Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.O(P(O[C:27]1[C@H:28]([CH3:44])[C@H:29]2[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]2[C:31]=1[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:45]([O:48][C:49]([N:51]1[CH2:55][C@@H:54]([SH:56])[CH2:53][C@H:52]1[CH2:57][CH:58]1[CH2:62][CH2:61][NH:60][C:59]1=[O:63])=[O:50])[CH:46]=[CH2:47].C(OCC)(=O)C>C(#N)C>[CH2:45]([O:48][C:49]([N:51]1[CH2:55][C@@H:54]([S:56][C:27]2[C@H:28]([CH3:44])[C@@H:29]3[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]3[C:31]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:53][C@H:52]1[CH2:57][CH:58]1[CH2:62][CH2:61][NH:60][C:59]1=[O:63])=[O:50])[CH:46]=[CH2:47]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CC1CCNC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3CCNC3=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 5 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
N,N-diisopropylethylamine (0.26 ml, 1.52 mmol) was dropwise added to a solution of allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (759 mg, 1.52 mmol) and (2R,4S)-N-allyloxycarbonyl-4-mercapto-2-(2-pyrrolidon-3-ylmethyl)pyrrolidine (432 mg, 1.52 mmol) in acetonitrile (11 ml) at -40° C. The reaction solution mixture was stirred at the same temperature for 3 hours and further at 5° C. for 16 hours. Ethyl acetate (60 ml) was added to the reaction solution. This solution mixture was washed sequentially with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (Wakogel™ C-300, 40 ml, acetone-ethyl acetate 2:3), and the fraction containing the desired product was concentrated to obtain allyl (1R,5S,6S)-2-[(2R, 4S)-N-allyloxycarbonyl-2-(2-pyrrolidon-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (420 mg, yield: 51.8%) in the form of foam.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:16]=3)=[C:9]([F:29])[CH:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:40]1[CH2:44]O[CH2:42][CH2:41]1.BrCCC=C>CN(C=O)C>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:42][CH2:41][CH:40]=[CH2:44])[N:16]=3)=[C:9]([F:29])[CH:8]=1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(Cc3ccccc3)nc2s1
Reactant: C1CCOC1
Agent: C=CCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCCC(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Reaction time: 0.21 h

Procedure:
Argon was bubbled through a slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-benzylthiazolo[5,4-b]pyridine (1.00 g, 2.46 mmol) in 20 mL DMF for 5 min. To the rapidly stirring reaction mixture was added LiHMDS 1.0M in THF (2.71 mL, 2.71 mmol) rapidly dropwise. The resulting deep blue reaction mixture was stirred for 2 min, at which point 4-bromo-1-butene (0.499 mL, 4.92 mmol) was added rapidly via syringe. The color of the reaction slowly became purple over 5 min, then brown over about 10-15 min additional. After 1.5 h, the reaction mixture was quenched with sat'd aq. NH4Cl and MTBE. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylpent-4-enyl)thiazolo[5,4-b]pyridine as an orange solid MS (ESI) m/z: Calculated: 460.2; Observed: 461.1 (M++1).
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].[CH3:10][NH2:11].Cl.[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22]Cl)=[CH:19][CH:18]=1)[CH3:15].[OH-].[Na+]>O.C(O)(C)C>[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:6][CH2:7][CH2:8][NH:9][C:5]([NH:11][CH3:10])=[CH:4][N+:1]([O-:3])=[O:2])=[CH:19][CH:18]=1)[CH3:15]
Reactant: O=[N+]([O-])C=C1NCCS1
Reactant: CN(C)Cc1ccc(CCl)o1
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
Combine 2-nitromethylene-thiazolidine (10.0 g) and isopropanol (40 mL). Add methylamine (14.7 g). Heat to 40° C. After 5 minutes, add 5-[(dimethylamino)methyl]-2-(chloromethyl)-furan hydrochloride (13.05 g) portionwise over 1.5 hours. After 3 hours, cool to ambient temperature. Add aqueous sodium hydroxide solution (11.6 g, 50% by weight) and water (20 g). Extract repeatedly with methyl isobutyl ketone. Combine the organic layers and evaporate in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:17][C:14]1([F:18])[CH2:15][CH2:16][C:7]2([CH2:6][C:5]3[C:9](=[CH:10][C:2]([C:25]4[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=4)[C:19]#[N:20])=[CH:3][CH:4]=3)[C:8]2=[O:11])[CH2:12][CH2:13]1
Reactant: O=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCC(F)(F)CC2)C3)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
In a 20 mL vial was placed 6′-bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-one (35 mg, 0.111 mmol), 3-cyanobenzeneboronic acid (23 mg, 0.157 mmol), PdCl2(PPh3)2 (8 mg, 0.011 mmol) and cesium carbonate (91 mg, 0.279 mmol). This solid mixture was dissolved in a Dioxane/water mixture (1.1 mL, 6:1 ratio, respectively). The reaction vial was capped and allowed to stir at 90° C. for 1 hour. At this time, the mixture was filtered through a Celite plug. The plug was rinsed with dichloromethane (5 mL) and water (5 mL). The phases in the filtrate were separated. The aqueous phase was back-extracted with dichloromethane twice (3 mL/each). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 3-(4,4-difluoro-1′-oxo-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-6′-yl)benzonitrile (30 mg, 0.089 mmol, 80% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH:7]=[C:8]1[C:20](=[O:21])[N:12]2[C:13]3[C:18]([CH:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[CH:15][CH:14]=3.C([O-])=O.[NH4+].C(O)C.O1CCCC1>[Pd].O>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH:8]1[C:20](=[O:21])[N:12]2[C:13]3[C:18]([CH:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: Cc1[nH]cnc1C=C1CCc2cc3ccccc3n2C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1[nH]cnc1CC1CCc2cc3ccccc3n2C1=O
Temperature: 60 °C
Yield: 89.7 %

