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2H), 1.86 (d, J = 2.5 Hz, 3H), 1.80 (s, 3H), 1.44-1.31 (m, 8H), 1.31 (m, 9H), 0.89 (t, J = 6.7 Hz, 3H); 13 C NMR (75 MHz, CDCl3): δ 205.3, 170.9, 155.3, 137.8, 131.3, 127.9, 126.4, 100.8, 94.4, 80.8, 78.2, 70.6, 51.8, 40.1, 36.3, 29.2, 29.0, 28.1, 22.7, 17.3, 14.2, 3.7; IR (thin film): ν 2926, 1957, 1742, 1698, 1165 cm -1 ; MS m/z (%) 468 (28), 320 (50), 276 (63), 91 (56), 57 (100); EI- HRMS calcd for C29H42NO4 m/z [M+1] + 468.3114; found 468.3082. BzN MeO 2C Bn 74a 2-(Benzoylbut-2-ynylamino)-2-benzylpenta-3,4-dienoic acid methyl ester (74a). Prepared by following general procedure F, using: 58b (450 mg, 1.40 mmol), NaH (123 mg of a 60% dispersion in mineral oil, 3.08 mmol), 1-bromo-2-butyne (183 µL, 2.10 mmol). Purification by flash chromatography (hexanes-EtOAc, 9 : 1, v/v) afforded 74a (438 mg, 84%). 1 H NMR (300 MHz, CDCl3): δ 7.68-7.65 (m, 2H), 7.46-7.41 (m, 3H), 7.32-7.22 (m, 5H), 5.97 (t, J = 6.6 Hz, 1H), 5.10 (dd, J = 9.3, 6.6 Hz, 1H), 5.05 (dd, J = 9.3, 6.6 Hz, 1H), 3.98 (d, J = 13.6 Hz, 1H), 3.76 (s, 3H), 3.73 (dq, J = 18.6, 2.3 Hz, 1H), 3.55 (dq, J = 18.6, 2.3 Hz, 1H), 3.43 (d, J = 13.6 Hz, 1H), 1.69 (t, J = 2.3 Hz, 3H); 13 C NMR (75MHz, CDCl3): δ 207.6, 172.4, 171.3, 136.2, 135.9, 131.1, 130.3, 128.2, 128.2, 127.9, 127.3, 126.8, 90.8, 80.4, 79.2, 75.9, 68.7, 52.2, 39.4, 39.0, 3.5; IR (thin film): ν 2949, 2228, 1958, 1744, 1641 cm -1 ; MS m/z (%) 372 (45), 342 (10), 282 (31), 105 (100); EI-HRMS calcd for C24H22NO3 m/z [M-1] + 372.1600, found 372.1618. BzN MeO 2C Bn 74b 2-(Benzoylprop-2-ynylamino)-2-benzylhexa-3,4-dienoic acid methyl ester (74b). Prepared by following general procedure F, using: 58b (495 mg, 1.54 mmol), NaH (154 mg of a 60% 176 • • H H H H
dispersion in mineral oil, 3.85 mmol), propargyl bromide (80% wt. in toluene) (257 µL, 2.31 mmol). Purification by flash chromatography (gradient elution; hexanes-EtOAc, 9 : 1 to 4 : 1, v/v) afforded 74b (364 mg, 66%). 1 H NMR (300 MHz, CDCl3): δ 7.66-7.64 (m, 2H), 7.46-7.40 (m, 3H), 7.27-7.24 (m, 5H), 5.94 (t, J = 6.6 Hz, 1H), 5.10 (app dd, J = 6.6, 2.9 Hz, 2H), 3.96 (d, J = 13.6 Hz, 1H), 3.76 (s, 3H), 3.73 (dd, J = 18.8, 1.8 Hz, 1H), 3.51 (dd, J = 18.8, 1.9 Hz, 1H), 3.45 (d, J = 13.7 Hz, 1H), 2.18 (s, 1H); 13 C NMR (75MHz, CDCl3): δ 207.7, 172.4, 171.1, 135.9, 135.5, 130.9, 130.4, 128.3, 128.1, 127.1, 126.9, 90.5, 80.5, 79.6, 72.8, 68.5, 52.3, 38.8, 38.6; IR (thin film): ν 3302, 2950, 2115, 1957, 1742, 1640, 1433, 1398, 1266, 1246 cm -1 ; MS m/z (%) 358 (35), 268 (42), 105 (100); EI HRMS calcd for C23H20NO3 m/z [M] + 358.1443, found 358.1451. BzN MeO 2C Me 74c 2-(Benzoylbut-2-ynylamino)-2-methylpenta-3,4-dienoic acid methyl ester (74c). Prepared by following general procedure F, using: 58c (200 mg, 0.816 mmol), NaH (65 mg of a 60% dispersion in mineral oil, 1.6 mmol), 1-bromo-2-butyne (142 µL,1.6 mmol). Purification by flash chromatography (gradient elution; hexanes-EtOAc, 9 : 1 to 4 : 1, v/v) afforded 74c (226 mg, 93%). 1 H NMR (300 MHz, CDCl3): δ 7.60-7.57 (m, 2H), 7.40-7.34 (m, 3H), 5.79 (t, J = 6.6 Hz, 1H), 4.95 (d, J = 6.6 Hz, 1H), 3.96 (q, J = 2.2 Hz, 2H), 3.71 (s, 3H), 1.82 (t, J = 2.2 Hz, 3H), 1.72 (s, 3H); 13 C NMR (75MHz, CDCl3): δ 208.2, 172.2, 171.8, 135.5, 130.2, 128.1, 128.1, 127.0, 92.5, 80.3, 78.9, 75.8, 63.4, 52.4, 43.0, 37.3, 20.5, 3.4; IR (thin film): ν 2949, 1957, 1742, 1637, 1398, 1264 cm -1 ; MS m/z (%) 297 (19), 258 (20), 238 (52), 105 (100); EI HRMS calcd for C18H19NO3 m/z [M] + 297.1365, found 297.1359. 177 • H H
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TRANSITION METAL-CATALYZED REACTION
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Transition Metal-Catalyzed Reaction
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List of Abbreviations Ac acetyl AcO
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Table of Contents 1.0 Introduction.
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Appendix A : X-ray crystal structur
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Table 4.8 Rh(I)-catalyzed cyclocarb
