Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:38])[N:24]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][C:26]([OH:28])=O)([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[C:59]([O:63][C:64](=[O:75])[C:65]1[CH:73]=[C:72]([NH2:74])[CH:71]=[C:67]([C:68]([OH:70])=[O:69])[CH:66]=1)([CH3:62])([CH3:61])[CH3:60].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:59]([O:63][C:64](=[O:75])[C:65]1[CH:73]=[C:72]([NH:74][C:26](=[O:28])[CH2:25][N:24]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:23](=[O:38])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:39])[CH:71]=[C:67]([C:68]([OH:70])=[O:69])[CH:66]=1)([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)O
Reactant: CC(C)(C)OC(=O)c1cc(N)cc(C(=O)O)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)Nc1cc(C(=O)O)cc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
17-[(2-tert-Butoxycarbonyl-ethyl)-carboxymethyl-carbamoyl]-heptadecanoic acid tert-butyl ester (0.130 g) was dissolved in dry DCM (5 ml). HOAt (0.36 mg) and DIC (0.045 ml) was added the mixture was refluxed for 1 h under nitrogen. The reaction mixture was cooled to room temperature and 5-amino-isophthalic acid mono t-Butyl ester (60 mg) was added. After stirring for 1 h DIPEA (0.050 ml) was added, the orange reaction mixture turns yellow. After stirring for 2 days, the reaction mixture was concentrated. The residue was redissolved in EtOAc and extracted with 0.1 N HCl (2×) and brine (1×), dried (Na2SO4), and concentrated to give an sirup, which solidifies on standing. 5-{2-[(2-tert-Butoxycarbonyl-ethyl)-(17-tert-butoxycarbonyl-heptadecanoyl)-amino]-acetylamino}-isophthalic acid mono-tert-butyl ester was obtained in a quantitative yield (214 mg), contaminated with an impurity. HPLC/MS 775 (M), rt 7.64 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.[CH3:18][N:19]=[C:20]=[O:21]>C(Cl)(Cl)Cl>[Cl:17][C:4]1[CH:3]=[C:2]([NH:1][C:20]([NH:19][CH3:18])=[O:21])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: CN=C=O
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)Nc1ccc(CN2OCC(C)(C)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1.4 grams (0.06 mole) of 2-(4-amino-2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone in 25 ml of chloroform, under an argon atmosphere, was added dropwise 5 ml of methyl isocyanate. Upon completion of addition the reaction mixture stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to a residual solid. The solid was recrystallized from ethanol to give 1.4 grams of 2-[2-chloro-4-(methylaminocarbonylamino)phenyl]methyl-4,4-dimethyl-3-isoxazolidinone; m.p. 227°-229° C.
Reaction SMILES: [NH2:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:4][C:3]1=S.[CH2:23]([O:25][C:26](=[O:31])[CH:27](Cl)[CH:28]=O)[CH3:24].C([O-])(O)=O.[Na+]>CCO>[CH2:23]([O:25][C:26]([C:27]1[CH:28]=[N:1][N:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:4][C:3]=12)=[O:31])[CH3:24]
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Nn1c(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)cc1=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cc12
Reaction time: 18 h
Yield: 61.6 %

Procedure:
A solution of 1-amino-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-1H-pyridine-2-thione (example C.22 step 6) (3.14 g, 9.28 mmol) and 2-chloro-3-oxo-propionic acid ethyl ester (example C.22 reagent 1) (4.19 g, 27.85 mmol) in EtOH (45 mL) was refluxed for 20 h, the added again 2-chloro-3-oxo-propionic acid ethyl ester (example C.22 reagent 1) (2.20 g, 14.61 mmol) and refluxing was continued for another 18 h. Poured into sat. NaHCO3-sol., extracted with EtOAc, washed the organic layer with brine, dried over Na2SO4 and evaporated to leave a residue, which was purified by flash chromatography (600 g SiO2) with heptane/EtOAc 9:1, followed by trituration with heptane (ca. 50 mL) at −70° C. to give the title compound as a light yellow solid (2.30 g, 62%). MS (ISP) 403 [(M+H)+]; mp 130° C.
Reaction SMILES: N#[C-].C(N(CC)CC)C.Cl[SiH](Cl)Cl.C(Cl)Cl.[F:17][C:18]1[C:19]([Si:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([N:24]=[C:25]=O)[CH:21]=[CH:22][CH:23]=1.N>>[F:17][C:18]1[C:19]([Si:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([N+:24]#[C-:25])[CH:21]=[CH:22][CH:23]=1
Reactant: C[Si](C)(C)c1c(F)cccc1N=C=O
Agent: Cl[SiH](Cl)Cl
Agent: N
Agent: [C-]#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [C-]#[N+]c1cccc(F)c1[Si](C)(C)C
Reaction time: 0.08 h

