Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1.C(O)(=O)C.C(O)(=O)C.C(N)CN.S([O-])(O)=O.[Na+]>CO>[O:1]=[C:2]1[C:6](=[CH:31][C:29]2[O:30][C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:33])([F:18])[F:34])[CH:21]=3)=[CH:27][CH:28]=2)[S:5][C:4](=[S:7])[N:3]1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccccc1NN1C(=O)CSC1=S
Reactant: O=Cc1ccc(-c2cccc(C(F)(F)F)c2)o1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CO
Solvent: NCCN
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1NN1C(=O)C(=Cc2ccc(-c3cccc(C(F)(F)F)c3)o2)SC1=S
Temperature: 25 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
A mixture of 2-(4-oxo-2-thioxo-thiazolidin-3-ylamino)-benzoic acid (0.090 g, 0.34 mmol), 5-(3-trifluoromethyl-phenyl)-furan-2-carbaldehyde (0.086 g, 0.36 mmol) (purchased from Aldrich Chemical Company) and ethylenediamine diacetate (0.065 g, 0.036 mmol) in methanol (8 mL) was stirred at room temperature for 17 h. The reaction mixture was poured into stirred 0.6 N aq sodium hydrogensulfite (50 mL). The mixture was vigorously stirred for 15 mm. The solid product was filtered off and washed on funnel successively with 0.6 N aq sodium hydrogensulfite (2 mL), water (2×2 mL), ether (2 mL) and hexanes (2 mL). The material was dried in a vacuum oven at 65° C. for 19 h to afford 2-{4-Oxo-2-thioxo-5-[1-[5-(3-trifluoromethyl-phenyl)-furan-2-yl]-methylidene]-thiazolidin-3-ylamino}-benzoic acid (130 mg, 79%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 6.53 (1H, m), 6.86 (1H, m), 7.29 (1H, m), 7.43 (1H, d, J=3.6 Hz), 7.59 (1H, d, J=3.6 Hz), 7.78 (1H, s), 7.82 (2H, m), 7.92 (1H, m), 8.16 (1H, m), 8.21 (1H, m). LC/MS: APCI 489.3, HPLC 97.1%
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].CN1C(=O)N(C)CCC1.[F:16][C:17]1([K])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]1[F:23].O>C1COCC1>[CH2:1]([C:19]1[C:18]([F:23])=[C:17]([F:16])[CH:22]=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: FC1C=CC=CC1(F)[K]
Reactant: CCCCCBr
Solvent: O
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCCCCc1cccc(F)c1F
Reaction time: 1 h

Procedure:
0.1 mol of pentyl bromide and subsequently 13 ml of DMPU are added dropwise to the solution of 1,2-difluorophenyl potassium in THF prepared according to 1c). After stirring below -85° C. for 60 minutes, the mixture is warmed in the course of 30 minutes to -40° C. and water is added at this temperature. The mixture is subsequently worked up as customary. b.p.30: 112 ° C. The following are prepared analogously:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6].CC(C)=[O:18].[Mn]([O-])(=O)(=O)=O.[K+].C(O)(C)C>O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5]([OH:18])=[O:6]
Reactant: CC(C)=O
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C(=O)O)c1OC
Temperature: 50 °C

