Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22]C)=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].C(OCC)(=O)C>CO.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Yield: 82.2 %

Procedure:
Methyl 2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg, 0.32 mmol) and sodium hydroxide (0.2 g, 5 mmol) was dissolved in methanol/water (10 mL/2 mL) and the reaction mixture was allowed to reflux for 1.5 h. Thin layer chromatography (petroleum ether:ethyl acetate=3:1, Rf=0.1) showed the reaction was complete. The solvent was removed in vacuo and the residue was acidified with 1 M hydrochloric acid solution to pH=6. The precipitated off-white solid was collected by filtration and dissolved in 50 ml of acetone, dried over sodium sulfate. Filtered and concentrated, the residue was recrystallization from dichloromethane/hexane to afford 78 mg of 2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, Yield: 82.1%, MS (ES+APCI) M+1=297.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:9][C:8]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)=[O:4].O.C(=O)(O)[O-].[Na+]>ClCCCl>[O:14]=[C:12]1[C:7]2[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[NH:9][C:8]=2[CH2:10][CH2:11]1
Reactant: COC(=O)c1ccc(CCC(=O)O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)c1cc2c([nH]1)CCC2=O
Temperature: 100 °C
Yield: 86.2 %

Procedure:
A suspension of polyphosphoric acid (115%, 109 g) and powdered 3-(5-(methoxycarbonyl)-1H-pyrrol-2-yl)propanoic acid (12.1 g, 51.8 mmol) in 1,2-dichloroethane (40 mL) was heated for 1 h at 100° C. with occasional mixing with a large spatula. Water (100 mL) was added and the mixture was carefully poured into a large Erlenmeyer flask containing solid sodium bicarbonate and ice. The reaction was neutralized (pH 7) and then extracted with EtOAc (5×150 mL). The combined organic extracts were washed with water, NaHCO3, brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0-80% EtOAc/Heptane) to afford 8.0 g of methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (86%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.93-2.98 (m, 2H), 2.99-3.04 (m, 2H), 3.90 (s, 3H), 6.98 (d, J=1.71 Hz, 1H), 9.42 (br s, 1H); LCMS-MS (ESI+) 180.0 (M+H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[NH2:17])\[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]#N)[CH:22]=[CH:23][C:24]=1[Cl:25].C(O)C.Cl>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]2[O:1][N:2]=[C:3]([CH2:4][O:5][C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]4)[N:17]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: N#CNc1ccc(Cl)c(Cl)c1
Reactant: N/C(COc1ccc2c(c1)CCC(=O)N2)=N/O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(OCc3noc(Nc4ccc(Cl)c(Cl)c4)n3)ccc2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 7 %