Procedure:
A deoxygenation then afforded the expected isonitrile. See Baldwin, J. E. et al., Tetrahedron , 39, 2989 (1983). Triethylamine (4.10 mL, 29.3 mmol) was added slowly at 0° C. to a 2 N solution of trichlorosilane in CH2Cl2 (8.40 mL, 16.8 mmol) followed, 5 min latter, by the compound prepared in Example (3) (2.35 g. 11.2 mmol). After 1 h 30 at 0° C. and 30 min at room temperature, the solution was saturated with NH3, filtered over Celite, washed with 5% NaH2PO4 and dried (Na2SO4). The crude obtained after evaporation of the solvent was then subjected to flash-chromatography (hexanes/AcOEt 95:5) to afford 1.42 g (66%) of a slightly purple liquid: IR (neat, cm-1) 2114, 1598, 1440, 1254, 1237, 1110, 943, 848, 793; 1H NMR (300 MHz, CDCl3) δ0.45 (d, J=1.8 Hz, 9H), 7.01 (br t, J=8.3 Hz, 1H), 7.17 (br d, J=7.7 Hz, 1H), 7.32 (ddd, J1 =J2 =8.0 Hz, J3 =6.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ0.1, 116.5 (d, JCF =26 Hz), 124.3, 131.6, 166.8 (d, JCF =243 Hz), 166.9; HRMS (EI) m/z calcd for C10H12FNSi (M+) 193.0723, found 193.0715; LRMS (EI) m/z 193 (M+), 178, 150, 116, 105.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH2:10][N:9]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH:8]([CH3:17])[CH2:7][CH:6]=1)=O.[C:18](=[S:21])([S-:20])[NH2:19].[NH4+]>CO.C(N)(=S)C1C=CN=CC=1>[CH3:17][CH:8]1[CH2:7][CH:6]=[C:5]([C:3]2[N:19]=[C:18]([SH:21])[S:20][CH:2]=2)[CH2:10][N:9]1[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12]
Reactant: NC(=S)[S-]
Reactant: C=CCOC(=O)N1CC(C(=O)CCl)=CCC1C
Agent: NC(=S)c1ccncc1
Agent: [NH4+]
Solvent: CO
Product: C=CCOC(=O)N1CC(c2csc(S)n2)=CCC1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a solution of allyl 5-(chloroacetyl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (0.50 g, 1.94 mmol) in methanol (10 ml) were added at 0–5° C. thioisonicotinamide (5 mg) and ammonium dithiocarbamate (0.32 g, 2.9 mmol). The reaction mixture was raised to room temperature, stirred for 10 minutes and then stirred at 60–70° C. for 50 minutes. The solvent was removed in vacuo. To the residue was added an aqueous 1N NaOH solution to made alkaline. To the solution were added ethyl acetate and hexane and the solution was separated with a separating funnel. After 6N hydrochloric acid was added to the aqueous layer and ethyl acetate was added thereto, the mixture was again separated with a separating funnel. The aqueous layer was extracted with ethyl acetate. The organic layer was washed twice with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed in vacuo to give allyl 2-methyl-5-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (368 mg, 64%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][C:12]=2[I:21])=[C:7]([I:22])[CH:6]=1)=[O:4].[OH-].[K+].O>C1COCC1>[I:21][C:12]1[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=1[I:22]
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)OC)cc2I)c(I)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(C(=O)O)cc2I)c(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
2,2′-Diiodo-biphenyl-4,4′-dicarboxylic acid dimethyl ester (3.24 g, 6.21 mmol) was dissolved in 20 mL THF and KOH (1.02 g, 2.5 eq.) was added, followed by 5 mL water. The reaction was stirred at room temperature overnight. The reaction was heated to 50° C. for 7 hours. The reaction was cooled to room temperature. Organic solvent was removed by rotovap. The aqueous layer was acidified with concentrated HCl to give pale white solid. The solid was filtered and dried on vacuum overnight to give the product 2,2′-Diiodo-biphenyl-4,4′-dicarboxylic acid (2.74 g, yield 89%).
Reaction SMILES: [NH2:1][C:2]([CH:17]([CH3:19])[CH3:18])=[C:3]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=O)[C:4]([O:6][CH3:7])=[O:5].CNS(C)(=O)=O.C(O)(C)(C)C.[C:31]([N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])#[N:32].CC(C)([O-])C.[Na+]>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH:17]([CH3:19])[CH3:18])[N:1]=[C:31]([N:33]([S:34]([CH3:37])(=[O:36])=[O:35])[CH3:38])[N:32]=2)=[CH:11][CH:12]=1
Reactant: CN(C#N)S(C)(=O)=O
Reactant: COC(=O)C(C(=O)c1ccc(F)cc1)=C(N)C(C)C
Agent: CC(C)(C)[O-]
Agent: CNS(C)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 44.8 %