Procedure:
2,3-Dimethoxy-6-nitrobenzaldehyde (40.0 g, 0.19 mole) was treated with acetone (275 mL) and warmed to 50° C. A solution of potassium permanganate in water (60 g/L) was added slowly at 50°-70° C. over a period of 16-20 hours until thin layer chromatographic analysis revealed complete absence of the starting material. Isopropanol (7.5 mL) was then added and the mixture was heated an additional hour. The precipitated manganese dioxide was removed by filtration and the filter cake was washed with 3% aqueous potassium hydroxide (ca 175-200 mL). The combined filtrates were acidified with hydrochloric acid and the precipitate was collected by filtration and dried in vacuo. The crude product was recrystallized from acetone to give the pure material, 28.3 g (67%), mp 187°-189° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=C([CH:8]=[CH:9][C:10]=1[O:11][C@H:12]([CH2:14][CH3:15])[CH3:13])C#N.[OH-:18].[Na+].[CH2:20]([OH:22])[CH3:21]>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:21]([CH:8]=[CH:9][C:10]=1[O:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[C:20]([OH:18])=[O:22]
Reactant: [OH-]
Reactant: CC[C@H](C)Oc1ccc(C#N)cc1C(F)(F)F
Reactant: CCO
Agent: [Na+]
Product: CC[C@H](C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
A solution of 550 mg (2.2 mmol) of 3-trifluoromethyl-4-(2-(S)-methylpropyloxy)benzonitrile (from Step A) in 5 mL of ethanol was treated with 1.5 mL of 5.0 N NaOH and was heated to 80° C. for 3 h. The reaction was then concentrated, treated with 2 N HCl, extracted with 30 mL of EtOAc, dried and concentrated to afford 600 mg of the title compound: 1H NMR (500 Mhz) δ 0.99 (t, J=7.3, 3H), 1.43 (d, J=5.9, 3H), 1.73-1.83 (m, 2H), 4.54 (septet, 1H), 7.02 (d, J=8.9, 1H), 8.21 (d, J=8.9, 1H), 8.32 (s, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:15][CH2:14]1)=[O:12])[CH3:10])=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[NH2:8][C@H:9]([C:11]([N:13]1[CH2:14][CH2:15][CH:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:18]1)=[O:12])[CH3:10]
Reactant: COC(=O)COC1CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)COC1CCN(C(=O)[C@H](C)N)CC1

Procedure:
Prepared from methyl N-(tert.butyloxycarbonyl-L-alanyl)-4-piperidinyloxy-acetate and 50% trifluoroacetic acid in methylene chloride analogously to Example XXIIIb.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH2:11]1[C:17](=O)[CH2:16][S:13](=[O:15])(=[O:14])[CH2:12]1.[NH2:19][C:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH:21]=1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]2[C:21]3[C:22](=[O:26])[CH2:23][CH2:24][CH2:25][C:20]=3[NH:19][C:17]3[CH2:11][CH2:12][S:13](=[O:15])(=[O:14])[C:16]2=3)[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: NC1=CC(=O)CCC1
Reactant: O=C1CCS(=O)(=O)C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CCCC2=C1C(c1cc(Br)ccc1O)C1=C(CCS1(=O)=O)N2
Yield: 31.7 %

