Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:15]([C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)[NH2:16]>CO.C(O)(=O)C>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[NH:15][N:16]=[C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: NNc1nc2ccccc2s1
Reactant: O=C(c1ccccn1)C1CCCCC1
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(C(=NNc2nc3ccccc3s2)C2CCCCC2)nc1

Procedure:
A mixture of cyclohexyl-(2-pyridyl)-methanone (0.77 g, 4.05 mmol) and 2-hydrazinobenzothiazole (0.60 g, 4.02 mmol) in 15 ml of methanol is refluxed for 15 hours after the addition of 5 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: petroleum ether:ethyl acetate (3:7)). The reaction mixture is stored over night in the refrigerator at approximately 5° C. The precipitate is filtered and recrystallized from a mixture of ethanol and water. Yield: 1.09 g (80% of theory).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[NH2:2][C:1](=[N:17][OH:18])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(N)=NO)CC1

Procedure:
A mixture of tert-butyl 4-cyano-1-piperidinecarboxylate (2.69 g, 12.8 mmol), hydroxylamine hydrochloride (4.45 g, 64 mmol) and sodium carbonate (6.78 g, 64 mmol) in water (40 ml) and methanol (40 ml) was heated under reflux for 5 hours. The cooled mixture was concentrated under reduced pressure and the remaining aqueous solution extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a white solid, 2.60 g.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:23]1(B(O)O)[CH2:25][CH2:24]1.C1(C)C=CC=CC=1>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2].O>[CH:23]1([C:2]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:25][CH2:24]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc([N+](=O)[O-])cc1C1CC1
Yield: 38.5 %

Procedure:
To a mixture of methyl 2-bromo-4-nitrobenzoate (871 mg), bis(tricyclohexylphosphine)palladium(II)dichloride (136 mg), tripotassium phosphate (3.98 g) and cyclopropylboronic acid (863 mg) were added toluene (10 mL) and water (0.4 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, and the obtained residue was purified by column chromatography (ethyl acetate:hexane) to give methyl 2-cyclopropyl-4-nitrobenzoate (285 mg). The obtained methyl 2-cyclopropyl-4-nitrobenzoate (285 mg) was dissolved in a solution of ethyl acetate and ethanol, and catalytic hydrogenation was performed using palladium carbon to give methyl 4-amino-2-cyclopropylbenzoate (189 mg). Using the obtained methyl 4-amino-2-cyclopropylbenzoate (189 mg) and 3-chloropropane-1-sulfonyl chloride (0.156 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (168 mg) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C[O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=1)=[O:18]>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:28][C:25]3[CH:26]=[CH:27][C:22]([CH:20]4[CH2:21][CH:19]4[C:17]([OH:18])=[O:16])=[CH:23][C:24]=3[F:29])[CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccc(SC2CCCC2)n1
Reactant: COC(=O)C1CC1c1ccc(O)c(F)c1
Product: O=C(O)C1CC1c1ccc(OCc2cccc(SC3CCCC3)n2)c(F)c1
Yield: 77 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.033 g, 0.14 mmol) obtained in Step C of Preparation Example 27 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.043 g, 77%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:8][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: BrCCCSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc(SCCCBr)cc1

Procedure:
To a solution of thioether from Example 1, (460 g, 2 moles) and propionyl chloride (202 g, 2.2 moles) in dichloromethane (8 L) at -15° C. was added in portions of approximately 30 g over 1 hour, aluminum chloride (320 g, 2.4 moles). After two hours at -15° C. the reaction mixture was quenched with ice until it became colorless. 1N HCl (2 L) was added and the reaction mixture was stirred until two clear phases were obtained (approximately 30 minutes). The organic layer was siphoned off and dried (Na2SO4). Evaporation afforded an oil which crystallized upon addition of hexane (2 L) and cooling in ice water bath; yield 470 g, m.p. 40°-41° C.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[O:20])[CH2:12][C:11](=[O:13])/[CH:10]=[CH:9]/[C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)[CH3:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)/C=C/c1ccc(Cl)cc1
Agent: [Na]
Product: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)cc1
Yield: 87.1 %