Procedure:
2.50 g (9.42 mmol) of methyl 3-amino-2-[1-(4-fluorophenyl)methanoyl]-4-methylpent-2-enoate were introduced into 2.08 g (28.3 mmol) of N-methylmethanesulphonamide and 3.49 g (47.1 mmol) of tert-butanol together with 3.79 g (28.3 mmol) of N-cyano-N-methylmethanesulphonamide. 1.87 g (18.8 mmol) of sodium tert-butoxide were added to this suspension at room temperature after the course of 15 min (exothermic). After 4 h at 76° C., the reaction suspension was poured onto 20 g of ice water. The suspension was stirred in an ice bath, and the precipitate was filtered off and washed with water (2×2.5 ml). After drying in a high vacuum, 1.61 g of methyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate were obtained in the form of a pale beige solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[OH:10][CH2:11][CH2:12][O:13][CH2:14][C:15](N)=[NH:16].CC(C)=O>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:15]([CH2:14][O:13][CH2:12][CH2:11][OH:10])[N:16]=1
Reactant: N=C(N)COCCO
Reactant: N#Cc1nccnc1N
Solvent: CCO
Solvent: CC(C)=O
Product: Nc1nc(COCCO)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 16.0 g (0.133 mole) of 3-amino-2-pyrazinecarbonitrile and the above solution of 2-(2-hydroxyethoxy)acetamidine in absolute ethanol. Refluxing time: 2 hours 30 minutes. Yld: 20.5 g (70%), m.p. 149°-151° C. (ethanol). An analytical sample was obtained by recrystallization from a mixture of acetone and ethanol. M.p. 159°-161° C.
Reaction SMILES: CC1C=CC([C:8](=O)[CH2:9][C:10](=[O:12])C)=CC=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:26])[CH:22]=[C:23]([CH3:25])[NH2:24])=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([C:22]2[CH:8]=[CH:9][C:10](=[O:12])[NH:24][C:23]=2[CH3:25])=[O:26])=[CH:19][CH:20]=1
Reactant: CC(=O)CC(=O)c1ccc(C)cc1
Reactant: CC(N)=CC(=O)c1ccc(C)cc1
Product: Cc1ccc(C(=O)c2ccc(=O)[nH]c2C)cc1

Procedure:
first using 1-(4-methylphenyl)-1,3-butanedione to prepare 3-(4-methylphenyl)-1-methyl-3-oxo-1-propenamine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:18][S@](C(C)(C)C)=O)([CH2:14][CH2:15][O:16][CH3:17])[C:9]([F:13])([F:12])[CH2:10][OH:11])[C:5]([F:25])=[CH:4][CH:3]=1.Cl.C(OCC)C.N>CO>[NH2:18][C@@:8]([C:6]1[C:5]([F:25])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)([CH2:14][CH2:15][O:16][CH3:17])[C:9]([F:12])([F:13])[CH2:10][OH:11]
Reactant: COCC[C@@](N[S@@](=O)C(C)(C)C)(c1nc(Br)ccc1F)C(F)(F)CO
Agent: Cl
Agent: N
Solvent: CCOCC
Solvent: CO
Product: COCC[C@@](N)(c1nc(Br)ccc1F)C(F)(F)CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of (S)-2-methyl-propane-2-sulfinic acid [(R)-1-(6-bromo-3-fluoro-pyridin-2-yl)-2,2-difluoro-3-hydroxy-1-(2-methoxy-ethyl)-propyl]amide (1.50 g, 3.33 mmol) in methanol (8.4 ml) was added 2M HCl in diethyl ether (6.56 ml, 13.11 mmol). The reaction mixture was stirred for 1.5 h at room temperature. 7 M ammonia in methanol (2.7 ml) was added to the reaction mixture and the resulting colourless suspension was evaporated in vacuo. The remaining solid was triturated with warm dichloromethane, cooled to rt, filtered and rinsed with dichloromethane. The filtrate was evaporated affording the title compound which was used without purification in the next step. 1.42 g colourless, viscous oil. 100% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:13]([Cu])#[N:14]>CN1C(=O)CCC1.O>[C:13]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6])#[N:14]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To a stirred solution of methyl 3-bromo-4-hydroxybenzoate (2.50 g, 10.775 mmol) in NMP (7.5 mL) was added CuCN (1.05 g, 11.853 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 200° C. for 4 h., cooled to RT, diluted with water (10 mL) and stirred for 10 min. The precipitated solid was filtered off and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford methyl 3-cyano-4-hydroxybenzoate (1.50 g, 78%) as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.O=[C:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1.[OH-].[K+]>CO>[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:13][CH:12]=2)=[CH:2]1
Reactant: c1cc2cc[nH]c2cn1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CC=C(c2c[nH]c3cnccc23)CC1
Temperature: 0 °C
Yield: 77.7 %