Procedure:
5-Bromosalicylaldehyde (0.201 g, 1.0 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (0.13 g, 1.0 mmol), 3-amino-2-cyclohexen-1-one (0.11 g, 1.0 mmol) and triethylamine (0.85 mL) were heated in ethanol (4 mL) to 80 ° C. in a sealed tube for 72 hours, cooled, and solvent evaporated. The crude intermediate in ethanol (5 mL) was treated with 1.0 M HCl in ether (1 mL), heated to reflux for 1 hour, cooled, the solid precipitate collected, washed with ethanol and dried to provide 0.13 g of the title compound as an orange-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:15][CH:16]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1cccc2c(C3=CCNCC3)c[nH]c12
Solvent: CO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3c(Cl)cccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 7-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.2 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.41 g, 2.2 mmol). The product was isolated as a white foam. Yield 370 mg (41%). mp 85°-90° C. FDMS m/e=421 (M+ of free base). α[D]589 =+3.62 (c=1.00, methanol/dimethylsulfoxide).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]([OH:32])[CH2:23][CH2:22][CH2:21]2)=[O:19])=[C:15]([CH3:17])[CH:16]=1)=[O:9].[Cl:33][CH2:34][CH2:35][N:36]=[C:37]=[O:38]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:31][C:29]1[CH:28]=[CH:27][C:26]2[N:20]([C:18](=[O:19])[C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=4[CH3:1])=[CH:16][C:15]=3[CH3:17])[CH2:21][CH2:22][CH2:23][CH:24]([O:32][C:37](=[O:38])[NH:36][CH2:35][CH2:34][Cl:33])[C:25]=2[CH:30]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Reactant: O=C=NCCCl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)NCCCl)c3cc(Cl)ccc32)c(C)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Tolvaptan (1.0 g, 2.2 mmol) was suspended in toluene (7 ml). 2-Chloroethyl isocyanate (0.28 ml, 3.3 mmol) and 4-dimethylaminopyridine (DMAP) (27 mg, 0.22 mmol) were added thereto, and the mixture was stirred at 80° C. for 24 hours. After cooling to room temperature, the insoluble materials were filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=54:46→33:67). The purified product was concentrated under reduced pressure to obtain 1.0 g of {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}(2-chloroethyl)carbamate as white amorphous solid.
Reaction SMILES: C1(C)C=CC(S(NN=[C:12]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=O)=O)=CC=1.C([Li])CCC.CN([CH:30]=[O:31])C>CCN(CCN(CC)CC)CC.CCCCCC>[C:12]1([CH:30]=[O:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)NN=C2CCCCCCCC2)cc1
Agent: CCN(CC)CCN(CC)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=CC1=CCCCCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To cyclononanone p-toluenesulfonyl hydrazone (2.0 g) suspended in N,N,N′,N′-tetraethylenediamine (20 ml) was added dropwise at −55° C. a 1.6 M solution of n-butyllithium in hexane (16.2 ml). The resulting mixture was stirred at room temperature for 30 minutes under an argon atmosphere, was then cooled with ice, was mixed with DMF (2.5 ml) and was stirred at room temperature for one hour. The reaction mixture was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent. The residue was subjected to purification using a silica gel column (ethyl acetate:hexane=1:10) to obtain cyclononene-1-carbaldehyde (0.7 g) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]([F:42])([F:41])[CH2:29][NH:30][CH2:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.CCOC(C)=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>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([CH2:31][NH:30][CH2:29][C:28]([F:42])([F:41])[F:27])[CH:33]=1
Reactant: OB(O)c1cccc(CNCC(F)(F)F)c1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(N1CCc2ccc(Cl)c(-c3cccc(CNCC(F)(F)F)c3)c2CC1)C(F)(F)F
Temperature: 80 °C

Procedure:
Dissolve 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.1 equiv.), 3-[(2,2,2-trifluoroethyl-amino)-methyl]-phenyl-boronic acid (465 mg, 2.0 mmol) and sodium carbonate (2 equiv.) in THF/water (2:1, 15 mL) and heat the mixture at 80° C. for 6 h. Cool the reaction mixture to ambient temperature, dilute with EtOAc and wash with water. Dry the organic fraction over MgSO4, filter and concentrate in vacuo to obtain 7-chloro-3-(2,2,2-trifluoroacetyl)-6-{3-[(2,2,2-trifluoroethyl-amino)-methyl]-phenyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine, suitable for use without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20]C(C)(C)C)=[O:19])=[CH:16][CH:15]=3)=[CH:7][CH:8]=2)[NH:3]1.[Br:27]Br.[Br-].[K+]>C(O)(=O)C>[Br:27][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:12][CH2:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)[NH:3][C:2](=[O:1])[CH2:11][CH2:10]2
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)c1ccc(COc2ccc3c(c2)NC(=O)CC3)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1CCc2cc(Br)c(OCc3ccc(C(=O)O)cc3)cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a suspension of tert-butyl 4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoate (550 mg, 1.56 mmol) in glacial acetic acid (5 mL) was added dropwise a solution of bromine (800 mg, 5.00 mmol) and potassium bromide (595 mg, 5.0 mmol) in acetic acid (10 mL) under an atmosphere of dry N2, and the mixture stirred at room temperature for 1 hour. The reaction mixture was warmed to 60° C. for 18 hours, then cooled, and the solvent evaporated under reduced pressure. The residue was poured slowly into water (40 mL) with stirring, diethyl ether (3 mL) was added, and the mixture sonicated, filtered, the solid thus obtained was washed with saturated sodium carbonate (30 mL), water (50 mL), diethyl ether (10 mL), and dried under reduced pressure to afford 4-((6-bromo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoic acid (334 mg, 0.89 mmol, 57%). LCMS mz 375.9 (M−H) and 377.9 (M+H), anal HPLC>91% in purity, 1H NMR (400 MHz; CD3CN) δ8.25 (bs, 1H); 8.09 (d, J=8.6 Hz, 2H); 7.65 (d, J=8.6 Hz, 2H); 7.42 (s, 1H); 6.62 (s, 1H); 5.26 (s, 2H); 2.91 (m, 2H); 2.53 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH:5]([OH:7])[CH:4]=C1.N1C=CC=CC=1.[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15]>>[CH3:15][C:14]([O-:17])=[O:16].[CH3:4][C:5]([CH2:6][C:2]([OH:16])=[O:1])=[O:7]
Reactant: OC1C=CC(O)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)CC(=O)O
Product: CC(=O)[O-]
Reaction time: 7.5 h