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List of Schemes Scheme 1.1 Three fo
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Scheme 3.24 Preparation of amide-te
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Scheme 4.16 Formation of bicyclo[5.
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1.0 Introduction 1.1 The Role of Di
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According to these guidelines, the
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Scheme 1.1 Three forms of diversity
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Another example from the Schreiber
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1.1.1 Transition Metal-Catalyzed Re
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37, , such reactions include transi
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the proximal olefin of allenyne 38
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2.0 Design and Synthesis of the Piv
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The allenic amino acid derivatives
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This protocol proved particularly u
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ZnCl2, which results in a Zn-chelat
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Scheme 2.7 Synthesis of trisubstitu
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THF), the yield was increased from
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the terminus of the alkyne led to d
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N-Alkylation of the glycine-derived
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circumvent this issue, variants suc
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BINAP as a chiral ligand to obtain
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stereochemistry of the exocyclic ol
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3.2 Rhodium(I)-Catalyzed Allenic Cy
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exocyclic olefin geometry is not re
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3.2.1 Preparation of Enol-ether Tri
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Scheme 3.15 Synthesis of cycloisome
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Scheme 3.17 Cycloisomerization of a
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Scheme 3.19 Tandem cycloadditions o
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Scheme 3.21 Intermolecular Diels-Al
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attractive, since additional functi
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increased yield of the triene (47%)
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as an isobutyl-amide 155b was prepa
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group) demonstrated that this cyclo
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in 1M HCl/dioxane (1 : 1) for 1h, t
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ppm (dd, J = 7.1, 4.6 Hz, 1H) assig
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http://ccc.chem.pitt.edu/). Using f
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Notably, exclusive cycloisomerizati
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intermediate in the reaction we sou
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epulsive dipole interactions (Schem
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Table 3.4 Diels-Alder reactions of
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allenic Alder-ene reaction, ene-all
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Figure 3.4 Examples of natural prod
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species onto the proximal double bo
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Scheme 3.49 Rh(I)-catalyzed ene rea
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y Magnus 144 and it involves the in
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usually is DMSO. Heating to 100 ºC
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that require high pressures of CO.