Procedure:
A suspension of 1H-pyrrolo[2,3-c]pyridine (0.95 g, 8.05 mmol), tert-butyl (4-oxocyclohexyl)carbamate (1.82 g, 8.54 mmol) and KOH (0.95 g, 17.0 mmol) in MeOH (10 mL) was heated at reflux overnight. The solution was added to ice-water (50 mL) and then MeOH (50 mL) was added. The resulting solution was concentrated to circa 50 mL and extracted three times with DCM/MeOH (9:1, 50 mL) and the organic layers were combined and concentrated. The residue was purified by flash chromatography (9:1 DCM/MeOH) to give the title compound as a white solid (1.96 g, 78%). MS (ESI+) m/z=314 (M+H)+.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([C:15]2[C:16]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: Brc1cccc2ccccc12
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: c1ccc2c(C3CC3)cccc2c1

Procedure:
Under this route, cyclopropylmagnesium bromide was added to a solution of bromonaphthalene in tetrahydrofuran stirred at 0-5° C. in the presence of a catalytic amount of [1,3-bis(diphenylphosphino)propane]dichloronickel(II) to form cyclopropylnaphthalene, which was diluted with ethyl acetate and washed.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[N:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)=O.CSC>C1COCC1>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[N:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Yield: 52.5 %

Procedure:
To a solution of 2,2-dimethyl-1-[4-(6-nitro-pyridin-3-yl)-piperazin-1-yl]-propan-1-one (1.0 g, 3.42 mmol) in THF (10 mL) was added BH3.DMS (0.6 mL, 6.84 mmol) at r.t. and the reaction was then heated to reflux for 6 h. The reaction was cooled, quenched with ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by column chromatography over silica gel (60-120 mesh) using 20% ethyl acetate/petroleum ether as eluent to afford 1-(2,2-dimethyl-propyl)-4-(6-nitro-pyridin-3-yl)-piperazine (0.5 g, 52.5%).
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[O:19]1[CH:21]2[CH2:22][CH:23]([O:28][CH3:29])[CH:24]([O:26][CH3:27])[CH2:25][CH:20]12>>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:20]2[CH2:25][CH:24]([O:26][CH3:27])[CH:23]([O:28][CH3:29])[CH2:22][CH:21]2[OH:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(O)cc1
Reactant: COC1CC2OC2CC1OC
Agent: O=C(O)c1ccccc1
Product: COc1ccc(OC2CC(OC)C(OC)CC2O)cc1
Yield: 96 %

Procedure:
A reaction was conducted as described in Example 6 except that benzoic acid and PGE were replaced with the same molar amounts of 4-methoxyphenol and 1,2-epoxy-4,5-dimethoxycyclohexane. Desired 2-(4-methoxyphenoxy)-4,5-dimethoxycyclohexanol was formed in analytical yield of 96% and isolated in a yield of 92%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:33])([F:32])[O:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](Cl)=[O:30])[CH:25]=[CH:26][CH:27]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:32])([F:19])[F:33])[CH:23]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)Cc1cccc(OC(F)(F)F)c1
Product: O=C(Cc1cccc(OC(F)(F)F)c1)Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Yield: 23.5 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]-pyridin-2(3H)-one and 2-(3-trifluoromethoxyphenyl)-acetyl chloride to afford the title compound (22 mg, 23.5%). 1H-NMR (δ, ppm, DMSO-d6): 3.71 (s, 2H, CH2), 6.43 (d, 1H, HPy,5, J=5.9 Hz), 6.83-6.86 (m, 1H, Harom), 7.24-7.47 (m, 8H, Harom), 7.78 (d, 1H, HPy,6, J=5.9 Hz), 10.37 (s, 1H, NHamide), 11.21 (s, 1H, NHPy7), 11.42 (s, 1H, NHPy9). LC-MS, tR=4.65 minutes, m/z: 445.04 (M+H)+, calculated for C21H16N4O4F3. HRMS (EI): m/z [M+H] calculated for C21H16N4O4F3: 445.1124; found: 445.1107.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[OH-].[Na+].[C:16]1([S:22]([C:25]2[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:19]2[CH:18]=[CH:17][C:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:21][CH:20]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)cc1
Reactant: CN(C)S(=O)(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)c1ccc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2)cc1
Temperature: 60 °C
Yield: 91.8 %