Procedure:
To a mixture of 1.50 grams (15 mmols) of 3,5-dihydroxycyclopent-1-ene and 1.0 milliliter (120 mmols) of pyridine was added 972 milligrams (9.5 mmols) of acetic anhydride, the addition being made over a period of 7.5 hours with stirring. The aftertreatment was then carried out as in Example 1 to obtain 0.62 gram of a crude product. When calculations were made from the results of the gas chromatographic analysis, the yields of monoacetate and diacetate were 22% and 5%, respectively.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](N1CCCC1)=[CH:13]2>O>[CH3:6][O:7][C:8]1[C:9]2[CH2:10][CH2:11][C:12]3[NH:5][C:1](=[O:4])[CH2:2][CH2:3][C:13]=3[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: C=CC(N)=O
Reactant: COc1cccc2c1CCC(N1CCCC1)=C2
Solvent: O
Product: COc1cccc2c1CCC1=C2CCC(=O)N1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 23 %

Procedure:
A mixture of acrylamide (146 g, 2.0 mol) and 1-(5-methoxy-3,4-dihydronaphthalen-2-yl)pyrrolidine (156 g, 0.68 mol) was heated at 80° C. for 2 h and then 130° C. for a further 0.75 h. The mixture was cooled and water (1L) was added. The resultant brown precipitate was collected by filtration, washed with water and dried in vacuo. Trituration with hot ethanol (2L) gave the title compound as a white solid (35.9 g, 23%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(N)cnc1-c1ccc(C(F)(F)F)cc1
Reaction time: 4 h

Procedure:
To a solution of the 3-methyl-5-nitro-2-(4-trifluoromethyl-phenyl)-pyridine (3.5 g, 10.56 mmol) in ethanol (50 mL) is added palladium (10%) on carbon (0.700 g, 20% by wt.). The reaction is charged to 15 psi under a hydrogen atmosphere and allowed to stir for 4 hours. The reaction is diluted with ethyl acetate and Celite is added, followed by water. This mixture is then filtered through a pad of celite. The solution is concentrated, diluted with ethyl acetate, poured into a separatory funnel and the organic layer is washed with water and brine. The organic layer is dried over anhydrous sodium sulfate and concentrated. The product is used directly in the next step (2.74 g, 10.87 mmol).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[Cl:31][C:32]1[N:37]=[C:36](Cl)[CH:35]=[CH:34][N:33]=1>CC#N>[Cl:31][C:32]1[N:37]=[C:36]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=2)[CH:35]=[CH:34][N:33]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)n2)c2ccccc12
Yield: 35.7 %

Procedure:
To a degassed solution of tert-butyl 4-hydroxynaphthalen-1-ylcarbamate (13.3 g, 51.3 mmol) and DBU (12.6 mL, 51.3 mmol) in MeCN (80 mL) under nitrogen was added 2,4-dichloropyrimidine (7.65 g, 51.3 mmol) in acetonitrile (19 mL) and the reaction mixture was heated to reflux for 4 hr. The solvent was evaporated in vacuo and the residue was taken up into DCM (100 mL) and was washed with water (2×100 mL) and brine (100 mL), then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 330 g, EtOAc in isohexane, 0-50%, gradient elution) to afford the title compound as a pale pink solid (6.80 g, 34%); Rt 2.50 min (Method 2); m/z 372/374 (M+H)+, (ES+)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10]([OH:12])=O)[CH:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])[CH:3]=1
Reactant: CNOC
Reactant: O=C(O)C=Cc1cc(Br)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.1 %