Procedure:
To a mixture of 8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (10.9 g), ammonium formate (17.2 g), ethanol (130 ml), and tetrahydrofuran (110 ml) was added a suspension of 10% palladium on carbon (3.3 g) in water (30 ml). The mixture was heated at 60° C. for 2 hours and then cooled. After filtration of the catalyst, the filtrate was evaporated in vacuo. The residue was dissolved in 10% methanol-chloroform. The organic layer was washed successively with aqueous sodium bicarbonate solution, water, and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The crystalline residue was recrystallized from chloroform-hexane to give 8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (9.85 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].CN(C)P(=O)(N(C)C)N(C)C.[H-].[Na+].[CH2:35]([N:37]([CH2:42][CH3:43])[C:38](=[O:41])[CH2:39]Cl)[CH3:36]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:39][C:38](=[O:41])[N:37]([CH2:42][CH3:43])[CH2:35][CH3:36])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCO
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CC(=O)N(CC)CC
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A solution of 15.0 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 250 ml. of hexamethylphosphoric acid triamide is treated under nitrogen at 5° C. with 0.055 mol of sodium hydride (2.5 g. of a 55% dispersion in mineral oil) and then stirred at the same temperature for 15 minutes. At 5°-10° C. a solution of 15 g. of N,N-diethylchloroacetamide in 40 ml. of ethanol is added thereto and the mixture stirred for 30 minutes at room temperature and subsequently heated for 4 hours at 80° C. The mixture is cooled and poured into 2.5 liters of ice-water. After the addition of 150 g. of sodium chloride, the separated product is removed by filtration under suction, washed with water and then dissolved in methylene chloride. The aqueous layer is separated, the organic phase dried over sodium sulfate, filtered and evaporated to dryness. The residue is triturated with 100 ml. of ether, the unreacted starting material crystallizes out. The latter is removed by filtration under vacuum and washed with ether. The ethereal filtrate is evaporated to dryness. The oily residue is cooled and triturated with ether, crystals being obtained. Recrystallization from ethanol yields 5-chloro-2-[(diethylcarbamoyl)methyl]-3-phenylisoindole-1-carboxylic acid ethyl ester; melting point 118°-120° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([SH:11])[CH:5]=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[CH3:1][C:2]1[C:7]2[C:8](=[O:10])[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[S:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(S)c1C(=O)O
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: Cc1cccc2sc(-c3ccccn3)nc(=O)c12
Temperature: 135 °C
Yield: 19.9 %

Procedure:
A mixture of 6-methyl-2-mercaptobenzoic acid (1.70 g, 10.1 mmol), 2-cyanopyridine (1.06 g, 10.2 mmol) and pyridine (30.0 ml) was refluxed at 135° C. for 18 hrs as described in Example 9. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography and eluted with ethyl acetate. The resultant product was recrystallized from ethanol to give the titled compound (0.51 g, 20%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][O:13][C:14]3[CH:19]=[C:18]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[C:16]([F:28])[CH:15]=3)[CH:8]=2)[N:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C.CCOC(C)=O.O>[F:28][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([C:20]2([O:26][CH3:27])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[CH:17]=1)[O:13][CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]1[N:29]=[N:30][N:31]=[C:2]1[CH:11]=[CH:10]2
Reactant: [N-]=[N+]=[N-]
Reactant: COC1(c2cc(F)cc(OCc3ccc4nc(Cl)ccc4c3)c2)CCOCC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC1(c2cc(F)cc(OCc3ccc4c(ccc5nnnn54)c3)c2)CCOCC1
Temperature: 130 °C