Procedure:
To a solution of (E)-N′-hydroxy-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetimidamide (0.1 g, 0.425 mmol) in ethyl acetate (10 mL) was added a 0.5M solution of zinc chloride (0.073 mL, 0.510 mmol) followed by N-(3,4-dichlorophenyl)cyanamide (0.080 g, 0.425 mmol) and stirred at room temperature for 12 h. Then reaction mixture was concentrated. Ethanol (10.00 mL) was added along with HCl (0.1 mL, 3.29 mmol) and the reaction mixture was heated at 80° C. for 6 h. The reaction mixture was concentrated and basified with sodium bicarbonate solution, then the resulting solid was filtered and was washed with acetonitrile to give 6-((5-((3,4-dichlorophenyl)amino)-1,2,4-oxadiazol-3-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as a white solid (12 mg, 6.8% yield). 1H NMR 400 MHz, DMSO-d6: δ 2.41 (t, J=15.20 Hz, 2H), 2.84 (t, J=15.20 Hz, 2H), 4.94 (s, 2H), 6.77-6.79 (m, 1H), 6.84-6.87 (m, 1H), 6.93 (d, J=2.80 Hz, 1H), 7.30 (s, 1H), 7.37 (s, 1H), 7.80 (s, 1H), 9.91 (s, 1H). LCMS: RT 1.963 min; LCMS (ES-API), m/z 403.0 [M−H]−.
Reaction SMILES: Cl[CH:2]([CH3:5])[C:3]#[N:4].Cl.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH:2]([CH3:5])[C:3]#[N:4])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1
Reactant: CC(Cl)C#N
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C#N)N1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 25 parts of 2-chloropropanenitrile, 61 parts of (4-fluorophenyl)(4-piperidinyl)methanone hydrochloride, 63 parts of sodium carbonate and 160 parts of acetonitrile is stirred and refluxed (100° C.) overnight. The reaction mixture is cooled, water is added and the layers are separated. The aqueous phase is extracted with 4-methyl-2-pentanone. The combined organic phases are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane, hexane and methanol (50:49:1 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 2,2'-oxybispropane. The product is filtered off, and dried yielding 17 parts of 4-(4-fluorobenzoyl)-α-methyl-1-piperidineacetonitrile; mp. 126.7° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CC([O-])(C)C.[Na+].[CH3:16][O:17][C:18]([C:20]1[S:31][C:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[S:30][C:22]=2[C:21]=1[OH:32])=[O:19].O>CN(C=O)C>[CH3:16][O:17][C:18]([C:20]1[S:31][C:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[S:30][C:22]=2[C:21]=1[O:32][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:19]
Reactant: COC(=O)c1sc2c(sc3ccccc32)c1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sc2c(sc3ccccc32)c1OCC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
tert-Butyl bromoacetate (0.082 ml, 0.56 mmol, 1.3 equiv) was added to a mixture of NaOt-Bu (50 mg, 1.2 equiv) and 1-hydroxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (113 mg, 0.43 mmol, 1 equiv) in DMF (10 ml). The resulting mixture was stirred at 60° C. for 16 hr. Addition of water followed by extraction with EtOAc and washing with water left crude product. Purification by column chromatography gave 140 mg (86%) of 1-tert-butoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester as an orange solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])(C)(C)C.[C:12]([O-:15])(=[O:14])[CH3:13].[Na+].[C:17](OO)(=O)C>C(Cl)Cl>[OH:11][CH:6]([C:5]([CH3:1])([CH3:10])[CH3:17])[CH2:7][CH2:8][CH2:9][CH2:13][C:12]([OH:15])=[O:14]
Reactant: CC(C)(C)C1CCCCC1=O
Reactant: CC(=O)OO
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(O)CCCCC(=O)O
Reaction time: 20 h

