Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@@H]1C(=O)N2C(C(OC(C3C=CC=CC=3)C3C=CC=CC=3)=[O:12])=C(C=C)CS[C@H]12.[CH:29]1([N:35]=[C:36]=[N:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.CN(C)C=O>[C:36]([NH:35][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)([NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:12]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
A solution of diphenylmethyl 7βamino-3-vinylceph-3-em-4-carboxylate (1.57 g., 4 mmole) in methylene dichloride (25 ml.) with dicyclohexylcarbodiimide (907 mg., 4.4 mmole) was treated slowly (over 10 minutes) with a solution of D-2-t-butoxycarbonylamino-2-phenylacetic acid (1.1 g., 4.4 mmole) in N,N-dimethylformamide (10 ml.). The mixture was stirred at 23° for 30 minutes and dicyclohexylurea removed by filtration. The filtrate was washed with water and dried and evaporated in vacuo to give a pale yellow solid. This material was crystallised from methanol, and the isolated material washed with ether, to give the crude title cpompound (2.2 g.) (contaminated with dicyclohexylurea). The crude compound in benzene :ethyl acetate (2:5) was filtered through a short column of Kieselgel 0.02 - 0.5 mm., 10 cm. × 2.5 cm.). Evaporation of the solvent in vacuo and washing the crystalline residue with ether gave the pure title compound (1.6 g., 64%) as small needles m.p. 200°-202°, [α]D - 129° (CHCl3), λmax 294.5 nm. (ε 14,400), νmax. 3395 (NH), 1780 (β-lactam), 1712 (CO2R), 1690 and 1500 (CONH) and 912 cm.-1 (CH=CH2),τ(CDCl3) 3.05 (CHPh2),3.03 (CH=CH2, dd, J 17 and 11 Hz). 3.08 (NH, d, J 9 Hz) 4.23 (C(7) -H, dd, J 9 and 4.5 Hz), 4.28 (CH-NH, d, J 7 Hz), 4.65 and 4.79 (CH=CH2, two d, J 17 and 11 Hz resp.), 4.77 (CH-NH, d, J 7 Hz), 5.10 (C(6) -H, d, J 4.5 Hz), 6.46 and 6.70 (C(2) -CH, AB-q, J 18 Hz) 8.58 (C[CH3 ]3). (Found: C, 66.6; H, 5.6; N, 6.4; S, 5.1. C35H35N3O6S requires C, 67.2; H, 5.65; N, 6.7; S, 5.1%).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].N(OCCC(C)C)=O>O1CCCC1>[F:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[CH:2]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:4]=[N:5]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1N
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1
Yield: 73.7 %

Procedure:
A stirred suspension of ethyl 5-amino-1-(4-fluoro-phenyl)-1H-pyrazole-4-carboxylate (7.48 g, 30.0 mmole), prepared as described in Preparation A, above, and isopentyl nitrite (7.03 g, 60.0 mmole) in 80 ml of tetrahydrofuran was refluxed for twenty-four hours and then evaporated in vacuo. The residue was triturated with 50 ml of methanol and filtered to furnish 5.18 g (74% yield) of off-white solid. The sample was recrystallized from ethanol, m.p. 119-21° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Cl[C:14]1[N:19]=[C:18]([NH2:20])[N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=1.O1CCOCC1.C([O-])(O)=O.[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.O>[NH2:20][C:18]1[N:19]=[C:14]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:12])[CH:5]=2)[CH:15]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Nc1nc(Cl)cc(Nc2ccccc2)n1
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: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(Nc3ccccc3)nc(N)n2)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To (4-cyano-3-fluorophenyl)boronic acid (197 mg, 1.20 mmol) and 6-chloro-N4-phenyl-2,4-pyrimidinediamine (330 mg, 1.50 mmol) in a sealable flask were added 1,4-dioxane (6 mL) and saturated aqueous NaHCO3 (3 mL). The mixture was degassed with nitrogen gas for 10 minutes. Pd(Ph3P)4 (86 mg, 0.075 mmol) was added and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto EtOAc and water. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The resulting residue was chromatographed on SiO2 (gradient: 99:1:0.1 CHCl3/CH3OH/NH4OH to 90:10:1 CHCl3/CH3OH/NH4OH) to afford the title compound (366 mg). LC-MS (ES) m/z=306 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH:23](/[C:29]#[N:30])=[CH:24]\[C:25]([F:28])([F:27])[F:26]>C(#N)C>[F:26][C:25]([F:28])([F:27])[CH:24]([N:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1)[CH2:23][C:29]#[N:30]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#C/C=C/C(F)(F)F
