8 mL screwcap vial was placed 1,1-dimethylethyl (3S)-3-({4-[2-fluoro-4-(7-quinolinyl)phenyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl}methyl)-1-pyrrolidinecarboxylate (0.161 mmol). Added to the vial was 4N HCl in dioxane (1 mL). The reaction mixture was capped and stirred at room temperature for 2 h. The solution was concentrated in vacuo. Added to the vial were dichloromethane (1 mL) and N,N-diisopropylethylamine (0.573 mmol). In a separate vial, N,N-dimethylaminocarbamoyl chloride (0.161 mmol) was dissolved in 1 mL dichloromethane and added to the starting material dropwise via pipette. The vial was capped and the reaction was stirred at room temperature for 2 h. An extra 2 mL dichloromethane was added to the vial, followed by the addition of saturated aq NH4Cl (2 mL). The vial was capped and lightly agitated for 1 min. The organic layer was separated, filtered through a plug of sodium sulfate, and concentrated in vacuo. Reverse phase HPLC (10-65% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (44 mg, 59%). MS(ES)+ m/e 461.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]2=[O:19])=[C:4]([CH2:20][CH3:21])[CH:3]=1.N1CCC[C@H]1C(O)=[O:25]>[OH-].[Na+].C(OCC)(=O)C.Cl.[Cu]I>[CH2:20]([C:4]1[CH:3]=[C:2]([OH:25])[CH:7]=[CH:6][C:5]=1[CH:8]1[C:9](=[O:19])[C:10]([CH3:18])([CH3:17])[O:11][C:12]([CH3:16])([CH3:15])[C:13]1=[O:14])[CH3:21]
Reactant: CCc1cc(Br)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCc1cc(O)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 200 °C

Procedure:
A mixture of 4-(4-bromo-2-ethylphenyl)-2,2,6,6,-tetramethylpyran-3,5-dione (1.00 g, 2.8 mmol), copper(I) iodide (0.108 g, 0.57 mmol), and L-proline (0.033 g, 0.28 mmol) in 1M aqueous sodium hydroxide solution (8.8 ml) is heated at 200° C. under microwave irradiation, until the reaction is judged to be complete by LCMS. The mixture is cooled to room temperature, diluted with ethyl acetate and 2 M aqueous hydrochloric acid and filtered through a plug of diatomaceous earth, washing with ethyl acetate. The organic phase is collected, and the aqueous phase is extracted with ethyl acetate. The organic solutions are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(2-ethyl-4-hydroxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:8]
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(OCc2ccccc2)c(Cl)c1
Yield: 73 %

Procedure:
In a 250 mL flask equipped with a reflux condenser, 2-chloro-4-nitrophenol 4.65 g (26.6 mmol), benzyl bromide 2.97 mL (27.0 mmol, 1 eq), K2CO3 9.4 g (54 mmol, 2 eq) and DMF (60 mL) were added and then heated to reflux. The procedure was conducted as Example 1, the residue was purified by column chromatography to obtain the title compound as brown solid, total yield: 73%.
Reaction SMILES: [N:1]([C@:4]1([C:43]([O:45]CC(=O)C2C=CC=CC=2)=[O:44])[C@@H:8]([CH2:9][CH2:10][CH2:11][B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH2:7][N:6]([C:21](=[O:42])[C@H:22]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:5]1)=[N+]=[N-]>C(O)(=O)C.[Zn]>[NH2:1][C@:4]1([C:43]([OH:45])=[O:44])[C@@H:8]([CH2:9][CH2:10][CH2:11][B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:19])([CH3:20])[O:13]2)[CH2:7][N:6]([C:21](=[O:42])[C@H:22]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=2)[NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)N1C[C@H](CCCB2OC(C)(C)C(C)(C)O2)[C@](N=[N+]=[N-])(C(=O)OCC(=O)c2ccccc2)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)N1C[C@H](CCCB2OC(C)(C)C(C)(C)O2)[C@](N)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A stirred solution of 2-oxo-2-phenylethyl (3R,4S)-3-azido-1-[N-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylalanyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-yl)propyl]pyrrolidine-3-carboxylate (Step 1) in acetic acid (9 mL) was treated with zinc (201 mg, 3.08 mmol, 10 equiv), and the heterogeneous mixture was stirred at room temperature. After 1.25 h, the reaction was filtered, the filter pad was washed with acetic acid and ethyl acetate, and the filtrate was concentrated and dried under reduced pressure to give the crude (3R,4S)-3-amino-1-[N-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylalanyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxylic acid (242 mg) as a clear film which was used without further purification. LC-MS ESI+ MS found for C29H43BF3N3O7 m/z 614.3 (M+H); ESI−MS m/z 612.3 (M−H).
Reaction SMILES: C(OC([NH:11][C@@:12]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:33]([OH:35])=[O:34])[CH2:13][CH2:14][C:15]([NH:17][C@@H:18]([C:28]1[NH:32][N:31]=[N:30][N:29]=1)[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:16])=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:36]([C@:12]([C:33]([OH:35])=[O:34])([CH2:13][CH2:14][C:15]([NH:17][C@@H:18]([C:28]1[NH:32][N:31]=[N:30][N:29]=1)[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[O:16])[NH2:11])([CH3:37])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)CC[C@@](NC(=O)OCc1ccccc1)(C(=O)O)C(C)(C)C)c1nnn[nH]1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CC[C@@H](NC(=O)CC[C@@](N)(C(=O)O)C(C)(C)C)c1nnn[nH]1
Reaction time: 6 h