Procedure:
The a 3-liter round-bottomed flask provided with a stirrer , thermometer, condenser and dropping funnel, there are added 353 g (2.3 mol) of 2-tert. butyl-cyclohexanone 14 g of anhydrous sodium acetate and 1.17 liters of methylene chloride. 370 g of ca. 40% peracetic acid are added at room temperature while cooling. The mixture is held first at room temperature for 20 hours with stirring and then for a further 48 hours under reflux temperature. After cooling, the mixture is poured on to ice, the layers are separated and the organic layer washed with an iron sulphate solution and then with water until a neutral reaction is obtained. The solvent is distilled off and the crude lactone distilled, there being obtained 274 g (70.3%) of the Σ-lactone of 6-hydroxy-7,7-dimethylcaprylic acid of boiling point 134° C/12 mm Hg; melting point 54°-58° C.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.O>C1COCC1>[C:1]([N:8]1[CH2:15][C@H:14]([O:16][CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: BrCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2cccc3ccccc23)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
Commercially available Boc-4(R)-hydroxyproline (5.00 g, 21.6 mmol) was dissolved in THF (100 mL) and cooled to 0° C. Sodium hydride (60% dispersion in oil, 1.85 g, 45.4 mmol) was added portionwise over 10 minutes and the suspension was stirred at RT for 1 h. Then, 1-(bromomethyl)naphthalene (8.00 g, 36.2 mmol) (prepared as described in E. A. Dixon et al. Can. J. Chem., (1981), 59, 2629-2641) was added and the mixture was heated at reflux for 18 h. The mixture was poured into water (300 mL) and washed with hexane. The aqueous layer was acidified with 10% aqueous HCl and extracted twice with ethyl acetate. The organic layers were combined and washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (49:49:2 hexane:ethyl acetate:acetic acid) to give the title compound as a colorless oil (4.51 g, 56% yield). 1H NMR (DMSO-d6) indicated the presence of two rotamers: δ8.05 (m, 1H), 7.94 (m, 1 H), 7.29 (d, J=14 Hz, 1H), 7.55-7.45 (m, 4H), 4.96 (m, 2H), 4.26 (br. s, 1H), 4.12 (dd, J=J=8 Hz, 1H), 3.54-3.42 (m, 2H), 2.45-2.34 (m, 1H), 2.07-1.98 (m, 1H) 1.36 (s, (3/9) 9H), 1.34 (s, (6/9) 9H).
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=O)C.[CH3:14][NH:15][CH3:16].[OH-].[Na+].Cl>C1COCC1.O>[OH:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:15]([CH3:16])[CH3:14])=[O:8]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
A mixture of acetylsalicyloyl chloride (3.4 g, 17 mmol) in 120 mL of THF was added dropwise to 30 mL of 40% aqueous dimethylamine (66 mmol). The mixture was stirred at room temperature for 3 hours and then sodium hydroxide (4 g, 0.1 mmol) was added. The mixture was stirred at room temperature for approximately 60 hours and then poured into 20 mL of water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated. The residue was purified on silica gel by flash chromatography eluting with 6% methanol/methylene chloride to give 2-hydroxy-N,N-dimethylbenzamide (2.4 g, 14.53 mmol), m.p. 145°-152° C.
Reaction SMILES: S(Cl)(Cl)(=O)=O.CS[S:8][CH3:9].C(SCl)C.[CH3:14][C@@H:15]1[CH2:29][C@H:28]2[C@@H:18]([CH2:19][C:20]3[C:30]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]2=4)[NH:22][CH:21]=3)[N:17]([CH2:31][CH2:32][CH3:33])[CH2:16]1>ClCCl>[CH3:14][C@@H:15]1[CH2:29][C@H:28]2[C@@H:18]([CH2:19][C:20]3[C:30]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]2=4)[NH:22][C:21]=3[S:8][CH3:9])[N:17]([CH2:31][CH2:32][CH3:33])[CH2:16]1
Reactant: CSSC
Reactant: CCCN1C[C@H](C)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: CCSCl
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCN1C[C@H](C)C[C@@H]2c3cccc4[nH]c(SC)c(c34)C[C@H]21
Reaction time: 8 h

Procedure:
A solution of sulphuryl chloride (0.74 g) in dichloromethane (15 ml) was added dropwise over 15 minutes at -20° C. to a stirred solution of dimethyl disulphide (0.46 g) in dichloromethane (15 ml). After allowing it to reach room temperature the solution of ethyl sulphenyl chloride was added dropwise to a suspension of 8β-methyl-6-propylergoline (2.4 g), in dichloromethane (150 ml) at -70° C. The reaction mixture was stirred and allowed to reach room temperature overnight. Ice cold ammonia solution was added and the mixture extracted with dichloromethane (3×100 ml). The combined extracts were washed with water, dried (MgSO4) and evaporated to dryness. Chromatography on neutral alumina (CH2CH2) and crystallisation from ethanol gave the title compound. The free base was converted to its maleate salt and crystallised from ethanol, m.p. 216°-219° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[O:8])[CH3:7].[CH:9](OC)(OC)[O:10]C.[C:16]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:16][O:8][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([O:10][CH3:9])[CH3:7]
Reactant: COC(OC)OC
Reactant: CC(=O)c1nccs1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(C)(OC)c1nccs1
Temperature: 50 °C

