Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:78])[C@H:4]([CH2:76]O)[NH:5][C:6](=[O:75])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:74])[C@H:13]([CH2:68][C:69]1[N:73]=[CH:72][NH:71][CH:70]=1)[NH:14][C:15](=[O:67])[C@H:16]([C@H:63]([CH2:65][CH3:66])[CH3:64])[NH:17][C:18](=[O:62])[C@H:19]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=1)[NH:20][C:21](=[O:53])[C@H:22]([CH:50]([CH3:52])[CH3:51])[NH:23][C:24](=[O:49])[C@H:25]([CH2:42][CH2:43][CH2:44][NH:45][C:46](=[NH:48])[NH2:47])[N:26]([C:30](=[O:41])[CH2:31][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH3:33])[N+:27]([O-:29])=[O:28].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>N1C=CC=CC=1.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:78])[C:4](=[CH2:76])[NH:5][C:6](=[O:75])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:74])[C@H:13]([CH2:68][C:69]1[N:73]=[CH:72][NH:71][CH:70]=1)[NH:14][C:15](=[O:67])[C@H:16]([C@H:63]([CH2:65][CH3:66])[CH3:64])[NH:17][C:18](=[O:62])[C@H:19]([CH2:54][C:55]1[CH:56]=[CH:57][C:58]([OH:61])=[CH:59][CH:60]=1)[NH:20][C:21](=[O:53])[C@H:22]([CH:50]([CH3:51])[CH3:52])[NH:23][C:24](=[O:49])[C@H:25]([CH2:42][CH2:43][CH2:44][NH:45][C:46](=[NH:47])[NH2:48])[N:26]([C:30](=[O:41])[CH2:31][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH3:33])[N+:27]([O-:29])=[O:28]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N(C(=O)CN(C)C(=O)OC(C)(C)C)[N+](=O)[O-])C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: C=C(NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N(C(=O)CN(C)C(=O)OC(C)(C)C)[N+](=O)[O-])C(C)C)[C@@H](C)CC)C(=O)OC
Reaction time: 2 h

Procedure:
3.0 g of t-butoxycarbonylsarcosylnitroarginylvalyltyrosylisoleucylhistidylprolylserine methyl ester is dissolved in 20 ml of pyridine and 10 ml of triethylamine. The solution is cooled in an ice bath. 0.51 g of tosyl chloride is added to the solution. At ten minute intervals, three additional 0.51 g batches of tosyl chloride are added. After standing for two hours, the reaction mixture is filtered. 200 ml of methylene chloride is added to the reaction. The solution is extracted three times with 5% ammonium hydroxide in water. The solution is then dried over sodium sulfate and stripped under vacuum. The residue istaken up in 2% methanol/methylene chloride and passed through a silica gel column to remove the colored impurities and afford the pure product t-butoxycarbonylsarcosylnitroarginylvalyltyrosylisoleucylhistidylprolyldehydroalanine methyl ester.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[N-:12]=[N+:13]=[N-:14].[Na+].C([O-])(O)=O.[Na+]>O>[N:12]([CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])=[N+:13]=[N-:14]
Reactant: O=C(CBr)c1cccnc1
Reactant: [N-]=[N+]=[N-]
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromoacetylpyridine hydrobromide (5 g, 17.8 mmol) in 20 mL of water was added sodium azide (1.16 g, 17.8 mmol) and the contents stirred at room temperature for 2 h. The reaction mixture was treated with saturated aqueous NaHCO3 until neutrality, extracted with ethyl acetate (3×30 mL) and the combined organic phases were dried over MgSO4. After solvent removal the crude residue was silica gel column chromatographed (dichloromethane/ethanol/98/2). 3-Azidoacetyl-pyridine was obtained as yellow solid (2.17 g, 71%).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[C:23]([NH:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)(=[O:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C(=O)C>[C:23]([NH:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:3]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cccc(-c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.10 g were added 3-(acetamido)phenylboronic acid 98 mg, sodium carbonate 72 mg and tetrakis(triphenylphosphine)palladium(0) 3.2 mg, and it was stirred at 110° C. for 4 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=2:1] to give tert-butyl 4-(3-(acetamido)phenyl)-2-(4-fluoroanilino)benzoate.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[N:12][C:13]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[C:45]#[C:46][C:47](OCC)=[O:48]>C1COCC1>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[CH:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[N:12]=1)[C:47](=[O:48])[C:46]#[CH:45]