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In contrast to the Mo(CO)6-mediated
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Scheme 4.15 Rh(I)-catalyzed allenic
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4.2 Rhodium(I)-Catalyzed Cyclocarbo
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lack of double bond selectivity, si
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Table 4.2 Cyclocarbonylation reacti
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Notably, the allenic cyclocarbonyla
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Scheme 4.22 Cyclocarbonylation reac
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neat or in solution. This decomposi
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the newly synthesized fulvenes (e.g
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stereocenters and mixture of E/Z is
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proximal double bond to give α-alk
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the methyl ester and Ha are syn. Sc
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that the major diastereomer in the
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We were motivated to first examine
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Scheme 4.42 Synthesis of pyrrole 29
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periodic acid (H5IO6). 209 These hi
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eaction failed to go to completion,
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4.5.2 Synthesis of a Library of Tri
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diketones 312{1-3,1-2} in yields ra
Page 143 and 144: Figure 4.2 Distribution for physico
Page 145 and 146: tricyclic pyrrole 314{3,2,26} (Figu
Page 147 and 148: 4.6 Synthesis of α-Alkylidene Cycl
Page 149 and 150: anched and linear carboxylic acid i
Page 151 and 152: eactivity of the species prepared i
Page 153 and 154: considerably lower than the ratio o
Page 155 and 156: diastereomer. Next, allenyne 328 wa
Page 157 and 158: Conclusions In summary, we have dem
Page 159 and 160: Experimental Section General Method
Page 161 and 162: General procedure A for esterificat
Page 163 and 164: F Bz N H 56f 2-Benzoylamino-3-(4-fl
Page 165 and 166: MeO2C Bz N H 58c 2-Benzoylamino-2-m
Page 167 and 168: MeO MeO2C Bz N H 58e 2-Benzoylamino
Page 169 and 170: mL) and MeOH (10 mL) instead of sat
Page 171 and 172: hexanes-EtOAc, 19 : 1 to 4 : 1, v/v
Page 173 and 174: which was immediately used in the C
Page 175 and 176: Boc TMS N H Bn 64f tert-Butyl-1-((4
Page 177 and 178: MeI (38 µL, 0.62 mmol). Yield 65a
Page 179 and 180: with brine and concentrated under v
Page 181 and 182: H MeO 2C • H Bn NHBoc tert-Butyl-
Page 183 and 184: TMS MeO 2C • 70 H H NHBoc 2-tert-
Page 185 and 186: 185 (10), 141 (21), 57 (100); EI-HR
Page 187 and 188: dispersion in mineral oil, 1.0 mmol
Page 189 and 190: EI-HRMS calcd for C30H26NO3 m/z [M-
Page 191 and 192: CbzN MeO 2C Me 73h 2-[Benzyloxycarb
Page 193: CbzN MeO 2C Me 2-(Benzyloxycarbonyl
Page 197 and 198: completion of the addition, the rea
Page 199 and 200: BzN MeO 2C S 74h 2-(Benzoylprop-2-y
Page 201 and 202: BzN MeO 2C Bn 75b 2-(Allylbenzoylam
Page 203 and 204: BzN MeO 2C TBSO 75e 2-(Benzoylbut-2
Page 205 and 206: Hz, 1H), 5.85 (s, 1H), 5.52 (dd, J
Page 207 and 208: 1H), 3.69 (s, 3H), 1.58 (d, J = 7.1
Page 209 and 210: µmol), [Rh(CO)2Cl]2 (1 mg, 3 µmol
Page 211 and 212: 1.25 (m, 6H), 0.88 (t, J = 6.9 Hz,
Page 213 and 214: 6.72 (d, J = 7.6 Hz, 0.5H), 6.68 (d
Page 215 and 216: BzN MeO2C Bn 122a Methyl-2-(N-(but-
Page 217 and 218: Bz N MeO2C Bn 1-Benzoyl-2-benzyl-4-
Page 219 and 220: 13.9, 5.3 Hz, 1H), 2.51-2.47 (m, 1H
Page 221 and 222: 15 min the solvent was removed unde
Page 223 and 224: Benzoyl chloride (0.169 mL, 1.46 mm
Page 225 and 226: mg, 0.11 mmol), [Rh(CO)2Cl]2 (4 mg,
Page 227 and 228: mL). kk The aqueous layer was extra
Page 229 and 230: ºC. After quenching the reaction b
Page 231 and 232: 129.8, 129.0, 128.7, 128.4, 126.2,
Page 233 and 234: MeO 2C O O O N H N R 1 O N Ph [10c-
Page 235 and 236: The crude residue was purified by f
Page 237 and 238: 14.4 Hz, 1H), 3.49-3.39 (m, 2H), 3.