Procedure:
To 9b (29 mg, 0.07 mmol) in DMF (1 mL) was added sodium azide (9 mg, 0.09 mmol). The reaction was heated at 130° C. overnight, then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (50% EtOAc in hexanes) to give the desired product, 9c.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:13]([F:12])=[CH:14][CH:15]=3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1ccc(F)cc1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(F)cc1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 4-fluorobenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.91-2.04 (m, 4H), 2.12 (s, 1H), 2.31 (d, J=14 Hz, 2H), 2.38 (s, 1H), 3.49 (s, 1H), 3.59 (s, 3H), 3.73 (s, 1H), 3.77-3.89 (m, 1H), 4.38 (s, 1H), 7.20 (t, J=9 Hz, 2H), 7.90 (dd, J=9, 5 Hz, 2H); MS (APCI/NH3) m/z 275 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[CH:5]=2)[CH2:3][CH2:2]1.[I:15]I.S(=O)(=O)(O)O.O>CC(O)=O>[CH:1]1([C:4]2[C:13]([I:15])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(C2CC2)cc1C
Reactant: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(I)c(C2CC2)cc1C
Temperature: 110 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a solution of methyl 4-cyclopropyl-2-methylbenzoate (compound 86.1, 2.68 g, 13.4 mmol, 95%) in AcOH (50 mL) were added NaIO4 (1.51 g, 7.08 mmol), iodine (3.58 g, 14.1 mmol), and sulfuric acid (106 μL, 2.0 mmol, 0.15 equiv). The reaction mixture was stirred overnight at 110° C. After cooling to ambient temperature, water (100 mL) was slowly added and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with Na2S2O3 (aq., sat., 3×30 mL) and brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/50) as the eluent to yield 2.0 g (45%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.O1CCCC1.C1(C)C=CC=CC=1.C[O:22][C:23](=O)[CH:24](NC)[NH:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].[Cl-].[NH4+]>O1CCCC1.O>[Br:1][C:2]1[C:3]([C:23](=[O:22])[CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:34])([F:36])[F:35])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CNC(NC(=O)c1ccccc1C(F)(F)F)C(=O)OC
Reactant: Brc1cncc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC(=O)c1ncc(Br)cc1Br)c1ccccc1C(F)(F)F
Temperature: -20 °C
Yield: 13.7 %

Procedure:
To 5.5 g of 3,5-dibromopyridine in 1 ml of tetrahydrofuran, 22.7 ml of a 1.0M tetrahydrofuran-toluene solution of 2,2,6,6-tetramethylpiperidinylmagnesium chloride-lithium chloride complex was added dropwise with stirring at −20° C., and after the addition, the mixture was stirred at the same temperature for 30 minutes. Then, to the reaction mixture, 3.0 g of the N-[2-methoxy(methyl)amino-2-oxoethyl]-2-(trifluoromethyl)benzamide prepared in Step 1 in Synthetic Example 17 in 17 ml of tetrahydrofuran was added dropwise, and after the addition, the mixture was stirred at the same temperature for another 1 hour. After completion of the reaction, the reaction mixture was mixed with 30 ml of saturated aqueous ammonium chloride and 20 ml of water and extracted with ethyl acetate (50 ml×2), the resulting organic layers were combined, washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 659 mg of the desired product as a pale yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH2:6].[CH3:18][S:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH:6][C:29]([C:24]1([CH2:23][CH2:22][CH2:21][CH2:20][S:19][CH3:18])[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:30]
Reactant: CSCCCCC1(C(=O)O)CCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(CCCCSC)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.1 %