Reactant: CCOC(=O)C#C[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Cc2c(F)cccc2F)nc1-c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C#CC(=O)C(c1ccc(CO)c(-c2ccc(F)cc2F)n1)c1c(F)cccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-(2,6-difluorobenzyl)-2-(2,4-difluorophenyl)pyridine (from Step D above, 4.63 g) in THF was added lithium bis(trimethylsilyl)amide (22.0 mL, 1.0 M in THF) at −78° C. After stirring ½ h at −78° C., ethyl 3-(trimethylsilyl)prop-2-ynoate (2.2 mL) was added. The mixture was warmed to 0° C. and stirred for a couple of hours until reaction complete. The reaction was quenched with 0.1 N HCl, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue in THF was added TBAF (25 mL, 1N in THF) at 0° C. and stirred for 1 h. The solution was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (100% methylene chloride) to give title compound (1.08 g).
Reaction SMILES: [C:1]([CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=2)[CH2:11][N:10]1CC1C=CC=CC=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.Cl.[Pd]>[CH2:1]([CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=2)[CH2:11][NH:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)C1Cc2cc(F)ccc2CN1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Fc1ccc2c(c1)CC(Cc1ccccc1)NC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.4 %

Procedure:
66 mg of 3-benzoyl-2-benzyl-6-fluoro-1,2,3,4-tetrahydroisoquinoline and 30 mg of 10% Pd—C were dissolved in 2 mL of ethanol and 2 mL of 4N hydrochloric acid, followed by stirring at room temperature for 48 hours under a hydrogen atmosphere. The reaction liquid was filtered through Celite, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified using silica gel chromatography (chloroform:methanol=5:1) to obtain 8 mg (yield 18%) of a title compound as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:38])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:15][C@H:16]([CH2:26][N:27]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)=[O:14])[O:10][C:11]=1[CH3:12].NN>CO>[NH2:27][CH2:26][C@@H:16]([NH:15][C:13]([C:9]1[O:10][C:11]([CH3:12])=[C:7]([C:6]2[N:5]([CH3:38])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:14])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=1
Reactant: Cc1oc(C(=O)N[C@@H](Cc2ccc(F)c(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Agent: NN
Solvent: CO
Product: Cc1oc(C(=O)N[C@H](CN)Cc2ccc(F)c(F)c2)cc1-c1c(Cl)cnn1C
Reaction time: 12 h

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-furancarboxamide (210 mg, 0.39 mmol) in methanol (5 ml) at 25° C. was added hydrazine (0.02 ml, 0.78 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was converted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of the title compound as an off-white solid: LC-MS (ES) m/z 409(M+H)+, 1H NMR (400 MHz, MeOD) δ ppm 2.38 (s, 3H) 2.98 (d, J=9.35 Hz, 1H) 3.01 (d, J=5.56 Hz, 1H) 3.23 (dd, J=13.01, 8.97 Hz, 2H) 3.73-3.83 (m, 3H) 4.56 (d, J=9.35 Hz, 1H) 7.17 (s, 1H) 7.18-7.32 (m, 3H) 7.57 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[CH2:17][C:18]([OH:20])=[O:19].C(N(CC)CC)C.C(OC(=O)C)(=O)C>O>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[C:17](=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: O=Cc1cccnc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1cccnc1)c1ccc(Cl)cc1Cl
Temperature: 150 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of pyridine-3-aldehyde (21.4 g), 2,4-dichlorophenylacetic acid (40.1 g), triethylamine (20 ml) and acetic anhydride (160 ml) was stirred and heated under reflux for 5 hours while maintaining a temperature of 150° C. After cooling, the reaction mixture was diluted with water (150 ml) and left to stand overnight. The crystalline solid that had separated was filtered off, washed thoroughly with water and dried. After recrystallization from ethanol (600 ml) 1 was obtained as pale yellow crystals; melting point 208-211° C.; yield 71%. The following elemental analysis results were obtained:
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=2)[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1)=[O:5])[CH3:3].CN([CH:26]=[O:27])C.C(OC(=O)C)=O.Cl>CCN(CC)CC.O>[CH:26]([NH:1][C@H:2]([C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=2)[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=1)=[O:5])[CH3:3])=[O:27]
Reactant: CN(C)C=O
Reactant: C[C@H](N)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: CC(=O)OC=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H](NC=O)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Temperature: 5 °C

Procedure:
A suspension of 1.0 g (3.3 mM) of 6-[4-(L-alanylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid, Example 4, and 6 ml of DMF was stirred at 5° C. Addition of 1.5 ml of Et3N gave a clear solution. A 3 ml portion of acetic-formic anhydride [Fieser & Fieser "Reagents for Organic Synthesis," Vol. 1, p. 4, 1967] was added and the mixture stirred at 5° C. for 30 minutes. Addition of 0.6 ml Et3N gave a clear solution which was stirred at 5° C. for 40 minutes. Another 2 ml of the anhydride was added and the mixture stirred at room temperature for 2 hours. The reaction mixture was poured into water and the pH adjusted to 8 with Et3N. The pH of the solution was lowered to 3.6 with aqueous HCl and the resulting solids filtered, washed with water and dried, giving 0.86 g of 6-[4-(N-formyl-L-alanylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; [α]D23 -50° (Cl, 75% DMF-pyridine; ##EQU18##
Reaction SMILES: [CH2:1]([CH:8]([C:12](O)=O)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NCC)C.C=O.Cl>O>[CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccccc1)C(=O)O
Agent: C=O
Agent: Cl
Solvent: O
Solvent: CCNCC
Product: C=C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a cooled (0° C.) mixture of benzyl malonic acid (3.37 g, 17.4 mmol) and diethylamine (1.34 g, 18.3 mmol) in water (10 ml) was added formaldehyde (37% solution in water, 2.1 g, 26.1 mmol) with stirring. The reaction was allowed to warm to room temperature and after 2 hours heated to reflux. After 16 hours, the reaction mixture was cooled to room temperature, then made acidic with hydrochloric acid. The mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined and dried over sodium sulfate, then the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography to yield 2.2 g (78%) of white solid. 1H NMR (CDCl3): δ 3.7 (s, 2H), 5.6 (s, 1H) , 6.4 (s, 1H) , 7.1-7.4 (m, 5H)
Reaction SMILES: Cl.CN([CH2:5][CH:6]1[C:11](=[O:12])[CH:10]=[C:9]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[I:21])[CH2:8][CH2:7]1)C.[CH3:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1>CN(C)C=O>[I:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C:9]1[CH2:8][CH2:7][CH:6]([CH2:5][N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH3:22])[C:11](=[O:12])[CH:10]=1
Reactant: Cc1ncc[nH]1
Reactant: CN(C)CC1CCC(NCc2ccccc2I)=CC1=O
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1nccn1CC1CCC(NCc2ccccc2I)=CC1=O
Yield: 43.7 %

Procedure:
A mixture of the product of Stage (ii) (350 mg) and 2-methylimidazole (350 mg) in dry dimethylformamide (25 ml) was heated at 100° under nitrogen for 24 h. The cooled reaction mixture was evaporated in vacuo and purified by flash chromatography (C) to give, as the second eluted major component, the title compound (153 mg) as a gum. T.l.c. (C), Rf 0.35
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][CH:9]([P:20](=[O:29])([O:25][CH2:26][CH:27]=[CH2:28])[O:21][CH2:22][CH:23]=[CH2:24])[P:10](=[O:19])([O:15][CH2:16][CH:17]=[CH2:18])[O:11][CH2:12][CH:13]=[CH2:14])=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-].Cl.C([O-])(O)=O.[Na+]>CO.[Zn].CCOC(C)=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([P:20](=[O:29])([O:25][CH2:26][CH:27]=[CH2:28])[O:21][CH2:22][CH:23]=[CH2:24])[P:10](=[O:19])([O:15][CH2:16][CH:17]=[CH2:18])[O:11][CH2:12][CH:13]=[CH2:14])=[CH:30][CH:31]=1