Procedure:
Using the procedure of Example 2, sodium pellets (6.33 g, 0.275 mol), (E)-4-(4-chlorophenyl)-but-3-en-2-one (45.16 g, 0.25 mol) and diethyl oxalate (43.8 g, 0.30 mol) were reacted to give (E)-6-(4-chlorophenyl-2,4-dioxo-hex-5-enoic acid ethyl ester (4; 61.1 g, 87%) as yellow crystals: mp 117-118° C.; 1H NMR (400 MHz, CDCl3) δ 14.80 (s, 1H), 7.68 (d, J=15.9 Hz, 1H), 7.53-7.35 (m, 4H), 6.62 (d, J=15.9 Hz, 1H), 6.53 (s, 1H), 4.38 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H); HRMS-ESI (m/z): calcd for C14H13ClO4, 280.050. found, 280.050.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([OH:22])[N:14]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:23]>CO>[NH2:23][C:2]1[C:11]2[N:12]=[C:13]([OH:22])[N:14]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: Oc1nc2c(Cl)nc3ccccc3c2n1Cc1cccnc1
Solvent: CO
Product: Nc1nc2ccccc2c2c1nc(O)n2Cc1cccnc1
Temperature: 165 °C

Procedure:
4-Chloro-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol (2.64 g, 8.52 mmol) and ammonia (40 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 165° C. for 42 hours and allowed to cool. A solid was present and was isolated by filtration and washed with diethyl ether to provide 1.2 g of 4-amino-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol. A second crop of solid (550 mg) was collected from the filtrate. A portion of the first crop was washed with dichloromethane, methanol, diethyl ether, and acetonitrile to provide a sample as tan needles, mp greater than 250° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:15][OH:16])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)(=[O:26])=[O:25].CN(C=O)C>C(OCC)(=O)C.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:20][C:19]([F:22])([F:21])[CH2:18][CH2:17][C@H:14]([NH:13][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:30]2[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=2)=[CH:3][CH:4]=1)[C:9]([F:12])([F:11])[F:10])[CH2:15][OH:16]
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Reactant: OC[C@H](CCC(F)(F)F)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc([C@H](N[C@H](CO)CCC(F)(F)F)C(F)(F)F)cc2)cc1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
A stream of nitrogen was passed through a suspension of (2S)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]amino}-5,5,5-trifluoropentan-1-ol (0.55 g), 2-(4-methanesulfonyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.59 g) 2.5 M K2CO3 (2.75 mL) and DMF (0.91 mL) for 20 minutes. [1,1′-Bis(diphenyl-phosphino)ferrocene]-palladium (II) chloride (1:1 complex with dichloromethane, 34 mg) was then added, the vessel sealed, and the reaction was warmed to 85° C. and stirred under nitrogen for 5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL) and shaken vigorously. The ethyl acetate layer was separated and washed 3 times with water, dried with magnesium sulfate, and filtered. Removal of the solvent left a residue that was purified by chromatography on SiO2 using a gradient of 10-30% ethyl acetate in hexanes. Rotary evaporation of appropriate fractions yielded (2S)-5,5,5-trifluoro-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}amino)pentan-1-ol.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43]([C:46](O)=[O:47])([CH3:45])[CH3:44])=[CH:33][CH:32]=2)=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.[OH:53][CH2:54][CH2:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43]([C:46]([N:59]4[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][OH:53])[CH2:57][CH2:58]4)=[O:47])([CH3:45])[CH3:44])=[CH:35][CH:36]=3)=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: OCCN1CCNCC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCCC(=O)NC(C)(C)C(=O)N2CCN(CCO)CC2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{4-[1-carboxy-1-(methyl)ethyl-carbamoyl]butyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH:13]2[CH2:15][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]2[CH2:15][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C2CO2)C1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H]([C@H]2CO2)C1
Reaction time: 6 h

Procedure:
(R)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (30 g, 140.6 mmol, 1.0 eq.) was combined with (S,S)-Salen Co(II) (418 mg, 0.7 mmol). Water (⅓ mL) was added and the resulting mixture was stirred vigorously for 6 hours. Hexanes (200 mL) was added. The resulting solids were crushed and stirred in hexanes to yield a yellow precipitate. The precipitate was purified by column chromatography (200-300 mesh, hexanes:EtOAc=1:3, 3 L) to yield (R)-(S)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].[CH3:16]I>C1COCC1>[CH3:16][O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h