Procedure:
To a solution of 6.60 g (0.0330 mole) of N,N-dimethyl-4-hydroxybenzenesulfonamide dissolved in 150 ml of DMSO was added 1.32 g (0.0330 mole) of NaOH. The mixture was heated at 60° C. for 10 minutes and 7.1 g (0.030 mole) of 4-fluorophenyl phenyl sulfone was added. The reaction mixture was heated at 100° C. for 3 hrs and at 125° C. for 3 hrs and cooled. The mixture was poured into a solution of 200 ml of 20% aqueous NaOH and 500 ml of water. The crystalline product was collected, washed well with water and dried, which gave 11.5 g (92% yield) of product. Recrystallization from aqueous DMSO followed by recrystallization from ethanol afforded purified N,N-dimethyl-4-(4-(phenylsulfonyl)phenoxy)benzenesulfonamide, mp 99°-100° C.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][C:7]3[NH:12][C:11]4[N:13]=[CH:14][CH:15]=[CH:16][C:10]=4[C:8]=32)[CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>CN(C=O)C>[N:23]1([C:21](=[O:22])[CH2:20][N:12]2[C:7]3[CH2:6][CH2:5][N:4]4[CH:9]([C:8]=3[C:10]3[CH:16]=[CH:15][CH:14]=[N:13][C:11]2=3)[CH2:1][CH2:2][CH2:3]4)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: c1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: O=C(CCl)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c2c(c3cccnc31)C1CCCN1CC2)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (120 mg, 0.565 mmol) in DMF (1 mL) was added a suspension of NaH (68.0 mg, 1.69 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-chloro-1-(piperidin-1-yl)ethanone (272 mg, 1.69 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 3 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was diluted with ice-water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography (10% MeOH-DCM) to yield 1-(piperidin-1-yl)-2-(2,3,5,6-tetrahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizin-7(11cH)-yl)ethanone;
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:5]([N:14]=1)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2.[F:15][C:16]([F:30])([F:29])[C:17]1[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>CC(C)CCO.[Cu]I>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:9]=[C:4]2[N:3]=[C:2]([N:26]3[CH2:27][CH2:28][N:23]([C:18]4[C:17]([C:16]([F:30])([F:15])[F:29])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:24][CH2:25]3)[NH:14][C:5]2=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cnc2nc(Cl)[nH]c2c1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: [Cu]I
Solvent: CC(C)CCO
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cnc2[nH]c(N3CCN(c4ncccc4C(F)(F)F)CC3)nc2c1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-6-trifluoromethyl-1H-imidazo[4,5-b]pyridine from step (d) above (45 mg, 0.203 mmol), 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (47 mg, 0.203 mmol, Fluorochem), triethylamine (59 μL, 0.406 mmol, Aldrich) and copper(I) iodide (1 mg, 0.005 mmol, Aldrich) in 3-methyl-butan-1-ol (0.5 mL, Aldrich) was subjected to microwave irradiation at 220° C. for 0.5 h. The reaction mixture was cooled to room temperature and was filtered. The filtrate was purified by preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile) to give the title compound as a colorless solid. MS (ESI, positive ion) m/z: 417 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=O)[C:5]2=1.C(=O)(O)O.[NH2:20][NH:21][C:22]([NH2:24])=[NH:23]>C(O)(C)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[N:20][NH:21][C:22](=[NH:23])[NH2:24])[C:5]2=1
Reactant: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: CC(C)O
Product: N=C(N)NN=C1CCCc2[nH]c3ccc(Cl)cc3c21
Temperature: 80 °C
Yield: 49 %

Procedure:
A suspension of 6-chloro-4-oxo-1,2,3,4-tetrahydrocarbazole (21.9 mg, 0.1 mmol) in isopropanol and concentrated HCl (50 μL) is treated with aminoguanidine bicarbonate (20.4 μg, 0.15 mmol), heated at 80° C. for 4 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by HPLC to give the title compound, 15.8 mg (49% yield), identified by mass spectral and HPLC analyses, (M+H) 276; retention time 3.72 min.