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C(F)(F)F)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
To a flask equipped with a mechanical stirrer, nitrogen inlet and thermowell was added compound 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 1424 g, 4.52 mol) and acetonitrile (14 L). The resulting suspension was added 4,4,4-trifluorocrotonitrile (32, 601.6 g, 4.97 mol, 1.1 equiv) followed by 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU, 67 mL, 0.452 mol, 0.1 equiv). A slight exotherm (5° C.) was noted upon the addition of the DBU. The reaction mixture was stirred at room temperature for 30 minutes when TLC and LCMS showed the reaction was deemed complete. The reaction mixture was then concentrated under reduced pressure to remove most of the solvent and the residue was purified by two silica gel columns (3 Kg each) for chromatography purification. The column was eluting with 2:1 heptane/ethyl acetate (30 L) followed by 1:1 heptane/ethyl acetate (30 L). The fractions containing pure desired product (33) were combined and concentrated under reduced pressure to afford racemic 4,4,4-trifluoro-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butanenitrile (33, Racemic SEM-protected compound, 1802 g, 1973 g theoretical, 91.3% yield) as a thick oil, which was directly used in subsequent chiral column separation without further purification. For 33: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.99 (s, 1H), 8.79 (s, 1H), 8.56 (s, 1H), 7.80 (d, 1H, J=3.7 Hz), 7.09 (d, 1H, J=3.7 Hz), 6.05 (m, 1H), 5.63 (s, 2H), 3.82 (dd, 1H, J=17.5, 10.6 Hz), 3.66 (dd, 1H, J=17.0, 4.9 Hz), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.2 Hz), −0.145 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 151.7, 151.3, 149.5, 140.8, 132.9, 130.4, 123.2 (JCF=282 Hz), 121.9, 116.2, 113.5, 100.2, 72.3, 65.7, 57.8 (JCF=32.4 Hz), 17.1, −1.46; C19H23F3N6OSi (MW, 436.51), LCMS (EI) m/e 437 (M++H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15]I>C1CCCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:14])[N:7]([CH3:15])[CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1CC=CCC1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)C1CC=CCC1
Yield: 64 %

Procedure:
Cyclohex-3-enyl-carbamic acid tert-butyl ester (Kampferer, P.; Vasella, A. Helvetica Chimica Acta 2004, 87, 2764-2789) (3 g, 15.2 mmol) and methyl iodide (0.95 ml, 15.2 mmol) were treated for 1 hour according to the method of Example 7 Step A. After work up and chromatography of the reaction mixture (silica, cyclohexane/ethyl acetate=10/1) the title compound (Rf=0.22, 2.04 g, 64% yield) was obtained as colorless solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:14]([CH3:16])[CH3:15])=[N:5][S:6][C:7]=1[N:8]=[C:9](Cl)[N:10]([CH3:12])[CH3:11])#[N:2].[F-:17].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>C(#N)C>[C:1]([C:3]1[C:4]([CH:14]([CH3:16])[CH3:15])=[N:5][S:6][C:7]=1[N:8]=[C:9]([F:17])[N:10]([CH3:12])[CH3:11])#[N:2]
Reactant: [F-]
Reactant: CC(C)c1nsc(N=C(Cl)N(C)C)c1C#N
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: CC(C)c1nsc(N=C(F)N(C)C)c1C#N
Yield: 20.9 %

Procedure:
A mixture of 12.8 g of N'-(4-cyano-3-isopropyl-5-isothiazolyl)-N,N-dimethylchloroformamidine, 2.9 g of potassium fluoride and a catalytic amount of 2,3,11,12 -dibenzo-1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene, in 60 ml of acetonitrile was stirred at ambient temperature for 12 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was recrystallized from diethyl ether to give 2.5 grams of N'-(4-cyano-3-isopropyl-5-isothiazolyl)-N,N-dimethylfluoroformamidine, mp 100°-102°. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: Br[CH2:2][C:3]([CH2:22][OH:23])([CH2:20][OH:21])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:8][CH:7]=1.[CH3:24][NH:25][CH3:26]>C(O)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([CH2:2][N:25]([CH3:26])[CH3:24])([CH2:22][OH:23])[CH2:20][OH:21])=[CH:7][CH:8]=1)(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNC
Reactant: O=C(c1ccccc1)c1ccc(OCC(CO)(CO)CBr)cc1
Solvent: CCO
Product: CN(C)CC(CO)(CO)COc1ccc(C(=O)c2ccccc2)cc1

Procedure:
Dissolve the {4-[3-bromo-2,2-bis(hydroxymethyl)propoxy]phenyl}(phenyl)methanone obtained in the previous stage in ethanol and treat it with excess of 40% aq. dimethylamine at reflux for 8 h. Remove the solvent in vacuo and purify the residue by column chromatography to provide the desired 2-(4-benzoylphenoxymethyl)-2-[(dimethylamino)methyl]propane-1,3-diol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([F:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(F)c2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The compound prepared in Step 1 was dissolved in ethanol (10 ml) and water (1.0 ml), added with iron (powder, 2.0 g) and ammonium chloride (1.0 g), and stirred at 80° C. for 2 hours. Then, the resultant was filtered with celite, distilled under reduced pressure to remove the solvent. The thus obtained target compound as a white solid was used in the subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][OH:21])[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N1CCCC(CO)C1)C1(c2ccc(Cl)cc2)CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
The amide derivative 1 (5.0 g, 16.3 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0° C. To this solution was added triethylamine (5.0 mL) followed by dropwise addition of methanesulfonyl chloride (2.05 g, 17.9 mmol). The reaction was stirred at 0 C. for 1 h, and then at room temperature overnight. The reaction mixture was washed successively with water, 1 N HCl, water, sat. sodium bicarbonate solution, and water (100 mL each). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (2:1) to give 2 (4.45 g, 71%) as a tan gum; C18H24ClNO4S, LRMS (m/z)=386 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Li]CCCC>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=Cc1ccccc1
Agent: [Li]CCCC
Product: COc1ccccc1N1CCN(CCc2ccccc2)CC1

Procedure:
According to GP, 2.22 mmol (=0.43 g) of 1-(2-methoxyphenyl)piperazine and 2.22 mmol (=0.23 g=0.25 ml) of styrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate/n-hexane (1:2) gives the product 1-(2-methoxyphenyl)-4-(2-phenyl-1-ethyl)piperazine as a yellow oil.
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=O)=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:22]([C:25]1([NH2:38])[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[CH:23]=[CH2:24].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:22]([C:25]1([NH:38][CH2:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]([S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:3])=[O:2])[CH:12]=2)[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[CH:23]=[CH2:24]
Reactant: C=CCC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=CCC1(NCc2cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Yield: 60.1 %

Procedure:
To a solution of 1-tosyl-1H-indole-3-carbaldehyde [50562-79-3] (1.90 g, 6.35 mmol) in 1,2-dichloroethane (30 mL) were added tert-butyl 4-allyl-4-aminopiperidine-1-carboxylate [741687-08-1] (1.52 g, 6.35 mmol) and acetic acid (381 mg, 6.35 mmol). The resulting solution was heated at 60° C. for 3 h. Then NaBH(OAc)3 was added and the reaction mixture was heated at 60° C. for 38 h. The mixture was cooled to rt, saturated NaHCO3 solution (30 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water and brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash-column chromatography over silicagel (eluent: 20% ethyl acetate/hexane) to yield the title compound (2.0 g, 60%). [LCMS RtE=0.34 min, [M+H]+=524.0]