Procedure:
To a solution of 1-Thiazol-2-yl-ethanone (7 g) in dry methanol (100 ml) was added trimethyl orthoformate (35 ml) and p-toluenesulfonic acid (10 g) and the resulting mixture was heated at 50° C. for 12 hours. The mixture was cooled to ambient and concentrated, partitioned between saturated sodium bicarbonate and diethyl ether (100 ml). The organic phase was removed and washed with saturated sodium bicarbonate and brine, dried (magnesium sulfate), filtered and concentrated to afford the sub-title compound as crude product. The product could be further purified if necessary by flash chromatography (20% ethyl acetate/petroleum ether) to afford the sub-title compound in quantitative yield as yellow oil (9.5 g); 1H NMR (400 Mhz, CDCl3) δ 1.75 (3H, s), 3.25 (6H, s), 7.3 (1H, s), 7.85 (1H, s); MS (ES+) 174.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([CH2:15][CH3:16])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].C1COCC1.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([CH2:15][CH3:16])=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(Nc2ccc(CC(=O)OC)cc2)cc(-c2cccc(Cl)c2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(Nc2ccc(CC(=O)O)cc2)cc(-c2cccc(Cl)c2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
An 18-mL vial was charged with methyl 2-[4-[[6-(3-chlorophenyl)-3-ethyl-2-methyl-4-pyridyl]amino]phenyl]acetate (8 mg, 0.02 mmol, 1 eq.) and lithium hydroxide monohydrate (13 mg, 0.31 mmol, 15 eq.). To this was added THF (1 ml) and water (0.4 ml). The resulting mixture was stirred at room temperature overnight. Then 2N HCl aq. (0.12 ml) was added. The volatile materials were removed under reduced pressure to give a residue, which was purified by chromatography on silica gel using 2˜4% of MeOH in dichloromethane as eluent to give 2-[4-[[6-(3-Chlorophenyl)-3-ethyl-2-methyl-4-pyridyl]amino]phenyl]acetic acid (7 mg, 91% yield). MW=380.87. 1H NMR (Methanol-D4, 360 MHz) δ 7.69 (s, 1H), 7.48-7.58 (m, 3H), 7.44 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 6.89 (s, 1H), 3.67 (s, 2H), 2.85 (q, J=7.5 Hz, 2H), 2.66 (s, 3H), 1.24 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([Br:11])=[C:8]([Br:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16].O>C1COCC1.CCOC(C)=O>[Br:11][C:7]1[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:9]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:8]=1[Br:10]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)c1nc(Br)c(Br)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1nc(Br)c(Br)n1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 101.9 %

Procedure:
To a cooled solution of 2-t-butyl-4,5-dibromoimidazole (1.4 grams, 5.0 mmol; Example 5, Step 2) in dry THF (10 mL) at 0° C. was added sodium hydride (95%, 0.15 grams, 6.0 mmol) portion wise. The reaction mixture was stirred for 10 minutes at 0° C., at room temperature for 40 minutes. The reaction was re-cooled to 0° C. and SEM-chloride (0.97 ml, 5.5 mmol) was added in dropwise. The reaction mixture was stirred overnight allowing the ice bath to expire and poured into a mixture of water (30 mL) and EtOAc (50 mL). The resulting layers were partitioned and separated. The organic portion was washed with brine, then water, dried (Na2SO4), and concentrated. The remaining residue was purified by flash chromatography (SiO2, 0-10% EtOAc in hexanes) to provide 2.1 g of 4,5-dibromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole: LCMS (m/z): 412.9 (MH+), tR=1.320 minutes; 1H NMR (400 MHz, CDCl3) δ 8.75 (dd, 1H,), 7.92 (dd, 1H,), 5.90 (s, 2H), 3.51 (m, 2H), 1.55 (s, 9H), 0.82 (m, 2H), 0.08 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([NH2:22])[C@H:12]1[OH:13].[C:23]([O:27][C:28]([NH:30][CH:31]([C:47](O)=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[CH:35][CH:34]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([NH:22][C:47](=[O:48])[CH:31]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[CH:37][CH:38]=2)[NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:29])[C@H:12]1[OH:13]
Reactant: CCOC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1N
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc1
Product: CCOC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1NC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Yield: 56.7 %

Procedure:
Ethyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-tert-butoxycarbonyl-β-(4-tert-butoxycarbonylaminophenyl)-D,L-alanylamino]-β-D-ribofuranuronate (380 mg) was prepared by reacting ethyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronate (308 mg) prepared in Example 63 with N-tert-butoxycarbonyl-β-(4-tert-butoxycarbonylaminophenyl)-D,L-alanine (380 mg) according to a similar manner to that of Example 64, mp. 160°-170° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[N:16](C)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[N:16]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:6][CH:7]=1
Reactant: CN1C2CCC1CC(Sc1ccc(F)cc1)C2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1C2CCC1CC(Sc1ccc(F)cc1)C2