Procedure:
To a stirred solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.5 g, 2.67 mmol) in THF (20 mL) at 0° C. was added NaH (60%, 0.077 g, 3.2 mmol) and the mixture was stirred for 15 min. Methyl iodide (0.2 mL, 3.2 mmol) was slowly added and the reaction was stirred for 18 h at ambient temperature. The reaction was quenched with water (5 mL) and extracted with DCM (3×10 mL). The combined organic extracts were washed with water (6 mL), brine (8 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by FCC eluting with DCM to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([S:11][CH2:12][CH3:13])[CH:3]=1.[CH3:14][C@@H:15]1[CH2:20][O:19][CH2:18][CH2:17][NH:16]1.CC(C)([O-])C.[Na+].CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O1CCOCC1>[CH2:12]([S:11][C:4]1[CH:3]=[C:2]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][C@H:15]2[CH3:14])[CH:9]=[C:8]([CH3:10])[C:5]=1[C:6]#[N:7])[CH3:13]
Reactant: CCSc1cc(Cl)cc(C)c1C#N
Reactant: C[C@@H]1COCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CCSc1cc(N2CCOC[C@H]2C)cc(C)c1C#N
Temperature: 100 °C
Yield: 22 %

Procedure:
4-Chloro-2-ethylsulfanyl-6-methyl-benzonitrile (synthesized according to the method described in section a) of example 2) (0.20 g, 0.95 mmol), (R)-3-methylmorpholine (0.14 g, 1.42 mmol) and sodium tert-butoxide (0.27 g, 2.85 mmol) are mixed together with dioxane (1 ml) in a microwave vial. The resulting mixture is degassed and flushed with argon for 20 min followed by the addition of (2-biphenyl)di-tert-butylphosphine (0.056 g, 0.19 mmol) and bis(dibenzylideneacetone)-palladium(0) (0.11 g, 0.19 mmol). The reaction mixture is heated at 100° C. in a microwave oven for 1 h. After completion of the reaction (monitored by TLC), the mixture is filtered through a pad of celite and the filtrate is concentrated to get the crude product, which is purified by column chromatography (silica gel, 8% acetone/hexane) to yield 2-ethylsulfanyl-6-methyl-4-[(3R)-3-methyl-morpholin-4-yl]-benzonitrile (0.06 g, 0.217 mmol, 22%).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(COc2ccc(Br)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of 4-(tert-butyl)benzyl bromide (6.252 g, 27.522 mmol), 4-bromo-2-nitrophenol (5.0 g, 22.934 mmol), potassium carbonate (12.679 g, 91.736 mmol) and dimethylformamide (40 ml) was stirred at 50° for 3 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with n-hexane to give the title compound (8.1 g, 97.0%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH2:20])=[CH:15][C:14]([C:21]2[N:25]=[C:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[O:23][N:22]=2)=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.S([O-])([O-])(=O)=O.[Mg+2].[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH2:43][CH2:44][CH:45]=O)[CH:37]=1.[BH4-].[Na+]>>[CH3:8][C:6]1[CH:5]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:45][CH2:44][CH2:43][CH2:42][C:38]2[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=2)=[CH:15][C:14]([C:21]2[N:25]=[C:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[O:23][N:22]=2)=[CH:13][CH:12]=3)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(-c4noc(CC(C)C)n4)cc3c2CCN)c1
Reactant: O=CCCCc1cccnc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-c4noc(CC(C)C)n4)cc3c2CCNCCCCc2cccnc2)c1
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
To a solution of 2-[2-(3,5-dimethylphenyl)-5-(5-isobutyl-[1,2,4]oxadiazol-3-yl)-1H-indol-3-yl]ethylamine (22 mg in 1.5 mL chloroform) at 0° C. was added anhydrous magnesium sulfate (38 nrg) followed by 4-(3-pyridyl)-butanal (11 mg) and the mixture stirred at low temperature for 15 minutes. At this time sodium borohydride (3.7 mg in 0.50 mL methanol) was added and the mixture stirred at 0° C. After 30 minutes, the reaction was quenched by the addition of water and the mixture extracted with ethyl acetate The organic portion was washed successively with saturated potassium carbonate and brine then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride: methanol, 92:8) gave the title compound (26.5 mg). m/e=522 (M+H)
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: CC(C)(C)OC(=O)Nc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CCOC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1N
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: [C:1]([C:4]1[CH:5]=[C:6]([C:20]([OH:22])=[O:21])[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2OC)=[CH:8][CH:9]=1)(=[O:3])[CH3:2].O=S(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]2[C:10]3[C:11](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[O:22][C:20](=[O:21])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2C(=O)O)c(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)oc(=O)c1cc(C(C)=O)ccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
The compound from Step C was mixed with 1,2-dichloroethane (60 ml) and SOCl2 (1.7 ml, 23 mmol) was added. The mixture was refluxed for 90 min and then cooled to 0° C. AlCl3 (2.3 g, 17.3 mmol) was added and the reaction stirred at room temperature overnight. The solvent was removed and the crude product chromatographed on silica gel with hexane/ethyl acetate (1:1) to yield 5.1 g (90%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 2.74 (3H, s, COCH3), 3.94 (3H, s, OCH3), 6.92 (1H, s, ArH), 6.99 (1H, d, ArH), 8.02 (1H, d, ArH), 8.11 (1H, d, ArH), 8.41 (1H, d, ArH), 8.91 (1H, s, ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1([C:15]#[C:16][C:17]2[CH:31]=[CH:30][C:20]([C:21]([C:23]3[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=3)=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.CC(N(C)C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:26]1[CH:27]=[CH:28][C:23]([C:21]([C:20]2[CH:30]=[CH:31][C:17]([C:16]#[C:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:18][CH:19]=2)=[O:22])=[CH:24][CH:25]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cccc(Oc2ccc(C(=O)c3ccc(C#Cc4ccccc4)cc3)cc2)c1
Temperature: 142 °C
Yield: 95 %