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:20]O>Cl.O1CCOCC1>[CH3:20][O:18][C:17](=[O:19])[CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)[CH:11]=1
Reactant: O=C(O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A mixture of [3-(1H-indol-4-yl)-phenyl]-acetic acid (4 g, 15.9 mmol), 4N HCl (20 drops) in methanol (30 mL) and dioxane was stirred at rt for 4 hours. The reaction was concentrated, diluted in ethyl acetate, washed with NaHCO3 (2×), brine (2×), dried and concentrated to give 3.72 g (88%) of [3-(1H-Indol-4-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH:18]=O)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:27]([C:29]([CH3:31])=[O:30])=[CH2:28].Cl>CCO.C1COCC1.CCOCC>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[CH2:18][CH2:31][C:29](=[O:30])[CH:27]=[CH:28]2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=CC(C)=O
Reactant: O=CC(c1ccc(OCc2ccccc2)cc1)c1ccccc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1C=CC(c2ccc(OCc3ccccc3)cc2)(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A solution of KOH (110 mg, 2.0 mmol) in EtOH (3 mL) was added at 0° C. to a stirred solution of 4 (2.52 g, 7.9 mmol) and methyl vinyl ketone (0.61 g, 8.7 mmol) in THF (60 mL). The resulting mixture was stirred at room temperature overnight. Ether (200 mL) and HCl (50 mL, 10% aqueous solution) were added. The organic phase was washed with HCl (50 mL, 10% aqueous solution), H2O (50 mL), NaHCO3 (50 mL, saturated aqueous solution), dried over Na2SO4 and evaporated under reduced pressure. The crude material was dissolved in EtOH (40 mL) and HCl (2 mL, 37% aqueous solution) was added. The mixture was heated at 50° C. for 30 min under stirring. After cooling to room temperature, H2O (50 mL) was added. The mixture was extracted with diethyl ether (3×100 mL) and the combined organic phase was washed with NaHCO3 (2×50 mL, saturated aqueous solution) and brine (50 mL), dried over Na2SO4 and evaporated under reduced pressure to yield 2.89 g crude material. Purification by column chromatography (heptane:ethyl acetate 4:1 to 2:1) yielded 2.41 g, 82% as an off-white solid. 1H-NMR (CDCl3) δ; 7.44-7.35 (m, 6H), 7.35-7.28 (m, 2H), 7.17 (dt, 1H, J=7.5 Hz and 1.4 Hz), 7.11 (d, 2H, J=8.9 Hz), 7.02 (dd, 1H, J=7.0 Hz and 1.4 Hz), 6.92 (d, 2H, J=8.9 Hz), 6.19 (d, 1H, J=10.3 Hz), 5.04 (s, 2H), 2.90-2.81 (m, 1H), 2.62-2.52 (m, 1H), 2.44 (at, 2H, J=6.6 Hz); 13C-NMR (CDCl3) δ; 199.0, 161.3 (d, J=249.6 Hz), 157.9, 154.9 (d, J=3.8 Hz), 137.1 (d, J=12.1 Hz), 132.0 (d, J=10.8 Hz), 129.5 (d, J=8.8 Hz), 129.3, 128.8, 128.7 (d, J=4.2 Hz), 128.2, 128.1, 127.7, 124.3 (d, J=3.5 Hz), 117.2 (d, J=22.7), 115.0, 70.3, 47.3 (d, J=1.9 Hz), 35.1, 35.0;
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:41]3[N:40]=[CH:39][N:38]=[C:27]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+]([O-])=O)=[CH:31][CH:30]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1(OC2C3N=CN(C=3N=CN=2)[C@@H]2O[C@H](CO[Si](C(C)(C)C)(C)C)[C@@H](O[Si](C(C)(C)C)(C)C)C2)[C:46]2[CH:47]=CC=[CH:50][C:45]=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+].C1(O)C2C(=CC=CC=2)C=CC=1>COCCOC>[Si:16]([O:15][C@@H:14]1[C@@H:13]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[O:12][C@@H:11]([N:23]2[C:41]3[N:40]=[CH:39][N:38]=[C:27]([O:28][C:29]4[C:34]5[C:33](=[CH:50][CH:45]=[CH:46][CH:47]=5)[CH:32]=[CH:31][CH:30]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:17])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4ccc([N+](=O)[O-])cc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: Oc1cccc2ccccc12
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4cccc5ccccc45)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 81 %

Procedure:
As described for the synthesis of 3′,5′-bis-O-(tert-butyldimethylsilyl)-O6-(4-nitrophenyl)-2′-deoxyinosine, this naphthyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol), Cs2CO3 (65.2 mg, 0.200 mmol) and 1-naphthol (15.9 mg, 0.110 mmol) in dry DME (1.0 mL) at 85° C. for 2 h. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 49.2 mg (81% yield) of the title compound as a yellowish-white foam. Rf (20% EtOAc in hexanes)=0.37. 1H NMR (500 MHz, CDCl3): δ 8.44 (s, 1H, Ar—H), 8.41 (s, 1H, Ar—H), 7.93 (d, 1H, Ar—H, J=8.8), 7.91 (d, 1H, Ar—H, J=8.3), 7.81 (d, 1H, Ar—H, J=8.3), 7.54 (t, 1H, Ar—H, J=7.8), 7.50 (t, 1H, Ar—H, J=7.6), 7.42 (t, 1H, Ar—H, J=7.6), 7.39 (d, 1H, Ar—H, J=7.3), 6.56 (t, 1H, H-1′, J=6.4), 4.67 (m, 1H, H-3′), 4.06 (q, 1H, H-4′, J=3.4), 3.92 (dd, 1H, H-5′, J=11.2, 4.4), 3.82 (dd, 1H, H-5′, J=11.2, 2.9), 2.71 (quint, 1H, H-2′, J=6.3), 2.50 (ddd, 1H, H-2′, J=12.9, 5.9, 4.1), 0.94, 0.93 (2 s, 18H, tert-Bu), 0.12 (s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 160.7, 152.7, 152.1, 148.6, 141.7, 134.9, 127.9, 127.3, 126.4, 126.2, 125.9, 125.5, 122.0, 121.9, 118.1, 88.1, 84.7, 71.9, 62.8, 41.4, 25.9, 25.7, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C32H47N4O4Si2 (M++H) 607.3136. found 607.3120.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].[C:13](Cl)(=[O:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>ClCCl>[N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][N:9]([C:13](=[O:15])[CH3:14])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of 124d (672 mg, 4.0 mmol) in dichloromethane (20 mL) was added acetyl chloride (936 mg, 12.0 mmol) and K2CO3 (1104 mg, 8.0 mmol). The mixture was stirred overnight. It was then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 124e as white solid (500 mg, 60%). MS: [M+H]+ 211.2
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5]2.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([F:27])([F:26])[F:15])=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCn1ccc2cc(Br)ccc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCCCn1ccc2cc(-c3ccc(C(F)(F)F)cc3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-butyl-1H-indole (Step 1 of Example 29) and 4-trifluoromethylphenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil, mp: 52-53° C. Mass spectrum (APCI, [M+H]+) m/z 318. 1HNMR (400 MHz, DMSO-d6): δ 7.91-7.88 (m, 3H), 7.76 (d, 2H, J=8.24 Hz), 7.59 (d, 1H, J=8.55 Hz), 7.49 (d, 1H, J=8.56 Hz), 7.43 (d, 1H, J=3.06 Hz), 6.51 (d, 1H, J=3.05 Hz), 4.20 (t, 2H, J=7.01 Hz), 1.74 (p, 2H, J=7.19 Hz), 1.25 (h, 2H, J=7.48 Hz), and 0.88 ppm (t, 3H, J=7.32 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.C(OCC)C.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20](=[O:26])[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:20]([C:19]3[CH:23]=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=3)([OH:26])[C:21](=[O:25])[NH:22]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)ccc2C1(O)c1ccc(Cl)cc1
Temperature: -25 °C
Reaction time: 2 h

Procedure:
A solution of 4-chlorophenyl magnesium bromide in diethyl ether (1.0 M, 25 mL, 25 mmol) (Aldrich) was added dropwise with magnetic stirring to a suspension of 6-chloroisatin (1.82 g, 10 mmol) in tetrahydrofuran (40 mL) under argon with cooling in a −25° C. bath at such a rate that reaction temperature was kept below −10° C. (approximately 30 minutes). Cooling bath was then removed and mixture allowed to warm to room temperature. After stirring for an additional 2 hour, 15% aqueous ammonium chloride solution (25 mL) and water (50 mL) were added and mixture extracted with ethyl acetate (2×75 mL). Ethyl acetate layers were then washed with water (75 mL), brine (75 mL), combined, dried (MgSO4), filtered and concentrated. Residue was stirred in dichloromethane (100 mL) at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-(4-chloro-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one as an off-white powder. This was used in the next step without further purification.