Procedure:
3-(4-Bromo-pyridin-2-yl)-acrylic acid (6.3 g, 27.6 mmol) prepared in Step 1, N,O-dimethylhydroxylamine hydrochloride (3.0 g, 30.4 mmol), HOBT (7.5 g, 55.3 mmol), EDAC (10.6 g, 55.3 mmol) and triethylamine (11.5 mL, 82.9 mmol) were added to N,N-dimethylformamide (100.0 mL). The reaction mixture was stirred at room temperature for 18 hours, quenched with a saturated solution of ammonium chloride, and then extracted with ethyl acetate. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 2.4 g of the titled compound as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33]C(C)(C)C)[C:28]=3O[SiH](C)C)=[CH:22][C:21]=2[Cl:42])[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)=[CH:22][C:21]=2[Cl:42])[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[SiH](C)Oc1c(OC(C)(C)C)cccc1Sc1ccc(CCCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CCCc2ccc(Sc3cccc(O)c3)cc2Cl)COC(C)(C)OC1
Reaction time: 0.17 h
Yield: 102.8 %

Procedure:
To a solution of the compound of Example 33 (1.10 g) in THF (20 mL), a 1 mol/L solution of tetrabutylammonium fluoride in THF (5 mL) was added. After 10 minutes, the reaction mixture was poured into water and was extracted with ethyl acetate. The organic phase was sequentially washed with water and a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain the desired product (900 mg) as a colorless powder.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1.C([O:43][C:44]([CH2:46][CH2:47][CH2:48][CH2:49]COS(C1C=CC(C)=CC=1)(=O)=O)=[O:45])C1C=CC=CC=1.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[O:7][CH2:49][CH2:48][CH2:47][CH2:46][C:44]([OH:45])=[O:43])(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCC(=O)OCc2ccccc2)cc1
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1OC(OCCCCC(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture that consists of 34.83 g (100 mmol) of 2,3,4,6-tetra-O-acetyl-glucopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 15.22 g (100 mmol) of DBU in 300 ml of tetrahydrofuran is cooled to 0° C. At 0° C., 54.37 g (150 mmol) of 5-tosyloxy-pentanecarboxylic acid benzyl ester, dissolved in 40 ml of tetrahydrofuran, is added in drops over 30 minutes while being stirred vigorously. It is stirred for three hours at 0° C. 300 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of tetrahydrofuran. 5 g of palladium (10%) on activated carbon is added thereto and hydrogenated until hydrogen absorption is completed. Then, catalyst is filtered out, it is rewashed with a little tetrahydrofuran and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate, and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].[OH-].[Li+].C(OCC)(=O)C>CS(C)=O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([NH:1][C:2]2[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:19]=1
Reactant: CC(C)c1ccc(N)c(C#N)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(Nc2cc(F)ccc2[N+](=O)[O-])c(C#N)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
Heat a solution of 2-amino-5-isopropyl-benzonitrile (1.21 g, 7.55 mmol) with 2,4-difluoro-1-nitro-benzene (1.20 g, 7.55 mmol) and lithium hydroxide (0.54 g, 22.66 mmol) in DMSO (15 ml) to 70° C. for 18 hours. Cool the reaction to ambient temperature and then pour into approximately 200 ml of ice water and stir for one hour. The title compound precipitates and is colleted by filtration. Purify the solid via flash chromatography eluting with a 95% hexanes: 5% ethyl acetate mobile phase to obtain 0.372 g (1.24 mmol, 16% yield) of the title compound as an orange amorphous solid: Mass Spectrum (m/e): 298 (M−1).