Procedure:
A mixture of 3-(4-fluorophenylsulfanyl)-8-methyl-8-azabicyclo-(3.2.1)-octane (the compound of Preparation 36, 8.20 g, 32.65 mmol), 2,2,2-trichloroethyl chloroformate (4.94 mL, 35.92 mmol), and potassium carbonate (4.96 g, 35.92 mmol) in benzene (140 mL) was refluxed overnight. The solvent was removed at reduced pressure and the residue was taken up in ethyl acetate. The organic phase was washed with aqueous bicarbonate and brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (3×4 inches) with elution proceeding as follows: hexane (350 mL), nil; 10% ethyl acetate/hexane (400 mL), discarded forerun; 10% ethyl acetate/hexane (600 mL), 20% ethyl acetate/hexane (500 mL), and 30% ethyl acetate/hexane (250 mL), 10.32 g (77%) of 3-(4-fluorophenylsulfanyl)-8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo-(3.2.1)-octane as an off white solid which had: mp 65-67° C.; NMR δ 7.40 (dd, J=5.5, 9 Hz, 2 H), 6.98 (long range coupled t, J=8.5 Hz, 2 H), 4.72 (ABq, Δv1-3 =60 Hz, J=12 Hz, 2 H), 4.35 (sym m, 2 H), 3.32 (septet, J=6 Hz, 1 H), 2.10-1.94 (m, 2 H), 1.94-1.58 (m, 6 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([F:19])[CH:10]=2)[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[CH:3]=1.[I:24](O)(=O)(=O)=O.II>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([F:19])[CH:10]=2)[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[I:24]
Reactant: COC(=O)c1cc(N)c(F)c(-c2ccc(C(F)(F)F)c(F)c2)n1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(C(F)(F)F)c(F)c2)c(F)c(N)c1I
Temperature: 25 °C
Yield: 255.7 %

Procedure:
Methyl 4-amino-5-fluoro-6-(3-fluoro-4-(trifluoromethyl)phenyl)picolinate (500 mg, 1.51 mmol) was dissolved in CH3OH (0.6 mL) in a round bottom flask. Periodic acid (123 mg, 0.542 mmol) and iodine (306 mg, 1.204 mmol) were added, and the reaction mixture was heated at reflux with a drying tube for 12 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was dissolved in Et2O and washed with 10% sodium thiosulfate (Na2S2O3; 2×5 mL). The organic extracts were combined, dried over anhydrous Na2SO4, filtered, and concentrated providing methyl 4-amino-5-fluoro-6-(3-fluoro-4-(trifluoromethyl)phenyl)-3-iodopicolinate (635 mg, 92%): 1H NMR (400 MHz, DMSO-d6) δ 7.93 (dd, J=14.8, 6.8 Hz, 1H), 7.90-7.82 (m, 2H), 6.89 (s, 2H), 3.88 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −60.02 (t, J=12.4 Hz), −115.50 (td, J=12.2, 7.6 Hz), −139.91 (s); ESIMS m/z 459.62 ([M+H]+).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH2:13]([N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(O)(=O)C.ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:13]([N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(Cn2cccc2)cc1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: O=C1C=C(c2cccn2Cc2ccccc2)C(=O)c2ccccc21
Yield: 18 %

Procedure:
3.16 millimol of 1,4-naphthoquinone were stirred with 25 millimol of N-benzylpyrrole and 3.16 millimol of copper acetate in 50 ml of acetic acid in a round-bottomed flask at room temperature for 1 hour. The reaction mixture was diluted with 300 ml of dichloromethane and the resulting mixture was then poured into a large volume of water (300 ml). The organic phase was then separated out and washed four times with 100 ml of water and finally with saturated aqueous NaCl solution. The resulting organic phase was dried over Na2SO4 and then concentrated under vacuum. The product 2-(1-benzyl-1H-pyrrol-2-yl)-[1,4]-naphthoquinone was thus isolated in a yield of 18% after purification by chromatography on a column of silica.