Reactant: C=CCOP(=O)(OCC=C)C(Cc1ccc([N+](=O)[O-])cc1)P(=O)(OCC=C)OCC=C
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCOP(=O)(OCC=C)C(Cc1ccc(N)cc1)P(=O)(OCC=C)OCC=C
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a solution of nitroarene 26 (460 mg, 0.98 mmol) in MeOH (9 mL) was added saturated aqueous NH4Cl solution (3 mL) and zinc powder (319 mg, 4.88 mmol). 15 drops of aqueous 1N HCl were added and the reaction was stirred at room temperature for 18 h. EtOAc and saturated NaHCO3 aqueous solution were added and the mixture was filtered through celite. The filtrate was transferred into an extraction funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with saturated NaCl solution once, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using a gradient of 0-5% MeOH in CH2Cl2 as eluant to provide aminobenzyl bisphosphonate 27 as a clear yellow oil (374 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 2.69 (tt, J=24.0, 6.1 Hz, 1H), 3.18 (dt, J=16.7, 6.2 Hz, 2H), 4.46-4.60 (m, 8H), 5.19-5.22 (m, 4H), 5.29-5.35 (m, 4H), 5.84-5.94 (m, 4H), 6.60 (d, J=8.6 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([NH:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH:9]=[CH2:10]>C1COCC1>[CH:8]([NH:11][C:12](=[O:24])[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:17][CH:18]=1)=[CH:9][CH3:10]
Reactant: C=CCNC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC=CNC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Yield: 85 %

Procedure:
To a solution of diisopropylamine (6.3 mL, 45 mmol) in THF 100 mL at −78° C., was added n-butyllithilum (18 mL, 45 mmol of a 2.5M solution in hexanes). After 10 min. a solution (10 mL THF) of N-Allyl-4-trifluoromethoxy-benzamide 11 (5 g, 20 mmol) was added dropwise to the reaction mixture. The resulting dark blue reaction mixture was allowed to warm to 0° C. where it was quenched by addition of aqueous ammonium chloride. Ether was added and the organic layer was separated, dried (sodium sulfate), and concentrated. The residue was purified by silica gel chromatography (20% ether/hexanes) to provide the title compound (colorless solid 85%). 1H NMR (400 MHz, CDCl3) δ7.85 (d, J=8.8 Hz, 2 H, Ar), 7.55 (s, 1 H, NH), 7.29 (d, J=9.5 Hz, 2 H, Ar), 6.95 (m, 1 H, NHCHCH), 5.35 & 4.99 (m, 1 H, CHCHCH3), 1.72 (m, 3 H, CH3)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[Br:13].CS(C)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CCCCCC.O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][C:11]([F:17])([F:16])[C:12]([Br:13])([F:15])[F:14])[CH:3]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Oc1cc(F)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCCCCC
Product: Fc1cc(Br)cc(OC(F)(F)C(F)(F)Br)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a flame dried, 1 L, three necked round bottom flask (1 L) equipped with a temperature controller, a mechanical stirrer, a condenser and a N2 inlet was charged 3-bromo-5-fluorophenol (57.3 g, 300 mmol), 1,2-dibromotetrafluoroethane (156.0 g, 600 mmol), dry DMSO (300 mL) and Cs2CO3 (146.6 g, 450 mmol) under N2. The reaction mixture was heated to 50° C. for 5 h. After cooling to rt, water (300 mL) and hexane (300 mL) were added. The resulting mixture was stirred at rt for 30 min. The organic phase was separated and the aqueous layer was extracted with hexane (300 mL). The combined organic extracts were washed with water (500 mL), sat. NaCl (500 mL), dried over MgSO4, filtered and concentrated in vacuo to give 1-bromo-3-(2-bromo-1,1,2,2-tetrafluoroethoxy)-5-fluorobenzene (104.2 g, 94% yield) containing 5% of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (5.2 g). 1-Bromo-3-(2-bromo-1,1,2,2-tetrafluoroethoxy)-5-fluorobenzene: 1H NMR (300 MHz, CDCl3) δ 6.91-6.94 (m, 1H), 7.18-7.23 (m, 2H).