Procedure:
To a suspension of 4-nitro-L-phenylalanine methyl ester hydrochloride salt (181.84 mmol, 47.41 g), 1-[4-(methylthio)butyl]cyclopentanecarboxylic acid (177.17 mmol, 38.33 g) in DMF (470 mL) were added HBTU (177.17 mmol, 67.2 g) and diisopropylethylamine (443 mmol, 77 mL) at room temperature. The clear solution was stirred for 15 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting materials. The reaction mixture was diluted with 600 mL of ethyl acetate then was washed in turn with 0.5N hydrochloric acid (2×250 mL), saturated sodium bicarbonate solution (2×250 mL) and brine (300 mL). The dried (MgSO4) organic layer was filtered and evaporated to dryness under reduced pressure. The crude product which was purified by silica gel column chromatography to afford 58.5 g (78%) of N-[[1-[4-(methylthio)butyl]cyclopentyl]carbonyl]-4-nitro-L-phenylalanine methyl ester as an amorphous colorless solid. HRMS: Obs. mass, 423.1940. Calcd. mass, 423.1953 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17](OCC)OCC)=[CH:13][CH:12]=2)([OH:10])[CH2:7]1)=[O:5])[CH3:2].[OH2:24].C([O-])(=O)C.[Na+].Cl.[NH2:31]O>CCO>[CH2:1]([O:3][C:4]([CH:6]1[CH2:9][C:8]([OH:10])([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[N:31][OH:24])=[CH:13][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC(O)(c2ccc(C(OCC)OCC)cc2)C1
Reactant: NO
Reactant: O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CC(O)(c2ccc(C=NO)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a solution of 3-(4-Diethoxymethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid ethyl ester (Preparation 1, 7 g, 21.73 mmol) in EtOH:H2O (80 mL, 1:1) was added sodium acetate (3.2 g, 39.31 mmol) followed by hydroxylamine hydrochloride (2.24 g, 32.60 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 16 hours. After consumption of starting material, reaction mixture was concentrated in vacuo and diluted with water (70 mL). Aqueous layer was extracted with EtOAc (3×70 mL). Combined organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to afford crude residue. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 40% ethyl acetate in hexane to afford yellowish oil (4.7 g, 87%). 1H NMR and LC-MS was consistent. 1H NMR (400 MHz, DMSO-d6) δ: 1.19 (t, J=7.16 Hz, 3H), 2.60-2.65 (m, 2H), 2.78-2.82 (m, 1H), 4.07 (q, J=7.1 Hz, 2H), 7.50-7.50 (m, 4H), 8.12 (s, 1H), 11.18 (s, 1H). LCMS (m/z): 246.10 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=[O:4].O.[C:16](Cl)(=[O:18])[CH3:17].Cl>[OH-].[Na+].CCOCC.C(OCC)(=O)C>[C:16]([NH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=[O:4])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: NC(C(=O)O)c1ccc2c(c1)CCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)NC(C(=O)O)c1ccc2c(c1)CCO2
Reaction time: 0.33 h

Procedure:
α-Amino(2,3-dihydro-5-benzofuranyl)acetic acid (10 mmole) is dissolved in 25 ml of water containing 20 mmole of sodium hydroxide. The temperature is maintained at 10° C. while 10.5 mmole of acetyl chloride in 10 ml of ether is added over a period of 10 minutes. The reaction mixture is stirred for 20 minutes. Ethyl acetate is added and the pH is adjusted to 2 with hydrochloric acid. The layers are separated, the organic layer is dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([O:10]C(=O)C)[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([CH2:38][NH:39][S:40]([CH2:43][CH:44]([CH3:46])[CH3:45])(=[O:42])=[O:41])=[N:18][C:19]=3[NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:7][C@@H:6]1[CH2:47][O:48]C(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[NH3:14].[OH:10][C@@H:9]1[C@H:5]([OH:4])[C@@H:6]([CH2:47][OH:48])[O:7][C@H:8]1[N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][C:17]([CH2:38][NH:39][S:40]([CH2:43][CH:44]([CH3:46])[CH3:45])(=[O:41])=[O:42])=[N:18][C:19]=2[NH:23][CH2:24][CH:25]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)CC(C)C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Product: N
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.3 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy) methyl]-5-(6-[(2,2-diphenylethyl)amino]-2-{[(isobutylsulfonyl)amino]methyl}-9H-purin-9-yl)tetrahydro-3-furanyl acetate (188 mg, 0.26 mmol) (Preparation 9) and sodium carbonate (140 mg, 1.32 mmol) in a mixture of water (2 ml) and methanol (10 ml) was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic phase was separated and the solvent removed under reduced pressure. The residue was then purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:0.88 ammonia (95:5:0.5 by volume) gradually changing to dichloromethane:methanol:0.88 ammonia (90:10:1 by volume) to afford the title compound (77 mg).