Page 239 and 240: 1H), 5.49 (dd, J = 17.3, 1.8 Hz, 1H
Page 241 and 242: was stirred at rt for 1 h when it w
Page 243 and 244: BzN HOOC 2-(N-(but-2-ynyl)benzamido
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°C and DIBAL-H (0.440 mL of a 1.0M
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129 (62), 91 (100); EI-HRMS calcula
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(d, J = 18.0 Hz, 1H), 4.14 (d, J =
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4.98 (dt, J = 7.7, 5.1 Hz, 1H), 4.1
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N Bz MeO2C OTBS 214 1-Benzoyl-2-(te
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270a (major diastereomer-eluting fi
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CDCl3): δ 7.42-7.17 (m, 13H), 7.04
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18.6 Hz, 1H), 4.34 (d, J = 18.0 Hz,
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Bz N MeO2C 2-Benzoyl-3,7-dimethyl-6
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v/v) afforded a mixture of compound
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(435 mg, 1.21 mmol), DMSO (429 µL,
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4.02 (s, 1H), 3.88 (s, 3H), 1.82 (s
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(207 mg, 96%) consisting of 287e (7
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procedure O, using: 74f (110 mg, 0.
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Bz N O H CO2Me BocN 287i 3-(2-Benzo
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4.17 (d, J = 15.0 Hz, 1H), 4.10 (d,
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137.1, 136.9, 130.4, 129.8, 128.5,
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H BzN MeO2C Bn H N C3H7 298b CO 2Me
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NMR (75 MHz, CDCl3): δ 172.3, 169.
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following the general procedure Q,
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H BzN MeO2C Bn H 5-Benzoyl-1,4-dibe
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119.9, 114.1, 109.9, 108.6, 73.0, 5
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4.11 (m, 1H), 4.07-3.98 (m, 1H), 3.
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126.8, 126.2, 109.0, 72.9, 58.7, 56
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NMR (75 MHz, CDCl3): δ 172.2, 169.
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3.0 Hz, 1H), 5.82-5.80 (m, 1H), 5.2
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87%). The diastereomeric ratio (288
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APPENDIX A: X-ray crystal structure
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APPENDIX B: X-ray crystal structure
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APPENDIX C: X-ray crystal structure
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APPENDIX D: X-ray crystal structure
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APPENDIX E: X-ray crystal structure
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APPENDIX F: QikProp property predic
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1 H and 13 C NMRs of 74b 293
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1 H and 13 C NMRs of 111a 295
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Page 317 and 318:
Page 319 and 320:
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1 H and 13 C NMRs of 270h 303
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Page 325 and 326:
1 H and 13 C NMRs of 307 307
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1 H and 13 C NMRs of 308n 309
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10. (a) Burke, M. D.; Schreiber, S.
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Hu, Y. J. Comb. Chem. 2006, 8, 286.
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49. For reviews on reactions of all
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69. (a) Trost, B. M.; Lautens, M.;
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containing cross-conjugated trienes
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Vaillancourt, J.; Rasper, D. M.; Ta
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130. Oppolzer, W.; Snieckus, V. Ang
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149. (a) Hicks, F. A.; Buchwald, S.
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Maiese, W. M. J. Antibiot. 2000, 53
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192. The mechanism of decomposition
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Boger, D. L.; Boyce, C. W.; Labroli
Page 351:
Generated Inhibitors of Human Mitog
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