Procedure:
In a 500 mL flask equipped with nitrogen inlet, overhead stirring assembly, Dean-Stark trap, and reflux condenser were placed 3-aminophenol (18.5 g, 0.17 mol), 4-phenylethynyl-4'-fluorobenzophenone (43.2 g, 0.14 mol), potassium carbonate (22 g, 0.16 mol), toluene (30 mL), and DMAc (200 mL). The mixture was heated to 142° C. for 8 h, then cooled to room temperature. The reaction mixture was poured into water and the resulting light yellow powder was collected by filtration. Recrystallization from water/acetone (50/50) (v) and sodium dithionite (0.5 g) afforded 51.8 g (95% yield) of the desired product: m.p. 137°-139° C. IR (KBr); 3414 and 3342 cm-1 (NH2); 3040, 1596, and 1499 cm-1 (aromatic C--H); 2216 cm-1 (C≡C), and 1646 cm-1 (C=O): Mass Spec. m/e (relative intensity): M+, 389.4 (100); FW=389.44 g/mol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[F:9][C:10]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:11]([NH:13][NH2:14])=O>CCCCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:11]([C:10]([F:25])([F:9])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:13][N:14]=2)[N:3]=1
Reactant: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCCCO
Product: FC(F)(c1ccc2ncccc2c1)c1nnc2ccc(Cl)nn12
Temperature: 130 °C
Yield: 53.5 %

Procedure:
3,6-Dichloropyridazine (160 mg, 1.07 mmol) and difluoro-quinolin-6-yl-acetic acid hydrazide (254 mg, 1.07 mmol) were added in n-BuOH (20 mL). The reaction mixture was heated at 130° C. for 12 h. The solvent was removed under reduced pressure. The crude was partitioned in aqueous solution of K2CO3 and EtOAc. The organic layers were combined and concentrated to give a solid, which was purified by silica gel column to give the title compound as black solid (190 mg, 53%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.62 (m, 2H), 7.90 (m, 1H), 8.22 (m, 1H), 8.35 (m, 1H), 8.65 (m, 2H), 9.02 (m, 1H).