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[C@@H:23]([CH2:24]I)[O:22][C@@H:21]([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][C:36](N=NC(C#N)(C)C)(C#N)[CH3:37]>C1(C)C=CC=CC=1>[Si:1]([O:18][C@@H:19]1[C@@H:23]([CH2:24][CH2:37][CH:36]=[CH2:35])[O:22][C@@H:21]([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn([C@H]2C[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CI)O2)c(=O)[nH]c1=O
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: C=CCC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 65 °C

Procedure:
A stirred solution of 3'-O-(t-butyldiphenylsilyl)-5'-deoxy-5'-iododthymidine (12, 1.77 g, 3 mmol), allytributyltin (2.97 g, 9 mmol) and AIBN (0.54 g, 3.3 mmol) in dry toluene (30 ml) was degassed completely and heated at 65° C. for 6 hr. The solution was cooled and concentrated under vacuo. The residue was purified by silica gel column chromatography and on elution with hexanes:EtOAc (1:1, v/v) furnished the title compound as homogeneous material. Appropriate fractions were pooled and evaporated to furnish 46, 0.75 g of a white foam, 50% yield. The structure was confirmed by 1H NMR.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].C1([PH2](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:31]([CH2:38][C:39](=[O:41])[CH3:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:40][C:39](=[O:41])[CH2:38][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(=O)COc1ccccc1
Agent: c1ccc([PH2](c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(C=CC(=O)COc2ccccc2)ccc1O
Reaction time: 3 h
Yield: 76.5 %

Procedure:
4-Hydroxy-3-methoxybenzaldehyde (2.1 g, 13.8 mMol) and 3-phenoxypropane-2-one triphenylphosphorane (2.8 g, 6.9 mMol) (prepared as described by LeCorre: C. R. Acad. Sci. Paris, 273 81 (1971)) are dissolved in 100 ml of toluene and warmed to reflux. After three hours, the solvent is evaporated and the residue is taken up in tHF. Sodium bisulfite (10.0 g) is dissolved in 100 ml of water and stirred with the solution for one hour. The THF is evaporated and the water is extracted with chloroform. Drying over magnesium sulfate and evaporation of the chloroform gives a yellow oil. Flash chromatography in ethyl acetate on silica gel gives 1.5 g (65%) of 1-(4'-hydroxy,3'-methoxyphenyl)-4-phenoxy-1-butene-3-one; mp=85°-87° C. C, H analysis: Calcd for C17H16O4 (71.81, 5.68); Found (71.85, 5.50).
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.[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH:15]1([CH2:18][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:17][CH2:16]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CC3CC3)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5 mmol), cyclopropylmethyl bromide (60.0 uL, 0.62 mmol, Aldrich, Cat. No. 242403), and cesium carbonate (500.0 mg, 1.5 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 120 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.Cl[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[C:20]([NH:19][CH2:18][C@@H:16]1[O:15][C:14](=[O:23])[N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:1]34[CH2:6][CH:5]3[CH2:4][N:3]([C:32]([O:34][CH3:35])=[O:33])[CH2:2]4)=[CH:12][CH:11]=2)[CH2:17]1)(=[O:22])[CH3:21]
Reactant: COC(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CC2CC2(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)C1
Temperature: 0 °C
Yield: 75.2 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (200 mg, 0.57 mmol) in DCM (25 mL), was added triethyl amine (0.3 mL, 2.27 mmol). The resulting solution was cooled to 0° C. and methyl chloroformate (0.07 mL, 0.86 mmol) was added dropwise. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with DCM (100 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.2:9.8 MeOH:CHCl3) to provide the title compound (160 mg, 74%) as white solid.