Procedure:
A solution of tert-butyl (4R)-4-{N-[N-(benzyloxycarbonyl)-αtert-butyl-(S)-γ-glutamyl]amino}-4-(tetrazol-5-yl)butyrate (0.320 g, 0.585 mmol) in ethanol (35 ml) was stirred with 10% Pd-C. (0.12 g) under a hydrogen atmosphere at ambient temperature. After 16 hours further 10% Pd-C. (0.09 g) was added and the mixture was stirred under hydrogen for a further 6 hours. It was then filtered through Celite and the filtrate was evaporated. Several portions of dichloromethane were added and evaporated to leave tert-butyl (4R)-4-[N-(α-tert-butyl-(S)-γ-glutamyl)amino]-4-(tetrazol-5-yl)butyrate as a crisp, colourless glass which was dried over phosphorus pentoxide and used without further purification. Yield 0.24 g; m.p. 92°-94° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:15][C:16](=[O:22])[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[C:8]1(O)[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.C[Si](C)(C)O[Si](C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)COC(=O)NC1C=CC(C2CCSCC=2)=C(F)C=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([NH:15][C:16](=[O:22])[O:17][CH2:18][CH:19]([CH3:20])[CH3:21])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1
Reactant: CC(C)COC(=O)Nc1ccc(C2(O)CCSCC2)c(F)c1
Agent: CC(C)COC(=O)Nc1ccc(C2=CCSCC2)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: CC(C)COC(=O)Nc1ccc(C2CCSCC2)c(F)c1
Reaction time: 5.5 h

Procedure:
To a slurry of 2-methylpropyl [3-fluoro-4-(tetrahydro-4-hydroxy-2H-thiopyran-4-yl)phenyl]carbamate (IV, EXAMPLE 2, 25.06 g, 76.54 mmol) in toluene (150 ml), hexamethyldisiloxane (48 ml, 225.84 mmol, 2.95 eq), and polymethylhydrosiloxane (27.0 ml, 452 mmol, 5.90 eq) is added a 55° mixture of anhydrous p-toluenesulfonic acid (114.3 g, 664 mmol, 8.68 eq) in toluene (100 ml) while maintaining the temperature from about 15 to about 20°. HPLC shows complete conversion to 2-methylpropyl[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]carbamate. Toluene (50 ml) at 55° is used as a rinse and the mixture warmed to 72° and stirred 5.5 hr. The resultant slurry is poured into a 15° mixture of potassium carbonate (67.60 g, 489 mmol, 6.39 eq) in water (250 ml) while maintaining the temperature less than 35°. The resultant liquid phases are separated at 40° and water (150 ml) is added to the aqueous phase. The aqueous phase is washed with toluene (250 then 150 ml) and the organic phases is dried over magnesium sulfate and concentrated. Methylene chloride (200 ml) is added followed by heptane (700 ml) and the mixture concentrated. Heptane (250 ml) is added and the mixture concentrated again. The resultant slurry is cooled to −2° and the product collected by vacuum filtration, washed with cold heptane and dried in a nitrogen stream to give the title compound, TLC Rf=0.34 (ethyl acetate/hexanes, 10/90); HPLC (method C) RT=7.58 min; NMR (CDCl3, 500 MHz) d 7.28, 7.10, 7.00, 6.78, 3.95, 2.88-2.81, 2.68, 2.09, 1.96 and 0.96; CMR (CDCl3, 125 MHz) d 160.3, 153.6, 137.5, 128.1, 127.8, 114.2, 106.3, 71.5, 36.4, 33.9, 29.3, 28.0 and 19.0; MS (CI, NH3) m/z (relative intensity) 312 (22), 311 (100), 255 (38), 238 (25) and 237 (85).